Clinical studies of prostatic cancer imaging with radiolabeled antibodies against prostatic acid phosphatase

Conventional antibodies against prostatic acid phosphatase, labeled with iodine-131, have been administered to patients with prostatic carcinoma for the external scintigraphic imaging of tumors containing prostatic acid phosphatase (radioimmunodetection). The method has been found to be safe and reliable for imaging of primary tumors and non-bone metastases, even differentiating between lung tumors of prostatic and pulmonary origin.     

Regression of prostatic cancer metastasis by high doses of diethylstilbestrol diphosphate

Diethylstilbestrol diphosphate (DES-P) has shown effective symptomatic relief in patients with metastatic carcinoma of the prostate. Although there is little known about its role in soft tissue metastasis, our experience in 3 patients with advanced carcinoma of the prostate infiltrating the trigone and ureterovesical junction revealed significant improvement of hydronephrosis. All patients failed to respond to conventional doses of stilbestrol. Diethylstilbestrol diphosphate is recommended in the treatment of advanced carcinoma of the prostate with soft tissue metastasis. It is safe and effective, and the tumor responses outweigh the side effects of the drug. The mechanism of action of this compound is discussed.     

Characterization of monoclonal antibodies raised against the prostatic cancer cell line PC-82

For production of monoclonal antibodies (McAbs), hybrid cells were prepared by fusion of spleen cells of BALB/c mice immunized with the human prostatic cancer cell line PC-82 and the P3-X6(3)Ag8.653 murine myeloma cell line. Supernatants of approximately 500 hybrid clones were screened for prostate specific antibodies using an ELISA on PC-82 cells. A selection of antibodies was further tested for their specificity on a large series of different tissues. A broad cross reactivity pattern was obtained. Most cross reactivity was with pancreatic tissue, kidney, and bowel. One antibody turned out to react with prostate stromal cells. Two McAbs (ER-Pr 1 and ER-Pr 2) reacted solely with prostatic epithelium. Monoclonal antibody affinity chromatography combined with SDS-PAGE showed that both antibodies were directed against a 35-kD protein. Immunoblotting revealed that this protein is identical to prostatic antigen (PA). The epitope detected by ER-Pr 1 and ER-Pr 2 was largely preserved after formalin-fixation of prostatic tissues which renders these antibodies very suitable for routine examination of tissue sections.     

Androgens during different modes of endocrine treatment of prostatic cancer

Summary Serum levels of testosterone (T), 17-hydroxyprogesterone (17OHP), 4-androstene-3,17-dione (A-4), dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS) and cortisol were measured before and after 6 months of treatment in prostatic cancer patients treated by orchidectomy (ORX) or with oral+parenteral estrogens (OE), single parenteral estrogens (PE; 160 or 320 mg polyestradiol phosphate i.m. every fourth week), estramustine phosphate (ECYT) or LHRH agonist without (LHRH) or with (LHRH-F) flutamide. Castration values of T and 170HP were reached in all types of treatment (PE at the higher dose). A-4 levels were suppressed by all treatment regimens except ECYT; DHA by OE and LHRH-F and DHAS by ORX, OE and LHRH-F. The most pronounced suppression was found in the LHRH-F group. Cortisol levels were markedly increased by OE and ECYT. The observed effects on the adrenal androgens A4, DHA and DHAS and on cortisol probably reflect different degrees of liver interaction rather than interaction with adrenocortical steroid synthesis.Part of this paper was presented at the 6th Congress of the European Society for Urological Oncology and Endocrinology, May 2–4, 1988, Innsbruck, Austria     

Prognostic significance of prostate specific antigen in endocrine treatment for prostatic cancer.

The prognostic value of prostate specific antigen was evaluated to predict disease progression after endocrine therapy in patients with prostatic cancer. A total of 73 patients was studied (6 with stage B2, 16 with stage C, 9 with stage D1 and 42 with stage D2 disease). Endocrine therapy included bilateral orchiectomy, diethylstilbestrol diphosphate and luteinizing hormone-releasing hormone analogue. Pre-treatment serum prostate specific antigen levels were determined in all patients with an enzyme immunoassay kit. During a followup of 4 to 68 months (average 24 months) clinical disease progression occurred in 24 of the 73 patients. The pre-treatment prostate specific antigen level by itself did not predict disease progression. Changes in prostate specific antigen level with treatment were correlated with the interval to disease progression in the 44 patients who had prostate specific antigen determinations at regular intervals after endocrine therapy and whose initial level was greater than 10 ng./ml. Patients who had a decrease in the prostate specific antigen levels of 80% or more within 1 month after the beginning of therapy survived significantly longer free of disease progression (p less than 0.001). Patients whose prostate specific antigen level remained elevated for more than 3 months had a high risk of disease progression within 2 years. Our study suggests that patients with the more favorable prognosis can be identified early, after 1 to 3 months of endocrine therapy, by the rapid decrease in the prostate specific antigen levels.     

Paraplegia and paraparesis due to prostatic cancer. Use of intravenous diethylstilbestrol diphosphate

Diethylstilbestrol diphosphate (Stilphostrol) administered intravenously is a safe, effective drug in the treatment of prostatic carcinoma. Its dramatic effectiveness in the amelioration of paraparesis and paraplegia from epidural metastases has been demonstrated in 62 per cent of patients receiving the drug in addition to laminectomy and/or hormonal manipulation. Diethylstilbestrol diphosphate was also effective in relieving bone pain associated with metastases in 93 per cent of patients. A unique combined chemo- and radiotherapeutic aspect of diethylstilbestrol diphosphate-P³² is suggested.     

Serum prostate specific antigen levels during hyperthermia treatment of benign prostatic hyperplasia.

To understand better the tissue and cell changes occurring in the human prostate as a reaction to heat, we used circulating prostate specific antigen as a marker to detect cell injury. The prostate in 18 patients with benign prostatic hyperplasia was heated to 42 +/- 1.5C with local microwaves at 915 MHz. Each treatment sessions lasted 1 hour and the patients underwent 5 treatment sessions. A total of 90 treatment sessions was performed among 18 patients. No significant difference was observed between pre-treatment and post-treatment serum prostate specific antigen levels. We conclude that local hyperthermia is an atraumatic treatment modality that does not exert its effect on the hyperplastic prostate via a cytotoxic insult to prostate epithelial tissues.     

Clinical evaluation of serum prostatic specific antigen in prostatic cancer: simultaneous assays of prostatic specific antigen, gamma-seminoprotein and prostatic acid phosphatase in 113 newly diagnosed patients with prostatic cancer

Serum prostatic specific antigen (PA), gamma-seminoprotein (gamma-Sm) and prostatic acid phosphatase (PAP) levels were measured in 113 untreated patients with prostatic cancer and in 137 patients with benign prostatic hypertrophy (BPH). We used a PA-TESTWAKO enzyme immunoassay kit, gamma-Sm enzyme immunoassay kit and PAP radioimmunoassay kit. Of the 113 patients, 81.4%, 73.5% and 69%, respectively, were detectable using a single assay. PA was more sensitive than the other two markers in all stages, especially in localized disease (stages A, B and C). Using the BPH group as a negative control, specificities of PA, gamma-Sm and PAP were 85.4%, 81.0% and 94.2%, respectively. Efficiency was, respectively, 81.2%, 79.6% and 82.8%. In the follow up period, 15 patients presented disease progression. At the time of clinical detectable progression, the sensitivities of PA and gamma-Sm were both 100% (15/15), while 67% (10/15) for PAP. Concerning the sensitivity within 6 months prior to progression, gamma-Sm and PA tended to be more sensitive than PAP in early detection of disease progression. This study shows that PA is more reliable than gamma-Sm and PAP in detecting and staging of prostatic cancer. gamma-Sm and PA appear to be more reliable in earlier prediction of disease progression.     

Endocrine treatment of prostatic cancer

Data are drawn from the pertinent literature supporting diethylstilbestrol for initial endocrine treatment of advanced prostatic cancer. When diethylstilbestrol is given in a dosage of 2 mg daily, the risk of cardiovascular complications is low. Bilateral orchiectomy is reserved for high-risk patients or those intolerant of estrogen. To prevent possible complications of uncontrolled tumor growth and perhaps to increase survival time, endocrine treatment of advanced prostatic cancer should be started early.     

Comparison of flutamide (SCH-13521) and diethylstilbestrol in untreated advanced prostatic cancer

A double-blind study comparing the efficacy of flutamide (SCH-13521) and diethylstilbestrol in 15 patients with advanced, previously untreated adenocarcinoma in the prostate is herein presented. Patients receiving diethylstilbestrol, I mg. daily, remained stable without evidence of progression of their disease for an average of 25.6 weeks while those receiving either high- or low-dose flutamide showed no objective progression for an average of thirty weeks. There were no complete remissions, and no significant side effects were seen with either of these agents. In this small series of hormonally untreated Stage D prostatic cancer patients, neither agent displayed significant superiority.     

Low-dose diethylstilbestrol for the treatment of advanced prostate cancer

ObjectivesThe purpose of this study was to assess the efficacy and safety of low-dose (1 mg) daily diethylstilbestrol (DES) for the treatment of castrate-resistant prostate cancer (CRPC).Materials and methodsA retrospective chart review was performed on patients treated with low-dose DES who had CRPC despite anti-androgen withdrawal. The study population consists of 63 patients treated in the pre- and post-chemotherapy settings based on a database review; 58 had sufficient data for efficacy, all were analyzed for safety.ResultsA PSA decrease of ≥50% was observed in 19 of 49 pre-chemotherapy patients (39%) with a median time to progression (TTP) of 30 weeks (95% CI, 21.9, 68.7). A PSA decrease of <50% was seen in another 16 patients (33%) with a median TTP of 16.4 weeks (95% CI, 13.0, 37.6). Fourteen patients (29%) had progressive disease by PSA testing; their median TTP was 6.9 weeks (95% CI, 5.6, 12.9). Thromboembolic events included 2 patients with DVTs and 1 patient who developed primary fibrinolysis syndrome. Additional adverse events included gynecomastia in 37 of 63 patients (59%). Secondary observations included PSA responses in 3 of 9 patients treated with DES after chemotherapy progression and a high rate of PSA responses in patients re-treated with DES after a drug holiday.ConclusionsLow-dose DES is safe and effective in a modern cohort of men with CRPC despite anti-androgen treatment. Its potential role in the post-chemotherapy setting and the suggestion of efficacy on re-challenge merits additional consideration.     

An evaluation of prostate specific antigen in prostatic cancer

Prostate specific antigen levels were measured in 118 patients with prostatic cancer and 138 control individuals. Prostate specific antigen was sensitive in detecting prostatic cancer. The levels of prostate specific antigen were elevated in 10 per cent of the patients with stage A, 24 per cent with stage B, 53 per cent with stage C and 92 per cent with stage D disease. However, prostate specific antigen levels also were elevated in 9 per cent of the patients with benign prostatic hypertrophy. This lack of specificity in the presence of benign prostatic hypertrophy probably precludes prostate specific antigen from being recommended as a screening test for prostatic cancer. The ultimate role of prostate specific antigen might be as the marker of choice to monitor therapy for prostatic carcinoma.     

General treatment of metastatic prostatic cancer

Most of advanced prostatic carcinoma are hormono-sensitive. The use of combined androgen blockade (CAB) appears to improve survival and quality of life but only with the use of chemical castration by LH-RH analogue and non steroidal antiandrogen. After CAB, further hormonal maneuvers remain efficacious as in a first time antiandrogen withdrawal before estrogens, aromatase inhibitors and after hormone resistance, chemotherapy. In bone lesions, bisphosphonates and strontium 89 produce pain relief. The use of new methods for evaluation for response and quality of life will allow the rapid identification of effective treatments and powered phase III trials.