The phase IV studies with Estracyt in prostatic cancer--supplementary report: results of long-term therapy]

Two hundred patients with prostatic cancer were enrolled in our previous study between 1984 and 1987. In this study, 96 patients of them were observed for 1 year or more after oral administration of Estracyt (estramustine sodium phosphate). Of these 96 cases, 33 patients were treated with Estracyt as primary treatment and 63 patient had been treated with other treatments before Estracyt treatment. Twelve patients were treated only with Estracyt and 84 patients also received other treatments. Thirty-eight patients were on primary therapy, 37 patients were on maintenance therapy, and 11 patients were on primary therapy, 37 patients were on maintenance therapy, and 11 patients were on the re-activated stage therapy and 10 patients were others. In conclusion, among the 67 cases in which the due judgement of the effect was possible, Estracyt was markedly effective in 10 cases (14.9%), effective in 16 cases (23.9%), slightly effective in 15 cases (22.4%) and ineffective in 26 cases (38.8%). The survival rate was 92.6% at the first year, 66.0% at the third year and 46.3% at the fifth year in the follow-up study. Adverse reactions were observed in 22 cases (22.9%), among which the administration was discontinued in 3 cases.     

The phase IV studies with Estracyt in prostatic cancer

Both anticancer and adverse reactions of Estracyt were investigated by oral administration to 200 patients with prostatic cancer. Two capsules of Estracyt were given twice a day and the administration was principally continued for more than six months. The 200 patients consisted of 68 and 132 patients who were previously untreated and treated, respectively. Thirty seven cases had been treated only with Estracyt and 132 cases also received other treatments. Seventy-five cases were of primary therapy, 71 cases were of maintenance therapy, and 27 cases were of the re-activated stage therapy and 27 cases were of other categories. In conclusion, among the 190 cases for which the due judgement of the effect was possible, Estracyt was markedly effective in 40 cases (21.1%), effective in 43 cases (22.6%), slightly effective in 38 cases (20.0%) and ineffective in 69 cases (36.3%). Adverse reactions were observed in 67 cases (33.5%), among which the administration was discontinued in 18 cases.     

Treatment of advanced prostatic carcinoma with estramustine phosphate (Estracyt).

Estramustine phosphate (Estracyt) was used in the treatment of 154 patients with carcinoma of the prostate in stage IV. Sixty-three patients were given Estracyt from the outset (primary treatment group) and 91 had previously received some other endocrine therapy (secondary treatment group). All of the patients were observed for more than one year. The drug was given intravenously and/or orally. Objective remissions occurred in 46 (73.0%) of the 63 patients in the primary treatment group and subjective remissions in all the objective responders and in 12 additional patients (92.0%). The corresponding figures for the secondary treatment group were 28 (30.7%) and 52 (57.1%) of 91. The side-effects were negligible, and the drug was well tolerated. No cumulative toxic effect was observed in patients who had been receiving the treatment for more than five years. In our opinion the compound is valuable in the treatment of advanced prostatic carcinoma (stage IV).     

Clinical effects of estramustine phosphate disodium (Estracyt) on prostatic cancer

Estramustine phosphate disodium (Estracyt) was used in the treatment of 40 patients with prostatic carcinoma. Of these 20 patients 18 were treated with Estracyt as primary treatment and 22 had been treated with diethyl stilbestrol dephosphate and/or bilateral orchiectomy for more than 4 months before the Estracyt treatment. The drug was given orally in a dose of 560 mg/day in 2 divided oral doses. The clinical evaluation was done after 3 months treatment. The response in subjective symptoms and objective signs were documented and evaluated according to 5 criteria. In this study, Estracyt showed 80% improvement of dysuria, 60% of nykturia, 35% of pain and 55% of general condition. In objective signs, it showed 52.5% improvement of size of the prostate, 42.5% of consistency and 70% of residual urine. It would be emphasized that Estracyt had almost equal efficacy in both the primary treatment group and secondary treatment group. As side effects of this drug, gynecomastia, gastro-intestinal disturbance, angina pectoris like chest pain were observed.     

Treatment of prostatic cancer with estracyt® (estramustine phosphate)

The experience gained with Estracyt, kindly supplied by AB LEO, Sweden, is reported. On the basis of former data in the literature we only used the drug in estrogen resistant and advanced cases. Estracyt (estramustine phosphate) is a nitrogen mustard derivative of the urethan type, attached to oestradiol-17-phosphate. In histologically verified cases, it was administered in daily doses of 300 mg intravenously for three weeks, follwed by maintenance doses of 300 mg a week in tablets for three months. During treatment, liver and bone marrow function was checked systematically. The changes in morphological picture were studied by means of biopsies during and at the end of treatment. In agreement with the data in the literature a favourable effect was observed in estrogen resistant patients, with no toxic effect whatever on the bone marrow. At the same time GOT and GPT and BSP retention examinations demonstratee a hepatotoxic side effect. The pathological values returned to normal after withdrawal of the drug. Histological examinations showed that the tumour cells had changed but failed to disappear after treatment.     

Role of gamma-seminoprotein (gamma-SM) and prostatic acid phosphatase (PAP) as tumor markers of prostatic cancer

Between June, 1986 and December, 1987, the serum gamma-Sm and PAP was measured in 29 men with untreated prostatic cancer, 45 with treated prostatic cancer (32 were well-controlled and 13 poorly controlled), 82 with benign prostatic hypertrophy and 10 with other urological diseases. All of the patients with prostatic cancer had histologically proven disease. Enzyme immunoassay for gamma-Sm and radioimmunoassay for PAP were used. The cut-off value for gamma-Sm was 4 ng/ml and that for PAP was 3 ng/ml. The mean values of gamma-Sm and PAP were statistically high in the untreated group and also in poorly-controlled group. In the untreated group, the rate of positivity for gamma-Sm and for PAP were 69% respectively and 83% of the patients had elevated values for either or both of these markers. In clinical stage A and B, gamma-Sm and PAP values were within the normal limit, however the concentrations of mean gamma-Sm and PAP correlated well with the stage of disease. In the poorly-controlled group, positive gamma-Sm values were detected in 75% and PAP in 67%, whereas almost all of the patients had normal values for these markers in the well-controlled group. In prostatic hypertrophy, elevated gamma-Sm values were detected in 15% and elevated PAP values in 6%. After the onset of treatment, elevated values were normalized in 66.7% of the patients for gamma-Sm and in 68.4% for PAP. In the untreated group, gamma-Sm tended to show a more prompt response. In the ill-controlled group, gamma-Sm and PAP returned to normal in 50% of the patients. gamma-Sm and PAP values were well correlated with the course of the prostatic cancer and the clinical usefulness became more obvious with a combination of these markers.     

Prostatic acid phosphatase and prostatic specific antigen measured by immunoenzyme assay

Prostatic acid phosphatase (PAP) and prostatic specific antigen (PA) were determined with a Cetus test kit (California, USA) for prostatic cancer and others. Abnormal values of PAP in untreated prostatic cancer were found in 0, 0, 50, 50, 0, 73% of stage A1, A2, CpN0, CNX, D1 and D2 cases, respectively, and those of PA were found in 25, 0, 50, 100, 100, 100% of the same stages, respectively. Grade was not related to the level of PAP or PA. Prostatic hypertrophy showed increased values of PAP and PA in 11.1% and 7.4%, respectively. The levels of PAP were not correlated to those of PA. Endocrine treatment decreased the elevated values of PAP and PA in 60% of the cases. Most of the PAP and PA levels in the cases controlled under endocrine therapy were within normal values, but after relapse most showed elevated levels.     

Immunohistochemical prostatic acid phosphatase level as a prognostic factor of prostatic carcinoma

To determine whether prostatic acid phosphatase (PAP) immunoreactivity in prostatic adenocarcinoma is a reliable prognostic factor, the PAP immunohistochemical distribution has been examined in 78 prostatic carcinoma cases. The intensity of PAP immunostaining was graded from 0 to 2, and the scores of the primary and the secondary staining patterns were added to assess the extent of the PAP expression in needle biopsy specimens. As a result, a higher cancer-specific survival rate was observed in patients showing a greater PAP immunostaining (P less than 0.01). Further, a multivariate analysis was made of possible prognostic factors (age, stage, Gleason score, serum PAP, PAP-immunostaining score, and the initial treatment) to estimate the extent of their impact on cancer-specific survival. Results have confirmed that the difference in PAP immunoreactivity is an excellent, independent prognostic factor for prostatic carcinoma.     

The evaluation of the effect of Estracyt on prostatic cancer

The clinical effect of Estracyt on untreated prostatic carcinoma was evaluated. The subjects consisted of 51 of 71 patients with prostatic carcinoma who were observed for 6 months or more after oral administration of 560 mg of estramustine phosphate. This drug was effective in all patients: markedly effective in 34 (66.6%), moderately effective in 13 (25.5%), and slightly effective in 4 (7.8%). During the observation period varying from 6 months to 2 years and 6 months, 7 patients had recurrence of progression. The interval between the drug administration and recurrence of progression varied from 6 months to 1 year and 10 months (mean, 15.8 months). Prostate acid phosphatase and gamma-seminoprotein remained normal between 3 and 15 months after the administration but became elevated due to recurrence of progression after 18 months or more in some patients. Blood testosterone, luteinizing hormone, and follicle stimulating hormone decreased while blood cortisol increased. Therefore, estrogen was acting effectively. Side effects were observed in 56.9% of the patients, the most frequent being mazoplasia in 33 patients (45.8%), and cardiovascular complications and apoplexy in 11 patients (15.3%). Estracyt was effective for untreated prostatic carcinoma but the problems such as recurrence of progression and side effects require further examination.     

Chemoendocrine therapy of newly diagnosed advanced prostatic cancer

From November 1981 to November 1987, 35 patients with newly diagnosed advanced prostatic cancer (6 Stage C cases and 29 Stage D2 cases) were treated by chemoendocrine therapy consisting of orchiectomy, diethylstilbestrol-diphosphate and cisplatin. Objective responses were assessed at 3 months after the start of treatment. Of the 35 patients, 8 had PR (partial response) and 27 was objective stable by NPCP criteria. Objective progression was not seen. In analysis of long-term results, the 3-year and 5-year survival rate for total cases were 75.8% and 60.7%, respectively. For Stage C cases, the 3-year and 5-year survival rates were 100% and 100%; for Stage D2 cases, they were 72.2% and 54.2%, respectively. Relapse was seen in 7 (24.1%) of the 29 Stage D2 cases. All of these 7 patients had poorly differentiated adenocarcinoma and most of them had more than 10 bone metastases. As for side-effects, gastroenteric symptoms (nausea and vomiting), anemia and slight liver dysfunction were seen. These results suggest that the chemoendocrine therapy is an effective treatment in newly diagnosed cases of advanced prostatic cancer.     

Clinical study of estramustine phosphate (Estracyt) on prostatic cancer

Clinical effect of Estracyt was investigated in prostatic cancer patients. Twenty seven patients had been previously treated and 20 had not received prior treatment. Improvement rate of subjective symptoms was 85% in the previously untreated patients and that of objective findings was 85%, while those rates were 44% and 50% in the previously treated patients, respectively. Most of the adverse reactions were changes in mamma and mammary papilla which were considered to be due to the estrogenic activity.     

Treatment of prostatic cancer: the EORTC experience--preliminary results of prostatic carcinoma trials

Six prospective studies in the field of prostatic carcinoma have been carried out to date by the EORTC Urological Group. In three phase II studies, adriamycin, procarbazine, vindesine, and mitomycin C have been studied. Two of the three protocols have been completed. In three phase III studies, 3 mg of diethylstilbestrol (DES) is compared to cyproterone acetate (CPA), medroxyprogesterone acetate (MPA), and Estramustin phosphate (Estracyt). These two protocols have been closed to entry. The current protocol compares DES, 1 mg, to castration and to cyproterone acetate plus castration. From the phase II studies, no drug has emerged that is recommended for treatment of hormone-resistant prostatic cancer. The endocrine protocols, designed for the primary treatment of T3, T4, and M1 carcinoma of the prostate, have resulted in several important observations. Responses to DES, 3 mg/day, and to Estracyt were very similar and amounted to 25-30%. There was somewhat less objective response in the CPA and significantly less (P = 0.005) in the MPA group. It has become evident that DES at a dosage of 3 mg/day carries a significantly higher risk of overall cardiovascular toxicity than does cyproterone acetate, but severe cardiovascular complications did not differ between treatment groups. Up to now, no differences in survival were observed within the different treatment groups. Grade, local tumor extension, and performance were found to have a significant impact on survival.     

Clinical efficacy of leuprolide acetate and combined treatment with estramustine for advanced prostate cancer]

BACKGROUND, PURPOSE: Twenty-two institutes have organized Keio University Prostate Cancer Study Group to study clinical efficacy and safety of Leuprolide acetate (Leuplin) for the treatment of advanced prostate cancer (clinical stage D1 and D2). Cotreatment of Leuplin and Estramustine phosphate disodium (Estracyt) has been performed to investigate its clinical efficacy. MATERIALS AND METHODS: One hundred and two cases of advanced prostate cancer were treated either with Leuplin alone (group I), Leuplin and Estracyt (group II) or Estracyt alone (group III). After 12 weeks treatment, clinical effects against subjective symptoms (pain, voiding difficulty, performance status and body weight), serum testosterone level, tumor size and serum PSA level were examined to investigate short-term effect of each treatment. The treatment had been continued for 24 months and the treatment effects including progression free survival and overall survival were analyzed. RESULTS: Clinical efficacy after 12 weeks treatment were examined among 97 cases (group I; 35 cases, group II; 36 cases, group III; 26 cases). The background of those patients in each group was statistically equal. Treatment effects against subjective symptoms and serum testosterone level statistically revealed no significant difference among 3 groups. Treatment effects against primary tumor, bone metastatic lesion, lymphnode metastatic lesion and serum PSA level were investigated and anti-tumor effect was characterized by total efficacy rate (complete remission rate plus partial remission rate) of each treatment group. Treatment efficacy rates for each lesion and PSA demonstrated no statistical difference among 3 treatment groups. Total efficacy rate of group I, II and III were 88.2%, 84.0% and 78.3%, respectively, which statistically revealed no significant difference. Total efficacy rate of each group after completing 24 months treatment was; group I 80.0%, group II 55.6% and group III 83.3%, which statistically showed no significant difference among 3 treatment groups. The median day for progression free survival of group I, II and III were 661, 731 and 517, respectively. The overall survival rate of group I, II and III after completing 24 months treatment were 77.5%, 83.0% and 72.4%, respectively. Both progression free survival rates and overall survival rates revealed no significant difference among 3 groups. Side effects during 24 months treatment were seen in 8.6% of group I, 47.2% of group II and 26.9% of group III, and these occurrence rates were significantly different among the groups (p = 0.0013). CONCLUSION: Although number of the cases had not been able to continue the treatment for their side effects, the statistical characterization demonstrated that cotreatment of Leuplin and Estracyt had no greater treatment effect than monotreatment of each drug.     

Serum half life of prostatic acid phosphatase

Summary Traumatic manipulation of the prostate can cause elevated prostatic acid phosphatase (PAP) values. To avoid falsely elevated PAP values after prostatic trauma we studied the serum half life of PAP and the time taken to return to preoperative levels in patients undergoing transurethral resection (TUR-P). Although we observed a broad variation in peak PAP values the half life of PAP is fairly constant at about 1.1–2.6 h. Preoperative values were reached within 30 h. We conclude that PAP determinations can safely be carried out 30 h after prostatic trauma without any risk of falsely elevated PAP values.     

Simultaneous determination of six tumor markers in patients with prostatic carcinoma and bladder tumors

Summary Serum levels of fucosyltransferase (FT), phosphohexoseisomerase (PHI), tissue polypeptide antigen (TPA), Tennessee antigen (TAG), carcinoembryonic antigen (CEA) and prostatic acid phosphate (PAP) were determined in 75 healthy individuals and in 86 patients with prostatic carcinoma and 38 patients with bladder tumors. The discrimination capacities of the different markers were compared by using inverse distribution plots. At a rate of 5% false positive values the sensitivities for bladder tumors were: FT 30%, TPA 24%, CEA 16%, TAG 15%. The sensitivities for prostatic carcinoma were: PAP 63%, PHI 36%, TPA 18%, CEA 14%, TAG 14%.     

Changes in tissue prostatic acidic phosphatase during endocrine treatment of patients with prostatic carcinoma

OBJECTIVE: We have previously developed methods for the quantification of different macromolecules in aspiration biopsy material and described the changes in prostate-specific antigen (T-PSA) during cancer treatment. We have now studied the changes in tissue prostatic acidic phosphatase (T-PAP) in 58 endocrine-treated patients with prostatic carcinoma and compared these data with cancer development data and tissue PSA (T-PSA) levels. MATERIAL AND METHODS: PAP and PSA were quantified in aspiration biopsies taken before treatment and after 6 and 12 months of treatment. Patients were followed until death or for >98 months. RESULTS: Pretreatment T-PSA was more strongly associated with survival than T-PAP. Both T-PSA and T-PAP decreased in responders during treatment. In non-responders, T-PSA and T-PAP increased after 12 months in 17/18 and 7/13 patients, respectively. Estrogen-treated responders had significantly higher T-PSA, but not T-PAP, treatment values than those treated with orchidectomy or gonadotropin-releasing hormone. CONCLUSIONS: The inferiority of serum PAP compared to PSA for monitoring cancer treatment may reflect its less pronounced changes at the tissue level, indicating different in vivo regulation of the two markers. Estrogen stimulation of PSA synthesis in vivo may underlie the higher PSA levels observed during estrogen treatment.     

Comparison of prostate secretory protein with prostate specific antigen and prostatic acid phosphatase as a serum biomarker for diagnosis and monitoring patients with prostate carcinoma

Serum prostate secretory protein (PSP) levels were measured in 49 patients with benign prostatic hyperplasia (BPH), 144 patients with various stages of prostatic carcinoma (CaP), and 82 CaP patients who were followed serially. PSP values were compared with serum levels of prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). In the BPH group, PSP was elevated (> 10 ng/ml) in 41% of patients, whereas PSA (> 4 ng/ml) and PAP (> 3.3 ng/ml) were elevated in 39% and 23% of the cases, respectively. PSP levels were elevated in 48% of the CaP pretreatment specimens, compared to 79% for PSA and 40% for PAP. PSP levels in cancer patients who had intracapsular disease were about two to three times higher than those observed for PAP. PSP was found to be the only marker elevated in eight (6%) pretreatment CaP patient serum specimens, while PAP was never found to be elevated when PSA was normal. PSP serum concentrations correlated with the clinical course of the disease in 79% of patients, compared with 90% for PSA and 66% for PAP. In certain patients, monitored over time, disease correlation was reflected in serum values with only a single biomarker, i.e., 1% with PAP, 8% with PSP, and 10% with PSA. This study has shown that PSP is a less sensitive serum biomarker than PSA, but more sensitive than PAP for detection and monitoring the early stages of prostate cancer. This suggests that PSP as a biomarker may be a useful adjunct for the management of a subpopulation of low-stage and -grade CaP. © 1993 Wilcy-Liss, Inc.     

Electrocardiographic left ventricular hypertrophy in renal transplant recipients: prognostic value and impact of blood pressure and anemia

Left ventricular hypertrophy (LVH) is an independent risk factor for death and cardiovascular disease in the general population and dialysis patients. However, the causes and consequences of LVH have not been well described in renal transplant recipients (RTR). A retrolective cohort study was conducted in 473 RTR who were alive and free of cardiac disease at 1 yr. LVH was defined using the Cornell electrocardiographic (EKG) criteria. A total of 416 patients had an interpretable first-year EKG (88%), and 284 had an interpretable fifth-year EKG (78% of 5-yr survivors). Baseline characteristics were similar in patients with and without EKG. Of 416 patients, 57 had LVH in the first year, whereas 38 of 284 patients had LVH in the fifth year, of which 18 cases were de novo. Baseline LVH was a risk factor for death (RR 1.9 [1.22, 3.22]) and congestive heart failure (CHF) (RR 2.27 [1.08, 4.81]) and was independent of other major prognostic variables. Persistent or de novo LVH in the fifth year predicted subsequent death (RR 2.15 [1.14,4.01]) and CHF (2.71 [1.17, 6.30]). Anemia and diastolic BP were independent risk factors for increasing Cornell voltage (a marker of LV mass) between first and fifth years. Systolic BP was the only predictor of de novo LVH at 5 yr. It seems that EKG LVH is a significant risk factor for death and CHF in RTR and that anemia and hypertension are risk factors for LV growth. Whether aggressive treatment of hypertension and anemia can improve outcomes merits further study.     

Evaluation of a monoclonal antibody-based enzyme immunoassay (IQ(Bio) PAP-AELIA kit) for prostatic acid phosphatase

The clinical application of enzyme immunoassay (EIA) for prostatic acid phosphatase (PAP) is reported. PAP concentration was measured by an IQ(Bio)PAP-AELIA kit. Serum samples were collected from 20 healthy individuals, 31 patients with benign prostatic hypertrophy, 14 patients with prostatis, 23 patients (47 samples) with prostatic cancer and 29 patients with various other malignancies. The coefficients of variation (%CV) in intraassay and interassay ranged from 2.3 to 4.4%, and from 3.0 to 3.6%, respectively. The recovery rate in the dilution test and recovery test were 106.2 +/- 8.9% and 101.3 +/- 6.9% respectively. A significant correlation (r = 0.994, p less than 0.01) was observed between EIA and RIA methods in the prostatic cancer patients. PAP concentration was elevated above 2.0 ng/ml in 0/2 (0%) of the treated patients with stage B prostatic cancer, 1/5 (20%) of those with stage C, 6/16 (38%) of those with stage D, and in 4/5 (80%) of the untreated patients with stage D prostatic cancer. False positive results were seen in 2/31 (6%) of the patients with benign prostatic hypertrophy, 3/14 (21%) with prostatis and 3/29 (10%) of the patients with various other malignancies. In the majority of the false positive cases, elevated levels were only just above the normal value. In conclusion, the PAP level measured by this EIA kit was correlated with the clinical response to hormone therapy for prostatic cancer.     

Investigation on serum neurone-specific enolase in prostate cancer diagnosis and monitoring: comparative study of a multiple tumor marker assay.

A quadruple tumor marker serotest assay (neurone-specific enolase, NSE, prostate-specific antigen, PSA, prostatic acid phosphatase, PAP, and carcino-embryonic antigen, CEA) was performed on sera from both 63 patients with untreated prostate cancer and 135 patients treated with orchiectomy, flutamide, diethylstilbestrol (DES), cyproterone acetate (CPA), and Estracyt. In untreated patients with local tumor elevated blood NSE concentrations were found more frequently (10/35, 28.6%) than in untreated subjects with disseminated disease (3/28, 10.7%). Elevated NSE values were measured more frequently in nonresponders to therapy 10/46 (21.7%), than in responders during prostate cancer partial remission (2/89, 2.2%). In none of NSE-positive neoplasms a small cell prostate cancer has been histologically detected. Many of NSE-positive tumors are also closely associated with elevated blood CEA values. The applied anticancer drugs were inefficient in the normalization of neither one from the pair of elevated NSE and CEA concentrations (regardless of the numerical values of the other two markers, PSA and PAP), but their values were found to decline occasionally only after surgical treatment. In patients with raised PSA, PAP, and CEA levels but with a normal NSE value, the application of the same treatment strategies was in the most of subjects sufficient to provoke either temporary or even lasting tumor response to therapy. Hence, it appears that the assessment of the NSE serotest, despite its minimal value in the overall tumor staging and monitoring, might furnish the decision-making step related to the treatment of aggressive prostate cancer with an additional and powerful tool.