M'Liss A. Hudson

Comparison of Digital Rectal Examination and Serum Prostate Specific Antigen in the Early Detection of Prostate Cancer: Results of a Multicenter Clinical Trial of 6,630 Men

&NA; To compare the efficacy of digital rectal examination and serum prostate specific antigen (PSA) in the early detection of prostate cancer, we conducted a prospective clinical trial at 6 university centers of 6,630 male volunteers 50 years old or older who underwent PSA determination (Hybritech Tandom‐E or Tandem‐R assays) and digital rectal examination. Quadrant biopsies were performed if the PSA level was greater than 4 &mgr;g./l. or digital rectal examination was suspicious, even if transrectal ultrasonography revealed no areas suspicious for cancer. The results showed that 15% of the men had a PSA level of greater than 4 &mgr;g./l., 15% had a suspicious digital rectal examination and 26% had suspicious findings on either or both tests. Of 1,167 biopsies performed cancer was detected in 264. PSA detected significantly more tumors (82%, 216 of 264 cancers) than digital rectal examination (55%, 146 of 264, p = 0.001). The cancer detection rate was 3.2% for digital rectal examination, 4.6% for PSA and 5.8% for the 2 methods combined. Positive predictive value was 32% for PSA and 21% for digital rectal examination. Of 160 patients who underwent radical prostatectomy and pathological staging 114 (71%) had organ confined cancer: PSA detected 85 (75%) and digital rectal examination detected 64 (56%, p = 0.003). Use of the 2 methods in combination increased detection of organ confined disease by 78% (50 of 64 cases) over digital rectal examination alone. If the performance of a biopsy would have required suspicious transrectal ultrasonography findings, nearly 40% of the tumors would have been missed. We conclude that the use of PSA in conjunction with digital rectal examination enhances early prostate cancer detection. Prostatic biopsy should be considered if either the PSA level is greater than 4 &mgr;g./l. or digital rectal examination is suspicious for cancer, even in the absence of abnormal transrectal ultrasonography findings.

Selection of optimal prostate specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristic curves.

A prospective clinical trial of prostate cancer screening was conducted at 6 university centers including 6,630 men 50 years old or older who underwent a serum prostate specific antigen (PSA) determination and digital rectal examination. Biopsies were performed if the PSA level was greater than 4.0 ng./ml. (Hybritech Tandem assay) or digital rectal examination was suspicious for cancer. We evaluated the effect on biopsy rate and cancer detection if the cutoff value was shifted from 4.0 to age-specific reference ranges recommended in the literature. In men 50 to 59 years old with normal digital rectal examination findings a decrease from 4.0 to 3.5 ng./ml. would have resulted in a 45% increase in the number of biopsies (39 of 87) and a projected 15% increase in cancer detection. An increase from 4.0 to 4.5 ng./ml. in men 60 to 69 years old would result in 15% fewer biopsies (35 of 238) and would miss 8% of the organ confined tumors (2 of 25). Increasing the cutoff to 6.5 ng./ml. in men 70 years old or older would result in 44% fewer biopsies (70 of 159) and would miss 47% of the organ confined cancers (7 of 15). The number of biopsies performed for each cancer detected with a PSA level of greater than 4.0 ng./ml. remains constant across age groupings, which suggests that the cutoff of 4.0 ng./ml. does not need to be altered in the older men, since it is apparently unaffected by the simultaneously increasing prevalence of benign prostatic hyperplasia and cancer with age. We conclude that a serum PSA concentration of 4.0 ng./ml. should be used as a general guideline for biopsy in all age groups.

Improved Detection of Recurrent Bladder Cancer Using the Bard BTA stat Test

OBJECTIVES To evaluate the BTA stat Test in the detection of recurrent bladder cancer. METHODS Sensitivity and specificity were determined using frozen voided urine samples from patients with recurrent bladder cancer, volunteers, patients with nonurologic conditions, and patients with a history of bladder cancer but free of disease. Results of cytology and the original BTA Test were compared with the sensitivity of the BTA stat Test in a large subgroup of the patients with cancer. RESULTS The BTA stat Test detected 147 (67%) of 220 recurrent cancers. For those urine samples with previous cytologic and BTA Test results available, cytology had a sensitivity of 23%, the BTA Test 44%, and the BTA stat Test 58% for detection of recurrent cancer (P < 0.001, stat versus cytology). The specificity of the BTA stat Test was 72% for benign genitourinary disease and 95% in healthy volunteers. CONCLUSIONS The BTA stat Test has high sensitivity and is significantly superior to voided urine cytologic analysis in the detection of recurrent bladder cancer.

EFFECT OF PATIENT AGE ON EARLY DETECTION OF PROSTATE CANCER WITH SERUM PROSTATE-SPECIFIC ANTIGEN AND DIGITAL RECTAL EXAMINATION *

This study was designed to determine the effects of age by decade on the efficacy of digital rectal examination (DRE) and serum prostate-specific antigen (PSA) for early detection of prostate cancer in men aged fifty and over. A prospective multicenter clinical trial was conducted at six university centers. All 6,630 male volunteers underwent a serum PSA (Hybritech, Tandem) determination and DRE. Quadrant biopsies of the prostate were performed if PSA was > 4 ng/mL or DRE suspicious. A total of 1,167 biopsies were performed, and 264 cancers were detected. The cancer detection rate increased from 3 percent in men aged fifty to fifty-nine to 14 percent in men eighty years or older (p < 0.0001). PSA detected significantly more of the total cancers than DRE at all age ranges (p < 0.05). The positive predictive values (PPV) for PSA were 32 percent (50-59 years), 30 percent (60-69 years), 34 percent (70-79 years), and 38 percent (80+ years). The corresponding PPVs for DRE were 17 percent, 21 percent, 25 percent, and 38 percent. Eighteen percent of the cancers were detected solely by DRE, whereas 45 percent of cancers were detected solely by PSA. Thus, the use of both tests in combination provided the highest rate of detection in all age groups. One hundred-sixty patients underwent radical prostatectomy and pathologic staging. Cancer was organ-confined in 74 percent (25/34) of men aged fifty to fifty-nine, 76 percent (65/86) of men aged sixty to sixty-nine, and 60 percent (24/40) of men aged seventy or over (chi 2, < 70 vs. > or = 70, p < 0.05). Early detection programs yield a lower, yet still substantial, cancer detection rate in younger men, and there is a greater likelihood for detection of organ-confined disease in this age range. Younger men have the longest projected life expectancy and, therefore, the most to gain from early prostate cancer detection.

Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies

OBJECTIVES Clinical staging of prostate cancer is inaccurate, often with significant upstaging on final pathologic review. We previously demonstrated the ability to predict extraprostatic extension of cancer by use of the Gleason score and serum prostate-specific antigen (PSA) measurements. Herein we present an interim analysis of data from an ongoing multi-institutional study to determine the predictive power of an enhancement of microvessel density analysis in combination with Gleason score and serum PSA to predict extraprostatic extension. METHODS We evaluated a total of 186 randomly selected biopsy samples and matched totally embedded radical prostatectomy samples with preoperative PSA concentrations and patient demographics. Gleason score and optimized microvessel density (OMVD) were determined from the needle biopsy samples; pathologic stage was verified by independent review of the radical prostatectomy samples. An automated digital image analysis system measured microvessel morphology and calculated the OMVD in the biopsy samples (Biostage; Bard Diagnostic Sciences, Seattle, Wash). RESULTS Prediction of extraprostatic extension was increased significantly when OMVD analysis was added to Gleason score and serum PSA concentration (P = 0.003). CONCLUSIONS Optimized microvessel density analysis significantly increases the ability to predict extraprostatic extension of cancer preoperatively when combined with Gleason score and serum PSA concentration. This method appears to be a useful tool that can assist with treatment decisions in selected patients.

Comparison of 2004 and 1973 World Health Organization Grading Systems and Their Relationship to Pathologic Staging for Predicting Long-term Prognosis in Patients With Urothelial Carcinoma

OBJECTIVES To compare the 1973 and 2004 World Health Organization (WHO) systems for the interval to tumor recurrence (TR), tumor progression (TP), and overall survival (OS) using either the superficial/muscle invasive or strict TMN pathologic staging in patients with urothelial carcinoma with ≥10 years of follow-up. METHODS A total of 269 tumors from an institutional review board-approved bladder tumor registry were graded using the 1973 and 2004 WHO systems. Kaplan-Meier plots, the log-rank test, the chi-square test, and the Cox proportional hazard model were used to relate the clinical and histologic variables. RESULTS The Cox model analyses, which were multivariate and included tumor stage (coded as pT1 or less versus pT2 or greater) as a significant covariate to grade, were performed and in all tumor stages were significant. The 2004 WHO grading system was more closely associated with TR (P = .025) and TP (P = .012) than was the 1973 WHO grading system (P = .47, and P = .046, respectively). OS was similar and significant for both. The OS plots for the 1973 WHO system showed a significant overlap between Stage pT1 or less, grade 2 and 3 tumors. For those with high-grade Stage pTa and high-grade Stage pT1 disease, TR and TP were similar; however, OS was significantly longer (P = .05, log-rank test) for those with Stage pTa. The OS was similar for those with high-grade Stage pT1 disease and those with Stage pT2 or greater (P = .069, log-rank test). For those with pTa, the 2004 system predicted TR and TP, but the 1973 system only predicted TP. Neither predicted OS. CONCLUSIONS The results of our analysis have shown that the 2004 WHO system is superior to the 1973 system for predicting clinical outcomes in patients with urothelial carcinoma, independent of pathologic stage. Its primary usefulness is in those with Stage pTa.

Oral bropirimine immunotherapy of bladder carcinoma in situ after prior intravesical bacille Calmette-Guérin

OBJECTIVES Bropirimine is an oral immunomodulator that has demonstrated anticancer activity in transitional cell carcinoma in situ (CIS) in both the bladder and upper urinary tract. Activity also has been documented in patients after prior therapy with bacille Calmette-Guérin (BCG). To more accurately estimate bropirimines efficacy in BCG-resistant bladder CIS, a Phase II trial was performed. A separate analysis was performed in additional patients intolerant of BCG toxicity. METHODS Patients received bropirimine 3.0 g/day by mouth for 3 consecutive days, weekly, for up to 1 year. Bladder biopsies and cytologic examination were performed quarterly. Complete response (CR) required negative biopsy and cytology results. RESULTS Twenty-one of 86 patients entered were not evaluable. CR was seen in 21 (32%; 95th percentile confidence interval [CI], 21% to 44%) of 65 evaluable patients, including 14 (30%, CI 17% to 43%) of 47 BCG-resistant, and 7 (39%, CI 16% to 61%) of 18 BCG-intolerant patients. Overall, by intent-to-treat analysis, CR was thus seen in 21 (24%) of 86 subjects. Most BCG-resistant patients were failures to BCG without relapse, and had received 12 to 36 (median 12) BCG treatments; intolerant patients had received 4 to 11 treatments (median 6). Response duration ranged from 65 to 810 days, with median not yet reached (but greater than 12 months). Thirteen (15%) of 86 stopped bropirimine due to toxicity. Progression to invasive or metastatic disease during or immediately after therapy was documented in only 4 patients (6%), all nonresponders. CONCLUSIONS Bropirimine may be an alternative to cystectomy for some patients with bladder CIS who have failed or have not tolerated BCG. Further evaluation to improve responses and durability is warranted.

URINARY INTERLEUKIN-8/CREATININE LEVEL AS A PREDICTOR OF RESPONSE TO INTRAVESICAL BACILLUS CALMETTE-GUERIN THERAPY IN BLADDER TUMOR PATIENTS

PURPOSE Our purpose was to determine whether urinary interleukin-8 (IL-8) levels could be used to predict a tumor-free response to intravesical bacillus Calmette-Guerin (BCG) therapy in bladder cancer patients. MATERIALS AND METHODS A total of 46 patients with superficial bladder cancer underwent an initial 6-week course of intravesical BCG therapy after transurethral resection. Voided urine samples were collected immediately before BCG instillations 1 and 6. Urine samples were centrifuged at 1,500 rpm for 8 minutes, and the supernatant was stored at -20 C. An enzyme-linked immunosorbent assay technique was used to measure urinary IL-8 levels. The Jaffé method was used to measure urinary creatinine. Results were expressed as the IL-8/creatinine ratio. Patients were followed with cystoscopy and urinary cytology every 3 months to detect bladder tumor recurrence. RESULTS IL-8/creatinine ratios were measured in 31 patients before BCG therapy and were undetectable in 15. After 5 weeks of intravesical BCG therapy, IL-8/creatinine ratios fell in 27 patients (59%), were unchanged in 10 (22%) and rose in 9 (19%). Mean followup was 20.9 months (range 3 to 48). There was no association between the direction of change in IL-8/creatinine ratio and response to intravesical BCG therapy (p = 0.5). CONCLUSIONS Urinary IL-8 levels obtained before intravesical BCG therapy and after instillation 5 of BCG were not helpful in predicting tumor recurrences in bladder cancer patients.

Bropirimine immunotherapy of upper urinary tract carcinoma in situ

OBJECTIVES Bropirimine has been shown to be effective in treating approximately 50% of patients with carcinoma in situ (CIS) of the bladder in recent clinical trials. Patients with upper tract CIS were treated with bropirimine to determine whether this oral drug might be effective in that setting. METHODS Twenty-four patients with negative radiographic findings and positive cytologic evidence for upper tract CIS in one or both ureters received bropirimine (3.0 g/day orally) for 3 consecutive days each week for up to 1 year. Ureteral collection of urine or barbotage for cytologic analysis was performed quarterly thereafter. RESULTS Ten (48%) of 21 evaluable patients had a negative ureteral cytologic analysis after 12 weeks (5 patients) or 24 weeks (5 patients). Of these 10 patients, 8 continue to have negative cytology for a period of 3 to 30 months (median, more than 9 months). In 2 patients, negative cytology reverted to positive at 6 and 9 months, respectively, during therapy. Twelve (50%) of the 24 patients reported no toxicity. Three patients stopped treatment at 2, 3, and 3 weeks due to pruritic rash, nausea and vomiting, and severe bone pain, respectively. Therapy was stopped in 1 additional patient between 4 and 5 months because of transient liver enzyme elevations, yet this patient has had a continuous negative cytologic analysis for more than 9 months. CONCLUSIONS Orally administered bropirimine may be effective therapy for CIS of the ureter or renal pelvis, with acceptable toxicity in most patients. Further efforts to better define this activity as well as the possible need for maintenance or intermittent long-term therapy are warranted.

Effect of Tumor Necrosis Factor and Interferon Gamma on Human Renal Carcinoma Cell Line Growth

Four human renal carcinoma cell lines (786-0, CaKi-1, TK-10 and TK-164) were studied in vitro for susceptibility to human recombinant interferon-gamma (IFN gamma) and/or human recombinant tumor necrosis factor (TNF). All four cell lines tested demonstrated a dose dependent sensitivity to the cytotoxic effects of TNF alone. The degree of sensitivity varied for each cell line. IFN gamma alone also mediated a dose dependent antiproliferative effect in three of the four cell lines. Combinations of IFN gamma and TNF produced diverse inhibitory effects. Preincubation of the cells for various time intervals with noninhibitory concentrations of IFN gamma prior to the addition of TNF resulted in distinct effects for each cell line. Pretreatment enhanced the cytotoxic effect of TNF for some cell lines; however, others became less susceptible and some demonstrated enhanced proliferation in the presence of both agents. Optimal pretreament times also varied from cell line to cell line. These results demonstrate variability in responsiveness by renal carcinoma cell lines to combination IFN gamma and TNF treatments and suggest that timing as well as concentration may be important in in vivo therapy.