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We conducted a phase II study to determine the activity and tolerability of weekly paclitaxel, 5-fluorouracil (5-FU) and folinic acid plus granulocyte colony-stimulating factor (G-CSF) support in anthracycline-pre-treated or -resistant metastatic breast cancer patients. The phase II study was designed following the Simon optimal-two stage method. Patients received paclitaxel 80 mg/m, folinic acid 10 mg/m and bolus infusion of 5-FU 300 mg/m every week plus G-CSF on day 3 for 24 consecutive weeks in the absence of disease progression. From May 1998 to May 2000, 51 patients entered the study. Patients received a median relative dose intensity of 97.5% (range 81-100%). No severe toxicities were observed. Seven patients (14%) experienced neutropenia grade 2. Seven patients (14%) experienced grade 2 anemia. Two patients (4%) experienced severe asthenia. Three out of 50 evaluable patients [6%, 95% confidence interval (CI) 2-12.6%] showed a complete response, whereas 23 (46%, 95% CI 32.2-59.8%) had a partial response, with an overall response rate of 52% (95% CI 38.2-65.8%). In addition, eight patients (15.7%) had stable disease. In the 13 patients untreated for metastatic disease, the overall response rate was 92.3% (CI 77.8-100), with one complete response and 11 partial responses (84.6% CI 65-100%). In the whole group, the median time to progression and overall survival were 8 (range 1-18) and 14 months (95% CI 11-17), respectively. Thus, in metastatic breast cancer patients pre-treated with anthracyclines, the weekly administration of paclitaxel, 5-FU and folinic acid with G-CSF support seems to be extremely tolerable and active.

Our objective was to identify a new active three-drug combination regimen consisting of paclitaxel (PTX), epirubicin (EPI) and cisplatin as first-line line chemotherapy for advanced ovarian carcinoma. A phase I study was carried out to evaluate the dose-limiting toxicity (DLT) and the maximally tolerated dose (MTD) of PXT and EPI in combination with a fixed dose of cisplatin every 4 weeks. Side-effects were recorded according to the NCI Common Toxicity Criteria. Patients were treated in cohorts of three with fixed-dose cisplatin 80 mg/m2 and EPI 80-->100 mg/m2 and PXT 100-->160 mg/m2 until DLT was reached. Once MTD was identified, a single-step phase II study was therefore carried out to test the clinical activity and panel of toxicity of such regimen. Objective responses were recorded according to the WHO criteria. Time to progression and overall survival (OS) were secondary endpoints. The DLT was myelosuppression and, in more detail, febrile neutropenia, which occurred at the fifth dose level (PTX 140 mg/m2, EPI 100 mg/m2 and cisplatin 80 mg/m2) in two out of three patients. Other side-effects were grade 3 mucositis in two out of three patients and grade 3 anemia in one case. The combination of cisplatin 80 mg/m2 plus EPI 80 mg/m2 and PCT 140 mg/m2 every 4 weeks was considered as the MTD. In the phase II study a complete response was observed in six patients (33%) and a partial response in nine cases (50%) for an overall response rate of 83% [95% confidence limits (CL) 59-96%]. Median time to progression of patients with measurable disease was 16.4 months. Median OS was not reached after a follow-up of 42 months. This study demonstrated that PTX and EPI can be safely administered in combination with cisplatin to fit patients with advanced epithelial ovarian carcinoma. The three-drug regimen of cisplatin 80 mg/m2, EPI 80 mg/m2 and PTX 140 mg/m2 every 4 weeks is very active, at least in terms of objective response rate. This level of activity overlaps with the 95% CL of the activity of cisplatin alone; however, it does encourage future trials of the combination.

Forty patients with chemotherapy-related diarrhea were randomized to receive (i) octreotide 0.5 mg three times per day s.c. or (ii) loperamide 4 mg three times per day p.o. until complete remission of diarrhea was achieved. In the octreotide group 80% of patients showed complete resolution of loose bowel movements within 4 days of therapy, while in the loperamide group this goal was obtained in only 30% of cases (p < 0.001). If after 4 days no benefit was seen, patients were considered to have failed antidiarrheal therapy. Failure was recorded in only one case (5%) treated with s.c. octreotide and in five patients (25%) who received loperamide. The mean duration of antidiarrheal therapy necessary to achieve remission was 3.4 days in the octreotide group and 6.1 days in the loperamide group (p < 0.001). Treatment with octreotide was very well tolerated with mild abdominal pain in 15% of cases and pain in the injection site in 15% of patients. Subcutaneous octreotide is highly effective in the management of chemotherapy-related diarrhea in cancer patients.

After informed consent 21 patients with advanced head and neck cancer resistant to folinic acid/5-fluorouracil (FA/5FU + cisplatin) were treated with weekly FA/5FU plus low dose hydroxyurea (HU) to evaluate if HU could further modulate 5FU antineoplastic activity. Five patients achieved a partial response (23.8%) which was short-lived (mean duration 6.5 months). Three patients (14%) had stable disease and 13 (62%) progressed. Among responders, four patients had epidermoidal carcinoma and one had clear cell carcinoma. Treatment was well tolerated and 5FU-related toxicity was not apparently worsened by the addition of HU. The most frequent toxicities were nausea/vomiting (81%), diarrhea (52%) and leukopenia (57%). Grade 3 nausea/vomiting and leukopenia were recorded in only 19 and 9% of cases, respectively. One patient had grade 1 cutaneous toxicity and a second patient showed a hand-foot syndrome. These results suggest that HU may further positively modulate 5FU antineoplastic activity.