Extended sector biopsy for detection of carcinoma of the prostate.

Purpose: To determine whether an extended sector biopsy of the prostate will increase the detection of prostate cancer, without causing an increase in morbidity. Materials and Methods: A total of 74 men with a mean age of 62.3 years (46-98 years) who either had an elevated PSA or an abnormal digital rectal exam underwent a transrectal ultrasound guided needle biopsy. Beginning on 7/1/98, an extended sector biopsy technique was performed on 74 patients by one urologist (RRB). Each transrectal ultrasound guided needle biopsy included 12 total cores (normal sextant biopsy, 2 in each peripheral zone, and 2 in the transition zone). We retrospectively reviewed the biopsy results for the location of cancer. PSA data and morbidity of the procedures were reviewed. Results: Of 74 total patients, 40 (54.1%) were positive for adenocarcinoma of the prostate. There were 10 positive results detected only in the additional zones. If one looks at the total number of cancers detected (40), then 10/40 (25%) of the cancers detected were found in the additional regions only or in 13.5% of all patients biopsied. Of the 10 patients with sector only prostate cancer, 8 were detected in the peripheral zone, 1 in the transition zone and 1 in both zones. All 10 patients had a Gleason pattern score 3+3=6 or 4+3=7. There were no atypical or PIN cores found in the sector zones only. PSA ranged from 1.2-142 (median 6.0 ng/ml). The median PSA was 6.2 ng/ml in all patients found to have cancer, and 6.0 ng/ml in the cancers detected only in the additional zones. There was 1 (1.4%) complication of urinary retention and fever. Conclusion: Our study suggests that an extensive sector biopsy may increase the detection of prostate cancer by 13.5% over a routine sextant biopsy, without demonstrable serious morbidity.

Carcinosarcoma of the urinary bladder--an aggressive tumor with diverse histogenesis. A clinicopathologic study of 4 cases and review of the literature.

OBJECTIVE: Carcinosarcomas of urinary bladder are rare malignant neoplasms. Seventy-eight cases have been previously described. The histologic composition of these tumors is variable, but diagnosis requires the presence of both epithelial and mesenchymal malignant components. We report 4 additional cases, with an emphasis on unusual histologic features. METHODS: Histologic and immunohistochemical examinations were performed on bladder tumors from 4 patients. Clinicopathologic features of previously reported and current cases were reviewed and summarized. RESULTS: Four patients (3 men, 1 woman) age 54 to 77 years were found to have polypoid masses in the urinary bladder. In all cases, histologic examination showed biphasic neoplasms with distinct mesenchymal and epithelial components. The morphologic and immunohistochemical characteristics of the tumors varied. One of the cases was remarkable for the presence of liposarcoma, malignant peripheral nerve sheath tumor, and micropapillary urothelial carcinoma. Two of the patients died 2 years after diagnosis, which is consistent with the previously reported aggressive nature of urinary bladder carcinosarcomas. CONCLUSIONS: Carcinosarcomas of the urinary bladder are rare, aggressive malignant neoplasms. To our knowledge, a liposarcomatous component has been reported in only 1 case previously, and components of micropapillary urothelial carcinoma and malignant peripheral nerve sheath tumor have not been reported previously in carcinosarcomas of the urinary bladder. Because of the aggressive biologic behavior of these tumors, they should be identified promptly and treated appropriately.

Pilot study of the tolerability and toxicity of intravesical valrubicin immediately after transurethral resection of superficial bladder cancer.

OBJECTIVES: To assess in a pilot study the safety, tolerability, and technical feasibility of administering intravesical valrubicin immediately after transurethral resection of bladder tumors (TURBT) in patients with superficial bladder cancer and to evaluate the optimal dose of valrubicin and its systemic absorption. METHODS: Twenty-two patients with recurrent or newly diagnosed Stage Ta or T1 transitional cell tumors received a single dose of 400 mg, 600 mg, or 800 mg of intravesical valrubicin immediately after TURBT. Four patients thought to be at high risk of recurrence were followed up with five additional doses of 800 mg valrubicin, given weekly. RESULTS: The use of valrubicin after TURBT was generally well tolerated. Little evidence was found to suggest a direct relationship among the dose of valrubicin, the time between the end of TURBT and drug instillation, and the occurrence of most bladder symptoms. The most commonly reported adverse events included dysuria (77%), hematuria (59%), and urgency/frequency (23%). Pharmacokinetic analyses revealed that the mean systemic exposure to valrubicin and its metabolites depended on the extent of the TURBT and the damage to the bladder wall. CONCLUSIONS: The results of this study indicated that administration of valrubicin immediately after TURBT is feasible.

Interferons and bladder cancer.

With the introduction of BCG, intravesical instillation of immunotherapeutic agents has become a mainstay of therapy in the treatment of superficial bladder cancer. Interferon is capable of inducing a non-specific cellular and humoral immune response towards tumor cells. It has shown promise in reducing the recurrence and progression rates of superficial bladder cancer. In contrast to BCG, intravesical interferon is associated with minimal side effects and a very low dropout rate. Current research has focused on the use of interferon in combination with immunotherapeutic and cytotoxic drugs.

Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group.

PURPOSE: We assess the efficacy and safety of intravesical valrubicin for the treatment of carcinoma in situ in patients with failure or recurrence after bacillus Calmette-Guerin (BCG) and who otherwise would have undergone cystectomy. Total anthracycline recovery in urine samples obtained within 24 hours of valrubicin administration was assessed in a subset of patients. MATERIALS AND METHODS: A total of 90 patients with recurrent carcinoma in situ after failed multiple prior courses of intravesical therapy, including at least 1 course of BCG, participated in this open label, noncomparative study. Each patient received 6 weekly instillations of 800 mg. intravesical valrubicin. Disease evaluations were made at baseline and 3-month intervals following treatment. Evaluations included cystoscopy with biopsy and urine cytology. Toxicity was noted throughout treatment and followup. No evidence of disease recurrence for 6 months or greater was considered a complete response. RESULTS: Of 90 patients 19 (21%) had a complete response, including 7 who remained disease-free at the last evaluation, with a median followup of 30 months. Additionally, 14 patients who did not meet the strict protocol definition of complete response had superficial Ta disease only. Median time to failure and/or last followup for complete responders was greater than 18 months. Recurrence has been noted in 79 patients to date, including only 2 with clinically advanced disease (stage T2). Of these 79 patients 44 (56%, 4 responders and 40 nonresponders) underwent radical cystectomy. Of the 41 patients with known pathological stage 6 (15%) had stage pT3 or greater at cystectomy. Four patients died of bladder cancer during the median followup of 30 months, none of whom was a complete responder or underwent cystectomy following valrubicin. The main side effects of valrubicin therapy were reversible local bladder symptoms. CONCLUSIONS: Valrubicin was effective and well tolerated in patients with carcinoma in situ of the bladder refractory to BCG therapy. Delaying cystectomy while attempting salvage therapy with valrubicin does not pose an undue risk to most patients.

NCCN Practice Guidelines for Prostate Cancer.

Systemic therapies for prostate cancer are likely to improve, and as they do, they will have enormous impact on the treatment of high-risk and locally advanced cancers. Further technical improvements in radiotherapy and alternative local modalities, such as cryoablation, are also likely, and will bring even more options for local control. It is certain these guidelines will continue to evolve.

Association of free PSA percent, total PSA, age, and gland volume in the detection of prostate cancer.

BACKGROUND: Measurement of the free fraction of total prostate-specific antigen (fPSA%) has been proposed as a useful addition to total PSA for the detection of prostate cancer. METHODS: We assessed the performance of fPSA% in differentiating men with prostate cancer from men without cancer in a group of 1,709 subjects studied in five institutions. RESULTS: On the basis of PSA testing, digital rectal examination, and ultrasound examination conducted at one or more visits, 229 cancers were diagnosed. The mean fPSA% in men with cancer was 9.1% compared to 18.9% in men without cancer. The fPSA% varied by age, with men under 60 having a mean fPSA of 13.9% compared to 17.5% in men 60-69 years old and 19.8% in men over age 70. Significant associations of fPSA% with gland volume and PSA level were also observed. The sensitivity, specificity, and positive predictive value of different fPSA% cutoff levels were assessed in 513 men who underwent sextant biopsy. Sensitivity of 85.4%, 32.1% specificity, and a 39.2% positive predictive value were observed using an fPSA cutoff of 15% in men with PSA in the 4.0-9.9 ng/ml range. Sensitivity of 96.9%, 12.3% specificity, and a 36.2% positive predictive value were observed using an fPSA cutoff of 20% in the same men. If 15% fPSA had been used as a biopsy criterion in men with PSA of 4.0-9.9 ng/ml, the number of biopsies performed could have been reduced by 21.2%, with a concomitant reduction in cancer detection of 14.6%. Using a 20% fPSA criterion, biopsies would have been reduced 12.7%, with a 3.1% reduction in cancer detection. CONCLUSIONS: These results provide some evidence that the detection of prostate cancer is enhanced by measuring fPSA% in addition to the established measure of total PSA level. Further research is needed to identify other markers that have better sensitivity and specificity.

Charge and length of hospital stay analysis of radical retropubic prostatectomy and transperineal prostate brachytherapy.

PURPOSE: For the treatment of clinically localized prostate cancer radical retropubic prostatectomy with its attendant hospital stay should be associated with higher charges than transperineal prostate brachytherapy. We report a comparative case series to determine patient charges and length of hospitalization of 2 modalities of monotherapy for localized prostate cancer. MATERIALS AND METHODS: A total of 35 consecutive patients with clinically localized prostate cancer underwent radical retropubic prostatectomy (16) or transperineal prostate brachytherapy (19) at the Arthur James Cancer Hospital and Research Institute. Complete charge and length of hospital stay data were collected for each patient. Total charges were calculated and the 2 modalities were compared. RESULTS: Charge data were available in 33 cases. Average total charges in the prostatectomy and brachytherapy groups were $15,097 and $21,025, respectively ($5,928 difference, p <0.0001). The difference increased further when outliers were excluded from study. Average length of hospital stay and average charge in the prostatectomy group were 3.8 days and $1,897. The higher charges for transperineal prostatic brachytherapy were due to dosimetry calculations, radioactive seeds and seed implantation. CONCLUSIONS: At our institution the average total charges for transperineal prostate brachytherapy are significantly higher than those for radical retropubic prostatectomy.

NCCN urothelial cancer practice guidelines. National Comprehensive Cancer Network.

Urothelial tumors represent a spectrum of diseases with a range of prognoses. Once a diagnosis is established at any point on the urothelial tract, the patient remains at risk for developing a new lesion at a different or the same location, at a similar or more advanced stage. Continued monitoring for recurrence is an essential part of management, as most recurrences are superficial and can be managed by endoscopic means. Within each category of disease, more refined methods to determine prognosis and guide management, based on molecular staging, are under development. These methods are aimed at optimizing the individual patient's likelihood of cure and chance for organ preservation. For patients with more extensive disease, newer treatments typically involve combined-modality approaches using recently developed surgical procedures, or three-dimensional treatment planning for more precise delivery of radiation therapy. While these are not appropriate in all cases, they do offer the promise of an improved quality of life and prolonged survival. Finally, within the category of metastatic disease, a number of new agents have been identified that appear to be superior to those currently considered to be standard therapies. It is thought, therefore, that the treatment of urothelial tumors will evolve rapidly over the next few years, with improved outcomes for patients with all stages of disease.

Seminal vesicle cystadenoma: a case report and literature review.

Primary tumors of the seminal vesicle are rare; most reported cases are carcinomas, with occasional reports of primary seminal vesicle sarcoma and an uncommon group of mixed epithelial-stromal tumors. The latter have been variably reported in the literature as cystadenoma, phyllodes tumor, and mullerian adenosarcoma-like tumor. We describe a 37-year-old man who presented with symptoms of bladder outlet obstruction and was found to have a pelvic mass. Resection of the mass yielded a biphasic tumor characterized by cystically dilated glandular spaces admixed with spindle-shaped stromal cells. There was no significant cytologic atypia or mitotic activity. The histologic features are most consistent with the reported cases of cystadenoma. The patient is alive, with no evidence of disease, 6 months after surgery. This case adds to the gradually growing body of literature on mixed epithelial-stromal tumors of the seminal vesicle.

All-trans-retinoic acid modulation of drug-metabolizing enzyme activities: investigation with selective metabolic drug probes.

PURPOSE: All-trans-retinoic acid (ATRA) is a retinoid analogue that has been shown to be effective in acute promyelocytic leukemia. It is currently being investigated for efficacy in the treatment and prevention of various types of cancer. One of the factors limiting its use is the observed increase in ATRA clearance and elimination which occurs shortly after treatment is started, leading to reduced levels of drug in the body and loss of effectiveness. ATRA efficacy may be enhanced if this autoinduction of metabolism can be overcome, for example through the inhibition of the activity of the induced specific metabolizing enzyme(s). This requires the identification of this induced enzyme(s) and development of approaches to selectively inhibit its activity. METHODS: In the course of a phase II evaluation of ATRA in prostate cancer, we investigated the activities of five specific cytochrome P450 (CYP) (CYPs 1A2, 2C19, 2D6, 2E1 and 3A4) and N-acetyltransferase enzymes using a newly developed five-drug cocktail involving caffeine, mephenytoin, debrisoquine, chlorzoxazone and dapsone respectively. Enzyme activities were assessed in 17 patients with hormone-refractory prostate cancer before the initiation of ATRA therapy, after 14 days of continuous ATRA administration and 7 days after cessation of drug therapy. RESULTS: After 14 days of ATRA therapy, the activities of CYP2E1 (chlorzoxazone hydroxylase) and N-acetyltransferase (in fast acetylators only) were increased by 83% and 29% (P < 0.05), respectively. Both activities returned to baseline by 7 days after cessation of therapy and the profiles were similar to the changes seen in the clearance of ATRA itself. There were no changes in the activities of any of the other enzymes investigated. CONCLUSION: This study shows that ATRA selectively modulates the activities of specific metabolizing enzymes and that this approach may be useful in identifying enzymes that can be explored in an attempt to mitigate ATRA autoinduction through selective modulation of enzyme activities. Further investigations are required to determine whether the elevated enzymes are also responsible for the increased clearance and elimination of ATRA.

Transperineal image-guided permanent brachytherapy for localized cancer of the prostate.

Traditionally, organ-confined adenocarcinoma of the prostate has been treated with radical prostatectomy or external beam radiotherapy (EBRT). Permanent implantation of iodine-125 (I-125) seeds into the prostate via a free-hand, retropubic approach was introduced in 1970. However, its popularity was short-lived because suboptimal results were obtained due to the inadequate and inhomogeneous distribution of seeds within the prostate gland. Over the last decade, there has been a resurgence in prostate brachytherapy due to the introduction of a transperineal approach, transrectal ultrasound imaging, fluoroscopy, three-dimensional visualization, and computerized treatment planning. Thus, the radioactive seeds can be placed more accurately and homogeneously within the prostate gland. Selection criteria for brachytherapy is based on the pretreatment prostate specific antigen level, clinical stage at presentation, and Gleason grade. Patients with high likelihood of organ-confined disease are treated with brachytherapy only, whereas those with more advanced disease are treated with brachytherapy in conjunction with EBRT and/or hormonal manipulation. I-125 (145 Gy) or palladium-103 (120 Gy) are the common radioisotopes used. Ten-year actuarial biochemical progression-free rates of 64 to 93% (which are comparable to those obtained by surgery or EBRT), with minimum associated morbidity, have been reported from centers routinely performing transperineal permanent prostate brachytherapy. Brachytherapy is a good treatment option for localized prostate cancer and the results very much depend on the expertise, skill, and experience of the brachytherapy team. Randomized clinical trials are required to firmly establish the role of brachytherapy in the management of localized prostate cancer.

Perineural invasion in transitional cell carcinoma and the effect on prognosis following radical cystectomy.

OBJECTIVES: The relationship between perineural invasion and prognosis has been demonstrated to be poor in a number of malignancies. This has not been evaluated in the bladder. We performed a study to determine the occurrence of nodal metastases, extranodal metastases, and disease-free survival in patients with perineural invasion (PNI) and/or angiolymphatic invasion (ALI) in transitional cell carcinoma of the bladder (TCCB) from radical cystectomy specimens. METHODS: A retrospective review of 27 patients treated with radical cystectomy for TCCB was conducted. Comparisons were performed between three groups: PNI with or without ALI (PNI +/- ALI, 12 patients), ALI alone (8 patients), and a control group (no PNI or ALI) (7 patients). RESULTS: The mean patient age was 70 years (range 49 to 83). The overall median follow-up period was 11 months (range 1 to 32). PNI +/- ALI was predominantly found in Stage T3b disease (14 of 20 [70%] cases). The overall 1-year disease-free survival was 48%, 67%, and 83% for the PNI +/- ALI, ALI alone, and control groups, respectively. Nodal metastases (for all stages combined) were found in 6 of 12 (50%), 3 of 8 (38%), and 1 of 7 (14%) patients in the PNI +/- ALI, ALI alone, and control groups, respectively. Similarly, extranodal metastatic disease was found in 5 of 12 (42%), 4 of 8 (50%), and 1 of 7 (14%) patients in the PNI +/- ALI, ALI alone, and control groups, respectively. The percentage of deaths for the PNI +/- ALI, ALI only, and control groups were 33%, 50%, and 14%, respectively. CONCLUSIONS: In TCCB, perineural invasion with or without angiolymphatic invasion and angiolymphatic invasion alone are associated with a higher incidence of nodal and extranodal metastases and death.

Initial report on intravesical administration of N-trifluoroacetyladriamycin-14-valerate (AD 32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder.

OBJECTIVES: This study was designed to assess the pharmacokinetics, safety, and antitumor activity of intravesically administered AD 32, a novel anthracycline, in patients with transitional cell carcinoma (TCC) of the bladder. METHODS: Six weekly doses of AD 32 (200 to 900 mg) were administered to 32 patients with superficial TCC who were candidates for intravesical treatment. Serum drug levels were measured during the 6-hour period after administration of the first, third, and sixth doses. Patients underwent bladder evaluations at 3-month intervals to determine responses to treatment. RESULTS: Very low levels of unmetabolized AD 32 and its two primary metabolites were measured in serum. The lack of systemic exposure was confirmed by the finding of only a few minor systemic adverse events. Local bladder irritation, the main toxicity associated with intravesical administration of AD 32, persisted for several days after each instillation. The maximum tolerated dose was 800 mg. Thirteen patients had complete responses to treatment, including 8 who remained disease free for 12.1 to 38.5 months. CONCLUSIONS: AD 32 is an active drug for the treatment of superficial bladder cancer. Further studies of intravesical administration of AD 32 are warranted.

A phase II trial of all-trans-retinoic acid in hormone-refractory prostate cancer: a clinical trial with detailed pharmacokinetic analysis.

Retinoids have been shown to have substantial anticancer activity in a number of preclinical and clinical situations. There are considerable epidemiologic, in vitro and in vivo data which indicate that retinoids may have a role in the prevention and therapy of human prostate cancer. Based on anecdotal evidence of response in one patient with hormone-refractory prostate cancer (HRPC), we conducted a phase II trial in HRPC during which we also examined changes in pharmacokinetics of all-trans-retinoic acid (ATRA) which occurred during therapy. Enrolled in the study were 17 patients with HRPC who received 50 mg/m2 ATRA three times daily orally on days 1-14, repeated every 22 days. The pharmacokinetics of ATRA were assessed with the first dose on day 1, again on day 14 and after a 7-day interruption in ATRA therapy on day 22. Patients were evaluable for response if they completed two 14-day courses of ATRA; among 13 such patients no responses were seen. Four patients were considered unevaluable for response owing to rapid disease progression in three and intercurrent illness in one. Apparent clearance of ATRA changed substantially during therapy: day 1 3779 +/- 4215 ml/min, day 14 7179 +/- 3197 ml/min, day 22 3213 +/- 2357 ml/min. Area under the curve was proportionately diminished on day 14 compared with day 1 and had returned to baseline by day 22. We conclude that ATRA is not active in HRPC. Failure of this agent in HRPC may be related to failure of drug delivery associated with enhanced mechanisms of ATRA clearance which occur within a few days of beginning ATRA treatment.