Mitomycin "C" and vinorelbine as second line chemotherapy for metastatic breast carcinoma.

AIMS AND BACKGROUND: Patients with metastatic breast carcinoma resistant to first line chemotherapy may require further treatment. Results o second line chemotherapy are still largely unsatisfactory. For this reason a phase II study on the combination of mitomycin C and vinorelbine was carried out. METHODS: Forty patients with anthracycline pretreated metastatic breast cancer were treated with a combination of mitomycin C 10 mg/m2 i.v. on day 1, and vinorelbine 25 mg/m2 i.v. on days 1 and 8. This cycle was repeated every 28 days. Responses were evaluated according to the WHO criteria. RESULTS: A major objective response was recorded in 16 cases (40%; 95% confidence limits 32%-48%), with 2 patients (5%) obtaining a complete response with a median duration of 8.0+ months, and 14 (35%) a partial response with a median duration of 7.3+ months. Nine patients (23%) showed no change, and 15 progressed. Patients who did not meet the minimal required criteria to be evaluable were considered as treatment failures. Responses were seen at all sites of disease, but skin, nodal, and soft tissue lesion were more chemosensitive than liver, lung, and bone ones. The mean survival of patients with complete and partial responses was 8.9+ months, whereas that of patients with no change or progressive disease was 7.8 and 6.0 months respectively. Treatment was very well tolerated by most patients. Gastrointestinal toxicity was mild. Grade 2 leukopenia was recorder in 45% of patients, and grade 3 leukopenia in only 10%. Grade 2 thrombocytopenia was seen in 5%. Reversible mild to moderate constipation occurred in 45%, but no case of severe neurotoxicity was observed. CONCLUSIONS: Our data suggest that the combination of mitomycin C and vinorelbine is active in metastatic breast carcinoma refractory to first line chemotherapy containing anthracyclines, and may be safely administered on an outpatient basis.

A phase I-II study of cyclophosphamide, epidoxorubicin, levofolinic acid/5-fluorouracil and recombinant human granulocyte colony stimulating factor in metastatic breast carcinoma.

Thirty patients with measurable metastatic breast carcinoma were treated with a combination of cyclophosphamide 600 mg/m2 on day 1, levofolinic acid 100 mg/m2 plus 5-fluorouracil 375 mg/m2 on days 1-3, and epidoxorubicin (EDXR) in three refracted doses on days 1-3 with G-CSF rescue for 10 days. In the phase I part of the study, groups of 3 patients received EDXR 20, 25, 30, 35, and 40 mg/m2/day until the dose limiting toxicity (DLT) was reached. At the dose of 40 mg/m2/day prolonged grade 4 leukopenia, severe proctitis, and grade 3 diarrhea represented the DLT. All subsequent patients were treated at the maximal tolerated dose of EDXR (35 mg/m2/day). In the group of 18 patients treated at 35 mg/m2/day the overall response rate was 78%, with 22% CR and 56% PR. Four patients did not respond. Objective responses were seen at all tumor sites including bone and viscera, which usually are rather chemotherapy insensitive. Toxicity was generally acceptable. Although the response rate was quite high, the duration of objective tumor regression and patients' survival were not impressive. In conclusion, we do not recommend routine use of such an aggressive regimen for palliation of advanced breast cancer. Results of the present and similar studies may, however, be useful for planning of neoadjuvant or adjuvant trials with curative intent.

Phase II study of lonidamine in metastatic breast cancer.

Thirty patients with previously treated metastatic breast cancer were entered in a phase II study with oral lonidamine. Twenty-eight patients are evaluable for toxicity and 25 for response. A partial remission was obtained in four patients (16%) and disease stability in 11 (44%): 10 patients progressed (40%). Toxicity was acceptable, consisting mainly of myalgias (39% of patients) and asthenia (21.4%). No myelotoxicity was observed. The drug is active in previously treated metastatic breast cancer and, because of its peculiar pattern of action and toxicity, deserves to be evaluated in combination with cytotoxic chemotherapy.

Phase II trial of recombinant alpha-2b interferon in the treatment of metastatic skin melanoma.

A pilot study was undertaken to evaluate toxicity and activity of recombinant alpha-2b interferon in patients with metastatic malignant melanoma. Interferon was administered at the dosage of 10 x 10(6) IU/m2, 3 times a week i.m. 21 patients entered the study, 17 pretreated with chemotherapy and/or immunotherapy and 6 untreated. We obtained 3 partial responses (14.3%; 95% CL, 3.0-36.3%); 9 patients had stable disease. All patients experienced flue-like symptoms and fever; most fatigue and worsening of performance status. Recombinant interferon alpha-2b at the dosage and schedule used has limited but definite activity in metastatic malignant melanoma; the substantial subjective toxicity must be taken into consideration. Further trials testing recombinant alpha interferon in combination with chemotherapeutic agents, like DTIC, are warranted.

Adjuvant tamoxifen in primary breast cancer: influence on plasma lipids and antithrombin III levels.

The possible estrogenic effects of tamoxifen on plasma lipids and antithrombin III levels were investigated in 91 breast cancer patients. Mean values of total, HDL and LDL cholesterol, triglycerides, glucose, uric acid, and antithrombin III were evaluated in 55 patients on adjuvant tamoxifen for at least 3 months and compared with those found in 36 patients on no therapy. Total cholesterol, LDL cholesterol, and antithrombin III levels were significantly lower in treated patients (p less than 0.05). Our results support the hypothesis of a partial agonist action of this antiestrogen, although general clinical practice suggests that tamoxifen-related thrombotic events are rare.

Cisplatin and 5-fluorouracil in refractory breast cancer patients: a phase II study.

24 patients with a median of 3 prior chemotherapy regimens were treated in our department with cisplatin 20 mg/m2 (with pre- and posthydration) and 5-fluorouracil 200 mg/m2 i.v. on day 1-5, every three weeks. 23 patients are evaluable; one had early death. 4 patients (17%) achieved a partial response, 8 had stable disease, and 11 progressed. Toxicity observed was moderate and no renal toxicity was noted. This study therefore shows tolerable toxicity but limited usefulness of adding cisplatin to 5-fluorouracil according to this schedule in these highly pretreated patients.

Sequential administration of cyclophosphamide, methotrexate, 5-fluorouracil, and folinic acid as salvage treatment in metastatic breast cancer.

Experimental data show that sequencing methotrexate (MTX) and 5-fluorouracil (5-FU) may result in synergistic antitumor activity. Moreover, the effect of 5-FU is increased by folinic acid (FA), and finally, cyclophosphamide (CPA) produces an expansion of tumor growth fraction, suggesting an increased cytotoxic effect of cycle-specific drugs subsequently administered. Based on these premises, we have performed a Phase II study with CPA (600 mg/m2 i.v., day 1), MTX (200 mg/m2 1-h i.v. infusion, day 7), 5-FU (600 mg/m2 i.v., day 8), and FA (500 mg/m2 2-h i.v. infusion, day 8 plus 15 mg p.o. every 6 h on days 8 and 9) administered every 3 weeks. Thirty-six patients with metastatic breast cancer were admitted into the study. Median age was 52 years, and all but two patients were postmenopausal. Dominant sites of metastases were soft tissues in 10 patients, bones in 7 patients, and viscera in 19 patients. All patients were pretreated with chemo- and/or hormone therapy. Sixteen patients achieved an objective response (44.5%: 1 complete response and 15 partial responses), 8 had stable disease (SD) (22.2%), and 12 progressed (33.3%). Twenty-one patients had previously received conventional CMF in an adjuvant setting (15 patients) or for metastases (6 patients): 1 complete response (CR) and 7 partial responses (PR) were obtained in the first group and 1 in the second. Major toxic effects were hair loss (56.4%), nausea and vomiting (72%), mucositis (52.5%), and leukopenia (61%). A randomized study could be useful to assess the role of sequential CMF versus conventional CMF in metastatic breast cancer patients.