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For almost a century surgical castration represented the initial standard therapy for metastatic breast cancer in premenopausal women with hormone dependent tumors. Today the suppression of ovarian function can also be obtained by the administration of supraphysiologic doses of luteinizing hormone releasing hormone (LHRH) agonists. From April 1987 to February 1989, 23 premenopausal patients with advanced breast cancer (median age 39 years, range 28-52, ER positive 20, unknown 3; prior chemotherapy 17) were treated with the LHRH agonist goserelin depot (Zoladex) at the dose of 3.6 mg. every 4 weeks. Twenty-two patients were evaluable. Serum levels of 17 beta estradiol, progesterone, FSH and LH were suppressed by goserelin and fell to postmenopausal values within 8 weeks of therapy in 77% of cases. Complete response (CR) plus partial response (PR) was documented in 7 of 22 (32%) and occurred in all major sites of disease. Five patients achieved CR (soft tissue 3, viscera 2). Response rate was higher in patients not previously treated with chemotherapy (4/6). In the present series, all responses were seen in women greater than 35 years old, regularly menstruating at the start of treatment. Time to progression for the entire case series was 22 weeks and for responders 64 weeks. Oophorectomy was performed after disease progression in four patients without success. Goserelin was well tolerated. Local cutaneous dyschromia occurred in 45% and hot flushes in 82%. Treatment efficacy of goserelin is comparable to that of oophorectomy, without the psychological trauma and the morbidity related to surgical castration.

Sixty-nine postmenopausal women with disseminated breast cancer previously treated with endocrine and cytotoxic therapy were treated with tamoxifen (20 mg/day). Complete plus partial response (CR+PR) was observed in 29 % (CR 16 %) and stable disease in 28 %. The objective response was higher in soft tissue sites (52 %) compared to osseous (12 %) and visceral (13 %) disease. No regression or disease stabilization was observed in the presence of liver involvement. Free-interval, length and type of menopause, and estrogen receptor status (carried out only 26 patients) did not statistically influence the percent of objective response. Only 1 of 16 patients (6 %) who did not respond to previous endocrine therapy responded to tamoxifen, while 3 of 9 previous hormonal responders (33 %) achieved objective regression with antiestrogen therapy. On the contrary, the response to previous chemotherapy failed to influence the subsequent response to tamoxifen. The median duration of the response was more than 12 months and the median survival more than 18 months. Treatment was generally very well tolerated and in only one patient was temporarily discontinued because of thrombocytopenia.

Mitomycin C was administered to 22 patients with metastatic breast cancer, refractory to hormonal therapy and conventional chemotherapy. Treatment was given by intravenous bolus injection at 20 mg/m2 of the drug and repeated at 6-week intervals. The overall response rate was 23%. Two complete remissions were seen in soft tissue lesions. Leukopenia occurred in 68% of the patients, thrombocytopenia in 36%, and anemia in 14%. One case of cardiotoxicity after previous treatment with adriamycin was observed. We conclude that mitomycin C is an active agent in disseminated breast cancer resistant to hormone therapy and chemotherapy. Combination of mitomycin C with other chemotherapeutic drugs will be tested.

Mitoxantrone was administered at the dose of 14 mg/m2 i.v. every 3 weeks to 25 consecutive women with measurable progressive disease who relapsed after adjuvant CMF and endocrine therapy. The treatment plan consisted in the delivery of 6 cycles, unless disease progression or severe toxicity occurred. All patients were evaluable for drug response and toxicity. One patient achieved complete remission and 6 partial remission, for a total response rate of 28%. Objective tumor response was observed in all major sites of disease. The median time to achieve remission was 3 months. The median duration of response was 7 months (range, 5-39+), and the median survival for the entire group was 10 months (range, 3-39+). Results were influenced only by the duration of disease-free status from the end of adjuvant CMF chemotherapy. In fact, all tumor responses were documented in woman with free intervals exceeding 1 year (7 of 17 or 41%). Treatment was generally well tolerated, with 10 patients developing leukopenia at some time during treatment. Only 2 patients received less than 75% of the projected dose because of granulocytopenia. Complete alopecia occurred in only 2 cases. Three patients developed a fall greater than 15% in left ventricular ejection fraction, but no episode of congestive heart failure was observed. We conclude that mitoxantrone is an effective and safe drug which can be utilized in women relapsing after adjuvant CMF.

Eighty-seven consecutive patients with metastatic breast cancer were treated with aminoglutethimide plus hydrocortisone. All patients were postmenopausal and had progressive disease following prior chemotherapy and endocrine therapy. Eighty-five women were evaluable for drug response. One patient showed complete remission and 14 patients partial response, for an overall response rate of 17%. The median duration of response was 11+ months. The response rate was highest in the presence of soft tissue involvement (36%). The most common side effects were transient skin rash, lethargy, and dizziness. Two patients discontinued treatment because of cutaneous allergy. Aminoglutethimide can be considered a moderately active agent when utilized as second- or third-line hormonal therapy.

The possibility to administer chemo-hormone- and immunotherapy on an out-patient basis has greatly increased because of the progress reached in the management of the out-patient departments. The improved knowledges on tossicological, pharmacodynamic and therapeutic data as well as the advent of the cyclic schedules determined the feasibility of medical treatments even when they are combined with surgical and/or radiotherapeutic modalities. To the patient, the possibility to be carefully and effectively treated on out-patient clinic, renders more acceptable, both from a psychologic and economic point of view, even a prolonged combined treatment. On the same time, also the Institutions have some advantages both on their organization (a shorter median stay in hospital and consequently a reduced waiting list) and for their scientific program (increased number of patients who can be treated according to a therapeutic program, possibilities to obtain statistically valuable information on the treatment program of a given disease and on the knowledge of its natural history). The last five year increasing activity of the Out-Patient Clinic for Medical Oncology Treatment of the Istituto Nazionale Tumori of Milan is illustrated in Text-figure 1, while Text-figure 2 represents its actual organization; this is obviously of a multidisciplinary type, both on its diagnostic and therapeutic phase. Table 1 shows the activity carried out in 1975; it is noteworthy that 2,570 patients have been followed, thus accounting for a total of 20,164 medical examinations and/or intravenous drug administrations. Table 2 presents the incidence of the different types of neoplasia followed in the out-patient department: the large majority was represented by breast cancer (40%); followed by malignant lymphomas (31.5%) and pediatric tumors (7.5%). During 1975, 22 therapeutic protocols have been applied, 10 of which (table 4) required an initial hospitalization and 12 (table 5) could be entirely carried out in the out-patient department. As shown in Table 6 chest x-rays accounted for 52% and skeletal survey for 18% of the 11.906 radiological examinations. Table 7 shows the number of off-hand required radiological reports carried out for patients not geographically accessible who, in one signle day, could have their radiological, and medical examinations as well as their hemogram and treatment performed. A total 467 scintiscans have been required, 86% of which of the liver (table 8). The hemato-pathology unit counted out about 16,000 hemograms with platelets (table 9). The hemograms were always performed within 1-2 hours with immediate communication of the counts to the out-patient department. In order to modify clinical situations which were deteriorated because either of the disease or of the treatment 358 blood units were transfused.

A combination of mitomycin C and vinblastine was administered as salvage treatment in 44 patients with heavily pretreated refractory breast cancer. Response rate was 23% (10 of 44) including one complete response of lung metastases. The highest response rate was seen in intrathoracic localizations (45%). Median duration of response was 6.5 months (range, 3+-17+). Treatment was generally well tolerated, and only 25% of patients developed nausea and vomiting. Neurologic toxicity was represented by paresthesia (8 patients) and constipation (one patient). Mild leukopenia was observed in 30 of 172 treatment cycles, but it exceeded grade 2 in only 5 patients. Considering the good compliance of this regimen and the poor prognosis of patients with advanced refractory disease, the combination of mitomycin C plus vinblastine appears to be useful as salvage treatment for metastatic breast cancer.