Primary endocrine therapy for advanced breast cancer: to start with tamoxifen or with medroxyprogesterone acetate?

BACKGROUND: The availability of compounds effective against metastatic disease and at the same time excellently tolerated even in long-term administration has determined the choice of tamoxifen as primary treatment for palliation in metastatic breast cancer. Other drugs or other hormonal approaches were hardly tested against tamoxifen, especially as first-line treatment. PATIENTS AND METHODS: 119 patients with metastatic breast cancer and no prior endocrine therapy were randomized to receive either tamoxifen (TAM) 20 mg/day orally (64 patients), or medroxyprogesterone acetate (MAP) 1g/day i.m. 5 days/week for 4 weeks and then 500 mg twice a week (55 patients). The subsequent endocrine therapy was also prospectively defined at study entry. RESULTS: A total of 111 events, contributing to the endpoint 'time to progression' have so far been observed: a study of similar size would have a 90% power to detect a hazard ratio of 1.85. Initial MAP was associated with a significantly higher remission rate (50% versus 30% for tamoxifen; p = 0.023) and a marginally significantly longer median time to progression (8.8 versus 5.4 months; p = 0.051). Overall survival was also longer for the MAP group (28 versus 20 months; p = 0.384). The use of MAP was associated with a significantly higher toxicity, mainly hypertension, weight gain and tremor. CONCLUSIONS: The implications of these results are that initial endocrine therapy in postmenopausal patients with metastatic disease should be MAP if the patient is willing to accept the side effects of high-dose progestins. Progestins should be tested in the adjuvant setting for postmenopausal women, especially those with no tendency to hypertension or obesity.

Reverse hemolytic plaque assay study of luteinizing and follicle-stimulating hormone and thyrotropin secretion in diabetic rat pituitary glands.

Numerous studies indicate that an impaired hypothalamopituitary axis plays an important role in reproductive and thyroid disorders in diabetic humans and animal models. Yet, several questions about the pathogenesis of these diabetic complications have not been answered. To evaluate the basal secretion of single gonadotrophs and thyrotrophs in vitro, uncultured pituitary cells from control rats and 1-mo streptozocin-induced diabetic (STZ-D) rats were studied with a reverse hemolytic plaque assay and morphometry. After light-microscopy immunocytochemistry for gonadotropin and thyrotropin (TSH), we recorded the ratio of plaque-forming to non-plaque-forming cells. The area of plaques produced by luteinizing hormone (LH), follicle-stimulating hormone (FSH), and TSH cells and the area of plaque-forming and non-plaque-forming cells were clearly smaller in diabetic than control rats. The plaque area, however, was more severely reduced than the cell area. The percentage of LH-, FSH-, and TSH-immunoreactive plaque-forming cells was greatly decreased in diabetic compared with control animals. In conclusion, our findings demonstrate that the LH-, FSH-, and TSH-secreting cells of diabetic rats released less hormone and were less numerous than the corresponding cells of control rats. Thus, several pathogenetic mechanisms might be involved in reduced gonadotropin and TSH release at the cellular level: 1) anatomical lesions of organelles involved in glycoprotein hormone synthesis and secretion, possibly due to insulin deficiency; 2) decreased gonadotropin-releasing hormone (GnRH) and thyrotropin-releasing hormone (TRH) receptors on pituitary cells; 3) inadequate GnRH and TRH stimulation; 4) high plasma corticosterone levels; or 5) a combination of points 1-4.

[Aortic valvular dysplasia in a dog]. / Dysplasie valvulaire aortique chez un chien.

A case of aortic valve dysplasia in a 6 year old male cocker spaniel is described. The dog was presented to the veterinarian because of strong dyspnea and frequent coughing. Clinical examination, EKG, radiographs and angiocardiography all pointed towards a tentative diagnosis of aortic insufficiency. Four months after the first appointment the dog was presented again with congestive heart failure, neural symptoms and strong abdominal pain. Electrocardiography and concentrations of LDH and CK were typical of myocardial infarction. Autopsy revealed a narrowing of the aortic valves in combination with a subaortic stenosis and several infarctions localized in the left ventricle as well as a recent infarction in the left kidney.

Reliability of an in vitro short-term assay to predict the drug sensitivity of human breast cancer.

The feasibility and reliability of an in vitro assay that evaluates drug interference on nucleic acid precursor incorporation were investigated on 135 previously untreated locally advanced breast cancers. The assay, which was carried out on tumor fragments incubated for 3 hours with drugs, proved to be feasible on a sufficiently high percentage of biopsy specimens (70%) for routine clinical use. In vitro drug activity evaluated with this assay appeared to reproduce the clinical patterns of sensitivity of the tumor type as well as of the individual tumors. In fact, in vitro response rates to conventional agents resembled the clinical response rates reported for the same agents used in monochemotherapy. From a retrospective--correlative study carried out on 41 patients treated in vitro and in vivo with the same drugs (Adriamycin [doxorubicin] and vincristine), in vitro effect of Adriamycin on 3H-uridine incorporation appeared significantly correlated with clinical response (overall agreement, 78%; P = 0.0032) with specific agreements of sensitivity and resistance of 75% and 81%, respectively.

[Effect of interferon-alpha 2 (E. coli) in hairy cell leukemia]. / Wirksamkeit von Interferon-alpha 2 (E. coli) bei der Haarzell-Leukämie.

Recombinant interferon-alpha 2 (E. coli) produced a clinically significant improvement in hemoglobin, granulocytes and platelets in 7 of 8 patients with hairy cell leukemia. Response to treatment was already noticeable in the fourth treatment week. In one case without improvement after 120 days, treatment was stopped. So far only one complete remission has been documented. Because of the remarkable improvement in the peripheral blood values, the induction of a complete remission may not be the ultimate goal of interferon treatment. The side effects of this subcutaneous low-dose treatment consisted mainly of mild flu-like symptoms of short duration. The results obtained with recombinant interferon-alpha 2 confirm the initial observation by Quesada et al. with partially purified leukocyte-interferon. In our experience, these results are superior to those obtained in similar conditions with chlorambucil.

High-dose ifosfamide in advanced osteosarcoma.

In a prospective study, 18 evaluable patients with recurrent osteosarcoma were treated with ifosfamide, 1.8 g/m2 daily for 5 consecutive days. Courses were repeated every 4 weeks. Additional mesna (2-mercaptoethane sulfonate) was given to prevent urotoxicity. All patients had measurable lung deposits and all but one had been pretreated with various cytotoxic agents. Six patients (33%) showed therapeutic response, two complete and four partial, with a median duration of 5.5 months (range, 3-47+). Toxicity included myelosuppression, alopecia, nausea, and vomiting. No severe urotoxicity or central nervous system toxicity was observed. Thus, high-dose ifosfamide in combination with mesna seems to be a safe and effective agent for the chemotherapy of osteosarcoma.

Pharmacokinetic studies in lung cancer patients.

Pharmacokinetic measurements to monitor and design cytotoxic treatments in cancer patients are being used more and more in order to optimize dosage and administration schedules. Ideally, information on drug concentrations over time should help reveal dose-response correlations. The cytotoxic drugs carmustine, etoposide, cyclophosphamide, iphosphamide, cis-diammineplatinum, Adriamycin (doxorubicin), and 4'-epi-Adriamycin have been monitored on different treatment programs of patients with advanced lung cancers. The collected experience emphasizes the many individual variables encountered in clinical practice complicating the effort of correlating pharmacokinetic data with clinical results. The examples, presented on the basis of the authors' experiences, pertain to drug instability, gastrointestinal absorption, enzymatic induction in the liver, drug interaction, and drug tissue concentrations.

Phase I trial of 4'-deoxydoxorubicin given weekly.

Twenty-six patients with various solid tumors entered a Phase I trial with 4'-Deoxydoxorubicin (Esorubicin, IMI-58), a new doxorubicin analogue. The drug was administered weekly i.v. for 3-4 weeks. Leukopenia proved to be dose limiting. The maximum tolerated dose (MTD) was reached at 20 mg/m2 weekly for 3 weeks. For Phase II trials, a weekly dose of 15 and 17.5 mg/m2 can be proposed for poor and good risk patients respectively. Non-hematologic toxicity was minimal. Phase II trials with this new anthracycline are warranted.

A phase II study of cisplatin in advanced gastric cancer.

Twenty patients with recurrent or metastatic gastric adenocarcinoma and prior chemotherapy were treated with cisplatin, 60-120 mg/m2 as a 6-hr infusion repeated every 3 weeks. There were 4 partial responses in 18 evaluable patients. Seven patients had stable disease. Time to progression ranged from 6 to 28 weeks. Median WBC nadir was 3.2 X 10(3)/mm3 (range, 1.5-7.1) and platelet nadir 120 X 10(3)/mm3 (range, 13-220). A transient increase in serum creatinine was observed in 6 cases, and nausea and vomiting in all. We conclude that this drug is active in stomach cancer and that it warrants further trials in combination chemotherapy.

T3b-T4 breast cancer: factors affecting results in combined modality treatments.

Two hundred and seventy-seven consecutive patients with T3b-T4 breast cancer referred to the Milan Cancer Institute between 1973 and 1980 were treated with a combined modality approach. Chemotherapy (CT) consisted of AV, i.e. adriamycin (60-75 mg/m2 day 1) and vincristine (1.2 mg/m2 days 1 and 8) and was given for three to four cycles prior to local regional modality. Local-regional treatment consisted of either radiotherapy (RT) in 198 patients or surgery (S) in 79 women. Additional chemotherapy was then administered to a total of 205 patients. In the absence of distant metastases, frequency of good local control was significantly inferior in patients given CT + RT (63.9 per cent) compared to those treated with CT + RT + CT (75.4 per cent) and CT + S + CT (82.3 per cent, P = 0.033). Also freedom from progression (FFP) and overall survival (SURV) were significantly superior in the groups receiving more prolonged chemotherapy treatment compared to patients treated with CT + RT (FFP: P less than 0.0001; SURV: P = 0.002). None of the variables examined was able to affect the response rate, while axillary nodal status and tumor size played a major role in the duration of FFP and SURV. Our findings indicate that a more aggressive treatment is needed to improve current results in this stage of disease. To overcome the problem of local-regional recurrence, treatment should probably begin with cytoreductive surgery followed by postoperative radiotherapy in all patients with the exception of those having inflammatory carcinoma. Systemic treatment should then be delivered to control distant micrometastases.

A phase I trial of marcellomycin with a weekly dose schedule.

Marcellomycin, a new anthracycline antibiotic, was administered intravenously on a weekly schedule to 22 patients with advanced malignant solid tumors. Patients were treated at 6 dosage levels ranging from 5 to 30 mg/m2 weekly for 4 weeks. Courses were repeated after a 3-week rest period. Hematologic toxicity was dose-limiting but unpredictable. Of 10 patients treated with weekly doses of 27.5 mg/m2, 3 patients exhibited myelosuppression and 2 died in agranulocytosis. Moderate to severe nausea and vomiting occurred in 19 of 22 evaluable patients. Other toxic effects were non-acute and consisted of mild stomatitis, diarrhea, phlebitis and moderate fatigue in 1-3 patients each. In 17 patients evaluable for antitumor activity no partial or complete responses occurred. One patient with advanced breast cancer showed a mixed response. Marcellomycin given on a weekly dose schedule has unpredictable and erratic hematologic toxicity. The maximally tolerated dose appears to be between 27.5 and 30 mg/m2 weekly. However, no firm recommendations can be given for a dose level that results in tolerable, predictable and reversible toxicity.

Phase I trial of 4-demethoxydaunorubicin with single i.v. doses.

Sixteen adult patients with a variety of solid tumors entered a phase I trial with 4-demethoxydaunorubicin, a new analogue of daunorubicin. The drug was given as a single i.v. dose of 5-18 mg/m2 repeated every 3-4 weeks. Myelosuppression, especially leucopenia, was dose-limiting. Other toxic effects included mild to moderate nausea and vomiting. The maximum tolerated dose for ambulatory treatment was 18 mg/m2, and 15 mg/m2 every 3-4 weeks is proposed as a starting dose for phase II trials in solid tumors.

[The combination methyl-CCNU, vincristine, 5-fluorouracil and streptozotocin in the treatment of advanced colo-rectal adenocarcinoma]. / L'association méthyl-CCNU, vincristine, 5-fluoro-uracile et streptozotocine dans le traitement de l'adénocarcinome colo-rectal avancé. Une étude pilote.

Sixteen patients with advanced colo-rectal cancer were treated with the combination methyl-CCNU, vincristin, 5-fluorouracil and streptozotocin (MOF-Strepto). Seven cases were previously untreated. A partial remission was observed only in one patient (6%, confidence limits to 95%: 1-17%). Marked gastrointestinal and hematologic toxicity was registered. Based on this experience the authors are unable to confirm other pilot studies claiming major antitumor activity for MOF-Strepto in the treatment of advanced colo-rectal cancer.

Multimodal treatment for locally advanced breast cancer. Result of chemotherapy-radiotherapy versus chemotherapy-surgery.

In a prospective randomized study, the efficacy of two combined modality approaches (chemotherapy plus radiotherapy or chemotherapy plus mastectomy) was tested in a total of 132 women with locally advanced breast cancer. Chemotherapy consisted of Adriamycin plus vincristine (AV) administered for three cycles before either local-regional modality and subsequently for seven additional cycles. Although a higher proportion of women achieved complete remission after mastectomy (100%) compared to women given radiotherapy (60%), the total response rate at the end of combined modality was identical (75%). There was no significant difference between the two treatment groups in terms of patterns of treatment failure, median duration of response, and total survival. Treatment was not influenced by menopausal or estrogen receptor status. Two patients of the surgical group showed Adriamycin-induced cardiomyopathy after cumulative doses less than 500 mg/m2. The results of present study failed to indicate that surgery per se improved the overall results including local control, over radiotherapy in a combined modality setting.

[Oral gestagen treatment of advanced breast neoplasms with norethisterone acetate]. / Perorale Gestagenbehandlung des fortgeschrittenen Mammakarzinoms mit Norethisteronacetat.

The medical records of 84 postmenopausal women treated with oral norethisterone acetate (NTA) for advanced breast cancer have been analyzed retrospectively. Treatment was devoid of significant toxicity. 21 patients were not evaluable for treatment response, either due to insufficient data or inadequate tratment trial. Among the 63 evaluable patients, complete plus partial response was obtained in 21 (33.3%) with a median duration of 10 months. Disease stabilization was observed in 16 patients (25.4%) for a median duration of 5 months, while 26 patients (41.3%) showed progressive disease while on treatment. The best response was observed in women with predominantly soft tissue metastases (CR + PR: 34.9%) and aged over 70 (CR + PR: 48%). The literature on norethisterone acetate is reviewed and compared with the present results. The role of progestational agents in the treatment of advanced mammary carcinoma is discussed.