EFFECTIVE TREATMENT OF ADVANCED BREAST-CANCER WITH VINORELBINE, MITOMYCIN-C PLUS HUMAN GRANULOCYTE-COLONY-STIMULATING FACTOR

A phase II trial was performed to evaluate the efficacy and tolerance of vinorelbine (VNB), mitomycin C (MMC), and recombinant human granulo cyte colony-stimulating factor (G-CSF) in advanced breast cancer. Betw een October 1992 and July 1994, 55 patients entered this trial. Nine p atients had locally advanced disease and 46 had distant metastases, in cluding 14 who had received previous palliative chemotherapy with (n=9 ) or without anthracyclines (n=5). Therapy consisted of VNB 40-50 mg m (-2) diluted in 250 ml saline infused over 30 min every 3 weeks, and M MC 15 mg m(-2) administered by intravenous bolus injection every 6 wee ks. G-CSF was given at 5 mu g kg(-1) day(-1) subcutaneously from days 2 to 7 following each cytotoxic drug administration. Treatment was con tinued in case of response or stable disease for a total of six course s. The overall response rate was 73% for all 55 patients (95% confiden ce interval, 59-84%), including 12 (22%) complete response (CR) and 28 (51%) partial response (PR); 13 patients (24%) had stable disease (SD ), and only two (4%) progressed. All nine patients with locally advanc ed disease were rated responsive (two pCR, seven PR) and underwent sur gery with curative intent. Eight out of nine remain disease free after a median observation period of Is months (range, 13.5-28 months). Amo ng the 32 previously untreated patients with metastatic disease, nine (28%) achieved CR, 15 PR (47%), seven SD (22%) and one PD (3%). Second -line chemotherapy with this regimen resulted in 7/14 (50%) objective remissions (one CR, six PR), six had SD and one PD. The median time to progression was 12 months (range, 2-24+months) in previously untreate d patients with disseminated disease, and 6.0 months (range, 2-22 mont hs) in those who had failed prior chemotherapy. After a median follow- up time of 20 months, 24 patients with distant metastases are still al ive with disease; median survival has not been reached yet. The dose-l imiting toxicity was myelosuppression: six (11%) and ten patients (18% ) had World Hearth Organization grade 3, and eight (14%) and nine pati ents (16%) had grade 4 leucopenia and granulocytopenia respectively. S evere (WHO grade 3) non-haematological toxicities included nausea/vomi ting in 7%, constipation in 9%, peripheral neuropathy in 5%, infectiou s episodes in 7%, phlebitis due to drug extravasation in 5%, alopecia in 9%, and acute reversible pulmonary toxicity in 11%. Our data sugges t that vinorelbine, mitomycin C plus G-CSF has an excellent anti-tumou r activity in advanced breast cancer, probably superior to most other available combination chemotherapy regimens. This combination does not seem to present significant cross-resistance with previous CMF or ant hracycline regimens. Apart from reversible, acute pulmonary, toxicity, a rare adverse reaction that had previously been described for VNB, a s well as the combination of natural vinca alkaloids with mitomycin C, and few episodes of grade 3 neurotoxicity (all of which occurred at t he initial 50 mg m(-2) VNB dose level), the tolerance of this regimen seems acceptable and justifies further evaluation in front-line and sa lvage therapy of advanced breast cancer.