Gerald W. Chodak

Results of Conservative Management of Clinically Localized Prostate Cancer

BACKGROUND The selection of treatment for patients with localized prostate cancer requires reliable information about the outcome of conservative management. Previous studies of this question are generally considered unreliable because they were uncontrolled and nonrandomized. METHODS We performed a pooled analysis of 828 case records from six nonrandomized studies, published since 1985, of men treated conservatively (with observation and delayed hormone therapy but no radical surgery or irradiation) for clinically localized prostate cancer. A Cox regression analysis was performed to determine which factors influenced survival among patients who did not die of causes other than prostate cancer (disease-specific survival). Kaplan-Meier curves for overall and metastasis-free survival among such patients were compared with use of the log-rank method and the Mantel-Haenszel test. RESULTS Factors that had a significant effect on disease-specific survival were grade 3 tumors (risk ratio, 10.04), residence in Israel (risk ratio, 2.48) or New York (risk ratio, 0.37), and age under 61 years (risk ratio, 0.32). Ten years after diagnosis, disease-specific survival (with data on men who died from causes other than prostate cancer censored) was 87 percent for men with grade 1 or 2 tumors and 34 percent for those with grade 3 tumors; metastasis-free survival among men who had not died of other causes was 81 percent for grade 1, 58 percent for grade 2, and 26 percent for grade 3 disease. These findings were not affected by the inclusion of men who had early-stage cancer, were older, had worse-than-average health, or underwent delayed radiation therapy or radical prostatectomy. CONCLUSIONS The strategy of initial conservative management and delayed hormone therapy is a reasonable choice for some men with grade 1 or 2 clinically localized prostate cancer, particularly for those who have an average life expectancy of 10 years or less. New treatment strategies are needed for men with grade 3 prostate cancer.

Use of a New Tumor Marker, Urinary NMP22, in the Detection of Occult or Rapidly Recurring Transitional Cell Carcinoma of the Urinary Tract Following Surgical Treatment

PURPOSE We evaluated the ability of an immunoassay for nuclear matrix protein 22 (NMP22 test kit) to predict the subsequent disease status of patients with transitional cell carcinoma of the urinary tract at approximately 10 days after transurethral resection of bladder tumor. MATERIALS AND METHODS A total of 90 patients with transitional cell carcinoma provided voided urine samples at least 5 days postoperatively. NMP22 was determined using a commercial test kit. At initial cystoscopic examination 3 to 6 months later the disease status was recorded, and the NMP22 values before and after transurethral resection of bladder tumor were compared. RESULTS Of 125 followup cystoscopic examinations (60 patients had 1, 26 had 2, 3 had 3 and 1 had 4 recurrences) transitional cell carcinoma was pathologically confirmed in 33. No malignancy was present at 79 examinations (if tumor was seen endoscopically, pathological evaluation indicated atypia, dysplasia or no abnormality). NMP22 values in these 2 populations were significantly different (malignancy median 20.81 units per ml. and no malignancy median 5.72 units per ml., Mann-Whitney U test for differences between 2 medians p = 0.00005). Of the 33 recurrences 23 (70%) had NMP22 values greater than the reference range (10 units per ml.). Additionally, NMP22 identified all 6 subjects (100%) who had invasive disease 3 to 6 months later. Of 72 patients with NMP22 less than 10 units per ml. 62 (86%) had no malignancy at subsequent cystoscopy. CONCLUSIONS NMP22 was highly predictive of tumor status at followup cystoscopy. This quantitative, noninvasive assay, with high negative predictive value (86%) and sensitivity to detect malignancy (100% for invasive disease and 70% overall), may be a helpful adjunct to cytology and endoscopy for monitoring disease status after endoscopic tumor resection.

Bicalutamide as Immediate Therapy Either Alone or as Adjuvant to Standard Care of Patients with Localized or Locally Advanced Prostate Cancer: First Analysis of the Early Prostate Cancer Program

PURPOSE We determine the efficacy and tolerability of bicalutamide as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with clinically localized or locally advanced prostate cancer. MATERIALS AND METHODS This international program consists of 3 ongoing, randomized, double-blind, placebo controlled clinical trials (trials 23, 24, and 25). Men with localized or locally advanced (T1-T4, Nx/N0, M0) prostate cancer were randomized to receive 150 mg. bicalutamide daily or placebo, in addition to standard care with radical prostatectomy, radiotherapy or watchful waiting. Primary end points are time to objective progression and overall survival. In this first analysis data from the trials were combined in a single overview analysis according to protocol. RESULTS Data are available for 8,113 patients (4,052 randomized to bicalutamide, 4,061 to standard care alone) at a median followup of 3.0 years. Treatment with bicalutamide provided a highly significant reduction of 42% in the risk of objective progression compared with standard care alone (9.0% versus 13.8%, hazards ratio 0.58; 95% confidence interval 0.51, 0.66; p <<0.0001). The overall result was reflected in 2 of the 3 trials (trials 24 and 25) with trial 3 (trial 23) showing a nonsignificant difference at this time. Reductions in the risk of disease progression were seen across the entire patient population, irrespective of primary treatment or disease stage. Overall survival data are currently immature and longer followup will determine if there is also a survival benefit with bicalutamide. The most frequently reported side effects of bicalutamide were gynecomastia and breast pain. CONCLUSIONS Immediate treatment with 150 mg. bicalutamide daily, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with localized or locally advanced prostate cancer. This benefit must be balanced with the morbidity associated with long-term hormonal therapy. Followup is ongoing to determine potential survival benefits of this treatment approach.

Complications of Laparoscopic Pelvic Lymph Node Dissection

Intraoperative and postoperative complications were assessed in the first 372 patients undergoing laparoscopic pelvic lymph node dissection at 8 medical centers. In 16 patients laparoscopic node dissection could not be completed due to patient body habitus or technical difficulties. Of these aborted procedures 14 occurred during the initial 8 dissections at each institution. A total of 55 complications (15%) occurred: 14 were noted in the intraoperative and 41 in the postoperative period. Of these patients 13 required open surgical intervention for the treatment of a complication. Complications included vascular injury (11 patients), viscus injury (8), genitourinary problems (10), functional/mechanical bowel obstruction (7), lower extremity deep venous thrombosis (5), infection/wound problem (5), lymphedema (5), anesthetic complications (2) and obturator nerve palsy (2). Based on our experience, there is a significant learning curve associated with performing laparoscopic pelvic node dissection. However, with experience and adherence to laparoscopic surgical principles, the risk of complications may be minimized.

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.

Assessment of Screening for Prostate Cancer Using the Digital Rectal Examination

An early detection study for prostate cancer was initiated to determine the effect of routine digital rectal examinations on the stage of prostate cancer at diagnosis. A prostate biopsy was recommended if induration, asymmetry or nodules were detected on the digital examination. During a 6-year period 4,160 examinations were performed on 2,131 men more than 45 years old. A prostate biopsy was performed on 144 men and 36 malignant tumors were detected, of which 68 per cent were clinically localized. Pelvic lymph node metastases were found in 6 per cent of the surgically staged cancer patients and in 10 per cent of the patients who had a high grade tumor. Surgical staging revealed that 50 per cent of the patients with clinical stage B disease were upstaged to stage C or D1 disease. These results suggest that mass screening programs using digital examination may not add sufficient benefit over conventional medical care to warrant the expense. Definitive proof that screening can lower the mortality rate from prostate cancer can be obtained only by a prospective randomized clinical trial.

Goserelin versus orchiectomy in the treatment of advanced prostate cancer: Final results of a randomized trial

OBJECTIVES To compare the efficacy and safety of goserelin and orchiectomy in patients with stage D2 prostate cancer. METHODS A randomized, open, multicenter study was conducted in 283 patients. Patients were allocated to goserelin, 3.6 mg every 28 days or to orchiectomy. Study end points were endocrine response, objective response, time to treatment failure, survival, and tolerability. Objective response was based on modified criteria of the National Prostate Cancer Project. RESULTS Serum testosterone decreased from baseline to castrate levels by week 4 in each group and remained below castrate levels thereafter. Acid phosphatase and alkaline phosphatase concentrations also decreased in each group. The goserelin and orchiectomy groups had similar results for objective response (82% versus 77%) and had similar medial times to treatment failure (52 versus 53 weeks) and survival (119 versus 136 weeks). No significant interactions between treatments and prognostic factors were observed. Adjusting for baseline testosterone concentration had no effect on survival outcome. Race had no influence on outcome or efficacy end points. Common adverse events in both groups were pain, hot flushes, and lower urinary tract symptoms. CONCLUSIONS Goserelin is well tolerated and as effective as orchiectomy in patients with Stage D2 prostate cancer.

Nuclear localization of androgen receptor in heterogeneous samples of normal, hyperplastic and neoplastic human prostate.

To facilitate an understanding of how androgens participate in the genesis of human benign hyperplasia and carcinoma we assayed androgen receptor in the epithelium and stroma of human prostatic tissue from 57 patients. Immunohistochemical staining of human androgen receptor was performed on 106 sections of normal prostate, benign prostatic hyperplasia (BPH) and prostate cancer. To determine variability of androgen receptor staining sections taken from different portions of the gland were studied. Frozen tissue sections were incubated with monoclonal antiandrogen receptor antibodies and staining was completed by the indirect avidin-biotin peroxidase method. Antibody staining was found mainly in the nucleus of prostatic epithelial cells, although some stromal cells also showed positive staining. Unlike normal prostate, there was a heterogeneous distribution of androgen receptor in BPH and prostate cancer. The androgen receptor content in well differentiated adenocarcinoma epithelium was significantly higher compared to moderately (p less than 0.05) and poorly (p less than 0.05) differentiated adenocarcinoma. Regardless of the origin of stromal tissue, some staining was observed. In each specimen studied the androgen receptor staining was consistent qualitatively and quantitatively for each pathological component throughout the specimen. These data confirm that androgen receptor is a nuclear receptor protein. Furthermore, they show the ability of monoclonal antibodies to reveal cellular/subcellular distribution of androgen receptor, and demonstrate a correlation between the degree of tumor differentiation and androgen receptor content in epithelial but not in stromal cells. These observations may have important implications for understanding the variable tumor response to hormone therapy.

Short-term outcomes after cryosurgical ablation of the prostate in men with recurrent prostate carcinoma following radiation therapy

OBJECTIVES Cryosurgical ablation of the prostate represents a possibly efficacious method of treating prostate carcinoma in men failing radiation therapy. In addition to eradicating the disease, cryosurgery has the potential to avoid some of the morbidity associated with other treatment modalities. Therefore, a prospective Phase II trial was conducted to determine the safety and efficacy of cryosurgery following radiation therapy in men with local recurrence. METHODS Cryosurgical ablation of the prostate was performed in men with prostate cancer previously treated by radiation therapy. All patients had biopsy-proven recurrent disease and no evidence of metastases. Initial follow-up occurred at approximately 3 months and included repeat biopsy and serum prostate-specific antigen (PSA) determinations. Biochemical disease-free survival defined as a PSA value less than 0.3 ng/mL was assessed using the Kaplan-Meier method. RESULTS Thus far, 23 patients have been treated with cryosurgery with follow-up ranging between 12 and 23 months. Approximately 3 months after treatment, sextant biopsies revealed no cancer in 19 of 22 (86%) of the specimens; however, 10 of 22 (45%) showed small amounts of benign glandular tissue. The PSA at 3 months postoperatively declined in 18 of 22 (82%) patients but reached female levels in only 8 men (36%). Nineteen of 22 (86%) patients followed up a minimum of 1 year after cryotherapy have a PSA level equal to or greater than 0.3 ng/mL. Complications occurred in 100% of the patients with 12 of 22 (55%) requiring at least one transurethral resection of sloughed, necrotic tissue. CONCLUSIONS Our preliminary results suggest that the current cryosurgical technique used in men failing radiation therapy has a low probability of biochemical cure and a high complication rate. Until more data are available, cryosurgery for men with locally recurrent disease after radiation therapy should be considered strictly experimental.

Adherence by African American men to prostate cancer education and early detection

This study was designed to identify factors that predict adherence by African American men to prostate cancer education and early detection.