R. Joseph Babaian

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.

PCA3 Molecular Urine Assay Correlates With Prostate Cancer Tumor Volume: Implication in Selecting Candidates for Active Surveillance

PURPOSE Prostate cancer gene 3 (PCA3) has shown promise as a molecular marker in prostate cancer detection. We assessed the association of urinary PCA3 score with prostatectomy tumor volume and other clinical and pathological features. MATERIALS AND METHODS Urine specimens were collected after digital rectal examination from 59 men scheduled for prostate biopsy and 83 men scheduled for radical prostatectomy. Prostatectomy findings were evaluable for 96 men. PCA3 and prostate specific antigen mRNAs were quantified with Gen-Probe DTS 400 System. The PCA3 score was defined as the ratio of PCA3 mRNA/prostate specific antigen mRNA x10(3). RESULTS The PCA3 score in men with negative biopsies (30) and positive biopsies (29) were significantly different (median 21.1 and 31.0, respectively, p = 0.029). The PCA3 score was significantly correlated with total tumor volume in prostatectomy specimens (r = 0.269, p = 0.008), and was also associated with prostatectomy Gleason score (6 vs 7 or greater, p = 0.005) but not with other clinical and pathological features. The PCA3 score was significantly different when comparing low volume/low grade cancer (dominant tumor volume less than 0.5 cc, Gleason score 6) and significant cancer (p = 0.007). On multivariate analysis PCA3 was the best predictor of total tumor volume in prostatectomy (p = 0.001). Receiver operating characteristic curve analysis showed that the PCA3 score could discriminate low volume cancer (total tumor volume less than 0.5 cc) well with area under the curve of 0.757. CONCLUSIONS The PCA3 score appears to stratify men based on prostatectomy tumor volume and Gleason score, and may have clinical applicability in selecting men who have low volume/low grade cancer.

Detailed Mapping of Prostate Carcinoma Foci Biopsy Strategy Implications

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.

The Efficacy and Complications of Salvage Cryotherapy of the Prostate

PURPOSE A phase I/II study was done to evaluate the efficacy and complications of salvage cryotherapy as a treatment for locally recurrent prostate cancer following full dose radiation therapy and/or systemic therapy. The efficacy of single and double freeze-thaw cycles was compared using posttreatment prostate specific antigen (PSA) levels and prostate biopsies as end points. MATERIALS AND METHODS A total of 150 patients with locally recurrent prostate cancer following radiation, hormonal therapy and/or systemic chemotherapy underwent salvage cryotherapy using a single (71 men, mean followup 17.3 months) or double (79 men, mean followup 10.0 months) freeze-thaw cycle. PSA was measured approximately every 3 months postoperatively and sextant biopsies were repeated 6 months postoperatively. Complications were assessed by retrospective chart review and a mailed quality of life survey. RESULTS Overall, 45 patients (31%) had persistently undetectable PSA. Patients with a history of radiation therapy only who underwent a double freeze-thaw cycle had a higher negative biopsy rate (93 versus 71%, p < 0.02) and lower biochemical failure rate (defined as an increase in serum PSA of 0.2 ng./ml. above the nadir value, 44 versus 65%, p < 0.03) than those who underwent a single freeze-thaw cycle. The main complications of salvage cryotherapy were urinary incontinence (73% of the patients), obstructive symptoms (67%), impotence (72%) and severe perineal pain (8%). CONCLUSIONS Salvage cryotherapy impacts local tumor control as evident by the high frequency of negative posttreatment biopsies. A double freeze-thaw cycle appears more effective than a single cycle. Like salvage prostatectomy, salvage cryotherapy causes significant morbidity.

Familial Patterns of Prostate Cancer: A Case-Control Analysis

Epidemiological data have not yet enabled physicians to look beyond age and race to identify men at increased risk for prostate cancer. We conducted a hospital-based case-control study of familial patterns of prostate cancer with self-reported data from a risk-factor questionnaire. There were 385 patients with histologically confirmed prostate cancer, and 385 race and age-matched (+/- 5 years) controls with other cancers. Family history, available for 378 patients and 383 controls, was positive for prostate cancer in 13.0% versus 5.7%, respectively. The difference was significant at p = 0.01. The over-all age-adjusted risk estimate for men with a first-degree relative with prostate cancer was significantly elevated (odds ratio of 2.41), as were the individual risk estimates for having a father or brother with prostate cancer (odds ratio of 2.24 and 2.66). Having a second-degree relative (grandfather or uncle) with prostate cancer also conferred elevated but not statistically significant risk. These data accord well with the few previously published case-control studies of familiarity of prostate cancer. On the basis of these findings, one should consider recommending participation in early detection programs for prostate cancer in a man whose father or brother has had the disease.

Analysis of clinicopathologic factors predicting outcome after radical prostatectomy

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.

Predictors of cancer in repeat extended multisite prostate biopsy in men with previous negative extended multisite biopsy

OBJECTIVES To evaluate the factors influencing the cancer detection rate in men whose initial and repeat biopsies were both performed using an extended multisite biopsy scheme. Sextant biopsy of the prostate is associated with a significant false-negative rate, as evident from the high cancer detection rate after repeat prostate biopsy. Extended multisite biopsy schemes have therefore been recommended to maximize cancer detection. METHODS Between June 1997 and August 2001, 939 men underwent prostate biopsy for early detection of prostate cancer using the extended multisite scheme (10 or 11 cores incorporating the anterior horn of the peripheral zone with or without midline peripheral zone and/or the transition zone). Of these 939 men, 89 (9.5%) underwent a repeat extended multisite prostate biopsy. The median prostate-specific antigen level was 6.9 ng/mL (range 0.7-36.1). Twenty-four men (27%) had an abnormal digital rectal examination at presentation. Most men (86%) in the group undergoing repeat biopsy had two or more risk factors for a positive biopsy. The median interval between biopsies was 4 months. RESULTS Of the 89 men, 15 (17%) had prostate cancer in the repeat biopsy specimen. Seven cancers (47%) were found only in the alternate biopsy sites, 5 (33%) cancers were found only in the sextant sites, and 3 in both sextant and alternate sites. Cancer was present in only one biopsy core in 11 (73%) of the 15 men, and the median Gleason score was 6 (range 6-8). On multivariate analysis, the presence of atypical glands suspicious for carcinoma (AGSC) was the only independent predictor of cancer in repeat biopsy (P <0.004). Of the 79 men without AGSC in the initial biopsy, 8 (10%) had a positive repeat biopsy. The total and percent free prostate-specific antigen level, digital rectal examination, ultrasound findings, and presence of high-grade prostatic intraepithelial neoplasia were not predictive of cancer detection. CONCLUSIONS The probability of a positive result for a repeat prostate biopsy is lower after an initial extended multisite biopsy compared with an initial sextant biopsy. The presence of AGSC was the only significant predictor of cancer in the repeat biopsy. Because nearly 50% of cancers detected in the repeat biopsy were in alternate sites only, using a sextant biopsy scheme for repeat biopsy would have missed these cancers.

The distribution of prostate specific antigen in men without clinical or pathological evidence of prostate cancer : relationship to gland volume and age

We estimated the in vivo prostate gland volume in 408 men (320 without clinical evidence of prostate cancer, and 88 with an abnormal digital rectal examination and/or transrectal prostate ultrasound and negative biopsies) using sequential step-section ultrasound analysis and correlated it to the serum prostate specific antigen (PSA) value. Of the men 331 (81.1%) had a PSA value of 4 ng./ml. or less. The PSA value was greater than 4 but less than or equal to 10 in 64 men (15.7%) and greater than 10 in 13 (3.2%). The men were subclassified by prostate gland volume at arbitrary break points. A total of 139 men (34.1%) had a gland of 25 cm.3 or less, 2.2% of whom had a PSA value of greater than 4. Further analysis revealed that the incidence of a PSA value greater than 4 increased as the prostate volume increased (18.4% for greater than 25 but less than or equal to 50, and 65.4% for greater than 50) and as age increased. We found a statistically significant association between prostate gland volume and patient age (p less than 0.00005) to the serum PSA concentration. The finding of a PSA value of greater than 10 was uncommon regardless of the prostate gland volume. Clinical implications of these results are discussed, and a statistical model to estimate the serum PSA by gland volume and patient age was constructed.

A streamlined three-dimensional volume estimation method accurately classifies prostate tumors by volume

Prostate tumor volume has been suggested to be an important pathologic variable that predicts for clinical significance and outcome. However, the determination of tumor volume using standard methods such as computerized planimetry or image analysis is labor intensive. We studied whether length (L), width (W), and height (number of cross sections × sectional thickness, CST) of a tumor focus could be used to estimate prostate tumor volume. We studied 1091 tumor foci from 365 selected serially sectioned radical prostatectomy specimens. We randomly divided the specimens into evaluation (182 specimens) and validation (183 specimens) groups. After analyzing the evaluation group, we derived the formula 0.4 (slope of the regression line) × L × W × CST to estimate volume. We then tested whether our three-dimensional volume estimation formula could accurately classify tumor volume for specimens in the validation set as insignificant (≤0.5 cm3) or significant (>0.5 cm3), and also into a five-category tumor volume scheme. Our three-dimensional estimate accurately classified tumors into insignificant and significant total volume categories in 94.0% of cases and into the five-category scheme in 85.8% cases. These accuracy rates were significantly better than rates for other methods. The three-dimensional estimate is an accurate and straightforward method for assessing prostate tumor volume.

Tumor volume and prostate specific antigen : implications for early detection and defining a window of curability

PURPOSE We attempted to determine the relationship between tumor volume and extent of localized prostate cancer, as well as the interrelationships of tumor volume with prostate specific antigen (PSA) level, grade and stage. MATERIALS AND METHODS Serial whole mount sections from 128 patients who underwent radical prostatectomy were analyzed using a computer assisted volumetric program. Statistical evaluations were performed using logistic and simple regression analyses. RESULTS The median tumor volume for patients with organ confined disease was significantly lower than for those with extraprostatic extension (1.25 versus 2.94 cc, p < 0.001). A significant incidence (32%) of small volume cancers (0.51 to 1.5 cc) exhibited extraprostatic extension while that of extraprostatic disease increased to 66% for patients with tumor volumes greater than 1.5 cc (p < 0.001). Of men with clinically significant (greater than 0.5 cc, or Gleason score 7 or more) pathological stage B disease 31% had a serum PSA value of 4 ng./ml. or less. Multivariate regression analysis of tumor volume as a function of PSA, grade and stage demonstrated that log PSA had the strongest association with tumor volume. Goodness-of-fit analysis (coefficient of determination) revealed that only 40 to 50% of the PSA levels are explained by tumor volume. CONCLUSIONS These data suggest that the window of curability for prostate cancer decreases significantly once the tumor grows to a volume greater than 1.5 cc, and that grade and tumor volume are more significantly related to stage than PSA.