A phase II clinical trial was set up in metastatic breast cancer patients who had not received previous cytotoxic drug therapy, involving the administration of cis-dichlorodiammine platinum (cis-DDP). Patients aged up to 75 years and with pathohistologically confirmed disease were entered on the trial. All patients had measurable disease, a performance status (Karnofsky) of greater than 40, and an expected survival of greater than 6 weeks. In all 38 patients entered the trial, and 35 have been evaluated. The predominating metastatic sites included soft tissues (19), visceral organs (12), and bones (7 patients). cis-DDP was administered in a daily dose of 30 mg/m2 IV by a 4-h drip for 4 days, with customary hyperhydration. The results indicate a pronounced antitumorigenic effect of cis-DDP and a response rate of 54% (19/35), with 13 complete remissions (37%) and six partial remissions (17%). In terms of site the best response was obtained in soft-tissue processes (13/19; 68%), followed by visceral organs (4/10; 40%); the response rate was lowest in bones (2/6; 33%). The menopausal status and prior hormone therapy did not essentially influence the results of treatment, unlike previous irradiation. Patients with a lower performance status (40-70) had a significantly lower response rate (36% vs 63%; P less than 0.05). Toxic side-effects were moderate and did not substantially affect the general condition of the patients. A transient increase of serum creatinine was observed in 4 patients, and neurotoxicity in 2 patients. The results of the trial warrant the conclusion that cis-DDP has a pronounced antitumorigenic effect in untreated metastatic breast cancer, particularly in soft-tissue metastases. These results call for additional clinical study of the cytotoxic effect of cis-DDP in untreated metastatic breast cancer.

Due to the favourable results previously obtained with cisplatin in breast cancer (54% response rate), we studied a second-generation platinum analogue, carboplatin, in patients with previously untreated breast cancer. A total of 20 patients were entered in the study and all were evaluable. The median age was 57 years and all patients were in menopause. Karnofsky scores of 80-100 and 40-70 were registered in 14 and 6 cases, respectively. The predominant metastatic site was soft tissue in 12 subjects, visceral organs in 5 and bone in 3; 14 patients had greater than 2 metastatic sites. Carboplatin was given i.v. at a dose of 400 mg/m2 on day 1, with a 3-week rest period. In 13 patients who did not respond or whose disease recurred after carboplatin treatment, the CMFVP, CAP or FAC regimen was given as second line treatment. Carboplatin activity was observed in 4 patients [2 complete remissions (CRs) and 2 partial responses (PRs)], for a response rate of 20% (4/20); the 2 PRs were observed in soft tissue and bone and the 2 CRs, in lung, liver and bone. Remission lasted 2-10 months (mean, 4 months). CMFVP given as second-line chemotherapy to 13 patients produced 7 PRs (7/13, 54%). Toxicity was moderate, producing no drug-related deaths. Anemia (grade I-II) was recorded in seven patients; grade I-II leukopenia, in six; and grade III-IV leukopenia in two (median leukocyte nadir, 1,600/mm3). Thrombocytopenia was observed in three cases (grades I, II and III; median platelet nadir, 47,800/mm3). Unpleasant nausea/vomiting was pronounced (12 cases of grade III-IV) in 19 subjects. There were no cases of neuro- or nephrotoxicity. Due to permanent myelosuppression, no more than five cycles could be given. Our study showed that, unlike cisplatin, carboplatin given at a dose of 400 mg/m2 has low antitumorigenic activity in breast cancer patients and produces pronounced myelotoxicity. Additional first-line chemotherapy studies using carboplatin are needed to define the antitumorigenic activity of this platinum analogue.

From January 1991 to August 1993,237 women with metastatic breast cancer were recruited into a multicentric phase II clinical trial designed to assess the cardioprotective activity of Cardioxane (ICRF-187). All patients were treated with 5-fluorouracil 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m² (FDC) and Cardioxane 1000 mg/m², in cycles repeated every 3–4 weeks. Cardiac functions were assessed at baseline by physical examination, ECG, and resting ultrasound left ventricle ejection fraction (LVEF). The same tests were repeated regularly after the 3rd, 6th, 8th cycle and every additional 100 mg/m² of doxorubicin. At the end of the study there were 212 evaluable patients. Prior to analysis, patients were stratified according to the presence of cardiac risks at study entry. One hundred thirty-three patients (63%) bore one or more cardiac risks. The average total cumulative dose of doxorubicin administered to the group was 311 mg/m² (range: 200–900 mg/m²). Overall response (CR + PR) was 49.5% (105/212), with 12% of patients entering complete remission. General toxicity (WHO grading) was mild and tolerable; no excessive myelosuppression or related symptoms were observed. Three patients from the risk group experienced cardiotoxity, with an LVEF fall below 45%, and had to be removed from the study. Another 3 patients (1 from the risk group) were removed from the study due to clinically documented congestive heart failure after 200, 300 and 400 mg/m2 of doxorubicin. In our study, Cardioxane (ICRF-187) did not influence the antitumor efficacy of FDC chemotherapy, nor did concomitant administration of Cardioxane and chemotherapy result in any other or severer toxicity than that already known for this regimen. Finally, the observation that 51 % of patients with preexisting cardiac risks received doxorubicin at dose range of 450–900 mg/m² without significant clinical or laboratory signs of cardiotoxicity supports the evidence that Cardioxane provided cardiac protection offering the possibility of longer doxorubicin chemotherapy.

The aim of this study was to examine antitumorigenic Cis DDP properties in metastatic brain tumors. Thirty-four untreated patients with brain metastases recorded by CAT scans or radionuclide scans plus neurological examinations underwent the treatment. Pathohistology of primary tumors mainly showed breast [8] and lung [8] carcinomas and melanomas [10]. Other localizations of primary tumors were infrequent. Cis DDP was administered in doses of 30 mg/m2 body surface daily over 4 days. All the patients received at least two cycles and 33 have been evaluated. No corticosteroids were administered concurrently. An objective response (seven complete and seven partial remissions) was observed in 14 out of 33 patients (42%). Six stable disease cases were also noted. A complete response (5-14 months) was observed in breast cancer [4], lung cancer [1], and melanoma [2]. Seven partial responses lasted 2-5 months. Antitumorigenic activity of Cis DDP was also noted in extracerebral tumor lesions, especially in breast cancer patients. Toxicity was moderate but tolerable. The results of this study have shown Cis DDP to possess antitumorigenic properties also in patients with metastatic brain tumors, a point that has not been proved so far.

The analgesic effect of salmon calcitonin was tested by a double-blind clinical randomized controlled trial in 40 female patients with painful osteolytic metastases. Twenty patients were administered (daily) 100 IU of salmon calcitonin subcutaneously over 28 days, while the other 20 were administered identical ampoules containing 2 ml of physiological solution over the same period of time. The basic treatment (chemotherapy, hormone therapy) was not changed during the trial, and had to be stabilized for a minimum of 3 months prior to the trial. The effect of calcitonin was monitored with respect to daily analgesic consumption, duration of pain, patient’s functional capacity, patient’s own assessment of pain, and assessment of efficacy by the investigator. Statistically significant differences were established in terms of reduced analgesic consumption, shorter duration of pain and the patient’s subjective assessment of pain duration and intensity; the difference was not statistically significant with regard to patient’s functional capacity. The objective assessment of the analgesic effect of calcitonin by the investigator showed the drug to be extremely useful in 3 patients and moderately useful in 11 patients; 3 instances of ‘moderately useful’ were observed in the placebo group. No changes were observed in serum calcium levels; there were likewise no skeleton changes as established by X-rays and bone scintiscans before and at the end of treatment. The trial has shown calcitonin to produce a pronounced analgesic effect in breast cancer patients with painful osteolytic metastases.