Validation of a prediction model for low volume/low grade cancer: application in selecting patients for active surveillance.

PURPOSE: We previously demonstrated that assessment of the number of positive cores, tumor length in a core, Gleason score and prostate volume significantly enhanced the accuracy of a prediction model for low volume/low grade cancer in men who had undergone extended biopsy. To determine the validity of the model, we applied it to an independent population of men with prostate cancer. MATERIALS AND METHODS: The study group included 170 men who had undergone radical prostatectomy without neoadjuvant therapy. In all cases, prostate cancer was diagnosed on only 1 positive core of a 10-core extended biopsy. We assessed the accuracy of the model, which consists of tumor length less than 2 mm, Gleason score 3+4 or less and prostate gland volume greater than 50 cc in predicting the occurrence of low volume/low grade cancer (defined as tumor volume less than 0.5 cc, no Gleason grade 4 or 5 disease, and organ confined disease). RESULTS: Of the patients 101 (59.4%) had low volume/low grade cancer. Our model using all 3 previously mentioned variables had the highest performance, demonstrating a positive predictive value of 70.4% (88 of 125), a negative predictive value of 71.1% (32 of 45) and a diagnostic accuracy of 70.6% (120 of 170). This model performed better than a model based on tumor length only (positive predictive value, negative predictive value and diagnostic accuracy 68.1%, 57.9% and 64.7%, respectively) or a model based on tumor length and Gleason score (positive predictive value, negative predictive value and diagnostic accuracy 70.0%, 60.0% and 66.5%, respectively). CONCLUSIONS: This study validates that our model with a combination of tumor length, Gleason score and prostate volume is predictive for low volume/low grade cancer in an independent population of men who demonstrated only 1 positive core in an extended biopsy. This model can be used as a tool for selecting men for active surveillance.

Adjuvant and salvage radiotherapy after radical prostatectomy for prostate cancer.

PURPOSE: The optimal role of radiotherapy (RT) to the prostate bed after radical prostatectomy (RP) is the subject of much debate. In this study, the results of adjuvant RT (ART) and salvage RT (SRT) were compared. METHODS AND MATERIALS: A total of 146 lymph node-negative patients were treated postoperatively after RP with RT to the prostate bed between 1987 and 1998. Of these, 75 patients had an undetectable prostate-specific antigen (PSA) level and were treated with ART for adverse pathologic features only to a median dose of 60 Gy (range 51-70). A positive margin was identified in 96%, and two of the three with negative margins had seminal vesicle involvement (SVI). SRT was administered for either a persistently detectable PSA level after RP (n = 27) or for a delayed rise in PSA (n = 44) to a median dose of 70 Gy (range 60-78). Adjuvant androgen ablation was given to 37 patients; 2 who had received ART and 35 had who received SRT. The median duration of androgen ablation was 24 months. The primary end point was freedom from biochemical failure (bNED), which was considered to be an undetectable PSA level. The median follow-up was 53 months for all patients: 68 months for the ART patients and 35 months for the SRT patients. RESULTS: For the ART group, 8 patients subsequently developed a rising PSA level. The 5-year bNED rate was 88%. SVI was the strongest predictor of outcome, with a 5-year bNED rate of 94% for those without SVI and 65% for those with SVI (p = 0.0002). SVI was the only significant factor in Cox proportional hazards regression analysis in the ART cohort. For the SRT group, 20 patients developed a rising PSA level after RT. The 5-year bNED rate was 66% for all SRT patients, and 43% and 78% in those with a persistently detectable PSA and those with a delayed rise in PSA, respectively. In the Cox proportional hazards regression analysis, this subdivision of SRT was statistically significant. Moreover, when the Cox model included all patients and variables, the timing of RT (ART vs. SRT) was an independent correlate of bNED, as was androgen ablation. CONCLUSION: For RP patients with high-risk pathologic features, the timing of postoperative RT and the PSA status after RP were strong determinants of outcome. Because of the potential confounding factors, direct comparisons of ART and SRT are problematic; however, ART is extremely effective and offers the surest approach for maintaining biochemical control.

Limiting the location of putative human prostate cancer tumor suppressor genes on chromosome 18q.

We studied loss of heterozygosity (LOH) on the long arm of human chromosome 18 in prostate cancer to determine the location of a putative tumor suppressor gene (TSG) and to correlate these losses with the pathological grade and stage of the cancer. Of 48 specimens analysed 17 (35.4%) lost at least one allele on chromosome 18q. All the specimens with allelic losses lost at least one allele within chromosomal region 18q21. Allelic losses picked at D18S51 (19%) and D18S858 (17%). A 0.58 cM DNA segment that includes the D18S858 locus and is flanked by the microsatellite loci D18S41 and D18S381, was lost in eight (47%) of 17 specimens with allelic losses. This segment was designated as a LOH cluster region 1 (LCR 1). Although Smad2 resides within LCR 1, it was not mutated in any of the six prostate cell lines (five prostate cancer cell lines and one immortalized prostate epithelial cell line) analysed, suggesting that it is not a candidate TSG in prostate cancer. A second LCR at 18q21, LCR 2, includes the D18S51 locus and is flanked by the D18S1109 and D18S68 loci, which are separated by 7.64 cM. LCR 2 was lost in six (35%) of the 17 specimens with chromosome 18q losses. These results suggest that chromosome 18q21 may harbor two candidate prostate cancer TSGs. The candidate TSGs DCC and Smad4 are located centromeric to the LCRs. No alleles were lost within or in close proximity to these genes, suggesting that they are not targets for inactivation by allelic losses in prostate cancer. Although there was no obvious correlation between chromosome 18q LOH and the pathological grade or stage, three (37.5%) of eight low-grade cancers and nine (32.1%) of 28 organ-confined cancers lost alleles at 18q21, suggesting that allelic losses are relatively early events in the development of invasive prostate cancer.

Reduced expression of hMSH2 and hMLH1 and risk of prostate cancer: a case-control study.

BACKGROUND: Although prostate cancer is the most common incident cancer in men, not much is known about its etiology. We tested the hypothesis that expression levels of hMSH2 and hMLH1 in unaffected (normal) tissue play a role in the etiology of prostate cancer. METHODS: Total RNA was extracted from peripheral blood lymphocytes of subjects ascertained by a case-control study (70 patients and 97 age- and ethnicity-matched controls). A multiplex reverse transcription-polymerase chain reaction assay was used to simultaneously evaluate the relative expression of hMSH2 and hMLH1, using beta-actin as the internal control. RESULTS: The relative gene expression levels of hMSH2 and hMLH1 were significantly lower in cases than in controls (P < 0.05 for both genes). When compared with the highest tertile of the controls, low expression levels (the middle and lowest tertiles) of hMLH1 were associated with significantly increased risk of prostate cancer in a dose-response relationship (ORs = 2.68, and 4.31; 95% confidence interval = 1.00-7.23 and 1.64-11.30, respectively) after adjustment for age, ethnicity, smoking status, and family history of prostate cancer. CONCLUSIONS: These results suggest that reduced expression of hMLH1 in peripheral lymphocytes may be a risk factor for prostate cancer. However, it cannot be ruled out that the reduced expression we observed may be caused by the disease status. Our findings and the factors that may affect the expression of hMLH1 need further confirmation in larger prospective studies.

Radical cystectomy for invasive bladder cancer in the octogenarian.

The incidence of bladder cancer increases with age. As the population lives longer, an increasing number of patients 80 years of age or older will develop invasive bladder cancer. In this study, we reviewed the outcome of 33 patients age 80 years or older treated with radical cystectomy and ileal conduit urinary diversion. Five patients received neoadjuvant chemotherapy, and 2 had salvage cystectomy after failure of external beam radiation therapy. The median age was 82 years, and the median hospital stay was 12 days. There were no perioperative deaths. Twenty-seven complications occurred in 20 patients (60.6%), of which 17 were minor (63%) and 10 were major (37%). There was no difference in the rate of complications in patients receiving neoadjuvant treatment compared to the group treated with cystectomy alone. The median survival was 3.5 years. Our results demonstrate that radical cystectomy and ileal conduit urinary diversion should not be withheld from patients on the basis of age.

Can complexed prostate specific antigen and prostatic volume enhance prostate cancer detection in men with total prostate specific antigen between 2.5 and 4.0 ng./ml.

PURPOSE: We assessed whether complexed prostate specific antigen (PSA) and complexed PSA referenced variables would enhance prostate cancer detection in men with serum total PSA between 2.5 and 4.0 ng./ml. MATERIALS AND METHODS: Transition zone and total prostate gland volumes were determined in 151 men who underwent prostate biopsy using an 11 core biopsy strategy. In addition to measuring the Bayer section sign complexed PSA assay, we also calculated 2 computed complexed PSA values (Hybritech parallel total PSA--Hybritech free PSA and Bayer total PSA--Hybritech free PSA). We calculated 8 volume referenced variables using total and complexed PSA, and 2 computed complexed PSA values by dividing each value by the total prostate and transition zone volumes. RESULTS: Of the 151 patients 37 (24.5%) had cancer. In 10 of the 37 men with cancer (27%) a positive core was present in only 1 or more of the 5 alternate regions not sampled by conventional sextant biopsies. At 92% sensitivity a cutoff value of 2.3 ng./ml. for complexed and 31% for free-to-total PSA provided 42% and 11% specificity, respectively (p <0.001). In the 116 men with a total prostate volume of 30 cc or greater at 92% sensitivity the specificity of complexed PSA density (55%) and complexed PSA adjusted for transition zone volume (52%) were better than that of complexed (40%) and free-to-total (11%) PSA. In the 35 men with a total prostate volume of less than 30 cc at 92% sensitivity the specificity of complexed PSA (50%), complexed PSA density (55%) and complexed PSA adjusted for transition zone volume (55%) were significantly better than that of free-to-total PSA (8%, p <0.001). The area under the curve of complexed PSA was almost identical to that of the 2 computed complexed PSA calculations. CONCLUSIONS: A substantial proportion of men with total PSA values between 2.5 and 4.0 ng./ml. had prostate cancer. Complexed and computed complexed PSA were more specific than the free-to-total PSA ratio when total PSA was between 2.5 and 4.0 ng./ml. A 2.3 ng./ml. threshold for complexed and computed complexed PSA appears to stratify prostate biopsy results in men with total PSA between 2.5 and 4.0 ng./ml. The computed complexed PSA calculation appears to be equivalent to the complexed PSA serum assay for detecting cancer. Volume referenced complexed PSA performed better than complexed PSA in men with a total prostate volume of 30 cc or greater compared to men with a total prostate volume of less than 30 cc.

Analysis of clinicopathologic factors predicting outcome after radical prostatectomy.

BACKGROUND: A variable biochemical failure rate has been reported for patients undergoing radical prostatectomy. The authors analyzed their 1987-1993 prostatectomy experience retrospectively to stratify the risk of failure in order to appropriately select patients who potentially may benefit from adjuvant therapy. METHODS: A stepwise logistic regression was used to identify variables associated with biochemical failure in 265 patients who underwent radical prostatectomy only. Prostate tumors were examined by one pathologist using 4-mm step sections. Numerous clinicopathologic variables were evaluated, and the neoplasms were subclassified into five pathologic categories based on tumor extent and margin status. Actuarial projections of biochemical failure were created using the Kaplan-Meier method. RESULTS: Pathologically, 56.2% of the tumors were organ-confined with negative margins, 12.8% had a positive surgical margin without evidence of extraprostatic extension (EPE), 24.2% had EPE (17% with negative margins and 7.2% with positive margins), and 6.8% had seminal vesicle involvement. The Gleason score was > or = 7 in 86.4% of the total population. Values for the preoperative prostate specific antigen assay were < or = 4.0 ng/mL in 23.4% of the men and > 10 ng/mL in 27.7%. The overall observed biochemical failure rate in this patient group with a minimum 48 months of follow-up was 15.5%. Overall, stepwise logistic regression analysis revealed that pathologic category was the variable most strongly associated with biochemical failure and that vascular invasion was the only other examined variable associated with failure. CONCLUSIONS: The combination of pathologic category and the prostatectomy Gleason score can stratify a patient's probability of biochemical failure into three distinct groups and can identify the appropriate patients who may benefit from novel adjuvant therapeutic strategies.

Early detection of prostate cancer: is PSA a reliable option?

A close relationship exists between prostate volume and prostate-specific antigen (PSA). Clinical decisions must be determined based on the variability of PSA. Screening with the PSA assay has contributed to early detection of prostate cancer. Some important undetermined issues are the optimal cutoff values of PSA, the proportion of free to total PSA, and the clinical usefulness of complexed PSA. Current articles demonstrating novel markers (human kallikrein-2, BPSA, and pro PSA) and artificial neural networks are introduced.

The incidence of prostate cancer in a screening population with a serum prostate specific antigen between 2.5 and 4.0 ng/ml: relation to biopsy strategy.

PURPOSE: It has recently been suggested that the diagnostic threshold for the prostate specific antigen (PSA) assay be lowered to enhance prostate cancer detection. A 22% incidence of prostate cancer has been reported in men with PSA between 2.5 and 4.0 ng/ml. We designed a study to confirm this observation. MATERIALS AND METHODS: Men who participated in our free early detection program and who had serum PSA between 2.5 and 4.0 ng/ml were asked to undergo prostate biopsy. Of 268 eligible men 151 (56%) agreed to participate in this free trial. All men underwent biopsy using an 11-core multisite directed biopsy scheme. All biopsy cores were color coded for location specificity and examined by 1 pathologist. RESULTS: Cancer was identified in 24.5% (37 of 151) of the men biopsied. The median age of men with cancer was 62 years (range 43 to 74). Conventional systematic sextant biopsies, which accounted for 6 of the 11 cores, detected 73.0% (27 of 37) of the cancers and the alternate site biopsies identified the remaining 10. Gleason score was 6 in 25 men, 3 + 4 in 5, 4 + 3 in 4 and 8 or greater in 3 (median Gleason score 6). There were 14 men who had 1 core positive for cancer, 9 had 2 and 14 had more than 2 (median number of positive cores 2). Of the 14 men with 1 positive core 11 had a less than 3 mm focus of cancer and 8 had only a positive alternate site biopsy. There were 11 cases of abnormal results on digital rectal examination, 5 of which were cancer, and 31 cases of abnormal results on ultrasonography, 13 of which were cancer. Median biological variability in PSA was +/-15% (range 0.4% to 440.0%). CONCLUSIONS: We found a significant incidence of cancer (24.5%, 37 of 51) in men with serum PSA between 2.5 and 4.0 ng/ml. In our study 67.6% of the detected cancers were significant based on the biopsy data. If the PSA threshold is lowered the conventional systematic sextant technique may be preferable to an extended strategy.

Leptin and prostate cancer.

BACKGROUND: Higher prostate cancer mortality rates among US immigrants from countries with lower rates suggest environmental influences on prostate carcinogenesis (e.g., diet, body composition). METHODS: In a study identifying determinants of clinically relevant prostate cancer, we compared plasma concentrations of leptin, an adiposity-related hormone, in 48 men with tumors 0.5 cc in volume or with histologic evidence of extraprostatic extension but without metastases ("high-volume disease"), matched by age (+/- 5 years) and year at diagnosis (+/- 1 year). RESULTS: Men with high-volume disease exhibited higher leptin concentrations overall and after stratification by age, testosterone level, height, and body mass index (BMI). Analysis revealed that men with elevated leptin concentrations had an increased risk of diagnosis with high-volume disease (odds ratio (OR) = 2.35, 95% confidence interval (CI) = 1.01-5.44), as did men with high leptin and high testosterone (OR = 9.73, 95% CI = 2.05-46.24) and men >/=5'8" with high leptin (OR = 3.67, 95% CI = 1.40-9.63). CONCLUSIONS: Leptin may affect the risk of clinically relevant prostate cancer through testosterone and factors related to stature and obesity.

Complexed prostate-specific antigen improvement in detecting prostate cancer.

This article presents the current reports of complexed prostate-specific antigen (PSA) aimed for the enhancement of prostate cancer detection. Further studies are needed to ascertain the variability of complexed PSA. Comparisons of percent free PSA, potential additive value of alpha(1)-antichymotripsin-bound PSA (PSA-ACT) and Bayer complexed PSA (cPSA) remains controversial in men with intermediate elevated total PSA concentration. Volume-referenced complexed PSA (PSA-ACT and cPSA) can enhance prostate cancer detection. Preliminary results show that PSA-alpha(2)-macrobloblin (PSA-a(2)M) and PSA-alpha(1)-protease inhibitor (PSA-API) are promising assays for improving cancer detection.

Computer-assisted diagnostics: application to prostate cancer.

Artificial neural networks (ANNs) have only recently been applied to solve problems in the diagnosis, staging, and prediction of treatment outcome in prostate cancer. A literature search provided information on 10 published journal articles that were selected for review and analysis. In all but one of the studies that compared the ANN output with logistic regression modeling, the ANN performed better. Specific training issues for neural networks are discussed and examples provided. We conclude that the continued development and refinement of computer-assisted diagnostic methodology are warranted to enhance conventional statistical approaches to the classification and pattern recognition found in data sets from men either suspected of having or known to have prostate cancer.

Detailed mapping of prostate carcinoma foci: biopsy strategy implications.

BACKGROUND: Prostate carcinoma exhibits considerable anatomic heterogeneity. Detailed characterization of prostate carcinoma distribution could lead to improved detection procedures and biopsy strategies. We mapped all 607 tumor foci from 180 serially sectioned whole mount radical prostatectomy specimens and used a computer algorithm to plot and summarize the distribution of these foci. We investigated whether specimen and clinical variables predicted differences in tumor distribution. METHODS: The volume and anatomic location of each tumor focus were determined and digitized. A computer-based algorithm was used to fit the digitized tumor foci to a paradigm prostate. Pseudo-color summary plots of tumor distribution then were computed for selected cases. RESULTS: Of the 180 specimens, 149 (83%) specimens had more than one cancer focus. Most foci (448 of 607 tumor foci, 74%) were in the peripheral zone (PZ). PZ foci near the apex had a significant midline component. Toward the base, PZ foci diverged laterally. Only 3 (2%) of 180 specimens contained foci solely in the transition zone (TZ). Total TZ cancer volume was

Epidemiologic determinants of clinically relevant prostate cancer.

While tumor volume and Gleason scores are the best available prognostic indicators for prostate cancer, contemporary predictive methods are unable to identify which men with Gleason scores of 7 have clinically insignificant tumors that will not progress and which men will develop highly aggressive prostate cancer. Our objective was to evaluate potential environmental determinants of significant prostate cancer. Subjects were patients identified from a university-based hospital and tertiary cancer center who had undergone radical prostatectomy for prostate cancer. Cases were 103 patients whose tumor volumes were

Correlation of non-random chromosomal aberrations in lymphocytes of prostate cancer patients with specific clinical parameters.

The purpose of this research was to correlate non-random chromosomal aberrations in the peripheral blood lymphocytes (PBLs) of prostate cancer patients with specific clinical parameters. Peripheral blood samples were analyzed from 59 informative prostate cancer patients. Non-random chromosomal alterations detected in the PBLs and their correlation with any specific clinical parameters were analyzed statistically. A comparison was made between specific chromosomal abnormalities in the patients having an early (<65 years) or late (> or =65 years) age at disease onset, low-grade (Gleason grade <7) or high-grade (Gleason grade > or =7) tumors, a low (<10 ng/ml) or high (> or =10 ng/ml) prostate-specific antigen (PSA) level, and androgen-sensitive or -insensitive disease. In examining the specific chromosomal breakpoints, the regions 1p13, 2q21, 3p21, 4q13, 5q31, 6p21, 7p15, 7p13, 7q32, 10p11, 10q26, 11p15, 11p11, 14q12, and 16q12 showed breaks in at least four cases. Chromosome 15 (P=0. 045) was significantly altered in patients having a PSA value greater than or equal to 10, while it (P=0.017) and chromosome 19 (P=0.036) were significantly altered in patients having a PSA value greater than or equal to 20. In addition, chromosomes 5 (P=0.032), 8 (P=0.020), 16 (P=0.009), and 20 (P=0.047) were significantly altered in patients having a Gleason grade greater than 7. Also, chromosomes 2 (P=0.020) and 3 (P=0.044) were significantly altered in patients who had early disease onset. Additionally, chromosome 10 (P=0.041) was significantly altered in patients having metastasis, and chromosomes 4 (P=0.006) and 7 (P=0.028) were significantly altered in patients having androgen-insensitive disease. In spite of the small subset of patients, chromosome 8 (p=0.003) was significantly altered in patients having small cell carcinoma of the prostate. From these results we conclude that non-random chromosomal aberrations present in PBLs of prostate cancer patients can be correlated with specific clinical parameters. These correlations can be used to identify a prostate cancer patient's risk response to therapy.

Strategy for repeat biopsy in patients with high grade prostatic intraepithelial neoplasia.

PURPOSE: The finding of high grade prostatic intraepithelial neoplasia in a biopsy specimen without prostate cancer warrants repeat biopsy because of the risk of concurrent cancer. However, to our knowledge the optimal repeat biopsy technique has not yet been defined. We determined the optimal subsequent biopsy strategy for detecting concurrent cancer in patients diagnosed with high grade prostatic intraepithelial neoplasia. MATERIALS AND METHODS: Of 63 men with isolated high grade prostatic intraepithelial neoplasia on initial biopsy 45 underwent repeat biopsy within 1 year. Certain biopsy patterns were used for repeat biopsy, including only the neoplasia site in 8 men, sextant in 12, sextant plus bilateral transition zone in 13 and 11 core multisite directed (sextant, bilateral transition zone, bilateral anterior horn of the peripheral zone and midline peripheral zone) in 12. We compared the location of high grade disease on the initial biopsy with the cancer site on repeat biopsy. RESULTS: Repeat biopsy revealed cancer in 10 of the 45 men (22%), and the sites of high grade prostatic intraepithelial neoplasia and cancer correlated in 6. Cancer was detected at the sextant locations in 9 men. Of the 15 cores positive for cancer 8 were at the original high grade neoplasia site, 6 at a random sextant biopsy site and 1 in the transition zone. High grade disease was discovered bilaterally in 1 man, while prostatic intraepithelial neoplasia and cancer were detected on the same side in the remaining 9. CONCLUSIONS: The optimal repeat biopsy strategy for patients with high grade prostatic intraepithelial neoplasia has not yet been determined but at a minimum it should include targeting the area of known high grade disease and the ipsilateral sextants.

Performance of a neural network in detecting prostate cancer in the prostate-specific antigen reflex range of 2.5 to 4.0 ng/mL.

OBJECTIVES: To explore the potential role of a neural network-derived algorithm in enhancing the specificity of prostate cancer detection compared with the determination of prostate-specific antigen (PSA) and free PSA (fPSA) while maintaining a 90% detection rate. Recent information suggests that the incidence of detectable prostate cancer is similar in men whose PSA values range from 2.5 to 4.0 ng/mL and from 4.0 to 10.0 ng/mL. If the PSA threshold triggering a prostate biopsy is lowered to 2.5 ng/mL, approximately 13% of men older than 50 would be added to the patient biopsy pool. METHODS: One hundred fifty-one men were enrolled in a prospective, Institutional Review Board-approved protocol to evaluate the incidence of cancer in a population of men who participated in an early-detection program and whose PSA level was between 2.5 and 4.0 ng/mL. All the men underwent biopsy using an 11-core multisite-directed biopsy scheme, and all biopsy specimens were examined by one pathologist. All men had a second blood specimen drawn before the biopsy for a determination of serum PSA, creatinine kinase, prostatic acid phosphatase, and fPSA. A new neural network algorithm was developed with PSA, creatinine kinase, prostatic acid phosphatase, fPSA, and age as input variables to produce a single-valued prostate cancer detection index (PCD-I). This new algorithm was then prospectively tested in the 151 men. Performance parameters (including sensitivity, specificity, positive and negative predictive values, and biopsies saved) were calculated, and a comparative analysis was performed to evaluate the differences among the new algorithm, percent fPSA, PSA density, and PSA density-transition zone. RESULTS: Cancer was histologically confirmed in 24.5% (37 of 151) of the men. The median age of the men was 62 years (range 43 to 74). At a sensitivity of 92%, the specificity for percent fPSA was 11%. The new algorithm (PCD-I) demonstrated an additional enhancement of specificity to 62% at 92% sensitivity. Clinically, the PCD-I would result in a savings of 49% (74 of 151) of all biopsies or 63.6% (71 of 114) of all unnecessary biopsies. CONCLUSIONS: A new generation algorithm, derived from a neural network (PCD-I) incorporating the parameters of age, creatinine kinase, PSA, prostatic acid phosphatase, and fPSA can significantly enhance the specificity and reduce the number of biopsies while maintaining a 92% sensitivity rate.

A comparative analysis of sextant and an extended 11-core multisite directed biopsy strategy.

PURPOSE: The 3 tumor locations unsampled by conventional sextant biopsies that have been identified on composite 3-dimensional reconstruction of 180 radical prostatectomy specimens are the anterior transition zone, midline peripheral zone and inferior portions of the anterior horn in the peripheral zone. We evaluated an 11-core multisite directed biopsy scheme incorporating these alternate areas and conventional sextant biopsies in 362 patients from 2 institutions. MATERIALS AND METHODS: Patients without a prior diagnosis of cancer underwent ultrasound guided 11-core biopsies which included conventional sextant and 3 alternate sites. All specimens were separated for specific location identification. Biopsy was performed in 183 patients at MD Anderson Cancer Center (group 1) and in 179 at Toronto General Hospital (group 2). All group 2 and 54% of group 1 patients (98 of 183) had a prior biopsy negative for cancer. RESULTS: Median prostate specific antigen was higher in group 2 than in group 1 patients (11.5 versus 9.5 ng./ml., p = 0.016). Overall a 33% increase (36 of 110 patients) in cancer detection was observed when biopsy technique included the alternate areas (p = 0.0021). The anterior horn was the most frequently positive biopsy site followed by the transition zone and midline sites. The 11-core technique had significantly better cancer detection rates when digital rectal examination and transrectal ultrasound were normal, and in men with serum prostate specific antigen between 4.1 and 10 ng./ml. CONCLUSIONS: Biopsies of the alternate sites suggested by our simulation studies are feasible and reproducible. This new strategy significantly enhanced (p = 0.0075) prostate cancer detection compared to conventional sextant biopsies in men undergoing a repeat procedure.