The role of the PCA3 assay in predicting prostate biopsy outcome in a South African setting

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? The PCA3 assay has shown significant potential amongst the initial studies carried out in Western countries. This assay performed in line with previous studies. We have shown this marker to perform independent of prostatic volume and have identified potential indications for its use in our setting. However, we have not observed the PCA3 assay to outperform the PSA level across the risk spectrum.

OBJECTIVES

• ? To evaluate the investigational role, ideal threshold and indications of the Prostate CAncer gene 3 (PCA3) assay in a South African context.
• ? To better define the universality of the above marker since this is the pioneer study on the continent of Africa.

PATIENTS AND METHODS

• ? We prospectively evaluated 105 consecutive South African men referred for a prostate biopsy at two tertiary centres in the capital city, Pretoria.
• ? Sequentially, PSA levels and post DRE urine samples were taken within 24 h before prostate biopsy.
• ? The urine specimen was tested using the PROGENSA^TM PCA3 assay and a score was generated as (PCA3 mRNA/PSA mRNA) × 1000.
• ? The performance of this assay in predicting biopsy outcome was assessed, and compared with that of serum PSA.

RESULTS

• ? Median patient age was 67 years with a positive biopsy incidence of 42.9%.
• ? The higher the PCA3 score the greater the probability of a positive biopsy (P = 0.003).
• ? This score performed independently of prostatic volume (P = 0.3889) or the presence of a concurrent primary malignancy (P = 0.804).
• ? A threshold of 60 revealed a positive predictive value of 60% with an odds ratio of 4, whereas setting a limit of 35 revealed a positive predictive value of 54% and odds ratio of 3.5.
• ? Using receiver operating characteristics for overall performance comparison, the PSA level (area under the curve 0.844) performed better than the PCA3 score (area under the curve 0.705).

CONCLUSION

• ? PCA3 assay has shown consistency and performed in line with previous studies but it did not surpass serum PSA in this population.
• ? A PCA3 assay threshold of 60 performed better than the conventional limit of 35.
• ? This assay may have a potential niche in a certain subset of South African men that includes patients with larger glands, previous negative biopsies and altered baseline PSA levels.

     

The ability of prostate-specific antigen (PSA) density to predict an upgrade in Gleason score between initial prostate biopsy and prostatectomy diminishes with increasing tumour grade due to reduced PSA secretion per unit tumour volume

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Due to sampling error, the Gleason score of clinically localized prostate cancer is frequently underestimated at the time of initial biopsy. Given that this may lead to inappropriate surveillance of patients with high‐risk disease, there is considerable interest in identifying predictors of significant undergrading. Recently PSAD has been proposed to be an accurate predictor of subsequent upgrading in patients diagnosed with Gleason 6 disease on biopsy. We examined the predictive characteristics of PSAD in patients with low‐ and intermediate‐risk disease on biopsy subsequently treated with radical prostatectomy. We found that although PSAD was a significant predictor of upgrade of biopsy Gleason 6 and 3 + 4 = 7 tumours, it failed to predict upgrading in patients with Gleason 7 tumours taken as a whole. When we explored reasons for this discrepancy, we found that the amount of PSA produced per unit tumour volume decreased with increasing Gleason score, thereby diminishing the predictive value of PSAD.

OBJECTIVES

• ? To analyse the performance of PSA density (PSAD) as a predictor of Gleason score upgrade in a large cohort stratified by Gleason score.
• ? We and others have shown that an upgrade in Gleason score between initial prostate biopsy and final radical prostatectomy (RP) pathology is a significant risk factor for recurrence after local therapy.

PATIENTS AND METHODS

• ? Patients undergoing RP with matching biopsy information were identified from two prospective databases.
• ? Patients were analysed according to the concordance between biopsy and final pathology Gleason score in three paired groups: 6/>6, 3 + 4/>3 + 4, 7/>7.
• ? Receiver‐operating characteristic (ROC) curves were generated stratified by Gleason score, and the area under the curve (AUC) calculated.
• ? Logistic regression models were fitted to identify significant predictors of tumour upgrade.

RESULTS

• ? From 1516 patients, 435 (29%) had an upgrade in Gleason score. ROC analysis showed a decline in AUC with increasing biopsy Gleason score, from 0.64 for biopsy Gleason score 6, to 0.57 for Gleason score 7.
• ? In logistic regression models containing pretreatment variables, e.g. clinical stage and number of positive cores, for Gleason score 6 and 3 + 4, PSAD was the strongest predictor of subsequent tumour upgrade (odds ratio [OR] 1.46, 95% confidence interval [95% CI] 1.18–1.83, P= 0.001 and OR 1.37, 95% CI 1.14–1.67, P= 0.002, respectively).
• ? Surprisingly, in tumours upgraded from Gleason score 7 to >7, PSAD was not predictive even on univariable analysis, whereas clinical stage and number of positive cores were significant independent predictors. To explore the relationship between serum PSA and Gleason score, tumour volume was calculated in 669 patients.
• ? There was a strong association between Gleason score and tumour volume, with the median volume of Gleason score 7 and Gleason score >7 tumours being approximately twice and four‐times that of Gleason score 6 tumours, respectively (P < 0.001).
• ? In contrast, the median serum PSA level per millilitre tumour volume decreased significantly with increasing grade, from 5.4 ng/mL for Gleason score 6 to 2.1 ng/mL for >7 (P < 0.001).

CONCLUSIONS

• ? There is a strong correlation between Gleason score and tumour volume in well/intermediate differentiated tumours, and as they produce relatively high amounts of PSA per unit volume of cancer, high PSAD is the strongest single predictor of tumour undergrading.
• ? However, as higher grade tumours produce less PSA per unit volume, PSAD loses its predictive ability, and other clinical markers of tumour volume such as palpable disease and numbers of positive cores become more predictive.

     

Magnetic resonance imaging does not improve the prediction of misclassification of prostate cancer patients eligible for active surveillance when the most stringent selection criteria are based on the saturation biopsy scheme

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

OBJECTIVE

• ? To investigate the role of magnetic resonance imaging (MRI) in selecting patients for active surveillance (AS).

PATIENTS AND METHODS

• ? We identified prostate cancers patients who had undergone a 21‐core biopsy scheme and fulfilled the criteria as follows: prostate‐specific antigen (PSA) level ≤10 ng/mL, T1–T2a disease, a Gleason score ≤6, <3 positive cores and tumour length per core <3 mm.
• ? We included 96 patients who underwent a radical prostatectomy (RP) and a prostate MRI before surgery.
• ? The main end point of the study was the unfavourable disease features at RP, with or without the use of MRI as AS inclusion criterion.

RESULTS

• ? Mean age and mean PSA were 62.4 years and 6.1 ng/mL, respectively. Prostate cancer was staged pT3 in 17.7% of cases.
• ? The rate of unfavourable disease (pT3–4 and/or Gleason score ≥4 + 3) was 24.0%. A T3 disease on MRI was noted in 28 men (29.2%).
• ? MRI was not a significant predictor of pT3 disease in RP specimens (P = 0.980), rate of unfavourable disease (P = 0.604), positive surgical margins (P = 0.750) or Gleason upgrading (P = 0.314).
• ? In a logistic regression model, no preoperative parameter was an independent predictor of unfavourable disease in the RP specimen.
• ? After a mean follow‐up of 29 months, the recurrence‐free survival (RFS) was statistically equivalent between men with T3 on MRI and those with T1–T2 disease (P = 0.853).

CONCLUSION

• ? The results of the present study emphasize that, when the selection of patients for AS is based on an extended 21‐core biopsy scheme, and uses the most stringent inclusion criteria, MRI does not improve the prediction of high‐risk and/or non organ‐confined disease in a RP specimen.

     

The relationship between Prostate CAncer gene 3 (PCA3) and prostate cancer significance

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Prior studies have shown that the PCA3 Score is indicative of prostate cancer significance and may aid in selecting men with clinically insignificant prostate cancer who could be candidates for active surveillance. This analysis of data from two studies enrolling 1,009 men shows that the PCA3 Score is associated with many biopsy and pathological features of the insignificant prostate cancer. The paper also provides guidance for the use of the PAC3 Assay in clinical practice.

OBJECTIVE

• ? To evaluate the relationship between Prostate CAncer gene 3 (PCA3) and prostate cancer significance.

PATIENTS AND METHODS

• ? Clinical data from two multi‐centre European open‐label, prospective studies evaluating the clinical utility of the PCA3 assay in guiding initial and repeat biopsy decisions were analysed.
• ? First‐catch urine was collected after digital rectal examination (three strokes per lobe) and the PCA3 score was determined using the PROGENSA® PCA3 assay.
• ? Transrectal ultrasound‐guided biopsy (≥8 cores) and radical prostatectomy (RP) specimens were analysed by the local pathologist. The relationship between biopsy and RP outcomes with the PCA3 score was assessed.

RESULTS

• ? Of the 1009 men enrolled, 348 (34%) had a positive biopsy. The median and mean PCA3 scores were statistically significantly lower in men with biopsy Gleason score <7 vs ≥7, with clinical stage T1c vs T2a–T2c, T3a cancers, with ≤33% vs >33% positive biopsy cores and with ‘biopsy indolent’ vs ‘biopsy significant’ prostate cancer (indolent prostate cancer defined by biopsy Epstein criteria).
• ? In all, 175 men with a positive biopsy had a RP: median and mean PCA3 scores were statistically significantly lower in men with pathological Gleason score <7 vs ≥7, and with pathological stage T2a–T2c vs T3a–T3b cancers.

CONCLUSIONS

• ? The PCA3 score may combined with traditional tools aid in identifying men with clinically insignificant prostate cancer, as shown by biopsy and RP pathological features including biopsy Epstein criteria, who could be candidates for active surveillance.
• ? Treatment selection should be based on a combination of clinical and pathological variables. If one wants to use a threshold point to guide treatment decisions in clinical practice, a PCA3 score threshold of 20 may have the highest utility for selecting men with clinically insignificant prostate cancer in whom active surveillance may be appropriate; a PCA3 score threshold of 50 may be used to identify men at high risk of harbouring significant prostate cancer who are candidates for RP.
• ? Although the association between the PCA3 score and prostate cancer aggressiveness needs further evaluation, the inclusion of the PCA3 score into patient management strategies may provide clinicians with another tool to more accurately determine the course of treatment.

     

Underestimation of Gleason score at prostate biopsy reflects sampling error in lower volume tumours

Study Type – Diagnostic (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The Gleason score of prostate cancer is frequently underestimated at the time of diagnostic biopsy, although the contribution of sampling error to its incidence is unknown. We show that under‐graded tumours are significantly smaller that tumours concordant for the higher grade, indicating that incomplete tumour sampling plays a significant role in Gleason score assignment error.

OBJECTIVE

• ? To determine the influence of tumour and prostate gland volumes on the underestimation of prostate cancer Gleason score in diagnostic core biopsies.

PATIENTS AND METHODS

• ? Patients undergoing radical prostatectomy with matched diagnostic biopsies were identified from a prospectively recorded database.
• ? Tumour volumes were measured in serial whole‐mount sections with image analysis software as part of routine histological assessment.
• ? Differences in various metrics of tumour and prostate volume between upgraded tumours and tumours concordant for the lower or higher grade were analysed.

RESULTS

• ? In all, 684 consecutive patients with Gleason score 6 or 7 prostate cancer on diagnostic biopsy were identified.
• ? Of 298 patients diagnosed with Gleason 6 tumour on biopsy, 201 (67.4%) were upgraded to Gleason 7 or higher on final pathology. Similarly, of 262 patients diagnosed with Gleason 3 + 4 = 7 prostate cancer on initial biopsy, 60 (22.9%) were upgraded to Gleason score 4 + 3 = 7 or higher.
• ? Tumours upgraded from Gleason 6 to 7 had a significantly lower index tumour volume (1.73 vs 2 mL, P= 0.029), higher calculated prostate volume (41.6 vs 39 mL, P= 0.017) and lower relative percentage of tumour to benign glandular tissue (4.3% vs 5.9%, P= 0.001) than tumours concordant for the higher grade.
• ? Similarly, tumours that were Gleason score 3 + 4 on biopsy and upgraded on final pathology to 4 + 3 were significantly smaller as measured by both total tumour volume (2.3 vs 3.3 mL, P= 0.005) and index tumour volume (2.2 vs 3, P= 0.027) and occupied a smaller percentage of the gland volume (6.3% vs 8.9%, P= 0.017) compared with tumours concordant for the higher grade.
• ? On multivariate analysis, lower prostate weight (hazard ratio 0.97, 95% confidence interval 0.96–0.99, P < 0.001) and larger total tumour volume (hazard ratio 1.87, 95% confidence interval 1.4–2.6, P < 0.001) independently predicted an upgrade in Gleason score from 6 to 7. In tumours upgraded from biopsy Gleason 3 + 4, only higher index tumour volume (hazard ratio 3.1, 95% confidence interval 1.01–9.3, P= 0.048) was a significant predictor of upgrading on multivariate analysis.

CONCLUSIONS

• ? Under‐graded tumours are significantly smaller than tumours concordant for the higher grade, indicating that incomplete tumour sampling plays a significant role in Gleason score assignment error.
• ? Surrogate measures of tumour volume may predict those at greatest risk of Gleason score upgrade.

     

Local recurrence after tumour enucleation for renal cell carcinoma with no ablation of the tumour bed: results of a prospective single-centre study

Study Type – Therapy (individual cohort)
Level of Evidence 2b What’s known on the subject? and What does the study add? Tumour enucleation was demonstrated to be an oncologically safe conservative treatment for small renal masses in agreement with the EAU guidelines. Nevertheless, the theoretical increased risk of positive surgical margins and local recurrence, led some authors to hypothesize a possible key role of laser or diathermy ablation of the tumour bed to free the kidney parenchyma from any tumour cells that extended in the kidney parenchyma. Our pathological and clinical results showed that tumour enucleation with no ablation of the tumour bed (e.g. diathermy, argon beam or Nd‐YAG laser) can ensure negative surgical margins and it is not associated with an increased risk of local recurrence.

OBJECTIVE

• ? To prospectively evaluate the risk of positive surgical margins and local recurrence after blunt tumour enucleation (TE) with no ablation of the tumour bed.

PATIENTS AND METHODS

• ? Between 2005 and 2007, data were gathered prospectively from 201 consecutive patients who had open TE with no ablation of the tumour bed.
• ? Overall, 164 consecutive patients had TE for single sporadic renal cell carcinoma (RCC).
• ? All patients had an abdominal computed tomography (CT) at the last follow‐up visit.

RESULTS

• ? The pathological review showed that 70.2% of tumours were pT1a, 18.9% were pT1b, 1.8% were pT2 and 9.1% were pT3a.
• ? The mean (range, interquartile range) tumour greatest dimension was 3.5 (0.5–12.5, 2.4–4.1) cm.
• ? Although no deliberate attempt to resect normal parenchyma was performed, the pathological analysis showed the presence of a thin layer of parenchyma with a mean (range) thickness of 0.97 (0.31–1.60) mm, around the tumour. None of the patients had positive surgical margins.
• ? At a mean (median, range) follow up of 40 (38, 25–62) months, three (1.8%) patients had local recurrence, of whom one (0.6%) had a true local recurrence at the enucleation site detected 35 months after surgery, while two had kidney recurrence elsewhere associated with concurrent systemic metastases diagnosed 16 and 13 months after surgery.

CONCLUSIONS

• ? TE with no ablation of the tumour bed is a safe technique with a local recurrence rate of 0.6%.
• ? The histopathological analysis showed the presence of a minimal tumour‐free surgical margin, although no deliberate attempt to resect normal parenchyma is performed.

     

Influence of obesity on tumour volume in patients with prostate cancer

Study Type – Prognosis (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Obesity is associated with more aggressive prostate cancer. Prostate cancer tumour volume is affected by excess weight, after adjustment for all possible clinical and pathological confounders.

OBJECTIVE

• ? To investigate the association between body mass index and tumour volume at radical prostatectomy in a large European population.

PATIENTS AND METHODS

• ? Recent data support the hypothesis that the hormonal environment in overweight and obese men may alter androgen‐dependent prostate growth. Body mass index (BMI) has been implicated in prostate cancer pathophysiology.
• ? We analysed 1275 patients with prostate cancer who underwent radical prostatectomy at a single tertiary care institution. Mean tumour volume (TV) was evaluated according to BMI WHO categories (normal <25 kg/m² vs overweight 25–30 kg/m² vs obese 30–35 kg/m² vs severely obese >35 kg/m²).
• ? Univariable linear regression analyses targeted the association between BMI and TV at radical prostatectomy. Multivariable analyses were adjusted for age, prostate‐specific antigen value, biopsy Gleason sum, clinical stage and prostate volume.

RESULTS

• ? Mean BMI was 26.3 kg/m² (median 26; range 16.7–42.0). Mean TV was 5.6 mL (median 3.3; range 0.1–61.2). The mean prostate‐specific antigen value was 10.3 ng/dL (median 6.6; range 0.3–327).
• ? The mean TV was 5.0, 5.8, 6.3 and 9.2 mL in normal, overweight, obese and severely obese patients, respectively (P= 0.03). TVs in men with a normal BMI were 84% smaller than in severely obese men (5.0 vs 9.2 mL).
• ? On univariable analysis, BMI was correlated with TV at radical prostatectomy (P < 0.001). On multivariable analysis, BMI reached the independent predictor status after adjustment for age, prostate‐specific antigen value, biopsy Gleason score, clinical stage and prostate volume (P= 0.03).

CONCLUSION

• ? We showed that BMI is independently associated with prostate cancer volume at radical prostatectomy. The present results confirm that obesity may play a key role in prostate cancer pathophysiology.

     

Implementation and external validation of preoperative aspects and dimensions used for an anatomical (padua) score for predicting complications in 74 consecutive partial nephrectomies

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Partial nephrectomy (PN) is the gold standard operation for small renal tumours. The decision for or against a PN has been based mostly on preoperative radiological evaluation of the tumour. Three nephrometry scoring systems have been recently proposed for prediction of postoperative complications of PN (RENAL, C‐index and PADUA). We validate externally the accuracy of the PADUA system and suggest for the first time a novel scoring system, based on the original PADUA system, which implements three other significant factors for the postoperative course of a partial.

OBJECTIVE

• ? To externally validate the Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) classification of renal tumours managed by partial nephrectomy (PN).

PATIENTS AND METHODS

• ? Seventy‐four consecutive patients in a single academic tertiary institution underwent open PN.
• ? Incidence of 90‐day complications was stratified by several clinicopathological variables, such as gender, age of the patient, hospital stay, pathology report, tumour characteristics and positive surgical margins. PADUA scores were given to each case.
• ? The severity of complications was also categorized with the Clavien system.

RESULTS

• ? The optimal threshold of PADUA for the prediction of complications was 8 with a sensitivity equal to 90.9% and a specificity equal to 77.8% (area under the curve [AUC], 0.89; 95% confidence interval [CI], 0.73–1.00).
• ? Multivariate analysis revealed that that PADUA is an independent predictor for the risk of complications.
• ? Also, PADUA score ≥8 identified a group of patients with almost 20‐fold higher risk of complications (hazard ratio [HR]= 19.82; 95% CI, 1.79–28.35; P= 0.015).
• ? Patients with papillary histology had greater risk for complications than those with clear‐cell tumours (HR = 4.88; 95% CI, 1.34–17.76; P= 0.016).

CONCLUSIONS

• ? The PADUA score is a simple anatomical system that predicts the risk of postoperative complications. This is the first external validation of this system for open PN from a single centre.
• ? The authors believe that PADUA is an efficient tool, since the only variable of the present study that predicted a higher incidence of complications was the histology type, which is determined after surgery.
• ? However, it should be applied to laparoscopic and robot‐assisted series and it could also include the ischaemia time and surgeon experience in the overall scoring to be complete.

     

The impact of nerve sparing on incidence and location of positive surgical margins in radical prostatectomy

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Nerve sparing radical prostatectomy has been associated with increased risk of positive surgical margins due to the close anatomical relationship of the neurovascular bundle to the posterolateral aspect of the prostatic fascia. Our study of 945 men who underwent radical prostatectomy be one experienced surgeon found no increased risk of positive surgical margins, whether the cancer was organ confined or extracapsular extension was present.

OBJECTIVE

• ? To examine whether nerve‐sparing surgery (NSS) is a risk factor for positive surgical margins (PSMs) in patients with either organ‐confined prostate cancer or extracapsular extension (ECE).

PATIENTS AND METHODS

• ? Clinicopathological outcome data on 945 consecutive patients treated with radical prostatectomy (RP) were prospectively collected.
• ? All patients underwent RP (bilateral, unilateral or non‐NSS) by one surgeon between 2002 and 2007.
• ? Risk of PSMs and their locations with respect to NSS was determined by multivariate logistic regression analysis adjusting for preoperative risk factors for PSMs within pT2, pT3a and pT3b tumours.

RESULTS

• ? Overall a PSM was identified in 19.6% of patients in an unscreened population with mean prostate‐specific antigen (PSA) level of 8.1 ng/mL.
• ? There was no significant difference in rates of PSMs between NSS groups on multivariate analysis (P= 0.147).
• ? There was no significant difference in pT2 (P= 0.880), pT3a (P= 0.175) or pT3b (P= 0.354) tumours.
• ? The only significant predictor of PSMs was preoperative PSA level (risk ratio 1.289, P= 0.006).
• ? There was no significant difference in the location of PSMs except for the pT3a group, where the patients that had bilateral NSS were at higher risk of a posterolateral PSM (P= 0.028).

CONCLUSIONS

• ? With appropriate selection of patients, NSS does not increase the risk of PSMs, whether the cancer is organ confined or ECE is present.
• ? The adverse impact of the NSS procedure in the hands of an experienced surgeon is minimal and is a realistic compromise to obtain the increase in health‐related quality of life offered by NSS.

     

Prediction of outcomes after radical prostatectomy in patients diagnosed with prostate cancer of biopsy Gleason score ≥ 8 via contemporary multi (≥ 12)-core prostate biopsy

Study Type – Prognostic (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Currently, controversy continues with regards to the efficacy of performing radical prostatectomy (RP) and the potential predictor of outcome after surgery in patients with prostate cancers of higher biopsy Gleason score. Among contemporary patients with biopsy Gleason score ≥8 who underwent RP alone, patients with pathologically organ‐confined disease demonstrated significantly better biochemical outcome than others. Serum PSA level and maximum tumour length in a biopsy core, independent predictors of organ‐confined disease, would be useful in the selection of candidates for RP among patients presenting with biopsy Gleason score ≥8.

OBJECTIVE

• ? To investigate the outcome of patients who underwent radical prostatectomy (RP) for prostate cancer of biopsy Gleason score ≥ 8 diagnosed via contemporary prostate biopsy.

PATIENTS AND METHODS

• ? We reviewed records of 151 patients who underwent RP for prostate cancer of biopsy Gleason score ≥ 8 detected via multi (≥12)‐core prostate biopsy without any neoadjuvant or adjuvant treatment.
• ? Preoperative predictors of pathologically organ‐confined disease along with biochemical recurrence‐free survival were analyzed via multivariate logistic regression and Cox proportional hazards model.

RESULTS

• ? For 151 total subjects, 5‐year estimated biochemical recurrence‐free survival rate was 41.0%. Patients with pathologically organ‐confined disease were observed to have much higher 5‐year biochemical recurrence‐free survival rate than those otherwise (72.1 vs 31.5%, P < 0.001).
• ? Serum PSA level (P= 0.031) and maximum tumour length in a biopsy core (P= 0.005) were observed to be significant preoperative predictors of having pathologically organ‐confined disease.
• ? As for biochemical recurrence‐free survival following RP, serum PSA (P= 0.023), biopsy Gleason score (P= 0.032), and percent of total tumour length in biopsy cores (P < 0.001) were observed be significant preoperative predictors on multivariate analysis.

CONCLUSION

• ? Among contemporary patients with biopsy Gleason score ≥ 8 who underwent RP alone, patients with pathologically organ‐confined disease demonstrated significantly better biochemical outcome than others. Serum PSA level and maximum tumour length in a biopsy core, independent predictors of organ‐confined disease, would be useful in the selection of candidates for RP among patients presenting with biopsy Gleason score ≥ 8.

     

Three-dimensional tumour volume and cancer-specific survival for patients undergoing nephrectomy to treat pT1 clear-cell renal cell carcinoma

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The positive association of tumour size (largest tumour dimension on pathology review) and risk of RCC progression and survival following nephrectomy is well documented. Moreover, several clinicopathological scoring systems (i.e. nomograms and algorithms) have been developed to predict outcomes for surgically treated RCC patients and each of these includes tumour size as an independent predictor of RCC outcome. There is still the question of whether information on three‐dimensional tumour volume (cm³) can provide additional prognostic information, particularly among patients with small pT1 tumours where the range of tumour size is more limited. Our study demonstrates that increasing tumour volume is associated with a greater risk of RCC‐specific death in patients with pT1 ccRCC, with a more pronounced association in pT1a tumours specifically. In addition, we observed evidence that tumour volume may provide more accurate prognostic information than tumour size alone in pT1a patients. Tumour volume may add prognostic information specifically in pT1a RCC.

OBJECTIVE

• ? To address whether information on three‐dimensional tumour volume can provide additional prognostic information for patients with small, localized renal cell carcinoma (RCC) superior to tumour size alone.

PATIENTS AND METHODS

• ? We identified 955 patients treated with radical nephrectomy or nephron‐sparing surgery for unilateral, sporadic, pT1, pN0/NX, M0, non‐cystic clear‐cell RCC (ccRCC) between 1980 and 2004, including 515 pT1a patients and 440 pT1b patients.
• ? We estimated tumour volume using three tumour dimensions recorded on pathological analysis and the equation for the volume of an ellipsoid [π/6 (length × width × height)]. For tumour size alone, we used the maximum tumour diameter recorded on pathological analysis.
• ? Univariate and multivariable associations with RCC‐specific death were evaluated using Cox proportional hazards regression models summarized with hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS

• ? Among pT1a patients, the risk of RCC death associated with having a tumour volume above the median (HR = 4.55; 95% CI, 1.30–15.83; P= 0.018) was markedly higher than having a tumour size above the median (HR = 2.55; 95% CI 0.83–7.85; P= 0.10).
• ? Comparison of concordance (c) index values further supported the idea that additional prognostic information was provided by tumour volume (c= 0.659) compared with tumour size (c= 0.600) for pT1a patients.
• ? Among pT1b patients, we noted that associations of tumour volume and tumour size with RCC‐specific death were similar.
• ? Multivariable adjustment did not alter our findings.

CONCLUSIONS

• ? Tumour volume could provide valuable prognostic information for patients with pT1a ccRCC but not pT1b ccRCC.
• ? Future investigations are needed to confirm this finding, explore other RCC subtypes and evaluate accuracy of tumour volume determination on radiographic imaging for potential patient management before surgery.

     

High Gleason grade carcinoma at a positive surgical margin predicts biochemical failure after radical prostatectomy and may guide adjuvant radiotherapy

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Only 30–35% of patients with positive surgical margins after radical prostatectomy develop recurrent disease. Adjuvant radiotherapy reduces the rate of biochemical relapse or metastasis and improves overall survival after radical prostatectomy. Various pathological factors, such as location and extent of positive margins, have been proposed as possible prognostic factors in men with margin‐positive prostate cancer, however, the recent International Society of Urological Pathology consensus meeting in Boston noted that there is limited data on the significance of Gleason grade of the carcinoma at a positive margin. The present study shows that the presence of high grade prostate cancer, i.e. Gleason pattern 4 or 5, at a positive surgical margin is an independent predictor of biochemical recurrence after radical prostatectomy. Moreover, patients with lower grade carcinoma at the margin have a similar prognosis to men with negative margins. Hence, assessment of Gleason grade at the site of positive margin may aid optimal selection of patients for adjuvant radiotherapy.

OBJECTIVE

• ? To establish predictors of biochemical recurrence by analysing the pathological characteristics of positive surgical margins (PSMs), including Gleason grade of the carcinoma at the involved margin.

PATIENTS AND METHODS

• ? Clinicopathological and outcome data on 940 patients who underwent radical prostatectomy (RP) between 1997 and 2003 were collected.
• ? Of these, 285 (30.3%) patients with PSMs were identified for pathological review, including assessment of location of margin, linear extent, number of PSMs, plane of margin and Gleason grade (3 vs 4 or 5) at the margin.

RESULTS

• ? At a median follow‐up of 82 months, the biochemical recurrence rate of the PSM cohort was 29%.
• ? On univariate analysis, the presence of Gleason grade 4 or 5 at the margin (34.4% of cases) was significantly associated with biochemical recurrence (hazard ratio [HR] 2.80, 95% confidence interval [CI]= 1.82–4.32, P < 0.001) compared with the presence of Gleason grade 3.
• ? Linear extent of margin involvement was also associated with recurrence (P= 0.009).
• ? Single vs multiple margin involvement, location, and plane of the involved margin were not significant predictors of recurrence.
• ? On multivariate analysis, Gleason grade 4 or 5 at the margin remained an independent predictor of recurrence (HR 2.14, 95% CI = 1.29–4.03, P= 0.003).

CONCLUSION

• ? The Gleason grade at the site of a PSM identifies patients at increased risk of biochemical recurrence and should aid stratification of patients for adjuvant radiation therapy.

     

Positive surgical margins are a risk factor for significant biochemical recurrence only in intermediate-risk disease

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Positive surgical margins (PSMs) after radical prostatectomy are common, although their impact on the risk of disease recurrence is unknown. We examined the impact of PSMs on the risk of ‘significant’ biochemical recurrence stratified by their risk of occult metastatic disease. We find that only in intermediate‐risk disease does the presence of a PSM have a significant impact on the risk of recurrence, and this represents a failure of technique. By contrast, for high‐ and low‐risk disease, the risk of recurrence is driven by intrinsic tumour biology, and the presence of a PSM has little impact on outcome.

OBJECTIVE

• ? To determine the impact of surgical margin status on the risk of significant biochemical recurrence (prostate‐specific antigen [PSA] doubling time <3, <6 or <9 months) after prostatectomy.

MATERIALS AND METHODS

• ? Patients undergoing radical prostatectomy with complete clinical and pathological data and detailed PSA follow‐up were identified from two prospectively recorded databases.
• ? Patients were stratified according to their risk of occult systemic disease (low risk: PSA < 10 ng/dL, pT2 stage and Gleason score ≤6; intermediate risk: PSA 10–20 ng/dL, pT2 stage and/or Gleason score 7; high: PSA > 20 ng/dL or pT3‐4 stage or Gleason score 8–10) and the impact of a positive surgical margin (PSM) within each stratum determined by univariable and multivariable analysis.

RESULTS

• ? Of 1514 patients identified, 276 (18.2%), 761 (50.3%) and 477 (31.5%) were classified as having low‐, intermediate‐ and high‐risk disease respectively.
• ? A total of 370 (24.4%) patients had a PSM and with a median follow‐up of 22.2 months, and 165 (7%) patients had a biochemical recurrence.
• ? Sufficient PSA data was available to calculate PSA doubling times in 151/165 patients (91.5%).
• ? The PSM rate rose significantly, from 11% in low‐risk to 43% in high‐risk disease (P < 0.001), with similar positive associations noted with tumour grade, stage and serum PSA (P < 0.001).
• ? Patients with low‐risk disease had essentially identical risks of significant biochemical recurrence over the study period, regardless of surgical margin status. By contrast, in patients with both intermediate‐ and high‐risk disease, a PSM was a strong predictor of significant biochemical recurrence on univariable analysis. On multivariable analysis, howver, PSM predicted significant disease recurrence in intermediate‐risk disease only.

CONCLUSIONS

• ? PSM is a risk factor for significant biochemical recurrence only in intermediate risk disease.

     

Targeting castration‐induced tumour hypoxia enhances the acute effects of castration therapy in a rat prostate cancer model

What’s known on the subject? and What does the study add? Castration therapy has rather modest effects on cell death in tumours but can be enhanced by other treatments targeting tumour stroma and vasculature. This study shows that the prostate becomes hypoxic following castration and that targeting hypoxic cells during castration therapy potently enhances the effects of castration.

OBJECTIVE

• ? To explore the effects of castration therapy, the standard treatment for advanced prostate cancer, in relation to tumour hypoxia and to elicit its importance for the short‐ and long‐term therapeutic response.

MATERIAL AND METHODS

• ? We used the androgen‐sensitive rat Dunning H prostate tumour model that transiently responds to castration treatment followed by a subsequent relapse, much like the scenario in human patients.
• ? Tumour tissues were analysed using stereological methods in intact, 1 and 7 days after castration therapy.

RESULTS

• ? Hypoxia was transiently up‐regulated after castration therapy and correlated with the induction of tumour cell apoptosis.
• ? When castration therapy was combined with tirapazamine (TPZ), a drug that targets hypoxic cells and the vasculature, the effects on tumour cell apoptosis and tumour volume were enhanced in comparison to either castration or TPZ alone.

CONCLUSION

• ? The present study suggests that castration‐induced tumour hypoxia is a novel target for therapy.

     

Predictors of early mortality after radical nephrectomy with renal vein or inferior vena cava thrombectomy – a population‐based study

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Surgical volume has been well established as a predictor of outcomes for several complex surgical procedures, yet few studies have evaluated this relationship with regards to radical nephrectomy with either renal vein or inferior vena cava thrombectomy. In addition, most published literature consists of single‐institution series from centres of excellence. We performed a population‐level analysis and identified surgeon volume as a significant predictor of short‐term mortality for this procedure. Such findings have potential implications regarding future policy and regionalization of care.

OBJECTIVE

• ? To study the short‐term mortality associated with radical nephrectomy with renal vein or inferior vena cava thrombectomy and the variables associated with this adverse outcome.

METHODS

• ? Using the Ontario Cancer Registry, we identified 433 patients in the province of Ontario, Canada undergoing radical nephrectomy with venous thrombectomy between 1995 and 2004.
• ? We determined mortality rates at postoperative days 30 and 90.
• ? Other variables analysed include pathological tumour characteristics, surgeon graduation year, hospital/surgeon academic status, surgery year and hospital/surgeon volume.
• ? We used multivariable logistic regression to assess outcomes.

RESULTS

• ? Overall mortality was 2.8% (30‐day) and 5.8% (90‐day).
• ? Surgeons performing a single nephrectomy with venous thrombectomy performed 14% of the cases and had the highest 30‐day (6.7%) and 90‐day (10%) mortality. The mortality rate for surgeons performing more than one surgery was 2.1% (30‐day) and 5.1% (90‐day).
• ? In recent years, this procedure was performed more commonly by the highest volume surgeons – 67% of cases in 2004 vs 40% in 1995.
• ? Significant predictors of 30‐day mortality included procedure year and low surgeon volume.
• ? Significant predictors of 90‐day mortality included procedure year, low surgeon volume, left‐sided tumour and increasing hospital volume.

CONCLUSIONS

• ? For radical nephrectomy with venous thrombectomy, surgeon volume predicts short‐term mortality, emphasizing the importance of experience in patient outcome.
• ? Despite a shift towards high‐volume surgeons, 13.8% of cases continued to be performed by low‐volume providers.
• ? If these results are confirmed in other jurisdictions, radical nephrectomy with venous thrombectomy should be regionalized and performed by surgeons who manage these cases regularly.

     

Racial differences in prediction of time to prostate cancer diagnosis in a prospective screening cohort of high‐risk men: effect of TMPRSS2 Met160Val

What’s known on the subject? and What does the study add? The TMPRSS2‐ERG fusion is a common gene fusion event in prostate tumours. Germline genetic variants that predict fusion in the tumour are under study. This study evaluates one germline genetic variant regarding predicting time to prostate cancer diagnosis among high‐risk men undergoing screening for prostate cancer. A specific genotype is associated with earlier time to prostate cancer diagnosis among Caucasian men with a family history of prostate cancer. The results suggest that such variants may be useful after further study in stratifying high‐risk men for individualized early detection approaches.

INTRODUCTION

• ? To evaluate the TMPRSS2‐ERG gene polymorphism with respect to self‐identified race or ethnicity (SIRE), time to prostate cancer (PCA) diagnosis, and screening parameters in the Prostate Cancer Risk Assessment Program, a prospective screening program for high‐risk men.

PATIENTS AND METHODS

• ? A total of 631 men aged between 35 and 69 years were studied. ‘High‐risk’ was defined as ≥ one first degree or two second degree relatives with PCA, any African American (AA) man regardless of familial PCA, and men with BRCA1/2 mutations.
• ? Men with elevated prostate‐specific antigen (PSA) concentrations or other indications for PCA underwent biopsy. Men were followed from time of study entry to PCA diagnosis.
• ? Cox models were used to evaluate time to PCA diagnosis by genotype.

RESULTS

• ? Genotype distribution differed significantly by SIRE (CT/TT vs CC, P < 0.0001). Among 183 Caucasian men with at least one follow‐up visit, PCA was more than doubled in men carrying CT/TT vs CC genotypes (hazard ratio = 2.55, 95% CI = 1.14–5.70) after controlling for age and PSA.
• ? No association was seen among AA men by TMPRSS2 genotype.

CONCLUSIONS

• ? The T‐allele of the Met160Val variant in TMPRSS2, which has been associated with the TMPRSS2–ERG fusion, may be informative of time to PCA diagnosis for a subset of high‐risk Caucasian men who are undergoing regular PCA screening.
• ? This variant, along with other genetic markers, warrant further study for personalizing PCA screening.

     

Secondary bladder cancer after upper tract urothelial carcinoma in the US population

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? It is known that a certain percentage of patients treated for upper tract urothelial carcinoma (UTUC) will go on to develop a secondary bladder cancer; however, the risk factors for developing a secondary bladder tumour have not been studied in a population‐based setting. Given the large changes in how UTUC has been diagnosed and managed in recent years, this study aimed to evaluate the natural history of UTUC in the US population over a 30‐year period, with a particular emphasis on the development of secondary bladder cancer.

OBJECTIVE

• ? To assess the natural history of upper tract urothelial carcinoma (UTUC) and the development of lower tract secondary cancer.

PATIENTS AND METHODS

• ? Patients diagnosed with UTUC between 1975 and 2005 were identified within nine Surveillance, Epidemiology and End Results registries.
• ? Baseline characteristics of patients with and without secondary bladder cancer were compared.
• ? A multivariate logistic regression model was fitted to test if the year of diagnosis predicted the likelihood of developing a secondary bladder cancer.

RESULTS

• ? Of the 5212 patients with UTUC, 242 (4.6%) had a secondary bladder cancer (range: 1.7–8.2%).
• ? There was a mean interval of 26.5 (95% CI: 22.2–30.8) months between cancer diagnoses.
• ? Compared with those without secondary tumours, patients with secondary bladder malignancy were more likely to present with larger tumours (4.2 vs 3.1 cm, P < 0.001) and with tumours located in the ureter (P < 0.001).
• ? Year of diagnosis was not a predictor of the likelihood of having a secondary bladder malignancy in a multivariate analysis controlling for demographic and tumour characteristics (odds ratio: 0.99; 95% CI: 0.95–1.03)

CONCLUSIONS

• ? Patients with larger urothelial tumours located in the ureter were those most likely to develop a secondary lower tract tumour.
• ? No longitudinal changes in the rate of secondary bladder cancer were noted among patients with UTUC over the 30‐year study period.

     

International validation of the prognostic value of subclassification for AJCC stage pT3 upper tract urothelial carcinoma of the renal pelvis

Study Type – Prognosis (inception cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Tumour stage is a powerful predictor of clinical outcomes and the most important factor driving clinical decision‐making after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). It has been suggested that renal pelvic pT3 subclassification into microscopic infiltration of the renal parenchyma (pT3a) versus macroscopic infiltration or invasion of peripelvic adipose tissue (pT3b) has strong prognostic value. This is an external validation study of the prognostic value of pT3 subclassification of renal pelvic UTUC in a large international cohort of patients treated with RNU. pT3b UTUC is associated with features of aggressive tumour biology, disease recurrence and cancer‐specific mortality. However, pT3 subclassification is not an independent predictor of clinical outcomes.

OBJECTIVE

• ? To externally validate the prognostic value of subclassification of pT3 renal pelvic upper tract urothelial carcinoma (UTUC) in a large international cohort of patients treated with radical nephroureterectomy (RNU).

PATIENTS AND METHODS

• ? The RNU specimens with pT3 UTUC of the renal pelvis from 284 patients at 11 centres located in Asia, North America and Europe were retrospectively evaluated. All specimens were reviewed by genitourinary pathologists at each institution. Tumours were categorized as pT3a (microscopic infiltration of the renal parenchyma) or pT3b (macroscopic infiltration of the renal parenchyma and/or infiltration of peripelvic adipose tissue).

RESULTS

• ? Overall, 148 (52%) tumours were classified as pT3a and 136 (48%) as pT3b. Patients with pT3b disease were more likely to have high‐grade tumours and sessile tumour architecture (all P≤ 0.02). Patients with pT3b tumours were at increased risk of disease recurrence (5‐year estimates: 55% versus 42%, P= 0.012) and cancer‐specific mortality (CSM) (5‐year estimates: 48% versus 40%, P= 0.04). Lymph node status, tumour architecture and tumour grade were independently associated with disease recurrence, whereas lymph node status, tumour architecture and lymphovascular invasion were independently associated with CSM. Subclassification of pT3 tumours was not associated with recurrence or CSM in multivariable analyses.

CONCLUSION

• ? Patients with pT3b UTUC were more likely to have tumours with aggressive pathological features and were at higher risk of disease recurrence and CSM after RNU compared with patients with pT3a disease. However, the pT3 subclassification did not remain an independent predictor of disease recurrence or CSM after controlling for tumour grade, lymph node status, tumour architecture and lymphovascular invasion.

     

Risk assessment of metastatic recurrence in patients with prostate cancer by using the Cancer of the Prostate Risk Assessment score: results from 2937 European patients

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Different tools allow the individual estimation of the various endpoints in patients with prostate cancer. The Cancer of the Prostate Risk Assessment (CAPRA) score is an easy to calculate prediction tool, based on a large population based database. However, little is known about the performance of this prediction tool in European patients. The data obtained in the present study demonstrate differences in tumour characteristics between European patients and the initial development cohort from the USA. However, the concordance index of the CAPRA scores for predicting biochemical recurrence and metastatic recurrence was 76.2 and 78.5, respectively, in European patients. Therefore, the CAPRA score also allows reliable prediction of the examined endpoints in European patients.

OBJECTIVES

• ? To assess the ability of the Cancer of the Prostate Risk Assessment Score (CAPRA) score for predicting biochemical recurrence (BCR) and metastatic recurrence (MR) by using a large cohort of European patients with prostate cancer.
• ? The CAPRA score was initially developed using patients treated in community‐based hospitals in the USA and allows a prediction of the risk of different clinical endpoints, without incorporating the surgical margin status.

PATIENTS AND METHODS

• ? BCR and metastatic recurrence rates were studied in 2937 patients who underwent radical prostatectomy in a tertiary referral centre after a mean (median, range) follow‐up of 49 (56, 12–220) months.
• ? The association between the examined endpoints, individual CAPRA scores and pathological features was analyzed by using Kaplan–Meier, proportional hazard and logistic regressions analyses.
• ? Graphical representation assessed the calibration of the CAPRA score for predicting both endpoints.

RESULTS

• ? Compared to the initial development cohort, worse tumour characteristics and a lower overall positive surgical margin rate (17.2% vs 32.4%) were detected in the European cohort.
• ? Overall, 530 (18.4%) and 58 (1.9%) of patients developed BCR and MR. Increasing CAPRA scores were related to less favourable pathological characteristics and higher BCR and metastatic recurrence rates.
• ? For example, the 5‐year BCR and metastatic recurrence rates were markedly different at the extremes of 0–1 vs ≥8 (9.2% vs 70.8% and 0.7% vs 16.4%, respectively).
• ? The concordance index for the prediction of BCR and metastatic recurrence was 76.2 and 78.5, respectively.

CONCLUSIONS

• ? Despite differences between the present cohort and the initial development cohort with respect to clinical features and the outcomes achieved, the data obtained in the present study shows the generalizability of the CAPRA score.
• ? Specifically, the data allow the precise identification of those European patients who are at high risk for BCR and MR.