Contribution of different scintigraphic techniques to the management of medullary thyroid carcinoma.

We compared three different scintigraphic techniques for the localization of neck recurrences and metastases in seven patients with medullary thyroid carcinoma one month to eight years after the first surgical intervention. Three successive scintigraphic studies were performed in five patients (6 x 3 studies) within two weeks using 201Tl chloride, 111In-labeled F(ab')2 fragments of the anti-carcinoembryonic antigen (anti-CEA) monoclonal antibody (MoAb) BW 431/31, and 131I meta-iodo-benzylguanidine (MIBG). Additionally, 11 studies were performed with the 111In-labeled MoAb fragment BW 431/31 (seven studies) or the 99mTc-labeled intact anti-CEA MoAb BW 431/26 (four studies). The gold standards for classifying scintigraphic results were biopsy, histology, surgery, and cytology. Six regions were classified as positive or negative in each study: thyroid region, four quadrants (lymph node regions) around the thyroid, and the region of the upper mediastinum. Of 36 sites, 201Tl was true positive (TP) in seven sites, false-positive (FP) in one site, true negative (TN) in 22 sites, and false-negative (FN) in six sites, resulting in a sensitivity of 54% and a specificity of 96%. 131I MIBG was TP in four sites, FP in none of the sites, TN in 23 sites, and FN in nine sites, with a sensitivity of 31% and a specificity of 100%. Immunoscintigraphy (102 sites overall) was TP in 16 sites, FP in five sites, TN in 77 sites, and FN in four sites, resulting in a sensitivity of 80% and a specificity of 94%. Immunoscintigraphy with 111In/99mTc anti-CEA F(ab')2 fragment/intact antibody is superior to scintigraphy with 201Tl and 131I MIBG.

[Indications for subtotal thyroidectomy in patients with amiodarone- (iodine-) induced hyperthyroidism]. / Indikation zur subtotalen Thyreoidektomie bei Patienten mit Amiodarone-(Jod-)induzierter Hyperthyreose.

Therapy with the antiarrhythmic drug amiodarone implies administration of free iodine in dosages between 6 and 36 mg/day. Especially patients from areas with low iodine intake are at risk to develop iodine-related hyperthyroidism. In 2 case reports the indication of subtotal thyroidectomy is discussed. In 1 patient decision for operation was made after 7 weeks of inefficient therapy with high-dose methimazole. For another patient decision for operation was made but performance had to be postponed because of acute myocardial infarction. Surgical therapy has the advantage of immediate and safe effectivity, low risk of relapse and provides the possibility of further iodine administration without major problems. The risk of operation has to be evaluated against the risk of a long-term treatment with antithyroid drugs preferentially from the thiomide type or against the risk of persistent hyperthyroidism.

[Comparative studies of prolactin, estrogen, progesterone and androgen receptor levels in human breast cancers]. / Vergleichende Untersuchungen zum Prolaktin-, Ostrogen-, Gestagen- und Androgenrezeptorgehalt menschlicher Mammakarzinome.

A receptor for lactogenic hormones (prolactin of several species and human growth hormone) was characterized in crude plasma membrane preparations of adult female rat liver. The binding of 125J-labeled prolactin to receptors was specific, saturable, reversible, and of high affinity (Kd = 0.23 x 10(-10)M). The maximum amount of prolactin specifically bound to liver of untreated female rats was 45 fmol/mg protein, whereas no specific prolactin binding was detected in plasma membrane preparations of adult male or immature rats. With this assay, a specific and reversible binding of ovine prolactin was detected in plasma membrane preparations of 25 human breast cancers, ranging from 2-29% of total activity. The estrogen-, progesterone- and androgen receptor content was determined in the breast cancer specimens using the dextran-coated charcoal method. Specimens with the highest specific prolactin binding showed the lowest steroid receptor concentrations, but no significant correlation between estrogen-, progesterone-, androgen-, and prolactin receptor content and other prognostic factors was observed in our series. We conclude, that steroid and prolactin receptors are expressed independently in human breast cancer.

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.

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.

Characterization of a prolactin-daunomycin ligand as a probe for drug targeting.

Conjugates of ovine prolactin and daunomycin were prepared for use as affinity-labelled drug carriers in cancer cells carrying the prolactin receptor. The binding affinity of the conjugates to prolactin receptors in rat liver membrane preparations and in viable granulosa cells derived from estradiol- and pregnant mare serum gonadotropin (PMSG)-treated immature female rats was less than an order of magnitude lower than prolactin. The toxicity of the conjugate in cultured granulosa cells was dependent upon the concentration of the daunomycin present in the culture. The cytotoxic effect of the ligand was abolished by the addition of free prolactin or NH4Cl to the granulosa cell cultures. These conjugates may be useful probes in drug targeting against hormone-sensitive cancer.

[Immunohistochemical studies of the determination of the hormone receptor status of breast cancer]. / Immunhistochemische Untersuchungen zur Bestimmung des Hormonrezeptorstatus von Mammakarzinomen.

Immunohistochemical examinations of 89 breast cancer specimens were performed using two different monoclonal antibodies. One marked the nuclear estrogen-receptor (ER) protein (anti-ER, Abbott), whereas the other marked an ER-related cytoplasmic protein (ER-D5 Amersham). Comparison of the results of the biochemical assay with those of the immunohistochemical markers revealed the following correlations: 75% anti ER and 71% ER-D5. Clinical follow-up studies are necessary to specify the relevance of these new immunohistochemical techniques in the anti-hormonal therapeutic management of breast cancer patients.

[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.

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.

[Mitomycin C and high-dosage medroxyprogesterone acetate in the therapy of metastasizing breast cancer. Results of a phase II study of the Workshop for Internal Oncology of the German Cancer Association]. / Mitomycin C und hochdosiertes Medroxyprogesteronacetat in der Therapie des metastasierenden Mammakarzinoms Ergebnisse einer Phase-II-Studie der AIO.

Combination therapy of mitomycin C 40 mg/m2 and medroxyprogesterone acetate 1.500 mg/day in patients with refractory metastatic breast cancer was tested within a phase II trial of the AIO. The overall response was 50% with 2 complete and 12 partial remissions. This combination therapy was tolerated well and hematologic toxicity was less than expected. More often pulmonary and renal toxicity appeared. This combination schedule seems to be useful even in patients with pretreated metastatic breast cancer. Hematologic, pulmonary and renal functions have to be observed.

[Combined drug/hormone therapy in metastatic breast cancer with vincristine, adriamycin, cyclophosphamide and high dose medroxyprogesterone acetate--VAC-MAP. Preliminary results of a phase II study of the German Cancer Society's Internal Medicine Oncology Task Force]. / Kombinierte Chemo-/Hormontherapie beim metastasierenden Mammakarzinom mit Vincristin, Adriamycin, Cyclophosphamid und hochdosiertem Medroxyprogesteronacetat--VAC-MAP. Zwischenergebnisse einer Phase-II-Studie der AIO (Arbeitsgemeinschaft für internistische Onkologie der Deutschen Krebsgesellschaft).

In a study of the AIO 67 patients with metastatic breast cancer were treated with VAC-MAP--a combination of chemo- and hormonal therapy consisting of vincristine 1 mg/m2 day 1, i.v.; adriamycin 40 mg/m2 day 1, i.v.; cyclophosphamide 200 mg/m2 day, 3-6, p.o. and medroxyprogesteroneacetate 1500 mg daily (day 1-42), 500 mg daily from day 42 until relapse. At present, 50 patients are evaluable. Remission rates of all patients correspond with those described in the literature for VAC, i.e. 58%. In CMF-resistant cases remissions were obtained in 50% of the patients and even 78.6% in hormone receptor positive tumors. Only 2 patients did not respond to the therapy. It appears that with a maintenance therapy of 500 mg MAP daily remission duration cannot be prolonged, apparently due to too low a dosage. MAP should improve the subjective tolerance of chemotherapy and bone marrow tolerance towards cytostatic drugs.

[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.

[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.

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.