Long-term outcomes of salvage radiotherapy for PSA-recurrent prostate cancer: validation of the stephenson nomogram

Purpose

Approximately one-third of patients who undergo radical prostatectomy for clinically localized prostate cancer will ultimately develop a biochemical recurrence. We report our long-term outcomes of salvage radiotherapy (SRT), and in so doing, validate a recently published prognostic nomogram.

Methods

A retrospective chart review was performed of all patients treated with SRT following radical prostatectomy for biochemical PSA recurrence at our institution between 1992 and 2003. We calculated the probability of 6-year biochemical progression—free survival following SRT and performed a goodness-of-fit test to ascertain whether the previously published nomogram correctly predicted our observations.

Results

During the study period, 96 patients were treated with SRT. At a median follow-up of 71 months, 44 (46%) had a durable PSA-free response. There was no significant difference between the observed progression-free survival and that predicted by the Stephenson nomogram (P = 0.7). Multivariate logistic regression analysis determined that PSA value at the initiation of SRT (P = 0.02) and pathologic Gleason Score (P = 0.04) were significantly associated with the probability of recurrence.

Conclusions

During the study period, nearly half of patients treated with SRT for PSA recurrence following radical prostatectomy had a durable treatment response. We found the predictive nomogram developed by Stephenson, et al. to be valid when tested on our independent cohort of patients.     

The Shared Equal Access Regional Cancer Hospital (SEARCH) nomogram for risk stratification in intermediate risk group of men with prostate cancer: validation in the Duke Prostate Center database

Study Type – Prognosis (cohort)
Level of Evidence 2a

OBJECTIVES

To validate the Shared Equal Access Regional Cancer Hospital (SEARCH) nomogram to better risk stratify men with intermediate‐risk pathology after prostatectomy (positive surgical margins, PSM, and/or extracapsular disease, ECE, without seminal vesicle or lymph node involvement) in a tertiary referral centre (the Duke Prostate Center, DPC).

PATIENTS AND METHODS

We retrospectively analysed 485 men in the DPC cohort with PSM and/or ECE but without seminal vesicle or lymph node involvement. The predicted risk of biochemical progression‐free probability at 1, 3 and 5 years was estimated by the SEARCH and updated Kattan postoperative nomograms. Calibration plots were generated and accuracy assessed with the concordance index.

RESULTS

The SEARCH nomogram appeared to be well calibrated, with the highest‐risk quartile having a predicted <60% progression‐free probability at 5 years, vs >80% for the lowest risk. In comparison, overall external calibration appeared to be similar for the updated Kattan nomogram, although there was less separation between the highest‐ and lowest‐risk quartiles. The SEARCH model had an overall predictive accuracy of 0.65, which compared favourably with the updated Kattan nomogram (0.57).

CONCLUSION

In an external dataset, the SEARCH nomogram to predict progression‐free probability for men at intermediate risk after prostatectomy was well calibrated and performed better than the updated postoperative Kattan nomogram.     

Re‐calibration and external validation of an existing nomogram to predict aggressive recurrences after radical prostatectomy

Study Type – Prognosis (case series)
Level of Evidence 4

OBJECTIVE

To re‐calibrate the previously published Duke Prostate Center (DPC) nomogram for the prediction of biochemical recurrence (BCR) after radical prostatectomy (RP) to not only predict overall BCR but also the clinically more relevant endpoint of an aggressive recurrence (i.e. a BCR with a postoperative PSA doubling time (PSADT) of <9 months).

PATIENTS AND METHODS

Using the established point‐scale system based upon the previously published DPC nomogram, we re‐calibrated this point system to predict not just BCR, but also aggressive BCR within 2599 men treated with RP from the DPC database. PSADT was computed on all patients meeting the recurrence definition who had a minimum of two PSA values, separated by at least 3 months, and ≤2 years after recurrence. External validation was performed using data from 1695 men treated with RP within the Shared Equal Access Regional Cancer Hospital (SEARCH) database by calculating the concordance index c and by plotting calibration curves.

RESULTS

The median follow‐up for patients with no BCR was 56 and 47 months for DPC and SEARCH, respectively. In the DPC modelling cohort and the SEARCH validation cohort, 645 (25%) and 557 (33%) men had BCR, while 83 (3.2%) and 71 (4.2%) patients had an aggressive recurrence. In external validation, predictive accuracy for an aggressive BCR was high (c = 0.83) and the nomogram showed good calibration.

CONCLUSIONS

We re‐calibrated an existing nomogram to not only predict overall BCR after RP but also aggressive recurrence after RP. Our new tool can provide valuable information for patient counselling and patient selection for adjuvant therapy trials.     

Postoperative prostate‐specific antigen nadir improves accuracy for predicting biochemical recurrence after radical prostatectomy: Results from the Shared Equal Access Regional Cancer Hospital (SEARCH) and Duke Prostate Center databases

Objectives: We previously showed that prostate‐specific antigen (PSA) nadir after radical prostatectomy (RP) significantly predicts biochemical recurrence (BCR). Herein, we sought to explore the effect of including PSA nadir into commonly used models on their accuracy to predict BCR after RP. Methods: This was a retrospective analysis of 943 and 1792 subjects from the Shared Equal Access Regional Cancer Hospital (SEARCH) and Duke Prostate Cancer (DPC) databases, respectively. The discrimination accuracy for BCR of seven previously published models was assessed using concordance index and compared with and without adding PSA nadir level in SEARCH. Using data from SEARCH, we developed a new nomogram incorporating PSA nadir to other known predictors (preoperative PSA, pathological Gleason score, PSA nadir level, surgical findings, prostate weight, body mass index and race) of BCR and externally validated it in the DPC. Results: In SEARCH, the mean concordance index across all seven nomograms was 0.687. After the inclusion of PSA nadir, the concordance index increased by nearly 7% (mean = 0.753). The concordance index of the new nomogram in SEARCH was 0.779 (bias‐corrected = 0.767), which was 5% better than the next best model. In DPC, the new nomogram yielded a concordance index of 0.778. Conclusion: The addition of postoperative PSA nadir to commonly used nomograms increased their accuracies by nearly 7%. Based upon this, we developed and externally validated a new nomogram, which was well calibrated and highly accurate, and is a potentially valuable tool for patients and physicians to predict BCR after RP.     

Cross‐cultural validation of a prognostic tool: example of the Kattan preoperative nomogram as a predictor of prostate cancer recurrence after radical prostatectomy

OBJECTIVE

To establish the predictive accuracy of the Kattan preoperative nomogram by comparing predictions at 5 years with actual progression in patients who had a radical prostatectomy (RP).

MATERIALS AND METHODS

We reviewed the data for 928 patients treated by RP as a first‐line treatment for localized prostate cancer, between 1994 and 2005. Recurrence was defined as one prostate‐specific antigen (PSA) level of >0.4 ng/mL. The 5‐year progression‐free probability (PFP) rate was evaluated on censured data using the Kaplan‐Meier method. Relationships between all predictor variables included in the Kattan nomogram (PSA level, biopsy Gleason scores and clinical stage) and survival were evaluated by Cox proportional‐hazards regression analysis. The discriminating ability of the nomogram was assessed by the concordance index (c‐index). Bootstrapping was used to assess confidence intervals (CIs), and then the calibration was assessed.

RESULTS

The median follow‐up was 60 months. Overall, 177 (19%) patients had a recurrence; the 5‐year PFP rate (95% CI) was 80.9 (78–83)%. Of the three variables included in the nomogram, all were associated with recurrence in a multivariate analysis (P < 0.001). The c‐index (95% CI) was only 0.664 (0.584–0.744). In general, the nomogram was not well calibrated.

CONCLUSIONS

There was a discrepancy between the predicted PFP as estimated by the Kattan nomogram and actual relapse in this group of patients. Clinicians should be aware that the nomogram is less accurate when used outside the population used to formulate the nomogram. Although more accurate tools are needed, the Kattan nomogram is still the best choice for urologists so far.     

Accuracy of the Kattan nomogram across prostate cancer risk-groups

Study Type – Diagnostic (exploratory cohort)
Level of Evidence 2b What’s known on the subject? and What does the study add? The Kattan nomogram is one of the most commonly used preoperative prediction tools for estimating individualized risk of biochemical recurrence after radical prostatectomy. However, little is known about this nomogram’s accuracy for patients at the extremes of the risk spectra, as only a small fraction of such patients comprised the cohort used in its development. We examined the accuracy of the Kattan nomogram across various risk groups, and confirmed its ability to accurately estimate risk of recurrence, even for patients with high and low‐risk prostate cancer.

OBJECTIVE

? To investigate the predictive ability of nomograms at the extremes of preoperative clinical parameters by examining the predictive ability across all prostate cancer risk groups.

PATIENTS AND METHODS

? The Columbia University Urologic Oncology Database was reviewed: 3663 patients underwent radical prostatectomy from 1988 to 2008. Patients who had received neoadjuvant or adjuvant therapy, or had insufficient clinical parameters for estimation of 5‐year progression‐free probability using the preoperative Kattan nomogram were excluded. ? A total of 1877 patients were included and stratified by D’Amico risk criteria. Mean estimated nomogram progression rates were compared with actuarial Kaplan–Meier survival statistics. ? A regression model to predict progression‐free survival was fitted with estimated nomogram score and concordance indices were calculated for the entire model and subsequently for each risk group.

RESULTS

? Of 1877 patients, 857 (45.6%) were low risk, 704 (37.5%) were intermediate risk, and 316 (16.8%) were high risk by D’Amico criteria. ? Mean estimated nomogram survival and actuarial Kaplan–Meier survival at 5 years were 90.5% and 92.2% (95% CI 89.2–94.3) for low‐risk, 76.7% and 77.8% (73.3–81.7) for intermediate‐risk, and 65.8% and 60.4% (52.0–67.7) for high‐risk groups, respectively. Using nomogram score in the regression model, the c‐index for the full model was 0.61. ? For low‐, intermediate‐ and high‐risk patients independently the c‐index was 0.60, 0.59 and 0.57, respectively. When low‐, intermediate‐ and high‐risk patients were independently removed from the model the c‐index was 0.64, 0.65 and 0.55, respectively. ? The c‐index for the full model using the categorical nomogram risk scores was 0.67. Similar to the D’Amico model, the c‐index improved to 0.69 when intermediate‐risk patients were removed from the model.

CONCLUSIONS

? The study confirms the ability of preoperative nomograms to accurately predict actuarial survival across all risk groups. ? The predictive ability of the nomogram varies by risk group, yet even at the extremes of high‐risk and low‐risk prostate cancer the nomogram accurately predicts outcome.     

Head-to-Head Comparison of the Three Most Commonly Used Preoperative Models for Prediction of Biochemical Recurrence After Radical Prostatectomy

Background

Several models can predict the rate of biochemical recurrence (BCR) after radical prostatectomy (RP).

Objective

We tested the three most commonly used models—the D’Amico risk stratification scheme, the Cancer of the Prostate Risk Assessment (CAPRA) score, and the Stephenson nomogram—in a European cohort of RP patients.

Design, setting, and participants

We relied on preoperative characteristics and prostate-specific antigen follow-up data of 1976 patients, as required by the three tested models. All patients were treated with an open RP between 1992 and 2006.

Measurements

Analyses included tests of accuracy (Harrell's concordance index) and calibration between predicted and observed BCR rates at 3 yr and 5 yr after RP. Additionally, we relied on decision curve analyses to compare the three models directly in a head-to-head fashion.

Results and limitations

The median follow-up of censored patients was 32 mo. BCR-free rates at 3 yr and 5 yr after RP were 80.2% and 72.6%, respectively. The concordance index for 3-yr BCR predictions was 70.4%, 74.3%, and 75.2% for the D’Amico, CAPRA, and Stephenson models, respectively, versus 67.4%, 72.9%, and 73.5% for 5-yr BCR predictions. Calibration results supported the use of either the CAPRA or Stephenson models. Decision curve analyses indicated a small benefit for the CAPRA score relative to the Stephenson nomogram. Our findings apply to German patients treated with RP at a high-volume tertiary care centre. Consequently, the rank order reported in this paper may not be the same in North American or other European cohorts.

Conclusions

Different methods yield different results, and it may be difficult to reconcile concordance index, calibration, and decision curve analysis findings. Our data suggest that the CAPRA score outperforms the other models when decision curve analysis and calibration were used as benchmarks. Conversely, the Stephenson nomogram outperformed the other models when concordance index was used as a metric.     

Long-Term Rates of Undetectable PSA with Initial Observation and Delayed Salvage Radiotherapy after Radical Prostatectomy

Background

Randomized trials have shown an improvement in progression-free survival rates with adjuvant radiation therapy (ART) after radical prostatectomy for patients with a high risk of cancer recurrence. Less is known about the relative advantages and disadvantages of initial observation with delayed salvage radiation therapy (SRT).

Objective

To examine the results of SRT in a large single-surgeon radical prostatectomy series.

Design, Setting, and Participants

From a radical prostatectomy database, we identified 859 men with positive surgical margins (SM+), extracapsular tumor extension (ECE), or seminal vesicle invasion (SVI) who chose to defer ART. Following a period of initial observation, 192 ultimately received SRT for prostate-specific antigen (PSA) progression.

Measurements

Survival analysis was performed to examine the outcomes of initial observation followed by SRT.

Results and Limitations

In patients with SM+/ECE and SVI, the 7-yr PSA progression-free survival rates with observation were 62% and 32%, respectively. Among those who had PSA progression, 56% and 26%, respectively, maintained an undetectable PSA for 5 yr after SRT. The long-term rates of undetectable PSA associated with an SRT strategy were 83% and 50% for men with SM+/ECE and SVI, respectively. In the subset of 716 men who did not receive any hormonal therapy, the corresponding long-term rates of undetectable PSA were 91% and 75%, respectively.

Conclusions

Following radical prostatectomy, initial observation followed by delayed SRT at the time of PSA recurrence is an effective strategy for selected patients with SM+/ECE. Some patients with SVI may also benefit from this strategy. However, additional prospective studies are necessary to further examine the survival outcomes following SRT.     

Multiparametric Magnetic Resonance Imaging Is an Independent Predictor of Salvage Radiotherapy Outcomes After Radical Prostatectomy

Background

The Stephenson nomogram is widely used to estimate the success of salvage radiotherapy (sXRT) for prostate cancer (PCa) recurrence after radical prostatectomy (RP).

Multi-institutional Validation of the CAPRA-S Score to Predict Disease Recurrence and Mortality After Radical Prostatectomy

Background

The University of California, San Francisco, Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score uses pathologic data from radical prostatectomy (RP) to predict prostate cancer recurrence and mortality. However, this clinical tool has never been validated externally.

Objective

To validate CAPRA-S in a large, multi-institutional, external database.

Design, setting, and participants

The Shared Equal Access Regional Cancer Hospital (SEARCH) database consists of 2892 men who underwent RP from 2001 to 2011. With a median follow-up of 58 mo, 2670 men (92%) had complete data to calculate a CAPRA-S score.

Intervention

RP.

Outcome measurements and statistical analysis

The main outcome was biochemical recurrence. Performance of CAPRA-S in detecting recurrence was assessed and compared with a validated postoperative nomogram by concordance index (c-index), calibration plots, and decision curve analysis. Prediction of cancer-specific mortality was assessed by Kaplan-Meier analysis and the c-index.

Results and limitations

The mean age was 62 yr (standard deviation: 6.3), and 34.3% of men had recurrence. The 5-yr progression-free probability for those patients with a CAPRA-S score of 0–2, 3–5, and 6–10 (defining low, intermediate, and high risk) was 72%, 39%, and 17%, respectively. The CAPRA-S c-index was 0.73 in this validation set, compared with a c-index of 0.72 for the Stephenson nomogram. Although CAPRA-S was optimistic in predicting the likelihood of being free of recurrence at 5 yr, it outperformed the Stephenson nomogram on both calibration plots and decision curve analysis. The c-index for predicting cancer-specific mortality was 0.85, with the caveat that this number is based on only 61 events.

Conclusions

In this external validation, the CAPRA-S score predicted recurrence and mortality after RP with a c-index >0.70. The score is an effective prognostic tool that may aid in determining the need for adjuvant therapy.     

A post‐radical‐prostatectomy nomogram incorporating new pathological variables and interaction terms for improved prognosis

Study Type – Prognosis (systematic review)
Level of Evidence 2a What’s known on the subject? and What does the study add? Nomograms are commonly used by urologists to assess a patient’s risk of developing biochemical failure (PSA recurrence) after radical prostatectomy. The nomograms currently available on websites and in the published literature do not take into account recent developments in pathological reporting which may improve our ability to more accurately predict patient prognosis. Furthermore, currently available nomograms treat all clinical predictors as independent variables without considering the possibility that these factors may be interlinked, which may alter their predictive value. Our study assesses the predictive value of several new pathological variables and demonstrates that the per cent of Gleason patterns 4 and/or 5 (% 4/5), intraductal prostatic carcinoma and prostate weight significantly improve the predictive value of a model based on established pathological variables. We also show that consideration of interactions between % 4/5, surgical margin status and extracapsular extension further improves our accuracy in predicting patient PSA recurrence. Finally, we find that published nomograms based on PSA recurrence defined as ≥0.4 ng/mL provide over‐optimistic predictions for prostate cancer patients where PSA recurrence was defined as ≥0.2 ng/mL.

OBJECTIVE

• ? To evaluate new variables in prostate pathology reporting including, the per cent of Gleason patterns 4 and/or 5 (% 4/5), presence or absence of intraductal carcinoma of the prostate (IDCP), tumour volume and the prostatic zone of tumour origin as predictors of post‐radical‐prostatectomy (RP) biochemical recurrence (BCR).
• ? To develop an optimal postoperative nomogram for patients with prostate cancer.

PATIENTS AND METHODS

• ? Our study cohort was 1939 eligible patients from the Abbott West Australian Prostatectomy Database.
• ? Multivariate Cox proportional hazard regression models were developed to predict BCR which was defined as prostate‐specific antigen (PSA) ≥0.2 ng/mL.
• ? Our models and the 2009 Kattan postoperative nomogram were compared in terms of discrimination and calibration, with internal validation of our final model performed using bootstrapping methods. Our final model is presented as a nomogram.

RESULTS

• ? The Kattan nomogram was accurate in discriminating our patients according to risk (concordance index: 0.791) but calibration analysis indicated underestimation of patient risk, particularly for high‐risk disease.
• ? Our nomogram incorporates % 4/5, IDCP and prostate weight plus interaction terms between % 4/5, positive surgical margins and extracapsular extension, giving improved predictive accuracy (concordance index: 0.828) and calibration.

CONCLUSIONS

• ? Nomograms that predict risk of BCR defined as PSA ≥0.4 ng/mL may not be optimal for patient cohorts where BCR is defined as PSA ≥0.2 ng/mL.
• ? If our findings are validated in other populations, current post‐RP nomograms may be improved to a modest degree by incorporating the new variables prostate weight, IDCP and % 4/5, and by considering interactions between predictive variables.

     

A pretreatment nomogram predicting biochemical failure after salvage cryotherapy for locally recurrent prostate cancer

Study Type – Prognosis (retrospective cohort)
Level of Evidence 2b

OBJECTIVE

To gather a pooled database from six tertiary‐care referral centres using salvage cryotherapy (SC) for locally recurrent prostate cancer, and develop a pretreatment nomogram allowing a prediction of the probability of biochemical failure after SC, based on pretreatment clinical variables.

PATIENTS AND METHODS

We retrospectively analysed 797 men treated at six tertiary‐care referral centres with SC for locally recurrent disease after primary radiotherapy with curative intent. The median duration of follow‐up from the time of SC to the date of last contact was 3.4 years. The primary study endpoint was biochemical failure, defined as a serum prostate‐specific antigen (PSA) level after SC of >0.5 ng/mL.

RESULTS

Overall, the rate of biochemical failure was 66% with a median of 3.4 years of follow‐up. A logistic regression model was used to predict biochemical failure. Covariates included serum PSA level at diagnosis, initial clinical T stage, and initial biopsy Gleason score. On the basis of these results, a pretreatment nomogram was developed which can be used to help select patients best suited for SC. Our pretreatment nomogram was internally validated using 500 bootstrap samples, with the concordance index of the model being 0.70.

CONCLUSION

A pretreatment nomogram based on several diagnostic variables (serum PSA level at diagnosis, biopsy Gleason grade, and initial clinical T stage) was developed and might allow the selection of ideal candidates for SC.     

Clinical outcomes after salvage radiotherapy without androgen deprivation therapy in patients with persistently detectable PSA after radical prostatectomy: results from a national multicentre study

Purpose

To assess oncologic outcomes after salvage radiotherapy (SRT) without androgen deprivation therapy (ADT) in patients with persistently detectable PSA after radical prostatectomy (RT).

Methods

Two hundred and one patients who failed to achieve an undetectable PSA received SRT without ADT. The primary endpoint was failure to SRT that was defined by clinical progression or use of second-line ADT. Clinicopathological parameters, 6-week PSA level, PSAV and pre-SRT PSA levels were assessed using time-dependent analyses.

Results

Median postoperative 6-week PSA and pre-SRT PSA levels were 0.25 and 0.48 ng/mL, respectively. Median time between surgery and SRT was 7 months. Failure to SRT was reported in 42.8 % of cases with the need for second-line ADT in 26.9 % of cases. Pre-SRT PSA was strongly correlated with postoperative 6-week PSA (p < 0.001) but not with PSAV. The risk of SRT failure was increased by threefold in case of Gleason score 8–10 (p = 0.036) or pT3b cancer (p = 0.006). Risk group classification based on these prognostic factors improved SRT failure prediction. Survival curves confirmed that 5-year ADT-free survival rates were significantly influenced by PSAV (p = 0.002) and pre-SRT PSA (p = 0.030).

Conclusions

In patients with persistently detectable PSA after RP and selected for local salvage treatment, SRT offers good oncologic clinical outcomes. The most powerful pathologic predictive factors of SRT failure include a pT3b stage, a Gleason score 8 or more cancer and high PSAV and pre-SRT PSA levels. Patients having a high PSAV >0.04 ng/mL/mo would be potentially better candidates for a systemic therapy due to a high SRT failure rate.     

Stage migration in localized prostate cancer has no effect on the post‐radical prostatectomy Kattan nomogram

Study Type – Prognosis (case series)
Level of Evidence 4

OBJECTIVE

To investigate the effect of prostate‐specific antigen (PSA) testing on stage migration in an Australian population, and its consequences on the prognostic accuracy of the post‐radical prostatectomy (RP) Kattan nomogram, as in North America widespread PSA testing has resulted in prostate cancer stage migration, questioning the utility of prognostic nomograms in this setting.

PATIENTS AND METHODS

The study comprised 1008 men who had consecutive RP for localized prostate cancer between 1991 and 2001 at one institution. Two groups were assessed, i.e. those treated in 1991–96 (group 1, the early PSA era), and 1997–2001 (group 2, the contemporary PSA era). Differences in clinicopathological features between the groups were analysed by chi‐squared testing and survival modelling. Individual patient data were entered into the post‐RP Kattan nomogram and the efficacy assessed by receiver‐ operating characteristic curve analysis.

RESULTS

Patients in group 2 had lower pathological stage disease (P = 0.01) and fewer cancers with Gleason score ≥8 (P < 0.001) than group 1. Multivariate analysis identified preoperative serum PSA level (P < 0.01) and Gleason score (P < 0.01) as strong predictors of biochemical relapse in both groups. In group 2 pathological stage was not significant, but margin involvement became highly significant (P = 0.004). There was no difference in the predictive accuracy of the Kattan nomogram between the groups (P = 0.253).

CONCLUSIONS

These findings show a downward stage migration towards organ‐confined disease after the introduction of widespread PSA testing in an Australian cohort. Despite this, the Kattan nomogram remains a robust prognostic tool in clinical practice.     

External validation of the SEARCH model for predicting aggressive recurrence after radical prostatectomy: results from the Duke Prostate Center Database

Study Type – Prognosis (retrospective cohort)
Level of Evidence 2b

OBJECTIVE

To validate a model previously developed using the Shared Equal Access Regional Cancer Hospital (SEARCH) database to predict the risk of aggressive recurrence after surgery, defined as a prostate‐specific antigen (PSA) doubling time (DT) of <9 months, incorporating pathological stage, preoperative PSA level and pathological Gleason sum, that had an area under the curve (AUC) of 0.79 using a cohort of men from the Duke Prostate Center (DPC).

PATIENTS AND METHODS

Data were included from 1989 men from the DPC database who underwent RP for node‐negative prostate cancer between 1987 and 2003. Of these men, 100 had disease recurrence, with a PSADT of <9 months, while 1889 either did not have a recurrence but had ≥36 months of follow‐up or had a recurrence with a PSADT of ≥9 months. We examined the ability of the SEARCH model to predict aggressive recurrence within the DPC cohort, and examined the correlation between the predicted risk of aggressive recurrence and the actual outcome within DPC.

RESULTS

The SEARCH model predicted aggressive recurrence within DPC with an AUC of 0.82. There was a strong and significant correlation between the predicted risk of aggressive recurrence based on the SEARCH tables and the actual outcomes within DPC (r= 0.68, P < 0.001), although the model predictions tended to be slightly higher than the actual risk.

CONCLUSIONS

The SEARCH model to predict aggressive recurrence after RP predicted aggressive recurrence in an external dataset with a high degree of accuracy. These tables, now validated, can be used to help select men for adjuvant therapy and clinical trials.     

A nomogram for predicting upgrading in patients with low‐ and intermediate‐grade prostate cancer in the era of extended prostate sampling

Study Type – Diagnostic (exploratory cohort)
Level of Evidence 2b

OBJECTIVE

To develop a nomogram to predict the probability that the pathological Gleason sum (GS) will be higher than that indicated by the biopsy, suggesting a higher risk for the patient presumed to be at low risk, as a substantial proportion of patients with low and intermediate grade on biopsy are upgraded on interpretation of the radical prostatectomy (RP) specimens, but a similar clarification of accurate Gleason scoring is not available in patients with no surgical histology.

PATIENTS AND METHODS

The study included 1017 patients who had RP after biopsy showing GS 6 and 7 (3 + 4) from 2000 to 2007. Nomogram predictor variables included age, race, digital rectal examination, prostate‐specific antigen (PSA) level, number of cores taken, number of positive cores, maximum percentage cancer in any core, number of previous biopsies, prostate volume, clinical stage, high‐grade prostatic intraepithelial neoplasia, atypical small acinar proliferation, inflammation and perineural invasion. We calculated the nomogram‐predicted probability in each patient. The area under the receiver operating characteristic curve was calculated as a measure of discrimination, and the calibration was assessed graphically.

RESULTS

The mean age of the patients was 60 years, the mean PSA level 6.62 ng/mL; 336 patients were upgraded (33%), 623 remained the same (61.3%) and 58 were downgraded (5.7%). A nomogram for predicting the possibility of upgrading was constructed that had a concordance index of 0.68. The nomogram was well calibrated.

CONCLUSIONS

Our nomogram for predicting upgrading provides important additional information for deciding on treatment to both the urologist and the patient with low‐ and intermediate‐grade prostate cancer. It might prove useful when the possibility of a more aggressive Gleason variant can change the management, and is especially meaningful when management options other than surgery are selected based on the inability to recognize the true pathological actual GS.     

Definition and preoperative predictors of persistently elevated prostate‐specific antigen after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

Study Type – Prognosis (inception cohort)
Level of Evidence 1b

OBJECTIVES

To define a level of persistently elevated prostate‐specific antigen (PSA) after radical prostatectomy (RP) that equates with high‐risk for disease progression, and to identify preoperative predictors of PSA persistence among men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.

PATIENTS AND METHODS

A total of 901 men treated with RP between 2001 and 2008 were separated into groups based upon PSA nadir within 6 months after RP. We explored the association between nadir groups and time to biochemical recurrence (BCR) using multivariate Cox proportional hazards and determined the preoperative predictors of PSA persistence using logistic regression.

RESULTS

Relative to men with undetectable PSA levels, those with a PSA nadir of 0.03 (hazard ratio [HR] 3.88, P < 0.001), 0.04 (HR 4.87, P < 0.001), 0.05–0.09 (HR 12.69, P < 0.001), 0.1–0.19 (HR 13.17, P < 0.001), and 0.2 ng/mL (HR 13.23, P < 0.001) were at increased risk of BCR while men with a nadir of 0.01 (HR 1.36, P = 0.400) and 0.02 (HR 1.64, P = 0.180) were not. Using the PSA persistence definition of a PSA nadir ≥0.03 ng/mL, 230 men (26%) had persistence. The independent preoperative predictors of PSA persistence were higher body mass index (BMI, P = 0.002), pathological Gleason score (relative to 2–6: 4 + 3–10, P = 0.001) and preoperative PSA level (P < 0.001).

CONCLUSIONS

Men with a PSA nadir ≥0.03 ng/mL after RP were at higher risk for BCR. Using a PSA persistence definition of a PSA nadir ≥0.03 ng/mL, persistence was predicted by known factors associated with aggressive disease (tumour grade, PSA level and BMI). Validation of the present definition in different populations using later end‐points remains necessary to assess its prognostic usefulness.     

The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up

Study Type – Prognosis (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Patients with biochemical recurrence after prostatectomy often develop subsequent metastases. However, the natural history of metastatic progression in men who have not received subsequent therapies before developing metastases has been understudied. Here, we describe the largest known cohort of men with PSA‐recurrent prostate cancer after prostatectomy who have not received additional treatments before metastasis. We characterize metastatic risk based on clinical variables, and we show that Gleason score and PSA doubling time are the strongest predictors of metastasis‐free survival. We present tables stratifying metastatic risk by these two variables.

OBJECTIVE

• ? To describe metastasis‐free survival (MFS) in men with prostate‐specific antigen (PSA) recurrence following radical prostatectomy, and to define clinical prognostic factors modifying metastatic risk.

PATIENTS AND METHODS

• ? We conducted a retrospective analysis of 450 men treated with prostatectomy at a tertiary hospital between July 1981 and July 2010 who developed PSA recurrence (≥0.2 ng/mL) and never received adjuvant or salvage therapy before the development of metastatic disease.
• ? We estimated MFS using the Kaplan–Meier method, and investigated factors influencing the risk of metastasis using Cox proportional hazards regression.

RESULTS

• ? Median follow‐up after prostatectomy was 8.0 years, and after biochemical recurrence was 4.0 years. At last follow‐up, 134 of 450 patients (29.8%) had developed metastases, while median MFS was 10.0 years.
• ? Using multivariable regressions, two variables emerged as independently predictive of MFS: PSA doubling time (<3.0 vs 3.0–8.9 vs 9.0–14.9 vs ≥15.0 months) and Gleason score (≤6 vs 7 vs 8–10).
• ? Using these stratifications of Gleason score and PSA doubling time, tables were constructed to predict median, 5‐ and 10‐year MFS after PSA recurrence. In different patient subsets, median MFS ranged from 1 to 15 years.

CONCLUSIONS

• ? In men undergoing prostatectomy, MFS after PSA recurrence is variable and is most strongly influenced by PSA doubling time and Gleason score. These parameters serve to stratify men into different risk groups with respect to metastatic progression.
• ? Our findings may provide the background for appropriate selection of patients, treatments and endpoints for clinical trials.

     

The outcome of patients with pathological Gleason score >or=8 prostate cancer after radical prostatectomy

OBJECTIVE

To analyse the outcome of patients undergoing radical prostatectomy (RP) for Gleason 8–10 clinically localized prostate cancer, and to evaluate the prognostic value of well‐known predictors of progression.

PATIENTS AND METHODS

In all, 1480 patients had RP between 1988 and 2006, of whom 180 had pathological Gleason score ≥8 and negative lymph nodes. Biochemical progression‐free survival was determined using the Kaplan‐Meier method. The effect of preoperative prostate‐specific antigen (PSA) level, pathological stage and margin status was assessed with univariate and multivariate analyses.

RESULTS

Of the 180 patients, the Gleason score in the RP specimen was 8, 9 or 10 in 70%, 27% and 3%, respectively; 24% had stage pT2 disease, 30% stage pT3a, 25% stage pT3b and 20% stage pT4a. The 5‐ and 7‐year biochemical progression‐free survival was 73 and 65% for stage pT2, 40% and 27% for stage pT3a, and 30% for stage pT3b (log rank test, P < 0.001). In the univariate model, preoperative PSA level, pathological stage and surgical margins were predictors of survival. In the multivariate analysis, preoperative PSA level and extracapsular extension predicted biochemical progression‐free survival.

CONCLUSION

Gleason 8–10 tumours have a poor prognosis. Patients with a PSA level of <10 ng/mL and stage pT2 disease have the greatest likelihood of having a longer progression‐free survival after RP.     

Impact of Early Salvage Radiation Therapy in Patients with Persistently Elevated or Rising Prostate-specific Antigen After Radical Prostatectomy

Background

Salvage radiation therapy (SRT) is a recommended treatment option for biochemical recurrence after radical prostatectomy (RP). However, its effectiveness may be limited to specific categories of patients.