High dose methotrexate in adult patients with osteosarcoma: clinical and pharmacokinetic results.

High dose methotrexate (HDMTX) with folinic acid rescue is widely used to treat osteosarcoma, which predominantly afflicts children; the study investigated HDMTX pharmacokinetics (pk) in adult subjects in neoadjuvant/adjuvant settings. Twenty five patients with advanced osteosarcoma (11 females--14 males, median age 26.0 years) were treated by 12 g/m2 HDMTX 4 hour iv infusion (64 total courses, range 1-7 courses). Pk was determined by non-compartmental analysis and population pk modeling. Median (range) bioavailability pk parameters were: C(max) (maximum MTX concentration) 1149.5 microM (692-2,200), AUC(tot) (total area under curve) 6,955.1 micromol*h/l (3,477-12,681). C(max)>1,000 microM gave increased histological responses (p < 0.05). Six covariates (height-weight-hemoglobin-AST-ALT-creatinine) were found to influence MTX volume of distribution (V) and elimination rate constant (K(el)). Toxicity was mild: only two reversible G4 events were observed, related to AUC(tot) >12,000 micromol*h/l (p < 0.001). HDMTX pk and interpatient variability in adults are comparable to those in children. No correlation between C(max)/AUC(tot) and subject age/sex was found, even in the population pk model. The excretion mechanism is not affected by sex/age differences. HDMTX can safely be administered to adults: as in younger patients, a good clinical response can be predicted by C(max), while severe toxicity depends on highest AUC(tot) values.

Clinical data and pharmacokinetics of a docetaxel-vinorelbine combination in anthracycline resistant/ relapsed metastatic breast cancer.

The aim of this study was to evaluate the pharmacokinetic parameters, efficacy and toxicity of a docetaxel and vinorelbine combination in metastatic breast cancer patients previously treated with anthracycline. A population of 40 patients was analyzed; 30 patients (75%) had visceral metastases as the dominant site of disease, including 20 patients (50%) with liver metastases. Three or more organs were involved in 43% of patients. All patients had received prior anthracycline therapy. Five patients (12%) had primary resistant disease, 10 patients (25%) secondary resistant disease and 25 patients (63%) had progressive metastatic breast cancer after first-line chemotherapy. Docetaxel and vinorelbine were given at 80 mg/m2 and 20 mg/m2 i.v., respectively, on day 1 every 3 weeks. After a median of 5 cycles, it was found that 5 patients had a complete remission (13%), 19 a partial remission (48%), 9 had stable disease (22%) and 7 had progressive disease (17%). Response rates in patients with visceral and liver metastases were 57% and 50%, respectively. After a median follow-up of 24 months (13-36), median time to progression was 8.5 months and median overall survival 17 months. Grade 4 neutropenia was observed in 78% of courses (febrile neutropenia in 9%). Possible pharmacokinetic interactions were studied in 23 patients by administering docetaxel immediately followed by vinorelbine (protocol A) or vinorelbine followed by docetaxel (protocol B). Patients in protocol B had significantly higher vinorelbine plasma levels and more pronounced neutropenia. Docetaxel plus vinorelbine is an effective combination in anthracycline resistant/relapsed metastatic breast cancer. The administration sequence docetaxel --> vinorelbine is safer than the reverse order.

Docetaxel and vinorelbine in recurrent head and neck cancer: pharmacokinetic and clinical results.

The purpose of this study was to evaluate pharmacokinetic parameters, efficacy, and toxicity of a combination of docetaxel (DTX) and vinorelbine (VNB) in recurrent heavily pretreated squamous cell head and neck cancer. Twenty-nine patients previously treated with concomitant chemoradiotherapy (n = 14), surgery plus radiotherapy (n = 13), surgery+concomitant chemoradiotherapy (n = 1) and radiotherapy alone (n = 1) were enrolled; 9 patients had received 1 or more courses of palliative chemotherapy. Twenty-one patients had a local-regional recurrence, and 8 patients had metastases. The doses were 80 mg/m2 for DTX and 20 mg/m2 for VNB on day 1 every 21 days for a maximum of 6 cycles. Pharmacokinetic evaluations were performed on 24 patients; in a group of 12 patients, VNB administration immediately followed DTX infusion (schedule A), and in 12 patients VNB administration was immediately followed by DTX infusion (schedule B). Twenty-nine patients received a total of 137 cycles (median per patient, 5). Neutropenia was the most frequent and severe side effect (grade IV in 79%; grade III in 21%). Grade IV (7%) and III (14%) infections were observed in the first 12 patients; ciprofloxacin prophylaxis in the following 17 patients reduced the severe toxicity to 0%. The overall response rate was 49%, which included 3 of 29 complete responses (10%) and 11 of 29 partial responses (38%). Median complete and partial response durations were 20+ and 5.5 months, respectively. Overall median survival was 10 months (range, 2-30+). The mean values of area under the curve, mean residence time (MRT), and C(max) of VNB were significantly lower for schedule A than for schedule B. The mean values of VNB clearance were significantly higher for schedule A than for schedule B. Neutrophil count at the nadir was much lower for patients receiving schedule B. The DTX-VNB combination is effective in heavily pretreated patients with a short-lasting manageable toxicity. Pharmacokinetic evaluations suggested that the sequence DTX --> VNB is safer than the sequence VNB --> DTX.