Phase II study of aminoglutethimide and medroxyprogesterone acetate in the treatment of patients with advanced breast cancer.

Forty-five women with far-advanced metastatic breast cancer were treated with a combination of aminoglutethimide (AG), 1000 mg p.o. daily, and medroxyprogesterone acetate (MPA), 1500 mg p.o. daily. Of 41 patients evaluable for treatment response, there were two complete responses, five partial remissions, 26 patients with minor tumor responses or no change, and eight nonresponders. Major side effects included those known for AG and MPA, i.e., impairment of mental functions, depressive syndromes, fatigue, ataxia, skin rash, changes in body weight, and transient increase of gamma-glutamyl-transferase. Most side effects disappeared spontaneously after 4 to 6 weeks of treatment. Plasma hormone measurements in 28 patients revealed no impairment of adrenocorticotropic hormone and cortisol levels. In conclusion, in the AG combination, it is feasible and safe to replace cortisol by MPA. Treatment results warrant further investigation of AG-MPA in patients with breast cancer of a more favorable prognosis.

Fluorouracil versus folinic acid/fluorouracil in advanced colorectal cancer--preliminary results of a randomized trial.

Patients with advanced colorectal cancer were randomized to receive either fluorouracil (5-FU) 370 mg/m2 IV days 1 to 5 followed by weekly applications of 5-FU 600 mg/m2 or the same doses of 5-FU preceded by folinic acid 200 mg/m2. Because of toxicity, the weekly 5-FU dose in the combination treatment schedule was reduced to 500 mg/m2 in the course of the study. As of November 1990, 135 patients entered the study; 71 have received combination therapy, and 64 monotherapy. Sixty-three and 59 patients, respectively, are included in the present interim analysis. The two groups are well matched for age, performance status, site of disease, number of metastatic sites, and biochemical parameters. Treatment results are evaluable in 118 patients. Thirty percent receiving combination treatment and 20% receiving monotherapy achieved a complete or partial remission. There is no survival time difference between the groups. However, time to progression is superior in the combination treatment group (median 26 weeks compared with 13 weeks). The main toxicity was diarrhea during the weekly therapy. This was especially true for patients receiving combination treatment before the reduction of 5-FU dosage. In contrast to only four of 56 patients with monotherapy, 14 of 39 with the combination treatment at the initial dosage had severe diarrhea with two treatment-related deaths in this latter group. By reduction of 5-FU dosage during the weekly therapy severe diarrhea could be clearly reduced with only one of 18 patients suffering from diarrhea of World Health Organization grade 3. Other toxicity was usually mild. In conclusion, a prolongation of time to progression could be achieved by combination treatment of folinic acid and 5-FU, which was well tolerated when the weekly dose of 5-FU did not exceed 500 mg/m2.

Metastatic breast cancer with constantly low CEA blood levels. A subgroup with unfavorable prognosis?

The capability of breast cancer to secrete CEA might have biological significance. In 105 patients with metastatic breast cancer serial CEA determinations and clinical follow-up data were available during progression of disease up to death. In this series, 39 patients (37%) had constantly low CEA levels (less than 10 ng/ml), whereas 66 patients (63%) showed CEA values exceeding 10 ng/ml with progression. The patients with low CEA levels had significantly shorter median survival times (P = 0.001) after mastectomy (39 versus 65 months) and after recurrence (18 versus 28 months) than the patients with high CEA levels. This difference was due first to a poor-risk group of 13 patients with rapidly disseminating tumors, very short survival (less than 12 months), and low CEA levels. Secondly, there were more patients with pulmonary involvement and unfavorable prognosis and fewer patients with osseous metastases and long survival in the low-CEA group. In conclusion, there might be a subtype of breast cancer with rapid progression and low CEA secretion. This clinical observation has to be confirmed by histological grading and CEA staining of these tumors.

Phase II study with etoposide in previously untreated advanced breast cancer.

A phase II study was carried out to evaluate the efficacy and safety of etoposide used as first-line chemotherapy for patients with advanced breast carcinoma. A total of 20 patients received 230 mg/m2 i.v. etoposide per day for 3 days (total, 690 mg/m2 per course) every 4 weeks. A total of 95 courses were given. Observed responses included 3 partial remissions (PR) and 14 cases of stable disease (NC). The median duration of response was 6 (PR) and 5.6 months (NC). Contrary to the severe hematological toxicity in heavily pretreated patients described in previous studies, no substantial problems were observed in this trial. No dose reduction was necessary, and only once did leukopenia lead to a 1-week delay in therapy. An increase in platelets up to a maximum of 685,000/mm3 was seen in all patients, particularly in those with bone metastases. No relation to the quality of remission or pretreatment was seen. Nausea, vomiting, and fatique were mild and transient, but alopecia occurred in all cases. One patient developed nonfatal anaphylactic shock after etoposide treatment.

[Panmyelopathy induced by aminoglutethimide. Report of a clinical case]. / Panmyelopathie unter Aminoglutethimid. Ein Fallbericht.

Aminoglutethimide inhibits the synthesis of oestrogens in adrenal and non-adrenal tissues and can be successfully used in the treatment of advanced breast cancer. In this article, a case with aplastic anaemia, a rare but severe side effect of aminoglutethimide is reported.

[Responsible risks in the choice of palliative chemotherapy]. / Verantwortbare Risiken bei der Wahl der palliativen Chemotherapie.

The risk of tumor chemotherapy is weighed against its therapeutical potential. If there is a chance of a curative or life-prolonging treatment, the choice of a rather aggressive form of chemotherapy is justified. In the majority of patients with metastatic malignant diseases, however, life-prolongation is not achievable and the choice of a chemotherapy with life-threatening side-effects contra-indicated. Potential benefits and risk of chemotherapy are further exemplified in breast cancer.

[Vindesine and adriamycin in the therapy of metastatic breast cancer]. / Vindesin und Adriamycin in der Therapie des metastasierenden Mammakarzinoms.

In a Phase II trial 30 patients with metastatic breast cancer and unfavorable prognosis were treated with a combination of adriamycin and vindesine (ADM 60 mg/m2 day 1 i.v.; VDS 3-5 mg/m2 day 1 i.v.; repeated every 3 to 4 weeks). Of these patients 20 had received no prior chemotherapy and 10 were pretreated. Complete and partial remission rates were 20% in the pretreated patients and 70% in the patients who had received no chemotherapy so far; median remission duration was 21 months. At present, 5 patients are still on study (4 X CR, 1 X PR). No cardiomyopathy was seen, serious leukopenias twice, and in general manageable gastrointestinal side effects as well as total alopecia occurred. A dosage increase from 3 to 5 mg/m2 vindesine was not tolerated in this combination. The combination shows rapid effects and is easily administered. In combinations containing adriamycin, vincristine can be replaced by vindesine, favoring vindesine due to its lower neurotoxicity.

Aminoglutethimide in the treatment of premenopausal patients with metastatic breast cancer.

Eighteen premenopausal patients with progressive metastatic breast cancer were treated with aminoglutethimide (AG)/cortisone. All patients received 1000 mg AG per day in combination with 2 X 25 mg cortisone acetate. Complete (CR) and partial remissions (PR) were achieved in 27.8%, a no change (NC) in 16.7% and progressive disease (PD) in 55.5% of all cases. The clinical results show that AG/cortisone acetate is effective in the therapy of premenopausal as well as postmenopausal patients with metastatic breast cancer. One hormone receptor negative tumour completely responded. Contrary to postmenopausal patients whose low oestradiol levels continuously decrease, oestradiol levels in premenopausal patients were not influenced by treatment. A distinct suppression of the ovarian activity does not occur. Thus concluding, a mechanism--at least partially different from those in the postmenopause and not necessarily of endocrine nature--must exist in the premenopause. We, therefore, no longer think it justified to assert that the therapeutic effect of AG is merely based on medical adrenalectomy.

[Medroxyprogesterone acetate (MAP) and aminoglutethimide (AG) in metastatic breast carcinoma. Preliminary report on a phase II study of the German Cancer Society's Internal Medicine Oncology Task Force]. / Medroxyprogesteronacetat (MAP) und Aminoglutethimid (AG) beim metastasierenden Mammakarzinom. Zwischenbericht über eine Phase-II-Studie der Arbeitsgemeinschaft für internistische Onkologie (AIO) der Deutschen Krebsgesellschaft.

In 114 patients with metastatic breast cancer resistant to chemo- and hormonal therapy another attempt was made to treat these patients with the hormone combination of aminoglutethimide (AG) 1000 mg daily and medroxyprogesteroneacetate (MAP) 1500 mg daily for 6 weeks, than 500 mg MAP daily. At present, the following results were obtained from 100 evaluable patients: Complete remission (CR) 4,4% [median remission duration (MRD) 34,8 weeks], partial remission (PR) 18,5% (MRD 34,5 weeks), a no change status (NC) in 44,5% (MRD 17,2 weeks), in 32,6% of the cases there was no response. 19 patients with hormone receptor positive tumors obtained CR + PR in 26,3%, NC 68,4%. Bone metastases seem to respond best to this therapy. 2/3 of all patients suffered from cerebral side effects, particularly contemporary personality disorders and depressive syndromes, 53% showed a short increase of their liver values. During the first 6 weeks the side effects were most pronounced. In 16 cases - entirely patients primarily in bad general condition - the therapy had to be stopped due to heavy subjective side effects. The combination AG/MAP represents a new highly effective therapeutic modality with a relatively broad therapeutic index. The treatment results are described. MAP can replace cortisone generally applied together with AG and seems to have an additive effect with AG.

Aminoglutethimide and medroxyprogesterone acetate in the treatment of patients with advanced breast cancer. A phase II study of the Association of Medical Oncology of the German Cancer Society (AIO).

One hundred twenty-eight women with advanced metastatic breast cancer were treated with a combination of aminoglutethimide (AG) (1000 mg orally, daily) and medroxyprogesterone acetate (MPA) (1500 mg orally, daily for six weeks and thereafter 500 mg orally, daily; omitting cortisone substitution). AG/MPA did not lead to side effects other than those described under AG or MPA monotherapy. Mental and personality changes seem to be more severe and frequent under combined therapy than under monotherapy. Impairment of mental functions, depressive syndromes, fatigue, ataxia, skin rash, and transient increase of gammaglutamyl transferase appeared and disappeared within the first 4 to 6 weeks of treatment. Objective remissions of at least 3 months duration from initiation of therapy were seen in 21 of 128 patients (21.9%) (3.9% complete remission [CR], 18% partial remission [PR]). A no change (NC) status occurred in an additional 25.8%. The remission duration (mean and range) was 19 (10.5-54) for CR, 16.5 (4.5-52+) for PR and 6 (3-27) months for NC patients. The highest response rate was registered for patients with only bone involvement (PR, 11; and NC, 11 of 26 patients). There was a distinct correlation of response to prior systemic treatment, receptor status of the primary tumor, disease-free interval, menopausal status, age and condition of the patient. PR was obtained in 4 of 20 patients with receptor-negative primary tumors. These results justify a prospective trial comparing AG/MPA with other forms of endocrine therapy in selected patient subgroups.

Intensive short-term chemotherapy in patients with advanced breast cancer.

Aiming at a high complete remission rate with an intensive induction regimen, 27 patients with advanced breast cancer were given three cycles of VAC chemotherapy consisting of vindesine 3 mg/m2 i.v. on days 1 and 12, adriamycin 40 mg/m2 i.v. on days 1 and 12, and cyclophosphamide 200 mg/m2 p.o. on days 3-6 and 14-17 together with medroxyprogesterone acetate (MPA) 1,500 mg p.o. daily during the induction phase and 1,000 mg p.o. thereafter until relapse. These VAC double cycles were repeated twice with 3-weekly intervals for a total induction period of 15 weeks. In responders, including no change, the chemotherapy was discontinued thereafter, and the patients were observed until relapse with a maintenance therapy of MPA 1,000 mg p.o. daily. A complete remission (CR) was achieved in 8 (29.6%) and a partial remission (PR) in 13 (48.2%) of the 27 patients (CR + PR 77.8%). A no change (NC) status was found in 6 patients (22.2%). There were no nonresponders. The median duration of the CR was 20 (5-42) months with two patients still in CR at 33 and 36 months, of the PR 8.3 (4-13.5) months, and of the NC 6.7 (2-13) months. The treatment was tolerated without life-threatening toxicity or interval prolongation by all patients. No dose-limiting cardiac toxicity was observed in these patients regularly controlled by left ventricular ejection fraction (LVEF). The high response rate of this intensive induction regimen warrants further investigation. Complete remission was achieved only in patients without previous chemotherapy, with marked tumor regression after the first chemotherapy cycle and when there was no extensive bone involvement.

[High dose medroxyprogesteroneacetate in metastasizing breast cancer: correlations between course of the disease and hormone profiles]. / Hochdosiertes Medroxyprogesteronacetat beim metastasierenden Mammakarzinom: Beziehung zwischen Krankheitsverlauf und Hormonprofilen.

Based upon preliminary observations that tumor response to MPA was correlated to cortisol suppression 42 patients were treated with MPA at different dose levels. 1500 mg MPA p.o. almost completely suppressed endogenous cortisol production in 23 out of 23 patients. Consequently, 51 patients with advanced stage metastatic breast cancer were treated with Medroxyprogesteroneacetate (HD-MAP) at a dosage of 1500 mg p.o. daily or 500 mg i.m. on 5 days per week. There were 5 complete and 7 partical remissions, 23 patients with no change and 10 with progressive disease. 7 patients were not evaluable. Clinical results correlated to plasma cortisol and prolactin blood levels bot not to LH, FSH, TSH, TBI, T3, T4, ACTH and aldosterone measurements. There was no patient with relapse and suppressed cortisol or normal prolactin measurements. The development of pituituary resistance to MPA is suggested. HD-MPA was equally effective in estrogen and/or progesterone receptor positive as in receptor negative patients. It is proposed that cortisol and prolactin determinations are useful to monitor for effective MPA treatment and the early detection of MPA resistance.

Pharmacokinetic and pharmacodynamic basis for the treatment of metastatic breast cancer with high-dose medroxyprogesterone acetate.

Postmenopausal patients with metastatic breast cancer were treated with medroxyprogesterone acetate (MPA) (Clinovir) in dosages between 500 and 1500 mg orally per day. The relation of MPA plasma concentrations and endocrine effects were studied in a longitudinal fashion. MPA exerted suppressive effects on the basal and gonadotropin-releasing hormone (GnRH) stimulated gonadotropin secretion, cortisol, dehydroepiandrosterone (DHEA), and estradiol (E2) in a dose-dependent manner leading to a complete suppression with 1500 mg orally per day. The depression of thyroid hormones (T3 and T4) coincided with a depression of the thyroxine-binding index (TBI). MPA did not affect human growth hormone (hGH), basal and thyrotropin-releasing hormone (TRH) stimulated thyroid-stimulating hormone (TSH) and aldosterone. Basal and TRH-stimulated prolactin (PRL) secretion showed a slight but distinct elevation. From these data it is concluded that in postmenopausal patients MPA exerts its antitumor activity by an interference with the hypothalamo-pituitary adrenal axis in the sense of a selective pharmacologic hypophysectomy leading to complete suppression of adrenal steroid secretion. Additionally, MPA inhibits tumor cell growth through the progesterone receptor. A dual mechanism for the antitumor activity of high dose is postulated MPA: ablative through suppression of the hypothalamo-pituitary-adrenal axis and subsequent estrogen deprivation, and additive via the progesterone receptor directly on the tumor cell. The significance of gonadotropin suppression in the postmenopause for breast cancer growth is unclear. The depression of T3 and T4 is due to a depression of thyroid hormone-binding proteins. The elevation of PRL secretion may be explained by a slight estrogenic activity of MPA metabolites.

Hyperprolactinemia is an indicator of progressive disease and poor prognosis in advanced breast cancer.

In a long-term follow-up study, prolactin levels were measured in 149 patients with advanced metastatic breast cancer. Control groups included 221 patients with primary operable breast cancer and 150 women with benign breast disease. Hyperprolactinemia (greater than 1,000 mIU/I; HYPRL) occurs in 44% of patients with metastatic breast cancer in the course of the disease (p less than 0.001 compared to patients with non-metastatic disease). HYPRL is associated with progressive breast cancer in 88% of cases. In patients experiencing several episodes of disease remission and relapse, incidence of HYPRL increases with each relapse. Prolactin blood levels return to normal if hyperprolactinemic patients experience remission after chemotherapy. Patients expressing HYPRL have a shorter survival time after mastectomy when compared to patients who never developed HYPRL (154/89 months, p = 0.01). It is concluded that HYPRL is of prognostic significance and a reliable indicator of progressive disease in advanced metastatic breast cancer.

[Medroxyprogesterone acetate as glucocorticoid in combination with aminoglutethimide in the treatment of metastatic breast cancer]. / Medroxyprogesteronacetat als Glucocorticoid in der Kombination mit Aminoglutethimid zur Therapie des metastasierenden Mammakarzinoms.

One of the central effects of MAP is the intrinsic glucocorticoid activity. In the therapy of metastatic breast cancer with high dose MAP the cortisol like effect could be shown even in long term treatment. The cortisol like activity of MAP leads via the suppression of ACTH to a decrease of endogenous cortisol secretion. This cortisol like activity of MAP is sufficient to replace the obligate cortisol substitution in the therapy of metastatic breast cancer with aminoglutethimide. Thus within the therapy of metastatic breast cancer the combination of two endocrine acting drugs is possible.

[High dose medroxyprogesterone acetate in metastatic breast cancer. Comparative clinical, pharmacokinetic and pharmacodynamic data of different forms of administration]. / Medroxyprogesteronacetate in hoher Dosierung beim metastasierenden Mammakarzinom. Vergleichende Klinik, Pharmakokinetik und Pharmakodynamik verschiedener Applikationsformen.

In the therapy of metastatic breast cancer MAP was used with different dosages and different forms of administration. Pharmacokinetics and pharmacodynamics were investigated. MAP plasma concentrations are dose dependent with great interindividual variation. The cortisol suppressive effect is dependent on plasma concentrations with only narrow interindividual variability. The oral administration of the crystal suspension is equivalent to the administration of tablets concerning plasma levels und endocrine effects. The therapy schedule for i.m. application used here leads to lower MAP plasma concentrations and correspondingly to a minor endocrine effect than in oral therapy. Tumor effective and cortisol suppressive plasma concentrations seem to have the same level.

[Megestrol acetate in various doses in the treatment of metastatic breast carcinoma--clinical and endocrinologic studies]. / Megestrolazetat in verschiedenen Dosierungen bei der Behandlung des metastasierenden Mammakarzinoms--Klinische und endokrinologische Untersuchungen.

Both medroxyprogesterone acetate (MPA) and megestrol acetate (MA) are effective in the treatment of metastatic breast cancer. Although the dose-dependent mode of actions of MPA have been extensively clarified, there is still some uncertainty regarding the mode of actions and dosage of MA. Thirty-three patients with metastatic breast cancer were treated with various dosages of MA under a phase-II study. Eight patients were given 200 mg, 9 X 400 mg, 10 X 600 mg and 6 X 800 mg MA daily per os. The LH, FSH, TBI, T3, T4, TSH, ACTH, aldosterone, testosterone, prolactin and cortisol levels were determined regularly during treatment to enable the investigation of the pharmacodynamics of MA. A complete remission was achieved in two patients, a partial remission in seven patients and there was no change in eight patients (total responder rate 51.5%). The clinical and endocrine changes therefore suggest that the dose-dependent mode of actions of MPA and MA are identical. Equivalent dosages of MPA are 1000-1500 mg per os and of MA 160-200 mg. Furthermore, similar relationships between the endocrine changes and remission behaviour of MA and MPA have been observed. Persisting tumour remissions are inevitable under cortisol suppression and normal prolactin, aldosterone and ACTH levels.

Medroxyprogesterone acetate and lipid metabolic changes.

Lipid metabolic changes under oral treatment with medroxyprogesterone acetate (MPA) were investigated in four groups of patients: group I; 10 patients aged 25-45 (mean 38) years received 50 mg MPA daily for pelvic endometriosis. Group II; 21 patients aged 55-77 (mean 62) years received 200 mg MPA daily for surgically treated endometrial carcinoma stage I. Group III; 14 praemenopausal patients aged 37-52 (mean 47) years received 1000 mg MPA daily for metastasized breast cancer. Group IV; 27 post-menopausal patients aged 53-78 (mean 68) years were treated with 1000 mg MPA daily for metastatic breast cancer as well. A fifth group of initially 86 patients aged 40-86 (mean 63) years after surgery for endometrial carcinoma stage I served as untreated control for groups II and IV. Cholesterol and triglyceride concentrations were measured enzymatically lipoproteins were determined by quantitative electrophoresis and precipitation and apolipoproteins A1 and B were quantified by kinetic rate nephelometry. Whereas in patients of group I no changes of lipid and lipoprotein parameters were observed, daily oral doses of 200 mg MPA and more led to a marked fall in alpha-lipoprotein-, HDL-cholesterol and apolipoprotein A1 levels. beta-Lipoprotein-, LDL-cholesterol and apolipoprotein B concentrations rose significantly in Groups III and IV. The relevance of these findings in terms of athero-genicity is discussed.

Clinical significance of circulating immune complexes in patients with metastatic breast cancer.

Serum circulating immune complexes (CIC) were repeatedly measured by means of the CIq binding assay (Cba) and the Raji cell assay (Rca) in 158 patients with metastatic breast cancer (mbc). Frequency of occurrence and levels of CIC were only slightly increased in mbc when compared to age-matched healthy women. They were identical to those of patients with localized breast cancer prior to mastectomy and to those of post mastectomy patients without evidence of recurrent disease. In mbc the results of the Cba and the Rca showed a poor correlation, whereas in a control group of patients with rheumatoid arthritis both tests showed significantly elevated levels of CIC. Patients with mbc were followed up clinically and biochemically by serially measuring CIC for an average of 10 months. Patients with positive CIC did not prove to be an unfavorable group regarding progression of disease and response to chemotherapy. When CEA and CIC levels were compared, CIC, unlike CEA, was a poor tumor marker. In conclusion, CIC as measured by CIq binding assay and Raji cell assay are not clinically significant tumor markers or prognostic indicators in patients with metastatic breast cancer.

[Determination of the carcinoembryonic antigen (CEA) for predicting the success of therapy in metastatic breast cancer]. / Bestimmung des carcinoembryonalen Antigens (CEA) zur Voraussage des Therapieerfolges beim metastasierenden Mammakarzinom.

In 53 patients with metastatic breast cancer and increased CEA serum levels (greater than 10 micrograms/l) the CEA titer within the first 8 weeks after commencement of chemotherapy was compared with results of therapy. Among 30 patients in whom CEA values had decreased by at least 30% of pretreatment values 12 showed remission, 15 no change and 3 progression of the malignancy. Among 23 patients with unchanged or increasing CEA values during therapy 19 had progression, 3 an arrest and one a remission of the disease. In the one patient with remission the course of the disease was unusual inasmuch as the CEA value increased to 240 micrograms/l serum and liver metastases regressed excessively at the same time. This lead to the assumption of CEA release by tumour necrosis during therapy. The results suggest that in metastatic breast cancer and increased CEA values remission generally cannot be expected should the CEA value remain unchanged or rise within the first 8 weeks after initiation of treatment. In contrast, a decrease of CEA within that time may be considered a prognostically favourable sign which, however, does not mean clinically relevant reduction of tumour size in every case. For evaluation of treatment sufficient precision of CEA determinations must be guaranteed.