Irinotecan combined with bolus 5-fluorouracil and folinic acid Nordic schedule as first-line therapy in advanced colorectal cancer.

BACKGROUND: This multicentre phase II study evaluated the efficacy and safety of irinotecan combined with the Nordic schedule of 5-fluorouracil (5-FU) and folinic acid (FA) as first-line therapy in patients with advanced colorectal cancer. PATIENTS AND METHODS: Seventy-four patients with measurable disease and a WHO performance status of 2 or less were treated with irinotecan 210 mg/m(2) as a 30-90 min intravenous infusion on day 1, followed by 5-FU 500 mg/m(2) and FA 60 mg/m(2) bolus on days 1 and 2, every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was the objective response rate. RESULTS: Twenty-nine out of 68 evaluable patients achieved a complete (n = 7) or partial (n = 22) response, leading to an overall response rate of 43% [95% confidence interval (CI) 31% to 55%]. The median duration of response was 10 months. The estimated median time to progression and survival were 6.4 months (95% CI 5.4-9.0) and 15.6 months (95% CI 13.3-19.0), respectively, in the intention-to-treat population. A total of 860 cycles were administered to 74 patients. Neutropenia was the main adverse event with grade 3-4 toxicity in 66% of patients and 17.5% of cycles. Grade 3-4 non-haematological toxicities were infrequent and included diarrhoea in 16% of patients and 2% of cycles and nausea/vomiting in 10% of patients and 1% of cycles. CONCLUSIONS: Irinotecan combined with the bolus Nordic schedule of 5-FU/FA is active in advanced colorectal cancer with an easily managed safety profile which ensures good schedule compliance. The low incidence of grade 3-4 non-haematological toxicity justifies the further evaluation of this combination in the context of randomised clinical trials.

A phase II study of docetaxel in patients with metastatic squamous cell carcinoma of the head and neck.

This study was designed to evaluate the activity, safety and tolerance of docetaxel (D) in a selected population with metastatic squamous cell carcinoma of the head and neck (SCCHN). Twenty-four patients with no prior palliative therapy were enrolled and received D 100 mg m(-2) by 1 h of infusion, every 3 weeks. All but two patients had been evaluated for efficacy on lung metastatic sites. No prophylactic administration of anti-emetics or growth factors was given. A pharmacokinetic study was performed in 22 patients. Twenty-one patients were assessable for response and 24 for toxicity. One hundred and four cycles were administered with a median of 4.5 (range 1-9) per patient. The median cumulative dose was 449 mg m(-2). Partial responses were achieved in five patients with a median duration of 18.7 weeks (range 13.1-50.3). The overall response rate was 20.8% with a median duration of 11.0 weeks (range 2.4-52.6). The most frequent side-effect was neutropenia (79.2% grade IV) but with a short duration (median 4 days) and no febrile neutropenia. The incidence of moderate/severe fluid retention was 29.2% with one treatment discontinuation. Other toxicities (all grades) were common (skin 75%, asthenia 50%, infection 29.2%, nausea 16.7%, diarrhoea 12.5%, stomatitis 16.7%, vomiting 8.3% and HSR 8.3%). A mean clearance of 19.6 l h(-1) m(-2) and an area under the curve of 6.00 microg ml(-1) h(-1) was found in the pharmacokinetic analysis. Docetaxel is active in this selected population with metastatic SCCHN, with a good tolerance.

[A retrospective study of 53 cases of resectable primary bronchopulmonary cancers associated with Pierre Marie syndrome]. / Etude rétrospective de 53 cancers broncho-pulmonaires primitifs résécables associés à un syndrome de Pierre Marie.

The prognosis of primary lung cancer associated with hypertrophic osteopulmonary arthropathy is not well known. Between July 1973 adn August 1995, we cared for 53 consecutive patients with resectable non-small-cell lung cancer associated with osteoplumonary arthropathy. There were 51 men and 2 women, mean age 56 years. In 83% of the cases the lung cancer was revealed by hypertrophic osteopulmonary arthropathy. The tumor generally involved the right lung (n = 38) and the upper lobe (n = 35). There was no peripheral or central predominance. Complete tumoral resection was performed in 47 patients, incomplete resection in 4 and exploratory thoracotomy in 2. The main histologies were adenocarcinoma (50%) and squamous cell carcinoma (40%). Among the 51 resected tumors, 27 were grade I, 5 grade II, 17 grade III and 2 grave IV. Overall 5-year survival was 39%, reaching 51% for grade I, 40% for grade II, 27% for grade III and 0% for grade IV. The pulmonary manifestations of hypertrophic osteopulmonary arthropathy regressed within the first postoperative hours in all the patients whose tumor was resected and in 1 of the 2 patients who underwent exploratory thoracotomy. AT follow-up, the hypertropic pulmonary arthropathy had disappeared in all resected patients except 1 with a grade I tumor. Tumor recurrence was proven in 18 resected patients, 5 of whom also had recurrent osteopulmonary arthropathy. Our results suggest that primary lung cancer associated with hypertrophic pulmonary arthropathy has characteristic features and that prognosis is comparable with primary lung cancer alone.

The pathophysiological mechanism of fluid retention in advanced cancer patients treated with docetaxel, but not receiving corticosteroid comedication.

AIMS: Fluid retention is a phenomenon associated with taxoids. The principal objective of this study was to investigate the pathophysiological mechanism of docetaxel-induced fluid retention in advanced cancer patients. METHODS: Docetaxel was administered as a 1 h intravenous infusion every 3 weeks, for at least 4-6 consecutive cycles, to patients with advanced breast (n = 21) or ovarian (n = 3) carcinoma, who had received previous chemotherapy, 21 for advanced disease. Phase II clinical trials have shown that 5 day corticosteroid comedication, starting 1 day before docetaxel infusion, significantly reduces the incidence and severity of fluid retention. This prophylactic corticosteroid regimen is currently recommended for patients receiving docetaxel but was not permitted in this study because of its possible interference with the underlying pathophysiology of the fluid retention. RESULTS: Fluid retention occurred in 21 of the 24 patients but was mainly mild to moderate, with only five patients experiencing severe fluid retention. Eighteen patients received symptomatic flavonoid treatment, commonly prescribed after the last cycle. Specific investigations for fluid retention confirmed a relationship between cumulative docetaxel dose and development of fluid retention. Capillary filtration test analysis showed a two-step process for fluid retention generation, with progressive congestion of the interstitial space by proteins and water starting between the second and the fourth cycle, followed by insufficient lymphatic drainage. CONCLUSIONS: A vascular protector such as micronized diosmine hesperidine with recommended corticosteroid premedication and benzopyrones may be useful in preventing and treating docetaxel-induced fluid retention.

Population pharmacokinetics of docetaxel during phase I studies using nonlinear mixed-effect modeling and nonparametric maximum-likelihood estimation.

Docetaxel, a novel anticancer agent, was given to 26 patients by short i.v. infusion (1-2 h) at various dose levels (70-115 mg/m2, the maximum tolerated dose) during 2 phase I studies. Two population analyses, one using NONMEM (nonlinear mixed-effect modeling) and the other using NPML (nonparametric maximum-likelihood), were performed sequentially to determine the structural model; estimate the mean population parameters, including clearance (Cl) and interindividual variability; and find influences of demographic covariates on them. Nine covariates were included in the analyses: age, height, weight, body surface area, sex, performance status, presence of liver metastasis, dose level, and type of formulation. A three-compartment model gave the best fit to the data, and the final NONMEM regression model for Cl was Cl = BSA(Theta1 + Theta02 x AGE), expressing Cl (in liters per hour) directly as a function of body surface area. Only these two covariates were considered in the NPML analysis to confirm the results found by NONMEM. Using NONMEM [for a patient with mean AGE (52.3 years) and mean BSA (1.68 m2)] and NPML, docetaxel Cl was estimated to be 35.6 l/h (21.2 lh-1 m-2) and 37.2 l/h with interpatient coefficients of variations (CVs) of 17.4% and 24.8%, respectively. The intraindividual CV was estimated at 23.8% by NONMEM; the corresponding variability was fixed in NPML in an additive Gaussian variance error model with a 20% CV. Discrepancies were found in the mean volume at steady state (Vss; 83.21 for NPML versus 1241 for NONMEM) and in terminal half-lives, notably the mean t1/2 gamma, which was shorter as determined by NPML (7.89 versus 12.2 h), although the interindividual CV was 89.1% and 62.7% for Vss and t1/2 gamma, respectively. However, the NPML-estimated probability density function (pdf) of t1/2 gamma was bimodal (5 and 11.4 h), probably due to the imbalance of the data. Both analyses suggest a similar magnitude of mean Cl decrease with small BSA and advanced age.