Biomedical subjects
M S Soloway
Publications and source records attributed to M S Soloway.
Bicalutamide in the treatment of advanced prostatic carcinoma: a phase II multicenter trial.
OBJECTIVES: The safety, efficacy, and pharmacokinetics of the nonsteroidal antiandrogen bicalutamide were investigated in a Phase II trial in 150 patients with metastatic prostate cancer. METHODS: Patients took bicalutamide, 50 mg daily, in an open-label multicenter North American trial. RESULTS: The objective response rate (modified European Organization on Research and Treatment of Cancer [EORTC] criteria) was 70% (57% partial, 13% stable); 59 (39%) of 150 patients had either a > 90% decrease in prostate-specific antigen (PSA) levels or a decline to < 4 ng/mL. Extent of disease on the bone scan was a significant predictor of response. Patients with < 6 metastatic lesions were more likely to respond. Breast pain and gynecomastia occurred in 76% and 60% of patients, respectively. Gastrointestinal toxicity was very infrequent (diarrhea, 5%) The mean drug plasma concentration was 8528 (+/- 2928) ng/mL. CONCLUSIONS: Bicalutamide, 50 mg daily, was well tolerated and has efficacy in metastatic prostate cancer. The percentage of men who had > 90% decline in PSA levels is less than observed with surgical or medical castration and has led to trials using this antiandrogen at higher doses as monotherapy.
Is there a role for induction androgen deprivation prior to radical prostatectomy?
The potential advantages of neoadjuvant androgen deprivation include decreased prostatic size, reduced vasculature, and reduced incidence of positive margins. The potential disadvantages are the side effects of hormonal medication, cost, tissue reaction, treatment "delay," and progression of androgen-independent clones. Many theories have been postulated to explain the observed reduction in the incidence of positive margins with neoadjuvant hormonal treatment. It is possible that the reduced prostate size and the frequently found periprostatic tissue reaction facilitate dissection, allowing better cancer clearance. It is possible, however, that the fibrosis may also increase the surgical difficulty, which critics argue may increase the risk of a positive margin. It is difficult to conceive of a research methodology that could resolve this issue. The occurrence of tumor cell death is likely a more significant explanation for the improved results. Whether tumor cells beyond the prostatic capsule are consistently affected to pathologically downstage the disease is unknown. The careful pathologic assessment in the randomized trials discussed previously suggests that pathologic downstaging is not as common as earlier reports have suggested. Difficulty in interpreting pathologic specimens after neoadjuvant treatment must be considered. At this point, neoadjuvant hormonal treatment prior to surgery would appear appropriate for those patients at high risk of having a positive surgical margin. Specifically, this includes clinical stage T2b, PSA elevation greater than 10 to 20 ng/mL, and a high Gleason score on the prostatic biopsy. Research to date suggests that neoadjuvant hormonal therapy prior to radical prostatectomy has a significant effect in reducing the incidence of positive surgical margins. The treatment is well tolerated with minimal side effects. Whether this will translate into improved disease-free survival remains to be determined. Fortunately, the randomized trials have been completed and follow-up data will be forthcoming.
Induction androgen deprivation therapy before radical prostatectomy for prostate cancer--initial results.
OBJECTIVE: To determine if androgen deprivation therapy (ADT) on induction decreases the incidence of positive surgical margins and the subsequent risk of disease progression. PATIENTS AND METHODS: Between January 1992 and July 1994, 160 men with prostate cancer underwent radical retropubic prostatectomy (RP) and bilateral pelvic node dissection (PLND). Forty men (mean age 64.2 years) with either a higher clinical stage or a significant increase in serum prostate-specific antigen (PSA) level (P < 0.001) received induction ADT with a luteinizing hormone-releasing hormone (LH-RH) analogue alone (six patients), or with an anti-androgen (34 patients), 3-20 months before undergoing RP. The remaining 120 men (mean age 64 years) underwent surgery alone and served as historical controls. Prostatectomy specimens were evaluated using step-sections at 2-3 mm intervals and whole-mount reconstruction. The clinical and pathological results were compared. RESULTS: There was a clinically significant decrease in the size of the prostate in almost all patients treated with ADT. After ADT the mean PSA level declined by > 95% from the levels before RP (P < 0.001). Of 40 men receiving ADT and the 120 controls patients, nine (22.5%) and 49 (40.8%) had positive margins (P < 0.05), nine (22.5%) and 18 (15%) had seminal-vesicle invasion (P = 0.90) and one (2.5%) and two (1.6%) had lymph-node metastases (P = 0.73), respectively. At a mean 17.6 months (range 2-29), 20 of the control patients were lost to follow-up. PSA levels were elevated (> 0.4 ng/mL) in seven (17.5%) of the men who received ADT and 14 (14%) of the control patients (P = 0.60). To date, all patients are alive. CONCLUSIONS: The results of this study suggest that neoadjuvant ADT before RP is beneficial in men with a high likelihood of having a positive surgical margin. A prospective randomized trial is necessary to determine if there is a benefit in progression-free and overall survival.
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.
A controlled trial of Casodex (bicalutamide) vs. flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Casodex Combination Study Group.
Between January 1992 and September 1993, 813 patients with stage D2 prostate cancer were enrolled in a multicentre, double-blind (for antiandrogen therapy) trial and randomised to antiandrogen therapy with Casodex (bicalutamide, 50 mg once daily) or flutamide (250 mg three times daily) and to luteinising hormone-releasing hormone (LHRH) analogue therapy with Zoladex (goserelin, 3.6 mg every 28 days) or leuprolide (7.5 mg every 28 days). Time to treatment failure was the primary efficacy endpoint. At a median follow-up time of 49 weeks, there was a significant (p = 0.005) difference between groups in time to treatment failure in favour of Casodex plus LHRH analogue. Overall, 168 (42%) of 404 patients in the Casodex plus LHRH analogue group and 218 (53%) of 409 patients in the flutamide plus LHRH analogue group reached a treatment failure endpoint. Although a cause-specific treatment-failure analysis was not performed, the difference between groups in treatment failure attributed to adverse events (mainly diarrhoea) was evident primarily in the first 7 months of therapy. The difference between groups in treatment failure for objective progression was most evident after 1 year of therapy. With further follow-up (median time of 95 weeks), the result for time to treatment failure, although no longer statistically significant, were consistent with the previous finding of an improvement in time to treatment failure associated with Casodex plus LHRH analogue therapy. With a median of 95 weeks of follow-up, 34% of deaths had occurred. The survival analysis was not dissimilar between the 2 groups. At 49 weeks median follow up, the incidence of diarrhoea was significantly (p < 0.001) lower among patients in the Casodex plus LHRH analogue group. Diarrhoea led to withdrawal from therapy for 2 patients in the Casodex plus LHRH analogue group, compared with 25 patients in the flutamide plus LHRH analogue group. In conclusion, Casodex plus LHRH analogue is well tolerated and effective with an improvement in time to treatment failure over flutamide plus LHRH analogue. Survival was not dissimilar between the 2 treatment groups.
The role of induction androgen deprivation prior to radical prostatectomy.
In patients with localised prostate cancer and a life expectancy of at least 10 years, radical prostatectomy is increasingly being performed. Pre-operative clinical staging of prostate cancer is, however, inaccurate with around 10-20% of clinical T1, 10-30% of clinical T2a, and 30-60% of clinical T2b cases having tumour at the surgical margin. There is no documented best treatment for patients with a positive surgical margin. Options include close observation, adjuvant radiation therapy or androgen deprivation. The role of induction androgen deprivation has, therefore, evolved in an attempt to improve upon the cure rate for radical prostatectomy, and in this review results from clinical trials are discussed. In the largest United States randomised trial in patients with stage T2b prostate cancer, pre-operative androgen deprivation resulted in a significantly lower rate of positive surgical margins, normalisation of prostate-specific antigen and a decrease in the size of the prostate. Sufficient follow-up is required from all of the completed prospective randomised trials before pre-operative androgen deprivation can be justified in all T2b patients.
Histopathological effects of androgen deprivation in prostatic cancer.
Thanks to earlier detection of clinically significant prostatic adenocarcinoma by measurement of serum prostate-specific antigen (PSA) levels, increasing numbers of patients are undergoing radical prostatectomy. However, the curative potential of this procedure is seriously limited by clinical understaging, which results in positive surgical margins and a marked increase in disease progression. In a multicenter study, histopathologic evaluation of radical prostatectomy specimens showed that presurgical androgen deprivation with leuprolide plus flutamide reduced the incidence of surgical margin involvement by 62%. In patients who received androgen deprivation therapy, characteristic and recognizable histopathologic changes in nontumor glands included atrophy, basal cell prominence, vacuolated luminal cell layers, and squamous and transitional cell metaplasia. Androgen deprivation markedly reduced the incidence of prostatic intraepithelial neoplasia (PIN) to 35%. The effects of androgen deprivation on prostatic carcinoma included smaller tumor glands, pyknosis and empty glandular spaces, and vacuolization and degeneration of tumor cells with an inflammatory response. Similar but less pronounced changes with no decrease in PIN were observed in finasteride-treated patients. It is important for pathologists to be aware of these histological changes and process tissue appropriately, because the changes affect the recognition and histological grading of tumors in radical prostatectomy specimens.
Neoadjuvant hormonal treatment before radical prostatectomy.
Randomized trials evaluating the use of androgen deprivation therapy (ADT) before radical prostatectomy have consistently shown significant decreases in prostate volume and in serum prostate-specific antigen (PSA) levels. All but one study have reported that hormonal pretreatment significantly reduces the incidence of positive surgical margins. However, androgen deprivation does not significantly influence seminal vesicle extension or lymph node involvement nor does it affect tumor grade. The fibrotic reactions that sometimes result from hormonal pretreatment can increase the difficulty of surgery but this has not been associated with a higher incidence of perioperative or postoperative complications. In closely monitored clinical trials, bothersome side effects of neoadjuvant hormonal therapy have been limited. Issues that remain to be addressed are the optimal duration of neoadjuvant treatment and whether the benefits of such therapy will translate into improved disease-free survival. At this time, patients with clinical stage T2b disease, PSA elevations greater than 10 to 20 ng/mL, and a high Gleason grade may be considered candidates for neoadjuvant hormonal treatment before surgery.
Urinary nuclear matrix protein as a marker for transitional cell carcinoma of the urinary tract.
PURPOSE: The purpose of this trial was to evaluate an immunoassay for urinary nuclear matrix protein, NMP22, as an indicator for transitional cell carcinoma of the urinary tract. MATERIALS AND METHODS: Three groups of subjects participated in this trial of NMP22: 1-175 with transitional cell carcinoma, 2-117 with benign urinary tract conditions and 3-375 healthy volunteers. Each subject provided a single (3 voids) urine sample for analysis at the time of study entry. Each sample was assayed for the level of NMP22. RESULTS: In normal healthy volunteers and in subjects with benign conditions median NMP22 levels were 2.9 and 3.3 units per ml., respectively. Median urinary NMP22 levels in patients with transitional cell carcinoma were significantly greater than in comparison subjects. Patients with active transitional cell carcinoma had significantly greater median urinary NMP22 levels than those with no evidence of disease (6.04 versus 4.11 units per ml., p = 0.027, 1-tailed Mann-Whitney U test). We noted no effect of tumor grade, extent of disease or exposure to intravesical therapy on urinary NMP22 levels. CONCLUSIONS: NMP22 is a promising urinary tumor marker for monitoring transitional cell carcinoma. Nuclear matrix proteins are a new class of tumor markers that represent the basis for the development of assays with increased efficacy for the detection and treatment of cancer.
Bilateral epidermoid cysts of the testis.
We present a case of bilateral testicular epidermoid cysts. These lesions were identified in a 22-year-old male who had previously experienced mild testicular trauma. Management consisted of inguinal exploration and wedge resection on one side and transscrotal exploration and excision on the other. This case represents the second reported case of bilateral conservative management of testicular epidermoid cysts in an adult male. The etiology and management alternatives for testicular epidermoid cysts are discussed.
Pathology of androgen deprivation therapy in prostate carcinoma. A comparative study of 173 patients.
BACKGROUND: Leuprolide, an agonist of luteinizing hormone-releasing hormone (LH-RH), and flutamide, an antiandrogen, increasingly are being used in the treatment of clinically localized prostate cancer. Only two small series (of 23 and 12 patients) have been published on the distinctive pathologic changes induced in the prostate by androgen deprivation therapy with discrepancies on the presence of squamous metaplasia, necrosis, and possible tumor destruction by combined androgen deprivation therapy. METHODS: One hundred and thirteen radical prostatectomy specimens obtained after at least 3 months of leuprolide-flutamide androgen inhibition therapy and 60 nonhormonally treated prostates in randomly selected clinical Stage T2 prostate adenocarcinoma patients were entirely sectioned. Distinctive histologic findings were tabulated and their statistical value determined. RESULTS: Resection margins of excision were involved by tumor in 43% of untreated and in 19% of androgen-deprived patients. Characteristic changes in androgen-inhibited nontumor glands included atrophy, basal cell prominence, vacuolated luminal cell layer, and squamous and transitional cell metaplasia. Prostatic intraepithelial neoplasia (PIN) was observed in 35% of treated patients. The presence of small tumor glands separated by stroma was the most frequently noted effect of androgen deprivation on prostate adenocarcinoma; pyknosis and branching empty spaces were less frequent. Large clear tumor cells within an inflammatory response was a third histologic pattern. Apparently unaltered tumor areas were observed in 43% of prostates exposed to androgen deprivation therapy. CONCLUSIONS: Androgen deprivation therapy results in histologically distinctive changes that can be recognized in both nonneoplastic and neoplastic prostate tissue. Residual tumor was present in all 113 treated radical prostatectomy specimens. In addition to glandular shrinkage, therapy was associated with statistically significant reductions in the frequency of high grade PIN and extension of cancer to prostate specimen margins of excisions.
Squamous cell carcinoma of the prostate: a transformation from adenocarcinoma after the use of a luteinizing hormone-releasing hormone agonist and flutamide.
We report a primary squamous cell carcinoma of the prostate that developed in a 57-year-old man, 3 years after treatment with leuprolide and flutamide for Stage D1 adenocarcinoma of the prostate. This is the first case that describes this transformation from adenocarcinoma to squamous cell carcinoma following the use of luteinizing hormone agonists.
Bicalutamide in the treatment of advanced prostatic carcinoma: a phase II noncomparative multicenter trial evaluating safety, efficacy and long-term endocrine effects of monotherapy.
PURPOSE: The safety, efficacy and pharmacokinetics of bicalutamide were investigated in 150 patients with stage D2 prostate cancer. MATERIALS AND METHODS: Patients received 50 mg. bicalutamide daily in an open label multicenter North American trial. RESULTS: The objective response rate (modified European Organization for Research in Cancer Therapy criteria) was 70%. Of 150 patients 59 (39%) met prostate specific antigen criteria for partial response, and 88 (59%) reached treatment failure end points and withdrew. Extent of disease was a significant predictor of response but baseline testosterone was not. Breast pain and gynecomastia developed in 76% and 60% of patients, respectively. Mean drug plasma concentration was 8,528 +/- 2,928 ng/ml. CONCLUSIONS: Bicalutamide (50 mg.) daily was well tolerated and efficacious. However, suboptimal effects on prostate specific antigen have led to additional trials to evaluate monotherapy at higher doses.
Quality of life: radical prostatectomy versus radiation therapy for prostate cancer.
PURPOSE: The impact of radical prostatectomy and external beam radiotherapy on the quality of life of patients was compared. MATERIALS AND METHODS: A total of 136 patients underwent radical prostatectomy and 60 underwent external beam radiotherapy for clinically localized prostate cancer. Patients were asked to complete a questionnaire containing The Functional Living Index: Cancer, the Profile of Moods States, and a series of questions evaluating bladder, bowel and sexual function. RESULTS: The radical prostatectomy group had worse sexual function and urinary incontinence, while the external beam radiotherapy group had worse bowel function. Of the patients 90% from both groups stated that they would undergo the treatment again. CONCLUSIONS: Radical prostatectomy and external beam radiotherapy have comparable impact upon quality of life.
Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Zoladex Prostate Study Group.
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.
Small cell carcinoma of the bladder and prostate.
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Prostate cancer after heart transplantation.
Prostate cancer has an unpredictable natural history if left untreated, particularly if the neoplasm is discovered when it is apparently organ confined. To our knowledge we report the first case of organ confined adenocarcinoma of the prostate in a cardiac transplant recipient. The therapeutic decision is complicated by the uncertainty of the impact of continued immunosuppression on tumor growth. Although the effect of immunosuppression on the growth of prostate cancer is unknown, our patient was treated within the accepted guidelines for similarly affected nonimmunosuppressed individuals. Improvements in long-term survival rates of patients undergoing cardiac transplantation warranted radical surgical ablation as treatment for this man with clinically organ confined prostate cancer.