Somatostatin analogues in the treatment of breast and prostate cancer.

Newly developed somatostatin analogues may be useful agents in the treatment of breast and prostate cancer. Potential mechanisms of antitumor action include suppression of circulating levels of trophic hormones and growth factors as well as direct effects at the tumor level, potentially involving autocrine/paracrine mechanisms. Pilot clinical trials conducted in heavily pretreated women with advanced breast cancer indicate that SMS 201-995 (Sandostatin R) has minimal toxicity and moderately suppresses stimulated growth hormone secretion and basal somatomedin-C level. Somatostatin analogues have also been found to retard the growth of experimental prostate cancer, particularly when used in combination with LHRH analogues. The therapeutic efficacy of these compounds used alone or in combination with other agents in the treatment of breast and prostate cancer remains to be established in larger clinical trials involving less heavily pretreated patients.

Endocrine effects of combined somatostatin analog and bromocriptine therapy in women with advanced breast cancer.

In this pilot clinical trial conducted in 10 postmenopausal women with advanced breast cancer, we evaluated the endocrine effects and toxicity of combined somatostatin analog and dopaminergic therapy in the attempt to suppress both growth hormone (GH) and prolactin (PRL) secretion. The patients' mean age was 63 years (range: 54-77) and the average number of previous treatments was 4.8 +/- 2 (SD). All patients were treated with the somatostatin analog SMS 201-995 (100-200 micrograms s.c. in a.m. and h.s.) and bromocriptine (2.5 mg orally twice a day). During treatment, GH levels following provocative testing (either L-DOPA or insulin-induced hypoglycemia) were suppressed in 7/9 patients. Basal somatomedin-S (Sm-C) levels declined in 6/9 women. Both GH and Sm-C levels decreased in 4 patients, while in the remaining 5 only one of the two parameters was lowered on treatment. PRL secretion (during provocative TRH testing) was almost totally abolished in 8/9 patients. The treatment did not affect circulating levels of FSH, LH, E1, E2, E1-S, T4, T3RU, or cortisol. Seven patients experienced no side effects. Nausea occurred in 3, but was severe enough in only one to require discontinuation of therapy. One patient experienced disease stabilization consisting of less than 50% regression of skin nodules and pleural effusion, a decline in CEA titer, and an improved performance status lasting 7 months. We conclude that combined SMS 201-995 and bromocriptine therapy is safe and frequently suppresses GH and PRL secretion. Its role in the treatment of metastatic breast cancer should be tested in patients with less advanced disease.

Transdermal testosterone therapy in the treatment of male hypogonadism.

Five hypogonadal men were treated with transdermal testosterone therapy, using a testosterone patch applied to the scrotal skin. Daily application of the patch, which contained 10 mg testosterone, produced an increase in serum testosterone concentrations from a pretreatment value of 45 +/- 12 (+/- SE; 1.5 +/- 0.4) to 436 +/- 80 ng/dL (15.1 +/- 2.8 nmol/L; P less than 0.001) after 4 weeks of treatment. Normal serum testosterone concentrations were achieved in all men after 6-8 weeks of therapy and were maintained during continued long term therapy for 9-12 months with a patch containing 15 mg testosterone. All men reported a subjective increase in libido and sexual function during therapy, and three men preferred it to testosterone injections. The serum testosterone and estradiol levels did not rise above the normal adult male range at any time during therapy. However, elevated serum dihydrotestosterone (DHT) concentrations occurred during treatment; the pretreatment DHT concentration was 95 +/- 3 ng/dL (3.3 +/- 0.1 nmol/L), and it increased to 228 +/- 40 ng/dL (7.8 +/- 1.4 nmol/L) after 4 weeks of treatment and remained elevated thereafter. The individual mean DHT to testosterone ratio increased from a pretreatment value of 0.2 (range, 0.1-0.3) to 0.6 (range, 0.4-0.7) after 2 weeks of therapy and remained high thereafter. Comparison of the serum DHT levels in patients during therapy with those in normal men who had similar testosterone concentrations [531 +/- 62 vs. 566 +/- 72 ng/dL (18.4 +/- 2.1 vs. 19.6 +/- 2.5 nmol/L); P greater than 0.05] revealed that the mean serum DHT concentration was significantly higher in the patients [315 +/- 69 vs. 87 +/- 6 ng/dL (10.8 +/- 2.4 vs. 2.9 +/- 0.2 nmol/L); P less than 0.001], as was the mean DHT to testosterone ratio [0.6 (range, 0.25- 1.1) vs. 0.16 (range, 0.09- 0.24); P less than 0.001]. The high serum DHT levels presumably were due to increased metabolism of testosterone to DHT by the 5 alpha-reductase in the scrotal skin. Serum 3 alpha-androstanediol glucuronide levels were not elevated in the patients. We conclude that transdermal testosterone therapy is an effective long term treatment for hypogonadism in men. It is, however, associated with high serum DHT levels, whose potential long term effects on the prostate and other tissues need to be investigated.

Inhibition of aromatase as treatment of breast carcinoma in postmenopausal women.

Recent treatment strategies have been directed toward blockade of estrogen action or inhibition of estrogen biosynthesis as a means of inducing regression of hormone-dependent breast cancer. The major source of estrogen in postmenopausal women is the peripheral conversion of androstenedione to estrone through the enzyme aromatase. It is known that aromatase activity increases proportionately with degree of obesity in women. To test the importance of this modulatory factor, we correlated body weight with estrogen excretion in our population of patients with breast cancer and found significant relationships. In situ production of estradiol from plasma precursors within breast cancer tissue may provide another source of estrogen. Major enzymes mediating estrogen biosynthesis were found to be present in tumor biopsy specimens. Aromatase activity was found to be present in 48/61 human tumors, sulfatase in 35/35, and 17 beta -hydroxysteroid dehydrogenase in 41/41. One inhibitor of aromatase, aminoglutethimide, has been extensively studied in patients with breast cancer. The additional effects of this drug on cholesterol side-chain cleavage and on 11-hydroxylase activity require coadministration of replacement glucocorticoid in treatment regimens. In pilot trials, 37% of patients experienced objective tumor regression with a combination of 1000 mg aminoglutethimide and 40 mg hydrocortisone daily. In randomized clinical trials with this regimen, aromatase inhibition with aminoglutethimide produced tumor regression with similar frequency as did surgical hypophysectomy, surgical adrenalectomy, or tamoxifen administration. The side effects of aminoglutethimide, including lethargy, skin rash, and ataxia complicate its use even though these problems are generally transient. Regimens of low-dose aminoglutethimide are being developed to reduce these side effects. Low-dose aminoglutethimide appears to block aromatase effectively and to have limited side effects, and is undergoing extensive clinical trial. A more specific aromatase inhibitor, 4-hydroxyandrostenedione, is now also being tested clinically, whereas MDL 18962, another new selective inhibitor, is undergoing study in animals.

Androgen depletion and repletion as a means of potentiating the effect of cytotoxic chemotherapy in advanced prostate cancer.

Seventy-five patients with stage D-2 prostate cancer refractory to orchiectomy have been entered in a controlled trial to test whether androgen priming enhances the efficacy of chemotherapy. All patients are treated with aminoglutethimide and hydrocortisone as a means of achieving medical adrenalectomy and are given cyclic i.v. chemotherapy with cytoxan, adriamycin and 5-fluorouracil. Patients in the stimulation arm (N = 39) receive, in addition, fluoxymesterone (5 mg p.o. b.i.d.) for 3 days before and on the day of chemotherapy. A similar response rate was observed in the stimulation and control arm (83% vs 74% respectively) when the analysis was restricted to evaluable patients. When all patients were included, a significantly higher response rate was observed in the control arm (64% vs 49%, P less than 0.05) as a result of the larger fraction of unevaluable patients in the stimulation arm (41% vs 14%). Median duration of response is 9 months in the stimulation and 10 months in the control arm. Median overall survival in the stimulation and control group is 12 months and 16 months respectively. Significant toxicity consisting of exacerbation of bone pain and, in two patients, development of reversible spinal cord compression was observed following androgen priming. Our results suggest that combined medical adrenalectomy and chemotherapy are highly effective in the treatment of advanced prostate cancer. Thus far, no additional benefit has been observed with androgen priming.

Aminoglutethimide therapy in breast cancer: relationship of blood levels to drug-related side effects.

Aminoglutethimide (AG) is now an established agent for producing a 'medical adrenalectomy' in patients with breast cancer. A number of annoying symptoms can occur in some patients placed on this medication. It has been suggested that the expression of symptoms may be related to the ability of the patient to acetylate AG to N-acetyl aminoglutethimide (NAG). Using high-pressure liquid chromatography (HPLC), we examined blood levels of AG and NAG in patients with breast cancer and compared the levels to the expression and frequency of drug symptoms. 43% of patients examined were judged to be slow acetylators in that 92% of the drug remained unacetylated irrespective of the dose administered. There was no significant correlation between acetylator status (rapid vs. slow) and the frequency of drug symptoms noted. In contrast, there was a significant correlation between the level of AG itself and the frequency of symptoms. 80% of patients with blood levels exceeding 12 mg/l had drug-related symptoms while only 36% of patients with levels below 8 mg/l showed symptoms (chi 2 p less than 0.05). 67% of patients with NAG levels in excess of 4 mg/l had symptoms. These findings indicate the presence of slow and rapid acetylators of AG in a breast cancer population and the importance of determining blood levels of the drug to minimize the onset of drug-related symptoms in some patients without losing drug efficacy.

Androgen priming and response to chemotherapy in advanced prostatic cancer.

A total of 67 patients with progressive stage D2 prostatic cancer refractory to orchiectomy was entered in a controlled clinical trial to test whether androgen priming enhances the efficacy of cytotoxic drugs. All patients were treated continuously with aminoglutethimide and hydrocortisone to lower adrenal androgen secretion and were given cyclic intravenous chemotherapy. In addition, the 34 patients randomized to the stimulation arm received fluoxymesterone for 3 days before and on the day of chemotherapy. There was 33 controls. The median duration of followup was 24 months. A modestly higher response rate (objective remission plus disease stabilization) was observed in the stimulation arm (85 versus 72 per cent, p less than 0.05) when the analysis was restricted to the evaluable patients. However, a larger fraction of unevaluable patients was present in the stimulation group (41 versus 16 per cent), mostly as a result of toxicity from fluoxymesterone, which prompted early discontinuation of treatment. Thus, when data analysis included all patients the response rate actually was slightly higher in the control than in the stimulation arm (60 versus 50 per cent, p not significant). No difference was observed in median duration of response (9 months in both groups) or over-all survival. Our data suggest that at least in those patients with advanced disease androgen priming does not seem to enhance significantly the antitumor effect of the combination of amino-glutethimide and chemotherapy, and is associated with significant toxicity. These largely negative results may be explained by the large number of hormone-resistant cells present in tumors that have become refractory to orchiectomy.

Hormone stimulation and chemotherapy in advanced prostate cancer: interim analysis of an ongoing randomized trial.

We report here in the interim analysis of an ongoing randomized clinical trial designed to test whether androgen priming enhances tumor chemosensitivity in men with stage D prostate cancer refractory to orchiectomy. All patients are continuously treated with aminoglutethimide and hydrocortisone, to lower adrenal androgen secretion, and are given cyclic chemotherapy. Patients in the stimulation arm receive also the synthetic androgen, fluoxymesterone, for 3 days before and on the day of chemotherapy. Of 57 patients entered to date, 41 have received adequate treatment to be evaluable. Response to therapy (objective remissions + stabilizations of disease) occurred in 17 of 18 evaluable patients (94%) randomized to the stimulation arm, and in 16 of 23 evaluable patients (70%) in the control group (p less than 0.025). Duration of response was not significantly different in the two groups (median: 9 months in the stimulation and 12 months in the control arm). With 30% of the total of 57 patients still alive, survival is not significantly different in the stimulation (median: 13 months) and control arm (median: 16 months). As expected, patients who responded to treatment lived significantly longer than those who failed to benefit. Two episodes of reversible spinal cord compression occurred during androgen administration. (The risk of this serious side effect may be reduced by performing a screening myelogram to rule out subclinical spinal metastasis). Our preliminary data suggest that androgen priming may enhance the tumoricidal effect of cytotoxic drugs in advanced prostate cancer. The lack of improvement in duration of response and survival may be explained by the large fraction of hormone-independent cells probably present in patients with tumors refractory to orchiectomy.

Aminoglutethimide-induced hematologic toxicity: worldwide experience.

Marked leukopenia and/or thrombocytopenia occurred in 12 of 1333 patients treated with aminoglutethimide (0.9% incidence). Depression of blood cell counts was evident within 7 weeks of starting treatment. No delayed toxicity was encountered. Blood cell counts recovered promptly upon cessation of aminoglutethimide in all but one patient, who died from septicemia and marrow aplasia.

Evaluation of CEA and GCDFP-15 plasma level during hormonally induced cancer stimulation.

Preliminary clinical trials indicate that transient stimulation of breast and prostate cancer growth by hormonal means may enhance tumor sensitivity to chemotherapy. In none of these studies, however, has an attempt been made to measure parameters that might reflect perturbations in cell kinetics induced by the treatment schedules. While conducting two, controlled, randomized clinical trials in advanced breast cancer and prostate cancer using a similar approach, we have measured plasma levels of two tumor markers, carcinoembryonic antigen (CEA) and breast gross cystic disease fluid protein (GCDFP-15). These served as a possible means of monitoring hormonal stimulation of tumor growth. Both markers failed to increase following administration of estrogens to patients with breast cancer and of androgens to men with prostatic carcinoma. In contrast, transient stimulation of tumor growth probably occurred as shown by exacerbation of symptoms and, in patients with prostate cancer, rise in acid phosphatase. We conclude that CEA and GCDFP-15 are not useful for monitoring pertubations in tumor cell kinetics induced by hormone stimulative protocols.

Adequacy of estrogen suppression with aminoglutethimide and hydrocortisone as treatment of human breast cancer: correlation of hormonal data with clinical responses.

Human breast neoplasms can be divided into hormone-dependent and hormone-independent subtypes. Estrogen is the major hormonal stimulus for growth of the dependent tumors. Failure to respond to estrogen suppression therapy could reflect either an incomplete lowering of estrogens or the hormonal independence of the tumor. To address this issue, we compared the levels of several estrogens and other hormones in women experiencing objective responses (the responders) and disease progression (the progression group) during therapy with the aromatase-steroidogenesis inhibitor, aminoglutethimide, and replacement hydrocortisone. Pretreatment hormonal profiles of the estrogens, and androgens, ketosteroids, thyroxine, polypeptide hormones, and carcinoembryonic antigen did not differ significantly among response groups. During treatment, the levels of all estrogens were suppressed to a similar degree in the progression group and in the responders. Urinary estrone, for example, fell to 16.7 +/- 3.2% of basal in the responders versus 16.3 +/- 3.8% of basal in the progression group. These data suggested that lack of estrogen suppression did not explain the response to treatment in the patients receiving aminoglutethimide-hydrocortisone. This finding differs from our results in a similarly analyzed control group of patients treated with surgical adrenalectomy. Levels of the weak androgens, dehydroepiandrosterone sulfate and androstenedione, were found to be higher in the progression group compared to the responders. This observation could not be explained by differences in duration of treatment between groups. Analysis at 1 to 12 weeks, 13 to 24 weeks, and 25 to 36 weeks after initiating treatment indicated higher androgen levels at each time point in the progression group. In addition, the results were not attributable to differing serum levels of aminoglutethimide among responder groups. While the finding of higher androgen levels in the responder group remains unexplained, this study indicates that incomplete estrogen suppression is not responsible for lack of tumor response in patients with progressive disease during amino-glutethimide-hydrocortisone therapy.

Cross-over comparison of tamoxifen and aminoglutethimide in advanced breast cancer.

Thirty-four postmenopausal patients with advanced breast cancer had an overall objective response rate of 47% when treated with aminoglutethimide and hydrocortisone initially and a response rate of 24% when crossed over to therapy with tamoxifen after progression on aminoglutethimide. A similar group of 32 patients experienced a response rate of 28% when treated with tamoxifen first and a 19% objective response rate on subsequent therapy with aminoglutethimide. Patients who failed to respond to the first therapy seldom responded on cross-over to the alternate therapy. Toxicities were acceptable with both forms of therapy. Tamoxifen and aminoglutethimide used sequentially are effective forms of palliative hormonal therapy in metastatic breast cancer.

A randomized trial comparing surgical adrenalectomy with aminoglutethimide plus hydrocortisone in women with advanced breast cancer.

We randomized 96 postmenopausal women with metastatic breast carcinoma to receive surgical adrenalectomy or medical therapy with an adrenal inhibitor, aminoglutethimide (AG), plus replacement hydrocortisone. Before randomization, women were stratified according to disease-free interval, site of dominant disease, and estrogen-receptor status. Of 40 evaluable women treated with AG and hydrocortisone, 53 per cent had objective responses, as compared with 45 per cent of 29 women undergoing surgical adrenalectomy (P value not significant). Responses lasted a mean of 17.2 months in the medical group and greater than 17.1 months in the surgical group (not significant). Estrogen levels fell similarly in response to either treatment, whereas AG and hydrocortisone preserved androgen production. A null hypothesis tested the single question asked by this study: "Is surgical adrenalectomy superior to treatment with AG and hydrocortisone?" Rejection at significance levels of P = 0.01 and P = 0.07 for differences of 20 per cent and 10 per cent, respectively, suggested that medical therapy with AG and hydrocortisone may be logically chosen in place of surgical adrenalectomy.