Side effects of endocrine treatment and their mechanisms: castration, antiandrogens, and estrogens.

Endocrine treatment of prostate cancer can be performed under several different regimes. They all have side effects which in different ways influence quality of life and the patient's general health. This paper is a survey of the most important early side effects of the different modes of endocrine treatment, their etiology, and possible ways to avoid or treat them.

[Treatment of advanced prostatic cancer]. / Behandling av avancerad prostatacancer.

In advanced prostate cancer when the tumor has metastasized, endocrine therapy is the primary treatment alternative. Endocrine therapy was introduced 60 years ago by Huggins and Hodges in the form of castration or estrogen treatment. Unfortunately we must now concede that no decisive breakthrough in the pharmacological treatment of prostate cancer has occurred since that time. We do have several different endocrine treatment alternatives at our disposal today--all with varying advantages and drawbacks. We do, however, eagerly await new therapeutic options for the pharmacological eradication of prostatic adenocarcinoma. Today our interest is focused on methods of tailoring endocrine therapy in ways that offer the individual patient an optimal combination of quality of life and anticancer efficacy. The various opinions and research results which inform current strategies of endocrine therapy are described briefly.

Parenteral estrogen versus total androgen ablation in the treatment of advanced prostate carcinoma: effects on overall survival and cardiovascular mortality. The Scandinavian Prostatic Cancer Group (SPCG)-5 Trial Study.

OBJECTIVES: To compare the effect on overall survival of total androgen ablation (TAA) with that of parenteral estrogen and to pay special attention to cardiovascular mortality. TAA (orchiectomy or a luteinizing hormone-releasing hormone analogue combined with an antiandrogen) has been proposed as superior to other endocrine treatments for patients with prostate carcinoma. Recently, the use of parenteral estrogen has been suggested to reduce or even negate the well-known cardiovascular side effects of oral estrogens. METHODS: Nine hundred fifteen patients were randomized to intramuscular injections of 240 mg polyestradiol phosphate (PEP) every second week for the first 8 weeks (5 doses) followed by a maintenance dose of 240 mg every month (n = 458) or to bilateral orchiectomy or triptorelin 3.75 mg every month combined with the antiandrogen flutamide 250 mg three times daily. The choice between orchiectomy and triptorelin was at the discretion of the clinician and patient. Patients were stratified according to performance status, presence of cardiovascular disease, and alkaline phosphatase level. An observer totally unaware of the treatment given classified all deceased patients. RESULTS: At a median follow-up of 18.5 months, no signs of a difference in overall survival were found between TAA and PEP (P <0.001). Of 458 patients, 266 (58.1%) had died in the PEP group compared with 269 (58.9%) of 457 patients in the TAA group. Within the TAA group, no difference in overall survival existed between patients who had undergone orchiectomy or who were given triptorelin. Furthermore, no differences in cardiovascular mortality were found (3.5% in the PEP group and 3.1% in the TAA group). CONCLUSIONS: The current parenteral estrogen regimen seems to be of comparable efficacy and cardiovascular safety as TAA in terms of overall survival. PEP has by far the lowest drug cost and also the lowest cumulative direct costs and thus has the highest cost-effectiveness. We suggest that parenteral estrogen be included as a therapeutic option in the endocrine management of prostate carcinoma.

Deferred treatment of locally advanced nonmetastatic prostate cancer: a long-term followup.

PURPOSE: We prospectively investigated long-term survival in select men with locally advanced, nonmetastatic prostate cancer managed with deferred treatment. MATERIALS AND METHODS: A total of 50 patients with prostate cancer clinically outside the prostatic capsule and without distant metastases were included in a surveillance protocol. The men were treated if and when symptoms occurred or upon request. The series was followed until December 1994. No patient was lost to followup. RESULTS: Median patient age at diagnosis was 71 years. All patients were followed more than 144 months or died before then. Actual (cumulative incidence) overall and disease specific survival rates at 5, 10 and 12 years were 68 and 90, 34 and 74, and 26 and 70%, respectively. A third of the patients had not received antitumor treatment at followup or before death. CONCLUSIONS: When managed with deferred treatment nonpoorly differentiated, locally advanced nonmetastatic prostate cancer seems to have a poorer survival outcome than similarly managed clinically localized prostate cancer. However, compared with other treatments and in terms of survival deferred treatment may be an option for select patients with such tumors and a life expectancy of 10 years or less.

The Scandinavian Prostatic Cancer Group. A short review of its history and work.

The Scandinavian Prostatic Cancer Group (SPCG) was founded in 1981 as one of eight collaborative groups instituted by the Scandinavian Association of Urology within different fields of urology. The purpose of these groups was to promote research, education and information provision within their different fields and to stimulate collaboration between the Nordic countries. The main purpose of the SPCG gradually evolved into conducting clinical trials. This paper presents a summary of the different clinical trials carried out by the group and reviews some of its history and other activities.

Deferred treatment of clinically localized low-grade prostate cancer: actual 10-year and projected 15-year follow-up of the Karolinska series.

OBJECTIVES: To review the outcome in patients with clinically localized prostate cancer managed conservatively. METHODS: A total of 122 patients with palpable, clinically localized, low-grade prostate cancer diagnosed from 1978 to 1982 at the Karolinska Hospital, Stockholm, Sweden, were prospectively followed in a surveillance protocol followed by treatment when the tumor progressed with symptoms. RESULTS: All patients but one had been observed for 10 years or more. No antitumoral therapy had been given to 58 (48%) patients at follow-up or before death. The chance of being untreated 5 and 10 years after diagnosis, if still alive, was 71% and 43%, respectively. The actual disease-specific survival rate at 10 years was 90%. Of the patients with a possible observation period of 15 years or more, 25% died of prostate cancer (ie, an actual disease-specific survival of 75%). Using a survival plot, the projected disease-specific survival rate at 15 years was 62%. The cumulative incidence of death from prostate cancer increased with possible observation time up to 15 years. CONCLUSIONS: Our data are mature up to 10 years of observation and, based on these data, deferred treatment is a valid option for patients with clinically localized low-grade prostate cancer with a life expectancy of 10 years or less. The data are not definitive beyond 10 years and firm conclusions will be speculative, but our findings indicate that there probably is room for efficacious local treatment in patients with localized prostate cancer and a life expectancy longer than 10 years.

Treatment of high-grade, high-stage prostate cancer with estramustine phosphate or diethylstilbestrol. A double-blind study. The SPCG-1 Study Group. Scandinavian Prostate Cancer Group.

Between 1984 and 1989, 197 patients with T1-4, NX, M1, G2-3 or G3 prostate cancer were randomized to treatment with 560 mg estramustine phosphate (EMP, Estracyt, Emcyt) or 3 mg diethylstilbestrol (DES) per day in a double blind study with stratification on presence or absence of cancer pain at start. A total of 194 patients were evaluated for efficacy of therapy. Time to progression (p = 0.054), to treatment failure (p = 0.036), cancer-specific survival (p = 0.068) as well as overall survival (p = 0.021) were longer in the DES group. There were more patients with prognostic parameters indicating bad prognosis in the EMP group. This trial was designed to study whether EMP had better effect than DES as the primary treatment of high-grade, disseminated prostate cancer. The results did not confirm this hypothesis. On the contrary, treatment with DES had relatively good effect on this very aggressive form of prostate cancer.

Evaluation and follow-up of patients with N1-3 M0 or NXM1 prostate cancer in phase III trials.

OBJECTIVES: The aim of this discussion is to review the design and conduct of phase III trials in metastatic prostate cancer, to seek ways of improving their study design, accuracy, relevance to clinical practice, acceptability to patients, and ease of participation by clinicians. We also aim to try to set uniform definitions for the evaluation of the different endpoints used in clinical trials on metastasized prostate cancer. METHODS: The work was started by correspondence between the participants in the group for the year before the consensus meeting. Two comprehensive questionnaires were circulated and the answers were distributed to all the members of the group. The statements were finalized during the consensus meeting. RESULTS: There were some differing opinions concerning the methods of evaluation of endpoints for follow-up, such as time to tumor progression and time to treatment failure. After the consensus conference, there were no major disagreements within the group. CONCLUSIONS: The aim of phase III trials is to influence clinical management. To obtain a credible result they require a sound statistical basis with appropriate power and encompassing patients from small urologic practices as well as large or academic institutions. However, deviation from routine practice may affect the accrual rate, and the trial procedure should therefore be as similar as possible to routine management. Trials inevitably involve extra work and cost. Both should be kept to a minimum to encourage participation and hasten a timely conclusion. It is mandatory to create uniform ways of designing and evaluating clinical trials in prostate cancer.

[Intramuscular depot estrogens (Estradurin) in treatment of patients with prostate carcinoma. Historical aspects, mechanism of action, results and current clinical status]. / Intramuskuläres Depotöstrogen (Estradurin) in der Behandlung von Patienten mit Prostatakarzinom. Historische Aspekte, Wirkungsmechanismus, Resultate und aktueller klinischer Stand.

More than 50 years ago, orally given estrogen was already used in the treatment of prostate cancer. Due to cardiovascular side-effects with a high morbidity of 25%, this treatment has not become standard. Recent investigations show that parenteral application reduces the risk of cardiovascular side-effects, because it avoids the first passage through the liver with high concentrations of estrogen which normally occur after oral application. Therefore, an increased synthesis of so-called "steroid-sensitive" liver proteins, such as coagulation factors (especially factor VII) can be avoided. This newer parenteral estrogen application shows encouraging results of a cheap and effective hormonal therapy with a low rate of side-effects in patients with prostate cancer.

Deferred treatment of clinically localized low grade prostate cancer: the experience from a prospective series at the Karolinska Hospital.

From 1978 to 1982, 172 patients with stages T1 to 3NxM0 prostate cancer were included in a surveillance protocol with deferred treatment on symptomatic progression. Median patient age at diagnosis was 68 years (range 38 to 89 years). Mean followup was 80 +/- 32 months. Of the patients 58% had local and 19% had distant progression, and 52% had received treatment at followup. Disease specific survival rate at 10 years was 80% for the total series, 84% for the subgroup with stage T1 or T2 tumor and 92% for those with stage T1 or T2 tumor who were less than 70 years old at diagnosis. For the subgroup with stage T3 tumor the disease specific survival rate at 9 years was 70%. In all subgroups the competing mortality rate was higher than the prostate cancer mortality rate. Deferred treatment appears to be an acceptable option for patients with tumor clinically confined to the prostate and a life expectancy of 10 years or less.

The TNM system of 1992. Comments from the TNM working group. Consensus Conference on Diagnosis and Prognostic Parameters in Localized Prostate Cancer. Stockholm, Sweden, May 12-13, 1993.

The TNM working group acknowledges the multinational agreement reached in the 1992 TNM classification, but nevertheless gives some suggestions for modifications. The main interest of the group has been to evaluate parameters suitable for further ramification of the system. The group found that parameters such as DNA ploidy, PSA, nuclear roundness factor, are not yet ready for this purpose. Grade is an established parameter and should be incorporated into the TNM-categories of localized disease. In metastatic disease a number of parameters are available to subdivide this category according to prognosis, and these will be more uniformly and extensively studied in the several large trials that are now in progress.

Squamous metaplasia in hormonally treated prostatic cancer. Significance during follow-up.

A prospective study of 59 hormonally treated prostatic cancer cases was undertaken during follow-up with sequential transrectal palpation and fine-needle aspiration. At initiation of therapy patients' ages ranged from forty-eight to eighty-two years (median, 68 years). The usual follow-up interval was 6 +/- 3 months, and follow-up periods ranged from six months to one hundred twenty months (median 48 months). The cytologic findings were categorized under four cytologic response types and palpation findings under five response grades. Four different degrees of squamous metaplasia (1+, 2+, 3+, 4+) were observed in smears, depending on semiquantitative determination of squamous metaplastic cells in relation to the total amount of benign and malignant epithelial cells in the smear. There were 341 follow-up observations in which both transrectal fine-needle aspiration cytology and palpation were done. In 306 of these, cytologic findings were found to be adequate. Comparison of squamous metaplasia with cytologic response types revealed a highly significant difference between the benign state and recurrence/frank malignancy. This was also true when frequency of squamous metaplasia was compared with palpatory response grades. It was found that squamous metaplasia can be a valuable adjunct to other cytomorphologic changes such as shrinkage of tumor cell size and decrease in size of nucleoli or its disappearance, in determining response to hormonal therapy.

DNA as a prognostic marker in advanced high-grade prostatic cancer. A preliminary report. SPCG-I study.

This is a presentation of some preliminary data from SPCG-I, a multicenter study started in 1984 by the Scandinavian Prostatic Cancer Group. It is a randomized double-blind study comparing estramustine phosphate and diethylstilbestrol in the primary treatment of 195 patients with T1-4, NX, M1, G2-3 prostatic cancer. The code is not yet broken. This presentation describes the impact of the pretreatment parameters performance status, pain, tumor burden, grade and DNA-ploidy of the prostate tumor, on time to progression and overall survival. DNA studies have so far only been completed in 66 of the 195 patients. For the whole group of 195 patients, pain (p less than 0.004) and tumor grade (p less than 0.02) had the most significant impact on time to progression, and performance status (p less than 0.01) and grade (p less than 0.03) on overall survival. In the small group of 66 patients where the DNA pattern of the primary tumor was evaluated, no parameter had any significant correlation to time to progression and overall survival. This study is still continuing.

The prognostic value of modal deoxyribonucleic acid in low grade, low stage untreated prostate cancer.

We selected for a prospective surveillance study 167 patients with untreated grades 1 and 2 prostate cancer. The tumors were classified regarding modal deoxyribonucleic acid value (ploidy) by flow cytometry, cytological grade by transrectal fine needle aspiration biopsy and local tumor stage. Of the patients 146 could be evaluated. Mean followup was 50 months. The initial ploidy was statistically correlated to cytological grade but not to initial local tumor stage, prostatic acid phosphatase activity or patient age. Initial ploidy and cytological grade had a prognostic value regarding local tumor progression when considered as single predictors and in combination. Two patients with diploid and 8 with nondiploid tumors initially had metastases during the surveillance. Five patients (1 with diploid and 4 with nondiploid disease) died of prostatic cancer. Modal deoxyribonucleic acid value and cytological grade were of prognostic value in untreated prostate cancer.