Serial biopsy results in prostate cancer screening study

PURPOSE: We evaluated prostate biopsy results in men with elevated prostate specific antigen (PSA) levels and/or suspicious digital rectal examination whose initial biopsies did not reveal cancer. MATERIALS AND METHODS: A total of 2,526 volunteers 40 years old or older underwent 1 or more prostate biopsies for serum PSA concentrations greater than 4.0 ng./ml. (before May 1995) or greater than 2.5 ng./ml. (after May 1995), or digital rectal examination suspicious of cancer. We evaluated compliance with the biopsy recommendation and the cancer detection rate with regard to digital rectal examination results and increasing PSA levels. RESULTS: Of the men who underwent up to 10 biopsy procedures the serial cancer detection rates were 29%, 17%, 14%, 11%, 9% and 7%, respectively, on biopsy procedures 1 through 6. No significant difference in the yield of cancer on serial biopsies was observed between the groups using the greater than 4.0 ng./ml. and greater than 2.5 ng./ml. cutoff. There was a trend for more cancers detected through serial screening to be organ confined compared with those detected on initial screening (78% versus 69%, p = 0.05). Also, more cancers detected using the greater than 2.5 ng./ml. cutoff were organ confined (80% versus 66%, p = 0.004). Only approximately 1% of the cancers fulfilled the published criteria for clinically insignificant tumors. CONCLUSIONS: Nearly a quarter of prostate cancers detected in this screening study were missed by the initial biopsy. Of the 962 prostate cancers detected 77% were detected with 1, 91% with 2, 97% with 3 and 99% with 4 biopsy procedures. Serial biopsies detect more organ confined cancers without over detecting clinically unimportant tumors. Future studies are needed to determine whether obtaining more biopsy cores initially would provide earlier prostate cancer detection and avoid unnecessary repeat biopsies.     

Percent of prostate needle biopsy cores with cancer is significant independent predictor of prostate specific antigen recurrence following radical prostatectomy: results from SEARCH database

PURPOSE: Recent studies have suggested that the percent of positive cores in the prostate needle biopsy is a significant predictor of outcome among men undergoing radical prostatectomy or radiation therapy for prostate cancer. We evaluate whether either percent of cores with cancer or percent of cores positive from the most and least involved side of the prostate needle biopsy was associated with a worse outcome among men treated with radical prostatectomy. MATERIALS AND METHODS: A retrospective survey of 1,094 patients from the SEARCH Database treated with radical prostatectomy at 4 different equal access medical centers in California between 1988 and 2002 was undertaken. We used multivariate analysis to examine whether total percent of prostate needle biopsy cores with cancer, percent of cores positive from each side of the prostate and other clinical variables were significant predictors of adverse pathology and time to prostate specific antigen (PSA) recurrence following radical prostatectomy. RESULTS: On multivariate analysis serum PSA and percent of positive cores were significant predictors of positive surgical margins, nonorgan confined disease and seminal vesicle invasion. Percent of positive cores (p <0.001), serum PSA (p = 0.008) and biopsy Gleason score (p = 0.014) were significant independent predictors of time to biochemical recurrence. On a separate multivariate analysis that included the variables of total percent of positive cores, percent of positive cores from the most involved side of the biopsy, percent of positive cores from the least involved side of the biopsy and whether the biopsy was positive unilaterally or bilaterally, only the percent of positive cores from the most involved side of the biopsy was a significant independent predictor of PSA failure following radical prostatectomy. Percent of positive cores was used to separate patients into a low risk (less than 34%), intermediate risk (34% to 50%) and high risk (greater than 50%) groups, which provided significant preoperative risk stratification for PSA recurrence following radical prostatectomy (p <0.001). Percent of positive cores cut points were able to further risk stratify men who were at low (p = 0.001) or intermediate (p = 0.036) but not high (p = 0.674) risk for biochemical failure based on serum PSA and biopsy Gleason score. CONCLUSIONS: Percent of positive cores in the prostate needle biopsy was a significant predictor of adverse pathology and biochemical failure following radical prostatectomy, and the cut points of less than 34%, 34% to 50% and greater than 50% can be used to risk stratify patients preoperatively. The finding that percent of positive cores from the most involved side of the biopsy was a stronger predictor of PSA failure than the total percent of cores involved suggests that multiple positive biopsies from a single side might be a better predictor of a larger total cancer volume and thus correlate with clinical outcome.     

Prostate specific antigen adjusted for transition zone epithelial volume: the powerful predictor for the detection of prostate cancer on repeat biopsy

PURPOSE: The indications for repeat prostate biopsy for persistently increased prostate specific antigen (PSA) in men with prostate cancer never detected on previous biopsy are not clear. In this study we determined that PSA adjusted for transition zone (TZ) epithelial volume is the most powerful predictor for detecting prostate cancer on repeat biopsy. MATERIALS AND METHODS: Repeat prostate biopsies including additional TZ cores were performed in 75 men with PSA between 4.0 and 10.0 ng/ml. TZ epithelial volume was calculated by multiplying TZ volume by the percent of epithelium, which was measured by morphometric analysis using image analysis computer software. RESULTS: Prostate cancer was detected on repeat biopsy in 19 of the 75 patients. Patients with prostate cancer had a significant smaller percent area of epithelium or glandular lumen than those without cancer. In patients without prostate cancer TZ epithelial volume significantly correlated with total PSA. According to ROC analysis PSA adjusted for TZ epithelial volume had the greatest AUC for cancer detection (0.879). This parameter was able to avoid more than 90% of unnecessary repeat biopsies with 90% sensitivity. Multiple logistic regression analysis showed that PSA complex adjusted for TZ epithelial volume was the significant independent predictor of cancer. CONCLUSIONS: PSA adjusted for TZ epithelial volume is the most powerful predictor of cancer in men who have undergone previous negative prostate biopsies and in whom PSA remains between 4.0 and 10.0 ng/ml.     

Predictors of prostate cancer after initial negative systematic 12 core biopsy

PURPOSE: We determined the cancer detection rate at initial systematic 12 core (S12C) biopsy and identified features associated with cancer at repeat S12C biopsy after an initial negative S12C biopsy in patients with prostate specific antigen (PSA) parameters associated with a higher risk of prostate cancer. MATERIALS AND METHODS: Between February 1999 and June 2002, 841 patients underwent initial S12C biopsy. Of these patients 99 underwent repeat S12C biopsy after initial negative S12C because of a percent free-to-total PSA of 15.0 or less and/or a yearly PSA velocity of 0.75 ng/ml or greater. The association between parameters revealed by initial biopsy and cancer at repeat biopsy was assessed. RESULTS: Of the 99 patients 21 (21.2%) had cancer at repeat biopsy. Age (p = 0.01), PSA transitional zone density (p = 0.05), and high grade PIN at initial biopsy (p = 0.01) were associated with cancer at repeat biopsy. CONCLUSIONS: In this select group of patients with PSA parameters associated with a higher risk of prostate cancer the cancer detection rate after initially negative S12C biopsy was 21%. Patients with high grade PIN on initial biopsy, advanced age and higher PSA transition zone density are at increased risk for cancer at repeat biopsy. Larger prospective studies are required to confirm these results and construct a nomogram that determines the probability of finding prostate cancer at subsequent biopsy.     

Effect of prostatic biopsy on free-to-total prostate-specific antigen ratio in patients with prostate cancer

BACKGROUND: We determined the effect of prostatic biopsy on the changes in total and free prostate-specific antigen (PSA) and free-to-total PSA ratio (F/T ratio) and examined if there are differences in these parameters between patients with benign and malignant histologic findings. METHODS: The concentration of total and free PSA and the F/T ratio were determined in 35 men before and 1 h after prostatic biopsy. The level of PSA was measured with a chemiluminescent enzyme assay. Of 35 patients, nine were diagnosed as having prostate cancer. RESULTS: In patients whose biopsy revealed cancer, the F/T ratio was lower than those without cancer, although there were no differences in total and free PSA value before prostatic biopsy. One hour after prostatic biopsy, there was an increase in the level of total and free PSA and the F/T ratio in all men. The increase in the F/T ratio was greater in patients whose biopsies revealed no prostate cancer. In patients with stage B cancer, these parameters increased more than those with stage C/D cancer. CONCLUSION: Prostatic biopsy causes a dramatic increase in total and free PSA. The F/T ratio also increased after biopsy. The PSA response to prostatic biopsy might be different in patients with and without prostatic malignancy. The response might also be different according to stage of prostate cancer.     

Predictors of prostate cancer on repeat prostatic biopsy in men with serum total prostate-specific antigen between 4.1 and 10 ng/mL

OBJECTIVES: We determine whether the different molecular forms of prostate-specific antigen (PSA) and other PSA variables can predict prostate cancer in men undergoing repeat prostate needle biopsy. METHODS: Between 1997 and 2001, repeat biopsy was performed in 97 patients who had undergone prior negative prostate biopsy. The ability of total PSA (tPSA), complexed PSA (cPSA), free PSA (fPSA), free-to-total PSA (fPSA/tPSA), free-to-complexed PSA (fPSA/cPSA), complexed-to-total PSA (cPSA/tPSA), tPSA density (tPSAD), cPSA density (cPSAD), transition zone tPSA density (tPSATZ) and transition zone cPSA density (cPSATZ) was assessed by univariate and multivariate analyzes as well as receiver operating characteristics (ROC) curves. RESULTS: Prostate cancer on repeat biopsy was detected in 24% of subjects (23 of 97) who had a negative initial biopsy. The PSA parameters cut-off to ensure a 96% sensitivity of cancer detection, were 29% using fPSA/tPSA, 32% using fPSA/cPSA, 0.18 ng/mL/cc using tPSATZ and 0.16 ng/mL/cc using cPSATZ. The fPSA/tPSA would have prevented 32% of negative biopsies, the fPSA/cPSA 28%, the tPSATZ 23% and the cPSATZ 30%. ROC curve analysis fPSA/tPSA, fPSA/cPSA ratios, tPSATZ and cPSATZ were significantly better predictors of repeat biopsy results than tPSA or cPSA, but there was no significant difference in the ROC curves among these four PSA parameters. In the multivariate logistic regression analysis these four PSA parameters were significant predictors for cancer detection in the repeat biopsy group (P < 0.001). CONCLUSION: fPSA/tPSA ratio, fPSA/cPSA ratio, tPSATZ and cPSATZ enhance the specificity of PSA testing compared to tPSA or cPSA when determining which patients should undergo repeat biopsy.     

Effects of systematic 12-core biopsy on the performance of percent free prostate specific antigen for prostate cancer detection

PURPOSE: The performance characteristics of percent free (f) prostate specific antigen (PSA) for differentiating between benign prostatic hyperplasia and prostate cancer were originally established using primarily sextant biopsy. We determined whether the addition of 6 laterally directed cores to the traditional sextant prostate biopsy affects the performance of percent fPSA. MATERIALS AND METHODS: We retrospectively evaluated a cohort of 350 consecutive biopsies in men with negative digital rectal examinations and PSA between 4 and 10 ng/ml who underwent systematic 12 core biopsy (S12C) biopsy at Scott Department of Urology between March 1999 and January 2003. The effects of 6 additional, laterally directed biopsies on the sensitivity, specificity and area under the ROC curve for percent fPSA was evaluated in the 277 men in whom percent fPSA was measured. RESULTS: Cancers detected exclusively in the 6 laterally directed cores were associated with percent fPSA values similar to those in patients with a benign S12C biopsy. This resulted in a modest and yet predictable decrease in the sensitivity of percent fPSA at each biopsy threshold value without affecting specificity. There was a nonstatistically significant decrease in the area under the ROC curve with the addition of 6 laterally directed cores to sextant biopsy (medial sextant cores 0.66 vs S12C 0.60). CONCLUSIONS: The 12 core biopsy strategies have a higher cancer detection rate than sextant biopsies and they are gaining widespread acceptance. The addition of 6 laterally directed cores to traditional sextant biopsy may result in a modest decrease in the sensitivity of percent fPSA at each selected biopsy threshold without affecting specificity.     

Prostate cancers scored as Gleason 6 on prostate biopsy are frequently Gleason 7 tumors at radical prostatectomy: implication on outcome

PURPOSE: Differentiation between Gleason score 6 and 7 in prostate biopsy is important for treatment decision making. Nevertheless, under grading errors compared with the actual pathological grade at radical prostatectomy are common. We compared the characteristics and outcomes of tumors that were scored 6 on prostate biopsy but were 7 on subsequent radical prostatectomy pathological evaluation to those in tumors with a consistent rating of Gleason score 6 or 7 at biopsy and surgery. MATERIALS AND METHODS: We performed a retrospective database analysis from our referral center (1989 to 2004). We compared pre-prostatectomy characteristics, radical prostatectomy pathological features and the post-radical prostatectomy prostate specific antigen failure rate, defined as any 2 consecutive detectable prostate specific antigen measurements, in 3 subgroups of patients, including 156 with matched Gleason score 6 in the prostate biopsy and radical prostatectomy, 205 with upgraded Gleason score 6/7, that is prostate biopsy Gleason score 6 and radical prostatectomy Gleason score 7, and 412 with matched Gleason score 7 in the prostate biopsy and radical prostatectomy. RESULTS: Radical prostatectomy Gleason score matched the prostate biopsy score in 38.2% of biopsy Gleason score 6 and 81.4% of biopsy Gleason score 7 cases. Higher prostate specific antigen was associated and an increased percent of cancer in the prostate biopsy was predictive of discordance between the prostate biopsy and radical prostatectomy Gleason scores (p <0.001). Margin (p = 0.0075) or seminal vesicle involvement (p = 0.0002), cancer volume (p <0.001) and the prostate specific antigen failures rate (p = 0.014) were significantly higher in under graded Gleason score 7 cancer compared to those in matched Gleason score 6 cases. However, they were comparable to those with a matched Gleason score 7 tumor grade (p = 0.66). CONCLUSIONS: Almost half of tumors graded Gleason score 6 at biopsy are Gleason score 7 at surgery. Upgraded Gleason score 6 to 7 tumors have outcomes similar to those of genuine Gleason score 7 cancer. For prostate biopsy Gleason score 6 tumors clinicians should consider the overall likelihood of tumor upgrading as well as specific patient characteristics, such as prostate specific antigen and the percent of tumor in the prostate biopsy, when contemplating treatments that are optimized for low grade tumors, including watchful waiting or brachytherapy.     

Long-term outcome following radical prostatectomy in men with clinical stage T3 prostate cancer

PURPOSE: We evaluated patients at our institution who underwent radical prostatectomy for clinical stage T3 prostate cancer to determine their long-term clinical outcomes. MATERIALS AND METHODS: We reviewed our prospective surgical database and identified 176 men who underwent radical retropubic prostatectomy for clinical stage T3 prostate cancer from 1983 to 2003. Clinical and pathological data were reviewed and evaluated in a Cox proportional hazards model to determine preoperative predictors of biochemical recurrence. Clinical progression following biochemical recurrence was evaluated and clinical failure was defined as the development of clinical metastases or progression to hormone refractory prostate cancer. RESULTS: Of the 176 patients with cT3 prostate cancer 64 (36%) received neoadjuvant hormonal therapy. At a mean followup of 6.4 years 84 (48%) patients had disease recurrence with a median time to biochemical recurrence of 4.6 years. The actuarial 10-year probability of freedom from recurrence was 44%. On multivariate analysis biopsy Gleason score, pretreatment serum prostate specific antigen and year of surgery were independent predictors of biochemical recurrence. Neoadjuvant hormonal therapy was not a significant predictor of biochemical recurrence. Following biochemical recurrence clinical failure developed in 30 of 84 (36%) men with a median time of 11 years. Overall the 5, 10 and 15-year probabilities of death from prostate cancer were 6%, 15% and 24%, respectively. CONCLUSIONS: More than half (52%) of our patients remained free of disease recurrence following radical prostatectomy. In our series neoadjuvant hormonal therapy offered no advantage with respect to disease recurrence. Radical prostatectomy remains an integral component in the treatment of select patients with clinical stage T3 prostate cancer.     

Clinical value of prostate specific antigen based parameters for the detection of prostate cancer on repeat biopsy: the usefulness of complexed prostate specific antigen adjusted for transition zone volume

PURPOSE: To our knowledge the indications for repeat prostate needle biopsy in men whose previous transrectal ultrasound guided biopsy results revealed no evidence of cancer have not yet been defined. We identified the most effective method for detecting prostate cancer on repeat biopsy. MATERIALS AND METHODS: One or more systematic repeat prostate biopsies were performed in 144 consecutive patients, including 86 with prostate specific antigen (PSA) levels between 4 and 10 ng./ml. at repeat biopsy. Men in whom cancer was detected on repeat biopsies were compared with their counterparts in terms of digital rectal examination findings, PSA based parameters and an atypical prostate on initial prostate biopsy. RESULTS: Prostate cancer was detected on repeat biopsy in 39 of the 144 patients and in 19 on subset analysis of 86. Serum PSA levels at repeat biopsy did not differ significantly in patients with and without prostate cancer. According to receiver operating characteristics analysis the alpha1-antichymotrypsin-PSA complex adjusted for transition zone volume had the greatest area under the curve values, that is 0.756 for all 144 patients and 0.768 for the subset analysis of 86. Multiple logistic regression analysis of the subset of 86 patients showed that alpha1-antichymotrypsin-PSA complex adjusted for transition zone volume was the only significant independent predictor of cancer. CONCLUSIONS: alpha1-Antichymotrypsin-PSA complex adjusted for transition zone volume was the most powerful predictor of cancer in men who had undergone previous negative prostate biopsies. This parameter may be used to avoid more unnecessary repeat biopsies with an acceptable decrease in sensitivity.     

The incidence of prostate cancer in men with prostate specific antigen greater than 4.0 ng/ml: a randomized study of 6 versus 12 core transperineal prostate biopsy

PURPOSE: The prostate cancer detection rate in patients with elevated prostate specific antigen (PSA) increases with extended needle biopsy protocols. Transperineal biopsy under transrectal ultrasound guidance is rarely reported, although notable cancer diagnoses are obtained with this technique. We describe the results of 6 and 12 core transperineal biopsy. MATERIALS AND METHODS: A total of 214 patients with PSA greater than 4.0 ng/ml were prospectively randomized to undergo 6 or 12 core transperineal biopsy. Each group of 107 patients was comparable in terms of clinical characteristics. The procedure was performed on an outpatient basis using local anesthesia. Specimens were obtained with a fan technique with 2 puncture sites slightly above the rectum (1 per lobe) under transrectal ultrasound guidance. Cores were taken from all peripheral areas, including the far lateral aspect of the prostate. RESULTS: The overall cancer detection rate was 38% and 51% for 6 and 12 core biopsy, respectively. In patients with PSA between 4.1 and 10 ng/ml the cancer detection rate was 30% and 49% for 6 and 12 core biopsy, respectively. CONCLUSIONS: The 12 core transperineal prostate biopsy is superior to 6 core biopsy. The technique provides optimal prostate cancer diagnosis. About half of the patients with PSA greater than 4.0 ng/ml and a slightly lower percent with PSA between 4.1 and 10 ng/ml have prostate cancer.     

12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer

PURPOSE: We reviewed the outcomes in men treated with permanent prostate brachytherapy (PPB). MATERIAL AND METHODS: A total of 1,449 consecutive patients with a mean age of 68 years treated with PPB between 1992 and 2000 and mean pretreatment prostate specific antigen (PSA) 10.1 ng/ml were included in this study. Of the patients 55% presented with Gleason 6 tumors and 28% had Gleason 7 disease. A total of 400 patients (27%) were treated with neoadjuvant hormones and 301 (20%) were treated in combination with external radiation plus PPB. Several biochemical freedom from recurrence (BFR) definitions were determined. Statistical analysis consisted of log rank testing, Kaplan-Meier estimates and Cox regression analysis. RESULTS: Median followup was 82 months with 39 patients at risk at for 144 months. Overall and disease specific survival at 12 years was 81% and 93%, respectively. The 12-year BFR was 81%, 78%, 74% and 77% according to the American Society for Therapeutic Radiology and Oncology (ASTRO), ASTRO-Kattan, ASTRO-Last Call and Houston definitions, respectively. The 12-year ASTRO-Kattan BFR using risk stratification was 89%, 78% and 63% in patients at low, intermediate and high risk, respectively (p = 0.0001). Multivariate analysis identified the dose that 90% of the target volume received (p <0.0001), pretreatment PSA (p = 0.001), Gleason score (p = 0.002), the percent positive core biopsies (p = 0.037), clinical stage (p = 0.689), the addition of hormones (p = 0.655) and the addition of external radiation (p = 0.724) for predicting BFR-ASTRO. Five-year disease specific survival was 44% in patients with a PSA doubling time of less than 12 months vs 88% in those with a PSA doubling time of 12 months or greater (p = 0.0001). CONCLUSIONS: PPB offers acceptable 12-year BFR in patients who present with clinically localized prostate cancer. Implant dosimetry continues as an important predictor for BFR, while the addition of adjuvant therapies such as hormones and external radiation are insignificant. In patients who experience biochemical failure it appears that PSA doubling time is an important predictor of survival.     

Percent free prostate specific antigen is not an independent predictor of organ confinement or prostate specific antigen recurrence in unscreened patients with localized prostate cancer treated with radical prostatectomy

PURPOSE: We studied the controversial relationship of percent free prostate specific antigen (PSA) with organ confined prostate cancer and PSA failure after radical prostatectomy. MATERIALS AND METHODS: We tested the characteristics of the percent free PSA monoclonal Immulite DPC Immunoassay (Diagnostic Products Corp., Los Angeles, California) for predicting organ confinement in 698 consecutive unscreened men treated only with radical prostatectomy between 1995 and 2000. In addition, we assessed the ability of percent free PSA to predict post-radical prostatectomy PSA failure, defined as PSA 0.1 ng./ml. or greater, in a subset of 581 men in whom followup was available. All statistical analyses were repeated for stage T1c cancer with PSA between 2 and 10 ng./ml. RESULTS: On univariate analyses percent free PSA achieved significance for predicting organ confined disease at all clinical stages (p <0.001) and for stage T1c cancer with PSA between 2 and 10 ng./ml. (p = 0.012). However, significance dissipated after controlling for total PSA, biopsy Gleason sum and clinical stage (p = 0.135 and 0.851, respectively). In univariate Cox models percent free PSA failed to predict PSA failure across stages (p = 0.341), as well as in stage T1c cancer (p = 0.93). In multivariate analyses controlling for traditional PSA biopsy grade and clinical stage (p <0.001), percent free PSA failed to contribute to predicting PSA failure (p = 0.342). In the stage T1c subset biopsy Gleason sum (p <0.001) and PSA (p = 0.018) remained significant, in contrast to percent free PSA (p = 0.237). CONCLUSIONS: Percent free PSA has no independent, statistically significant association with organ confined status or posttreatment PSA outcome in unscreened patients who undergo radical prostatectomy for localized prostate cancer.     

Predictors of subsequent prostate cancer in men with a prostate specific antigen of 2.6 to 4.0 ng/ml and an initially negative biopsy

PURPOSE: Almost 75% of men with a prostate specific antigen (PSA) of 2.6 to 4.0 ng/ml have no evidence of prostate cancer on biopsy. Deciding whether and when to repeat the biopsy is challenging. We determined if patient specific variables might identify men at increased risk for the subsequent detection of prostate cancer. MATERIALS AND METHODS: We analyzed the records of 24,893 men from a community based prostate cancer screening study. Our study group consisted of 1,202 men with PSA 2.6 to 4.0 ng/ml and a previously negative prostate biopsy. Patient specific variables were analyzed for their value in predicting a future diagnosis of prostate cancer. RESULTS: Of 1,011 men with adequate followup 136 (13.5%) were subsequently diagnosed with prostate cancer. Mean followup +/- SD in men without prostate cancer was 72 +/- 36 months. Prostate cancer was subsequently diagnosed in 35% of men with high grade prostatic intraepithelial neoplasia (HGPIN) on initial biopsy (p <0.0001), in 18% with abnormal or suspicious digital rectal examination (DRE) (p = 0.02) and 16% with an annual PSA velocity of 0 ng/ml (p = 0.002). Multivariate analysis identified HGPIN, initial PSA 3.6 to 4.0 ng/ml, abnormal DRE, family history of prostate cancer and annual PSA velocity 0 ng/ml as predictors of prostate cancer. CONCLUSIONS: Men with a PSA of 2.6 to 4.0 ng/ml and negative biopsy should be advised to undergo repeat biopsy if they have HGPIN, initial PSA 3.6 to 4.0 ng/ml, abnormal DRE, a family history of prostate cancer or a PSA velocity of 0 ng/ml or greater.