Combining platinum, paclitaxel and anthracycline in patients with advanced gynaecological malignancy

Two meta-analyses have suggested that the addition of an anthracycline to platinum-based chemotherapy may improve survival in advanced ovarian cancer, and two randomised trials have demonstrated superiority of paclitaxel over cyclophosphamide in platinum combinations. A combination of platinum, anthracycline and paclitaxel would, therefore, be a reasonable experimental arm of any future randomised trial in patients with epithelial ovarian carcinoma (EOC). Patients who required chemotherapy for EOC but were ineligible for standard trials or had other gynaecological tumours that required similar platinum-based chemotherapy were considered for this pilot. The platinum/anthracycline/paclitaxel regimen (G-CAT) was given 3-weekly and consisted of doxorubicin 50 mg/m(2) or epirubicin 60 mg/m(2) intravenously (i.v.) bolus, paclitaxel 175 mg/m(2) (i.v.) over 3 h and either cisplatin 75 mg/m(2) (i.v.) or carboplatin AUC 6, with granulocyte colony-stimulating factor (G-CSF) at the neutrophil nadir. Different combinations were used in order to determine the least toxic regimen. Toxicity and response were assessed according to CTC and WHO criteria, respectively. 26 patients entered the study, 13 with EOC and 13 with other gynaecological cancers (peritoneal, fallopian tube, mixed Mullerian). Median age was 49 years (range: 27-67). 8 patients received carboplatin/doxorubicin/paclitaxel, 8 cisplatin/doxorubicin/paclitaxel and 10 carboplatin/epirubicin/paclitaxel. A total of 135 cycles of chemotherapy were delivered, with a median of 6 cycles per patient (range: 2-6). 54 (40%) cycles required G-CSF support and 17 (65%) patients required at least one dose reduction. All patients experienced grade 4 neutropenia and 13 (50%) patients developed grade 3-4 thrombocytopenia (12 of whom had received carboplatin). There were 4 (15%) patients with grade 3/4 infections but no septic deaths. Non-haematological toxicities were manageable, lethargy occurred in 75% of cisplatin-treated patients. Grade 1/2 cardiotoxicity, as assessed pre- and post-treatment by left ventricular ejection fraction, was observed in 6/13 (46%) patients who had received doxorubicin and 2/7 (29%) epirubicin-treated patients. No clinically detectable cardiac toxicity was encountered. The response rate in 25 evaluable patients was 76% (12 CR, 7 PR). Dose intensity was highest in the carboplatin/epirubicin/paclitaxel combination. G-CAT shows high activity and can be administered safely, but only very fit patients are suitable for this regimen as it is associated with considerable toxicity. Carboplatin/epirubicin/paclitaxel was the best tolerated regimen overall.