Human glandular kallikrein 2 levels in serum for discrimination of pathologically organ-confined from locally-advanced prostate cancer in total PSA-levels below 10 ng/ml

BACKGROUND: We measured serum levels of human glandular kallikrein 2 (hK2) in patients treated with radical retropubic prostatectomy (rrP) for clinically localized prostate cancer (PCa) with a total PSA (tPSA)-level below 10 ng/ml to investigate whether hK2 can be applied to preoperatively distinguish organ-confined (pT2a/b) from nonorgan-confined (> or = pT3a)-PCa more accurately than total PSA. Further, we evaluated hK2, free- and tPSA-concentrations in all pathologic stages of PCa. METHODS: 161 serum samples from men scheduled for rrP were collected 1 day before surgery prior to any prostatic manipulation. Pathologic work-up revealed > or = pT3a-PCa in 48 and pT2a/b-PCa in 113 patients. HK2-levels in serum were measured using an immunofluorometric assay with an analytical sensitivity of 0.5 pg/ml, a functional sensitivity of 5 pg/ml and insignificant cross-reactivity with PSA (< 0.005%). Total (tPSA) and free PSA (fPSA) levels were measured using a commercially available assay from which we calculated %fPSA and an algorithm that combined hK2 and PSA-levels [hK2] x [tPSA/fPSA]. Means, medians, and ranges were calculated for pT2a/b vs. >/= pT3a-PCa and for all pathologic stages. Statistical significance of differences was calculated using Mann-Whitney-U and Kruskal-Wallis tests. Calculation of receiver-operator-characteristic (ROC) curves were performed for hK2, [hK2] x [tPSA/fPSA] and tPSA to compare diagnostic performance. RESULTS: A mean tPSA level in serum of 6.12 ng/ml in > or = pT3a-PCa was not significantly different (P = 0.366) from 5.78 ng/ml in pT2a/b-PCa. Also, there were no statistically significantly different levels of fPSA (P = 0.947) or %fPSA (0.292) for these two groups. By contrast, mean hK2-level in pT2a/b-PCa of 80 pg/ml was significantly different (P = 0.004) from a mean hK2 level of 120 pg/ml in > or = pT3a-PCa as shown by Mann-Whitney-analysis Moreover, the algorithm of [hK2] x [tPSA/fPSA] was significantly lower (P = 0.0004) in pT2a/b-PCa vs. > or = pT3a-PCa. Calculation of areas under curve (AUC) by receiver-operator-characteristics (ROC) demonstrated that the AUC for hK2 (0.64) was larger and the AUC for [hK2] x [tPSA/fPSA] (=0.68) significantly larger (P = 0.007) compared to the AUC of tPSA (0.55). Furthermore, Kruskal-Wallis Test revealed a highly significant correlation to pathologic stage using hK2 (P = 0.008) and [hK2] x [tPSA/fPSA] (P = 0.0015) compared to no significant differences in serum concentration of tPSA (P = 0.296). Also at tPSA-levels from 10-20 ng/ml, the hK2-levels in pT2a/b-PCa were close to significantly different (P = 0.051) from those in men with >/= pT3a-PCa, while the algorithm of [hK2] x [tPSA/fPSA] in that tPSA-range was significantly lower (P = 0.002) in pT2a/b-PCa compared to > or = pT3a0-PCa. CONCLUSIONS: Highly significant differences in serum concentration enable hK2 to be a powerful predictor of organ-confined disease and pathologic stage of clinically localized prostate cancer, especially in the PSA-range below 10 ng/ml. As such, there are important clinical consequences for the application of hK2 for the adequate treatment of prostate cancer patients, i.e., the option of nerve-sparing surgery. (c) 2001 Wiley-Liss, Inc.     

Serum human glandular kallikrein 2 (hK2) for distinguishing stage and grade of prostate cancer

BACKGROUND: Human glandular kallikrein (hK2) has been shown to add important information regarding the early detection and staging of prostate cancer. Preliminary analysis pointed out that hK2 may discriminate between pT2 and pT3 tumors, and that hK2 may predict Gleason grade 4/5 cancer volume, better than prostate-specific antigen (PSA) or percent free PSA (%fPSA). We investigated the role of hK2 serum values for predicting pathological stage, grade and Gleason score. METHODS: Prostate-specific antigen, free PSA and hK2 were measured on 222 untreated prostate cancer patients who had received radical prostatectomy at the Charité Hospital, Berlin, Germany. Pathological work up revealed pT2-cancer in 111 patients and pT3-cancer in 111 patients. Grade 2 was found in 118 patients whereas grade 3 tumors were found in 104 patients. RESULTS: For pT2 and pT3 patients, the %fPSA (P=0.006), the ratios hK2/fPSA (P=0.08) and hK2xtPSA/fPSA (P=0.002) were all significant different whereas hK2 (P=0.143) and PSA (P=0.1) did not differ. Between grade 2 and grade 3 tumors, the hK2 alone (P=0.27), the %fPSA (P=0.13), the ratios hK2/fPSA (P=0.94) and hK2xtPSA/fPSA (P=0.12) did not separate, whereas PSA (P=0.039) showed a difference. The same relationships were found between the two groups in Gleason score<7 and >or=7. Neither the hK2 ratio, nor % fPSA was different. CONCLUSION: Human glandular kallikrein was not different between pT2 and pT3, nor between G2 versus G3 or Gleason scores<7 and >or=7 prostate cancer. Together with %fPSA, hK2 may only help to distinguish preoperatively between pT2 and pT3 prostate cancer but cannot add further information.     

Generation of monoclonal antibodies specific for human kallikrein 2 (hK2) using hK2-expressing tumors

BACKGROUND: Human kallikrein 2 (hK2) and prostate-specific antigen (PSA) are serine proteases in the human kallikrein gene family that are 80% identical at the protein level. Like PSA, hK2 is expressed primarily in the prostate, making it an attractive bio-marker for prostate cancer development. In addition, its potent enzymatic activity may functionally affect the biology of prostate cancer. In order to further elucidate the possible roles of hK2 in prostate cancer, we have generated a panel of hK2-specific, non-PSA cross-reactive monoclonal antibodies. METHODS: A novel tumor-immunization strategy was used to produce monoclonal antibodies. Human hK2 cDNA was transfected into a BALB/c tumor cell line and used to immunize both BALB/c and PSA-expressing BALB/c.PSA transgenic mice. Because the BALB/c.PSA transgenic mouse showed a biased response towards hK2, a B cell fusion was performed using spleen cells from a transgenic mouse immunized in this fashion. RESULTS: A panel of monoclonal antibodies was produced and shown to be hK2-specific using newly developed hK2-specific sandwich ELISA and ELIspot assays. One of the monoclonal antibodies (6B7) was used to detect hK2 in human prostate by immunohistochemistry. Interestingly, two of the antibodies affected the function of hK2. The 1F8 antibody enhanced the enzymatic activity of hK2 whereas the 3C7 antibody inhibited its function. CONCLUSIONS: These hK2-specific antibodies illustrate a novel approach for constructing B-cell hybridomas and provide useful reagents to examine the role of hK2 in the biology and detection of prostate cancer.     

Similar rates of exponential decrease in serum concentrations of free prostate-specific antigen (PSA), PSA complexed to alpha-1-antichymotrypsin, and human glandular kallikrein 2 (hK2) in prostate cancer patients treated with GnRH-analogues

BACKGROUND: Our recently reported finding of rapid bi-exponential elimination of free prostate-specific antigen (PSA) after radical retropubic prostatectomy in patients with moderately elevated PSA levels, which contrasted a very slow, linear elimination of PSA complexed to alpha-1-antichymotrypsin (ACT), prompted us to study whether these elimination rates were applicable for patients selected for castration treatment with very high pretreatment concentrations of PSA in serum. In addition, serum concentrations of hK2, the activator of proPSA, were measured. METHODS: Pretreatment serum was obtained from 21 previously untreated prostate cancer patients due for hormonal treatment with a GnRH-analog. Samples were also collected during treatment up to a minimum of 24 weeks at 2-week intervals and analyzed with immunofluorometric assays for free PSA (PSA-F), PSA complexed to alpha-1-antichymotrypsin (PSA-ACT), total PSA (PSA-T), and human kallikrein 2 (hK2). For pharmaco-kinetic analysis the serum concentrations of hK2 and PSA forms for each patient were plotted against time both before and after logarithmic transformation and the half-lives were calculated as ln2/k. RESULTS: Median pretreatment serum concentrations were 322 ng/ml (range, 1.9-2210) for PSA-T, 27.8 ng/ml (range, 1.14-259) for PSA-F, and 207 ng/ml (range, 0.8-2080) for PSA-ACT. All patients had castrate levels of serum testosterone (< 2.5 nmol/l) in less than 21 days after initiation of GnRH-analog treatment. It was possible to evaluate data from 19/21 patients which showed an exponential decrease of all PSA concentrations in serum, with mean half-lives of 12.9 days (range, 7.3-30) for PSA-T, 15.5 days (range, 7.7-37.5) for PSA-F, and 12.3 days (range, 6.6-30) for PSA-ACT. Median pretreatment percent free PSA (PSA-F/PSA-T) was 12% compared to 18% at nadir. The median pretreatment level of hK2 was 3.5 ng/ml (range, 0.29-30.3). There was an exponential decrease in hK2 concentrations in serum after initiation of hormonal treatment with a mean half-life of 18.7 days (range, 7.5-37.5). CONCLUSIONS: For the majority of patients with hormonally treated prostate cancer the serum concentrations of PSA-T, PSA-F, PSA-ACT, and hK2 decreased slowly in parallel and mono-exponentially after initiation of treatment. Mean half-lives were between 12 and 19 days.     

Interpreting a rising prostate‐specific antigen after brachytherapy for prostate cancer

The aim of the present study was to review the English language literature on the topic of prostate‐specific antigen bounce after brachytherapy and present a summary of the current knowledge. Although ultimately prostate‐specific antigen is a reliable measure of success after prostate brachytherapy, it can be very misleading in the first 3 years because of the frequency with which temporary benign rises in prostate‐specific antigen occur. We have reviewed the English language literature on the topic of prostate‐specific antigen bounce under the following headings: prostate neoplasms, brachytherapy, biochemical definition of prostate‐specific antigen failure, “benign prostate‐specific antigen bounce” and “prostate‐specific antigen spike”. We included brachytherapy delivered as either low dose rate or high dose rate, and either as monotherapy or as a boost combined with external beam radiotherapy. A benign self‐limited rise in prostate‐specific antigen after prostate brachytherapy is seen in an average of 35% of patients, but increases in frequency with younger age. In patients aged less than 55 years, it is observed in up to 68%. Other factors, such as sexual activity, dose, prostate volume and the use of high dose rate versus low dose rate have been implicated in affecting the frequency of the benign bounce. Benign increases in prostate‐specific antigen are frequent after prostate brachytherapy. It is important to recognize and correctly diagnose this phenomenon in order to avoid unnecessary salvage treatment.     

Clinical utility of human glandular kallikrein 2 within a neural network for prostate cancer detection

OBJECTIVE

To assess, using artificial neural networks (ANNs), human glandular kallikrein 2 (hK2), prostate‐specific antigen (PSA), and percentage free/total PSA (f/tPSA), for discriminating between prostate cancer and benign prostatic hyperplasia (BPH).

MATERIAL AND METHODS

Serum samples from 475 patients with prostate cancer (n = 347) or BPH (n = 128) within the PSA range of 1–20 ng/mL were analysed for tPSA, fPSA and hK2 (research assay, Toronto, Canada). Data were analysed in the ranges of 1–4, 2–4, 4–10, and 2–20 ng/mL tPSA. Back‐propagation ANN models with the variables PSA, f/tPSA, and hK2, hK2/fPSA and hK2/(f/tPSA) were constructed. The diagnostic validity was evaluated by receiver‐operating characteristic (ROC) curve analysis.

RESULTS

Whereas the median concentration of hK2 was not significantly different between patients with BPH or prostate cancer in any of the tPSA ranges, the f/tPSA, hK2/fPSA and hK2/(f/tPSA), and the hK2‐based ANN outputs were always significantly different between patients with prostate cancer or BPH. Using ROC curve comparison, all variables were significantly better than hK2 in all ranges. The hK2‐based ANN performed better than f/tPSA except in the 4–10 ng/mL tPSA range. At 90% and 95% sensitivity, the hK2‐based ANN was also significantly better than f/tPSA in the 1–4 ng/mL tPSA range. hK2/(f/tPSA) achieved equal results to the hK2‐based ANN except in the range 2–20 ng/mL tPSA.

CONCLUSIONS

The hK2‐based ANN improves the outcome of f/tPSA but not hK2/(f/tPSA) in almost all analysed subgroups. When comparing the results at 90% and 95% sensitivity the hK2‐based ANN only performed significantly better than f/tPSA in the lowest tPSA range. Only in lower tPSA ranges do hK2‐based ANNs show an advantage for further improving prostate cancer detection.

     

Prostate specific antigen and human glandular kallikrein 2 in early detection of prostate cancer

PURPOSE: Several tumor markers have recently been applied for prostate cancer screening. We analyze the effectiveness of prostate specific antigen (PSA), age specific PSA, PSA velocity, volume adjusted PSA densities, change in PSA level following antibacterial therapy, free-to-total PSA ratio, alpha1-antichymotrypsin bound PSA, alpha2-macroglobulin bound PSA, alpha1-protease inhibitor bound PSA and human glandular kallikrein 2 in detecting prostate cancer. MATERIALS AND METHODS: We conducted a review of the literature between September 2000 and February 2001. A total of 7,250 abstracts and articles published during the previous 12 years were retrieved from MEDLINE using the key words PSA and human glandular kallikrein 2. Of these reports 135 are included in this review. RESULTS: We analyzed and systematized data from studies regarding the effectiveness of PSA and human glandular kallikrein 2 and their derivatives in the detection of prostate cancer. CONCLUSIONS: Improvement in the specificity and sensitivity of PSA is imperative. Free-to-total PSA ratio, transition zone PSA density and change in PSA level increase the specificity of PSA to some extent. Protocols investigating the effectiveness of different combinations of these 3 measurements seem necessary for improving the effectiveness of prostate cancer screening among men within the diagnostic "gray zone." PSA velocity, age adjusted PSA levels and PSA density might be used in limited cases. alpha1-Antichymotrypsin, alpha2-macroglobulin and alpha1-protease inhibitor bound PSA, and human glandular kallikrein 2 are promising experimental methods.     

Immunoreactivity of recombinant human glandular kallikrein using monoclonal antibodies raised against prostate-specific antigen

The gene encoding human glandular kallikrein (KLK2) was expressed in Escherichia coli, and the corresponding protein (hK2) was produced by fermentation. The hK2 was characterized by Western blotting and epitope map using monoclonal antibodies (MAbs) specific for another protease, prostate-specific antigen (PSA) with high structural identity (80%). MAbs that recognized three different epitopes were bound to hK2, representing 7 out of 23 MAbs tested. One epitope was localized to the sequence region around amino acid position 78, which is believed to be glycosylated in hK2. The affinities of MAbs recognizing hK2 were similar to those for PSA, suggesting that common epitopes seem to contain very conserved structures. The result may help in designing specific diagnostic assays for the assessment of prostate cancer. Prostate 31:84–90, 1997. © 1997 Wiley-Liss, Inc.     

Transrectal high‐intensity focused ultrasound for treatment of localized prostate cancer

Objectives: To assess the long‐term outcomes of transrectal high‐intensity focused ultrasound (HIFU) for patients with localized prostate cancer. Methods: From May 2003 to present, 137 consecutive patients with T1‐2 prostate cancer were treated using the Sonablate 500 and then followed for more than 12 months after their last HIFU treatment. A prostate biopsy was routinely carried out at 6 months and serum prostate‐specific antigen (PSA) was measured every 3 months after HIFU. Oncological outcomes as well as treatment‐related complications were assessed. Disease‐free survival (DFS) was judged using the Phoenix definition (PSA nadir + 2 ng/mL), negative histological findings and no local or distant metastasis. Results: The median follow up after HIFU was 36 months (range 12–84 months). No patients received adjuvant therapy during this period. The PSA nadir occurred at 2 months after HIFU and the median level was 0.07 ng/mL (0.01–2.01 ng/mL). Of the 133 patients who underwent prostate biopsy or transurethral resection of the prostate at 6 months or later after HIFU, six were positive for cancer cells (4.5%). There were no major postoperative complications, but urge incontinence (16 cases) and dysuria (33 cases) occurred after removal of the urethral catheter. The 5‐year DFS rate was 78% based on these criteria, and 91%, 81% and 62% in the low‐, intermediate‐ and high‐risk group, respectively. Conclusions: HIFU represents an effective, repeatable and minimally invasive treatment. It is particularly effective for low‐ and intermediate‐risk patients, and it should be considered as an option for localized prostate cancer.     

The role of transperineal template prostate biopsies in restaging men with prostate cancer managed by active surveillance

Study Type – Diagnostic (exploratory cohort) Level of Evidence 3b What's known on the subject? and What does the study add? The optimal method of active surveillance in prostate cancer remains unknown. This study is one of the first to report on the role of transperineal template prostate biopsies in active surveillance. It demonstrates that around one third of men are reclassified with more significant prostate cancer at an early stage in their management. This is a higher proportion than reported in contemporary cancers using standard transrectal biopsies for restaging.

OBJECTIVE

• ? To evaluate the role of transperineal template prostate biopsies in men on active surveillance.

PATIENTS AND METHODS

• ? In all, 101 men on active surveillance for prostate cancer underwent restaging transperineal template prostate biopsies at a single centre.
• ? Criteria for active surveillance were ≤75 years, Gleason ≤3+3, prostate‐specific antigen (PSA) ≤15 ng/mL, clinical stage T1–2a and ≤50% ultrasound‐guided transrectal biopsy cores positive for cancer with ≤10 mm of disease in a single core.
• ? The number of men with an increase in disease volume or Gleason grade on transperineal template biopsy and the number of men who later underwent radical treatment were assessed.
• ? The role of PSA and PSA kinetics were studied.

RESULTS

• ? In all, 34% of men had more significant prostate cancer on restaging transperineal template biopsies compared with their transrectal biopsies.
• ? Of these men, 44% had disease predominantly in the anterior part of the gland, an area often under‐sampled by transrectal biopsies.
• ? In the group of men who had their restaging transperineal template biopsies within 6 months of commencing active surveillance 38% had more significant disease.
• ? There was no correlation with PSA velocity or PSA doubling time.
• ? In total, 33% of men stopped active surveillance and had radical treatment.

CONCLUSIONS

• ? Around one‐third of men had more significant prostate cancer on transperineal template biopsies.
• ? This probably reflects under‐sampling by initial transrectal biopsies rather than disease progression.

     

Primary whole‐gland ablation for localized prostate cancer with high‐intensity focused ultrasound: The important predictors of biochemical recurrence

Objectives

To identify predictive factors of biochemical recurrence for patients undergoing high‐intensity focused ultrasound treatment for localized prostate cancer.

Methods

We retrospectively identified patients receiving whole‐gland prostate ablation with high‐intensity focused ultrasound for localized prostate cancer from 2009 to 2015. All the patients received pre‐high‐intensity focused ultrasound radical transurethral resection of the prostate. We included perioperative parameters as follows: age, preoperative prostate volume, stage of operation, initial prostate‐specific antigen, T stage, postoperative prostate‐specific antigen nadir, Gleason score, time to prostate‐specific antigen nadir and the presence of prostate‐specific antigen biochemical recurrence. Multivariable Cox regression and Kaplan–Meier analysis were used for investigating predictors of recurrence, and receiver operating characteristic analysis was used for the cut‐off values of prostate‐specific antigen nadir.

Results

Among 182 patients, 26.9% had prostate‐specific antigen biochemical recurrence after high‐intensity focused ultrasound during the median follow‐up period of 32.21 months. Gleason score ≥7 (Gleason score 7, hazard ratio 2.877, P = 0.027), stage ≥T2b (T2b, hazard ratio 3.16, P = 0.027) and prostate‐specific antigen nadir (hazard ratio 1.11, P < 0.001) were statistically significant, whereas there was no significance in prostate volume and initial prostate‐specific antigen. We posit that a cut‐off level of prostate‐specific antigen nadir 0.43 ng/mL might be considered as an independent predictive factor for prostate‐specific antigen biochemical recurrence in high‐intensity focused ultrasound patients in multivariate analysis (P < 0.001, hazard ratio 7.39, 95% confidence interval 3.56–15.37), and created a new nadir‐related prediction model for biochemical recurrence prediction.

Conclusions

Postoperative prostate‐specific antigen nadir of 0.43 ng/mL can be considered an important predictive factor for biochemical recurrence in primary whole‐prostate gland high‐intensity focused ultrasound treatment, and the nadir‐related prediction model might provide a reference for early salvage treatment. Furthermore, Gleason score ≥7, stage ≥T2b might be associated with unfavorable outcomes, although prostate volume and higher initial prostate‐specific antigen appear not to be associated with biochemical recurrence for the high‐intensity focused ultrasound treatment.

     

Community‐based prostate cancer screening in Japan: Predicting factors for positive repeat biopsy

Objectives: To assess possible predictors in determining criteria for repeat biopsy in a prostate cancer screening population. Methods: A total of 50 207 men over 55 years‐of‐age have participated in a prostate cancer screening program in Otokuni, Kyoto, Japan for 12 years. Transperineal systematic biopsy was carried out in case of positive digital rectal examination (DRE) or positive transrectal ultrasonography (TRUS) or a prostate‐specific antigen (PSA) value greater than 10.0 ng/mL. For those with a PSA level from 4.1 to 10.0 ng/mL, and negative DRE and TRUS findings, biopsy was indicated only when PSA density (PSAD) was greater than 0.15. The same indication was applied for the repeat biopsy. Results: A repeat biopsy after an interval of more than 2 years was carried out in 140 patients and was positive in 50 (36%) patients. The PSA value at the diagnosis of cancer declined from the initial value in six (12%) patients. On multivariate logistic regression analysis, PSA velocity (PSAV) as well as PSAD and DRE findings at latest screening were independent predictors for positive repeat‐biopsy outcome. The odds ratio (95% confidence intervals) of PSAV >0.48, latest PSAD >0.33 and positive latest DRE were 4.17 (1.05–18.5), 4.15 (1.31–14.0), and 3.62 (1.06–13.2), respectively. A combination of three variables defined as positive if any of these were positive, reduced 31% of unnecessary biopsies while missing 8% of low volume, low grade cancers. Conclusions: A combination of latest PSAD, PSAV and positive DRE at latest screening might help to reduce unnecessary repeat biopsies in high‐risk patients with an initial negative biopsy.     

The specific role of isoflavones in reducing prostate cancer risk

AIMS: To evaluate the effectiveness of supplementing a group of early stage prostate cancer patients, with 60 mg of soy isoflavones in producing a change in hormonal and proliferative risk parameters that are implicated in prostate cancer promotion. METHODS: Seventy six eligible prostate cancer patients with a Gleason score of 6 or below, between ages 50 and 80 were admitted and supplemented with soy isoflavones or placebo for a 12 week period and changes in PSA and steroid hormones were analyzed at baseline and post intervention. RESULTS: Fifty-nine patients completed the 12-week intervention. Serum free testosterone was reduced or showed no change in 61% of subjects in the isoflavone group compared to 33% in the placebo group. Serum total PSA decreased or was unchanged in 69% of the subjects in the isoflavone treated group compared to 55% in the placebo group. However, we did not see an increase in SHBG levels. Nineteen percent of subjects receiving soy isoflavones reduced total PSA by two points or more during the intervention period. CONCLUSIONS: These data suggest that supplementing early stage prostate cancer patients with soy isoflavones, even in a study of short duration, altered surrogate markers of proliferation such as serum PSA and free testosterone in a larger number of subjects in the isoflavone supplemented group than the group receiving placebo. The study establishes the need to explore further the effects of prolonged and consistent soy consumption, which could potentially delay onset of histologic disease in this patient population.     

The distribution of serum prostate-specific antigen levels among American men: implications for prostate cancer prevalence and screening

BACKGROUND: The purpose of this study was to describe the distribution of serum prostate-specific antigen (PSA) among American men and to estimate the number of prevalent cases of biopsy detectable prostate cancer among men with normal serum PSA. METHODS: We analyzed data of the National Health and Nutrition Examination Survey 2001-2002 (NHANES 2001-2002) data and combined these results with published data from the Prostate Cancer Prevention Trial (PCPT). RESULTS: Most men in the US have a serum PSA < or = 4.0 ng/ml, and mean and median serum PSA values rise steadily with age. There are an estimated 1,607,585 (95% CI 1,370,848-1,844,322) prevalent cases of biopsy detectable prostate cancer in men aged 62-85 years with a serum PSA < or = 4 ng/ml. Among men aged 62-75 years, there are an estimated 1,252,143 (95% CI 1,054,677-1,449,609) prevalent cases, including an estimated 195,499 (95% CI 140,234-250,764) high-grade tumors. CONCLUSION: A large number of prevalent cases of biopsy detectable prostate cancer exist in American men with a normal PSA.     

Prognostic significance of a positive surgical margin in pathologically organ‐confined prostate cancer

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

OBJECTIVE

To identify risk factors of a positive surgical margin (PSM) and the significance of a PSM after radical prostatectomy (RP) on biochemical recurrence (BCR) in exclusively pathologically confirmed organ‐confined (OC) prostate cancer, as despite an excellent prognosis after RP, some patients with pathologically confirmed OC disease have BCR, and the prognostic significance of a PSM in these men remains unclear.

PATIENTS AND METHODS

We assessed 932 men with pathologically OC disease who were treated with RP by nine different surgeons between 1992 and 2004. The prognostic significance of clinical and pathological variables, including tumour volume (TV) and percentage of high‐grade TV (%HGTV) were assessed. Logistic and Cox regression models were fitted to identify risk factors of a PSM and BCR. BCR was defined as a prostate‐specific antigen (PSA) level of 0.1 ng/mL and increasing after an undetectable PSA level.

RESULTS

The total PSM rate was 12.9% (120 men); the mean TV (P < 0.001), but not %HGTV (P= 0.2) was significantly higher in patients with PSM. TV, nerve‐sparing RP technique and surgical volume were independent risk factors for a PSM (P= 0.03). After a median follow‐up of 35 months the overall BCR rate was 8.8% (82 men). Patients with a PSM had significantly higher BCR rates (21.7% vs 6.9%; P < 0.001). In univariable analysis, a high %HGTV (70.4%) was the most informative risk factor of BCR, followed by RP Gleason score (65.8%) and PSM (65.7%). Removal of PSM from a multivariable Cox model decreased the accuracy by 12.1% (P < 0.001).

CONCLUSIONS

Our findings show that in OC prostate cancer, the risk of a PSM depends on TV, surgical technique and surgical volume. PSM is a significant risk factor for BCR. However, only 20% men with OC disease and a PSM develop BCR; conversely, 80% of men are cured despite a PSM. Therefore, adjuvant therapy must be considered, with caution to avoid unnecessary overtreatment.     

Prostate‐specific antigen screening impacts on biochemical recurrence in patients with clinically localized prostate cancer

Objective

To clarify the impact of prostate‐specific antigen screening on surgical outcomes of prostate cancer.

Methods

Patients who underwent radical prostatectomy were divided into two groups according to prostate‐specific antigen testing opportunity (group 1, prostate‐specific antigen screening; group 2, non‐prostate‐specific antigen screening). Perioperative clinical characteristics were compared using the Wilcoxon rank‐sum and χ²‐tests. Cox proportional hazards models were used to identify independent predictors of postoperative biochemical recurrence‐free survival.

Results

In total, 798 patients (63.2%) and 464 patients (36.8%) were categorized into groups 1 and 2, respectively. Group 2 patients were more likely to have a higher prostate‐specific antigen level and age at diagnosis and larger prostate volume. Clinical T stage, percentage of positive cores and pathological Gleason score did not differ between the groups. The 5‐year biochemical recurrence‐free survival rate was 83.9% for group 1 and 71.0% for group 2 (P < 0.001). On multivariate analysis, prostate‐specific antigen testing opportunity (hazard ratio 2.530; P < 0.001) was an independent predictive factor for biochemical recurrence after surgery, as well as pathological T stage, pathological Gleason score, positive surgical margin and lymphovascular invasion. Additional analyses showed that prostate‐specific antigen screening had a greater impact on biochemical recurrence in a younger patients, patients with a high prostate‐specific antigen level, large prostate volume and D'Amico high risk, and patients meeting the exclusion criteria of the Prostate Cancer Research International Active Surveillance study.

Conclusions

Detection by screening results in favorable outcomes after surgery. Prostate‐specific antigen screening might contribute to reducing biochemical recurrence in patients with localized prostate cancer.