Vinorelbine/docetaxel combination treatment of metastatic breast cancer: a phase I study.

PURPOSE: The aim of this study was to investigate the combination of vinorelbine (VRL) alternating intravenous (i.v.) and oral in combination with docetaxel (DCT) as first-line chemotherapy of patients with metastatic breast cancer. PATIENTS AND METHODS: Tested doses were 60 or 70 mg m(-2) given on day 1 for DCT, 20 to 25 mg m(-2) for i.v. VRL on day 1, 60 mg m(-2) on day 8 or day 15 for oral VRL. Day 1 was administered every 3 weeks. Three to six patients were treated per dose level. RESULTS: The median age of the 30 treated patients was 60 years. Four patients were non evaluable for the maximum tolerated dose (MTD) and were replaced. Reported dose-limiting toxicities were 11 omissions of oral VRL for neutropenia, two cases of febrile neutropenia and two grade 4 neutropenia >or=7 days. Dose levels using DCT doses >60 mg m(-2) and/or i.v. VRL doses >20 mg m(-2) met the criteria for MTD. Most frequent toxicities were febrile neutropenia in seven patients and neutropenic infection in four patients (one fatal). Therefore, the recommended schedule was established at i.v. VRL 20 mg m(-2) with DCT 60 mg m(-2) on day 1 and oral VRL 60 mg m(-2) given on day 15 every 3 weeks. At this recommended schedule, only one of six patients experienced febrile neutropenia. Among 22 patients evaluable for tumour response, 2 complete and 10 partial responses were reported. Pharmacokinetics of combined VRL and DCT demonstrated the absence of mutual interaction. CONCLUSIONS: This phase I study established the recommended doses and schedules of the combination alternating i.v. and oral VRL with DCT, this recommended regimen being further explored in a phase II study.

Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients.

PURPOSE: A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial. PATIENTS AND METHODS: Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined. RESULTS: A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase. CONCLUSION: Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.

Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicentric randomized trial in patients with locally advanced head and neck carcinomas.

A significant link between 5-fluorouracil (5FU) plasma concentration and its therapeutic activity has been demonstrated in colon and head and neck cancer patients for 5FU used as a continuous infusion. Dose adjustment based on pharmacokinetic follow-up has been proposed to decrease hematological and digestive toxicities, but the clinical impact of this approach has not yet been demonstrated. A randomized multicentric study was conducted to evaluate the clinical interest of 5FU dose adaptation guided by pharmacokinetics. One hundred twenty-two head and neck cancer patients were randomly assigned to receive induction chemotherapy with cisplatin (100 mg/m2, day 1) and 5FU (96-h continuous infusion), either at standard dose (St-arm; 4 g/m2) or at a dose adjusted according to the 5FU area under the curve (AUC0-48h; PK-arm). In total, 106 patients were evaluable for toxicity and response. In the PK-arm (n = 49), 5FU doses and area under the curve were significantly reduced during cycle 2 and cycle 3 (P < 0.001) as compared with the St-arm (n = 57). Grade 3-4 neutropenia and thrombopenia were significantly more frequent in the St-arm as compared with the PK-arm (17.5% versus 7.6%, respectively; P = 0.013). No grade 3-4 mucositis occurred in the PK-arm, whereas 5.1% was observed in the St-arm (P < 0.01). The objective response rate was comparable in the two treatment arms: 77.2% in the St-arm versus 81.7% in the PK-arm. The present study is the first to demonstrate, in a randomized design, the clinical interest of an individual 5FU dose adaptation based on pharmacokinetic survey, in terms of therapeutic index improvement.

Pharmacokinetics and pharmacodynamics of nitrosourea fotemustine: a French cancer centre multicentric study.

The nitrosourea, fotemustine, was given intravenously in 1 h constant-rate infusion to 66 patients in a multicentric study to assess both fotemustine pharmacokinetic behaviour and the pharmacokinetic-pharmacodynamic relationships. Depending on the tumour type treated, two administration and sampling protocols were used: 100 mg/m2/week as a conventional dose (six samples, 44 patients) and 300-500 mg/m2/day as a high dose (10 samples, 22 patients). The 91 time-concentration curves were best described by either a one-(55) or a two-compartment (36) model, and their mean clearance values did not differ significantly (85.3 +/- 6.5 and 101.3 +/- 9.5 l/h, respectively, P = 0.1727). Fotemustine pharmacokinetics were not influenced by repeated treatment (time-independence) nor by dose level (dose-independence). The pharmacodynamic effect observed on white blood cell count was expressed by a logit regression model involving the area under the curve mainly and the total administered dose. White blood cell toxicity could be predicted as a function of the dose for a given patient with a known fotemustine clearance value.

Phase I pharmacological study of intra-arterially infused fotemustine for colorectal liver metastases.

Fotemustine was investigated in 17 patients with progressive hepatic metastases from colorectal carcinoma to define the maximally tolerated dose for a daily hepatic intra-arterial infusion (HAI) schedule. Haematotoxicity was delayed, dose-dependent and related to pretreatment, with thrombo- and leucocytopenia being dose-limiting. Local side-effects at the liver were mild. Infection (WHO grade III) occurred in 1 patient due to neutropenia. Other side-effects, particularly renal, pulmonal, neurological or cardiac toxicity, mucositis and diarrhoea, hair loss or allergic reactions did not occur. Pharmacokinetic analysis indicated a short plasma half-life (t1/2 = 25.8 +/- 11.5 min) and a high body clearance (CL = 2193 +/- 870 ml/min) with large inter- and intra-individual variations. Of 15 evaluable patients, one complete and three partial responses were observed (ORR = 27%; CI95% [4.5-49.5%]). All tumour remissions appeared at higher dose levels in previously untreated patients. Considering the absence of mucosal side-effects, such as mucositis/diarrhoea and of hepatic toxicity, this agent was well tolerated. The recommended intra-arterial dose for consecutive phase II trials is 125 mg/m2/day1-3.

Comparative responses of the central adrenaline- and noradrenaline-containing neurons after reserpine injections.

The responses of the noradrenaline (NA)- and adrenaline (A)-containing neurons to a reserpine treatment have been studied in the rat brain by using biochemical indices of the neuronal activity. Three days after multiple reserpine injections, tyrosine hydroxylase activity was significantly increased in the locus coeruleus (LC), A1-C1 and C2 regions. No change in this activity was observed in the A2 region. Furthermore, the NA and A endogenous levels were markedly reduced both in NA and A cell bodies and/or terminals, suggesting a reserpine action on NA and A neurons. The NA turnover was unchanged in all the regions analyzed. Conversely, the A turnover was reduced in the LC, A2 and C2 regions and in the nucleus periventricularis of the hypothalamus. This result suggests a different degree of sensitivity and/or response of the NA and A neurons following reserpine administration.

Changes in tyrosine hydroxylase and dopamine-beta-hydroxylase activities but not in phenylethanolamine-N-methyltransferase activity within central adrenaline neurons after 6-hydroxydopamine administration.

By using a new microdissection procedure allowing the noradrenaline (NA) and adrenaline (A) cell groups of the A2-C2 region to be sampled preferentially, it was possible to study the biochemical response of these two neuronal populations after 6-hydroxydopamine (6-OHDA) administration. Five days after an intraventricular 6-OHDA injection, tyrosine hydroxylase (TH) activity increased (+104%, P less than 0.01) in the adrenergic C2 region, in the locus coeruleus (LC) and in the A1-C1 region, while the NA A2 region exhibited no significant increase. Twenty-one days after 6-OHDA administration, dopamine-beta-hydroxylase (DBH) activity had decreased in both the noradrenergic regions (LC, A1-C1 and A2 regions) and in the C2 adrenergic region. Conversely, phenylethanolamine-N-methyltransferase (PNMT) activity was not modified either in the cell bodies or in the terminals located in the tractus intermediolateralis of the spinal cord and in the hypothalamic nuclei. These data suggest: (i) that adrenaline-containing neurons could be sensitive to the neurotoxic action of 6-OHDA since they exhibit changes in TH and DBH activities; and (ii) that the determination of PNMT activity may not be sensitive enough to estimate the functional integrity of the A cell bodies or terminals.

Hepatic intra-arterial infusion of fotemustine: pharmacokinetics.

Fotemustine is a new nitrosourea derivative that contains an alpha-aminophosphonic acid and has a short half-life and a high plasma clearance. As myelosuppression occurs as the dose-limiting toxicity, local drug delivery has been investigated in the treatment of liver metastases arising from colorectal cancer. A pharmacokinetic study was undertaken in patients who received either i.v. or hepatic intra-arterial (HIA) infusion of 100 mg/m2 fotemustine so as to estimate the advantage of local chemotherapy, considering the pharmacokinetic differences between the two routes together with the resultant toxicities (when available). Our findings substantiated the hypothesis that a 4-h HIA infusion of foetmustine would result in a lower exposure of healthy tissues to the drug, since the AUC measured in systemic plasma was reduced by approximately 50% following such treatment as compared with i.v. infusion. This reduction in AUC should indicate a manyfold increase in exposure of the liver tumour to the alkylating properties of the drug, since it represents the proportion of the dose that has degraded within the liver. The first-pass liver-extraction ratio of fotemustine given as a 4-h HIA infusion, which ranged from 0.4 to 0.9 as estimated in patients receiving i.v. and HIA infusions in a cross-over study, argues for further investigation of HIA foetemustine infusion for the treatment of liver metastases so as to increase the response rate and decrease the occurrence of major toxic side effects in such patients.

Modelling of ftorafur and 5-fluorouracil pharmacokinetics following oral UFT administration. A population study in 30 patients with advanced breast cancer.

PURPOSE: The pharmacokinetics of ftorafur, 5-fluorouracil (5FU) and uracil were investigated in order to built a population pharmacokinetic model for the anticancer drug UFT, administered with leucovorin and vinorelbine. METHODS: A total of 31 patients with metastatic breast cancer were treated with escalating oral doses of UFT (300 to 500 mg per day) plus leucovorin (90 mg per day) in combination with intravenous vinorelbine (15 to 25 mg/m(2)). Concentration-time data were obtained on days 1, 8, 15 and 21 of cycle 1. RESULTS: Of the 31 patients treated, 30 were available for the pharmacokinetic analysis. Ftorafur, 5FU and uracil appeared rapidly in plasma and showed large interpatient variations. Ftorafur concentrations were higher than those of 5FU and uracil. AUC significantly increased between day 1, and days 8, 15 and 21. Ftorafur C(max) and AUC values were proportional to UFT dose, whereas C(max) and AUC values of 5FU and uracil were not linearly related to UFT dose. The pharmacokinetics of ftorafur were ascribed to a two-compartment open model in which 5FU was produced from the central compartment. The absorption and exponential distribution rate constants were assumed equal. The effect of uracil on 5FU elimination was straightforward, since no reasonable curve-fitting could be obtained for 5FU data when this covariate was not taken into account. The uracil concentration inducing a 50% reduction in 5FU elimination was 2.67 micro mol.l(-1). This result confirms the important role played by uracil as a competitive inhibitor of 5FU catabolism. CONCLUSION: A pharmacokinetic model for ftorafur and 5FU was developed and should be useful to further study drug interactions and establish dosing guidelines.

Population pharmacokinetics of topotecan: intraindividual variability in total drug.

The inter- and intraindividual variabilities in topotecan clearance (CL) were explored using a population pharmacokinetic approach. Total (lactone + hydroxy acid) topotecan plasma concentrations were obtained in 31 women with metastatic epithelial ovarian cancer treated by the 30-min intravenous infusion on 5 subsequent days. The data corresponding to three occasions (days 1 and 5 of cycle 1, and day 1 of cycle 2), were analyzed using the nonlinear mixed effect model program. A large interindividual variability was observed, with CL varying from 9.1 to 42.51 per hour (mean 21.0). Topotecan CL was related to serum creatinine level, and age. A close relationship was also observed between topotecan CL and creatinine clearance. Intraindividual variability both within cycle 1 and between the two first cycles was limited, with a mean variation of -2+/-17%, and + 5+/-20%, respectively. A limited sampling strategy using Bayesian estimation based on two samples (5 min before the end of the 30-min infusion, and 4 h after the end of infusion) was developed. The results of this study combine relationships between topotecan pharmacokinetic parameters and patient covariates that may be useful for a priori dose adjustment, and convenient sampling procedure that can be used for further studies and drug monitoring.

Population pharmacokinetics of short intravenous vinorelbine infusions in patients with metastatic breast cancer.

PURPOSE: To develop a population pharmacokinetic model of vinorelbine administered by short intravenous infusion in metastatic breast cancer patients. METHODS: Vinorelbine was administered as infusions of 5-10 min at 15, 20 or 25 mg/m(2) to 30 patients. Blood samples were collected over 18 h. Plasma concentrations of vinorelbine were determined by HPLC. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modeling method. RESULTS: Vinorelbine concentration-time profiles were best described by a three-compartment open model. Plasma clearance (CL) was high and positively related to lean body weight (LBW) and body surface area (BSA) or to a combination of height and body weight (BW). Elevated serum alkaline phosphatases had a negative effect on CL. Typical population estimates of CL and central distribution volume (V(1)) were 74.2 l/h and 7.8 l, respectively. The interindividual population coefficients of variation for CL and V(1) were 17.0% and 32.0%, respectively. The stability and predictive performance of the final population pharmacokinetic model were assessed using 200 bootstrap samples of the original data. CONCLUSION: This study identified combined effects of BSA and serum alkaline phosphatases on clearance. These results partly support the conventional dose adjustment of vinorelbine based on BSA, but suggest dose modification in cases of extreme values of serum alkaline phosphatases.

Time course study of changes in the activity of the catecholamine synthesizing enzymes in the rat medulla oblongata after intraventricular injection of 6-hydroxydopamine.

Recent data have shown that 5 days after intraventricular injection of 6-hydroxydopamine (6-OHDA), the tyrosine hydroxylase activity (TH) was increased within the locus coeruleus (LC). We sought to determine if such an alteration occurs within the A1 and A2 noradrenergic (NA) and C1 and C2 adrenergic (A) neurons of the rat medulla oblongata. The TH activity within the cell bodies was significantly increased 2 days after 6-OHDA injection with a maximum at 5 days (LC, + 109%, P less than 0.001; A1-C1, + 40%, P less than 0.01; A2-C2; + 24%, P less than 0.01) while a significant decrease was present 21 days after 6-OHDA. Conversely, dopamine-beta-hydroxylase (DBH) activity exhibited a decrease which was maximal at 21 days (LC,-41%; A1-C1,-33%; A2-C2,-35%, P less than 0.001). Both the TH (-47% at 5 days) and the DBH (-82% at 12 days) activities were decreased within the terminals of the tractus intermediolateralis (TIML). The phenylethanolamine-N-methyltransferase (PNMT) activity was never altered in the cell bodies nor in the terminals analyzed. These data demonstrate that the NA neurons of the rat medulla oblongata and of the LC exhibit a similar pattern of response to the neurotoxin 6-OHDA. Conversely, the lack of change in the PNMT activity confirms the hypothesis of a resistance of the A neurons to 6-OHDA or questions the validity of the PNMT as an A marker.

Central and peripheral changes in catecholamine-synthesizing enzyme activities after systemic administration of the neurotoxin DSP-4.

In brain regions containing noradrenergic (NA) cell bodies or terminals, DSP-4 induces changes in the activity of catecholamine-synthesizing enzymes which suggest that central NA neurons are lesioned by this neurotoxin. In contrast, the lack of change in the same enzymatic activities in an area containing mostly adrenergic (A) neurons (C2 region), favors the hypothesis of a resistance of the A neurons to DSP-4. Furthermore, the enzymatic changes observed in peripheral organs suggest a peripheral activation of the NA cell bodies in response to lesioning of the sympathetic terminals by DSP-4.

Hepatic arterial infusion of the nitrosourea derivate fotemustine for the treatment of liver metastases from colorectal carcinoma.

The chloroethylnitrosourea derivate diethyl-1-(3-(2-chloroethyl)-3-nitroso-ureido)-ethyl phosphonate fotemustine (FM) was investigated in a open monocentric clinical-pharmacological trial. Seventeen patients, with a median age of 57 years and progressive hepatic metastases from colorectal carcinoma received regional treatment with a stepwise dose-escalated regimen of FM to define the maximally tolerated dose. Thrombo- and leukocytopenia were dose-limiting with median nadir at day 29 (range, 19-79) and day 39 (range, 19-78), respectively. Local side-effects in the liver were mild with only transiently elevated enzymes. No other severe side-effects, except pain (WHO grade III) in one patient after the infusion of FM was noted. The maximally tolerated dose was 125 mg/m(2)/day. Plasma profiles followed a mono-exponential law (one-compartment-model). Systemic concentrations measured as area under the time-concentration curve (AUG) indicated a short plasma half-life (t(1/2)=25.8+/-11.5 min) and a high body clearance (C-L=2.193+/-870 ml/min) with large inter- and intra-individual variations. Of fifteen evaluable patients examined with CT-scan, one complete, three partial, one minor response and seven patients with stable disease were observed [ORR=27%, IC95% (4.5-49.5%)]. In summary, hepatic arterial infusion of FM appears to be effective treatment for liver metastases from colorectal carcinoma. Considering the absence of mucositis/diarrhea and hepatic toxicity, FM could be explored as an alternative to 5-FUDR or 5-FU in previously untreated patients with isolated liver metastases.

Clinical randomized study of 5FU monitoring versus standard dose in patients with head and neck cancer: preliminary results.

Prospective studies of dose adaptation of continuous 5FU infusion combined with cisplatin have shown that pharmacologically guided dosing was feasible in the treatment of head and neck carcinomas. Adaptative dosing results in reduced haematological toxicity, but few data are available for clinical response rate. Preliminary results (38 patients) of a randomized trial comparing standard dose of 5FU (20 patients) and monitoring of 5FU based on pharmacokinetic information (half-cycle area under the curve, 18 patients) indicate that haematological tolerance and complete response rate were improved. Severe (GIII-GIV) thrombocytopenia and neutropenia were significantly reduced during cycle 2 (0% versus 11.1% and 5.5% versus 27.7% respectively, p < 0.01) and cycle 3 (0% versus 27.7% and 6.6% versus 33.3% respectively, p < 0.001). The complete response rate was increased in the group with monitoring of 5FU doses (55.5% versus 40.0%, p < 0.001). These interesting results will be confirmed at the end of the trial, which is expected to include 126 patients.

Docetaxel combined with vinorelbine: phase I results and new study designs.

This was a phase I dose-finding and pharmacokinetic study of vinorelbine (Navelbine) and docetaxel (Taxotere) as first-line chemotherapy for metastatic breast cancer. Vinorelbine dose, 20 or 22.5 mg/m2, on days 1 and 5, was followed on day 1 by docetaxel every 21 days, in doses increasing from 60 to 100 mg/m2. Two maximum tolerated doses were reached, the first at 75 mg/m2 of docetaxel and 22.5 mg/m2 of vinorelbine, and the second at 100 mg/m2 of docetaxel and 20 mg/m2 of vinorelbine. Symptomatic peripheral neuropathy was not observed. The recommended doses for phase II studies are 75 to 85 mg/m2 of docetaxel on day 1 and 20 mg/m2 of vinorelbine on days 1 and 5, every 3 weeks. The treatment regimen, which included 3-day corticosteroid prophylaxis, resulted in only mild fluid retention. Responses were seen at all dose levels, with an 80% overall response rate at the higher recommended dose; the overall response rate for patients at all dose levels was 66%. A high rate of response, including a complete response, was observed in patients with liver metastases.

UFT plus oral calcium folinate/vinorelbine for advanced breast cancer.

This phase I study was undertaken to define the maximum tolerated dose, dose-limiting toxicity, and recommended dosage of UFT (uracil and tegafur) plus oral calcium folinate (Orzel) and vinorelbine (Navelbine) in combination treatment of metastatic breast cancer in patients who have received one prior chemotherapy regimen. The pharmacokinetics of UFT and vinorelbine were also evaluated. Starting doses were UFT 300 mg/day, plus a fixed calcium folinate dose of 90 mg/day, both administered in three divided daily doses on days 1 through 21 and vinorelbine 15 mg/m2 on days 1, 8, and 15. The regimen was repeated every 4 weeks. At least three patients were treated at each dose level before escalating to the next level. Prophylactic granulocyte colony-stimulating factor was not routinely given. The preliminary results are reported as we await further follow-up of this ongoing study.

Rate of tryptophan hydroxylation in vivo in brain nuclei of genetically hypertensive rats of the Lyon strain.

The rate of tryptophan hydroxylation in vivo is unaltered in brain areas of 5, 9 and 21 week-old Lyon genetically Hypertensive (LH) rats as compared to both Lyon Normotensive (LN) and Low Blood Pressure (LL) rats, except for a decrease in the C1 area of the medulla oblongata in 9 week-old animals.

Adrenaline and noradrenaline neurons in rat lower brain stem: anatomical and pharmacological neurochemistry.

Since there was no study available on the comparative anatomical neurochemistry of the noradrenaline (NA) and adrenaline (A) containing neurons of the lower brain stem, we studied the distribution of the activities of the three major catecholamines (CA)-synthesizing enzymes in coronal sections of the rat medulla oblongata dissected into microcubes. In the dorso-medial region, there was a 1500 micron rostro-caudal difference in the localization of the peak of PNMT activity compared with the peaks of TH and DBH activities. This result led to a new microdissection technique allowing the preferential microdissection of the C2 A neurons versus the A2 NA neurons. The response of these two populations of CA neurons was then studied after a sustained decrease in blood pressure induced in young SHR by a 14 days dihydralazine treatment. The C2 adrenergic region exhibited an overall increase in TH, DBH and PNMT activity (+69%, +45% and +33%; p less than 0.01 respectively) while the A2 noradrenergic region was unaffected. Thus, the NA and A neurons of the rat dorso-medial lower brain stem do not seem to exhibit the same biochemical response after a prolonged hypotension. This preliminary result favors the hypothesis of a different functional role for the neighboring A2 and C2 neurons in central control of blood pressure.