Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer.

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)-leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m(2)/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m(2), as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU-LV occurred in

A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma. International Organization for Cancer Chronotherapy.

BACKGROUND: The combination of 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (I-OHP) was shown to be both more active against metastatic colorectal carcinoma and better tolerated if the drug delivery rate was chronomodulated according to circadian rhythms rather than constant. This allowed the authors to intensify the three-drug chronotherapy regimen and to assess its activity as the initial treatment of metastatic colorectal carcinoma patients in ten centers from four countries. METHODS: Patients with previously untreated and inoperable measurable metastases from colorectal carcinoma received a daily administration of chronomodulated 5-FU (700 mg/m2/day, peak delivery rate at 04:00 hours), LV (300 mg/m2/day, peak delivery rate at 04:00 hours), and 1-OHP (25 mg/m2/day, peak delivery rate at 16:00 hours) for 4 days every 14 days. Intrapatient escalation of 5-FU dose was performed if toxicity was less than World Health Organization (WHO) Grade 2. RESULTS: Of 90 enrolled patients, 35 had a WHO performance status of 1 or 2; 49 had metastases in > or = 2 organs. The liver was involved in 79 patients, 30 of whom had clinical hepatomegaly. The main dose-limiting toxicities were WHO modified Grade 3 or 4 diarrhea (41% of patients, 8.2% of courses), stomatitis (30% of patients, 5.1% of courses), and Grade 2 cumulative peripheral sensory neuropathy (19% of patients after 12 courses). Two patients died with severe gastrointestinal toxicity. Using the intent-to-treat method, the overall objective response rate was 66% (95% confidence limits, 56-76%). Surgical removal of previously inoperable metastases was successful in 31 patients (34%). Histologic necrosis of metastases was >90% in 7 patients and complete in 1 patient. The median progression free survival and survival durations were 8.4 months (range, 5.9-10.9 months) and 18.5 months (range, 13.2-23.8 months), respectively, with 38% of the patients alive at 2 years of follow-up. CONCLUSIONS: The objective response rate appeared to be approximately 3-fold as high as that achieved with current 5-FU-based regimens and translated into an approximately 50% increase in median survival. The hypothesis that this intensified, ambulatory, chronotherapy regimen can increase survival currently is being investigated in a multicenter randomized study conducted by the European Organization for Research and Treatment of Cancer Chronotherapy Study Group.

[Pulmonary surfactant in neonatal pathology]. / Le surfactant pulmonaire dans la pathologie néonatale

Following some preliminary remarks on the role of the surfactant in pulmonary physiology and physiopathology, a physiochemical study of the lungs of 26 infants who died in the neonatal period is reported. Two techniques for measuring the decrease in surface tension are set out. The results in the first case (tensiometric method) allow an explanation of the physiopathological aspect of respiratory distress; in the second case (manometric method) the diagrams obtained are characteristic of different clinical states (normal subjects; subjects born prematurely without any hyaline membrane etc...). Furthermore, the second method gives rise to certain hypotheses as to the physiochemical structure of the substances responsible for the tensio-active properties of the surfactant.

[Measurement of differences in oxygen between arteries and veins. Application to the study of cerebral metabolism]. / Mesure des différences artério-veineuses en oxygène. Application à l'étude du métabolisme cérébral

The cerebral metabolic exploration requires a precises measurement of the arterio-venous differences and this, for each metabolite. As far as oxygen is concerned, there are many techniques to measure the blood contents (CaO2 - CvO2). Direct methods give accurate results but their high technicality makes it difficult to adapt them to the increasing medical demand. The authors report the principle and the technique of the indirect method based upon the measurement of the total hemoglobin concentration and the saturation in oxygen. They recall the possible causes of errors, the main of which - induced by an insufficient homogenization of the sample - is (by the way) to be found in both groups of methods although to a lesser degree in the indirect method. Therefore, the latter, that all normally equipped laboratories can carry into practice, seems quite adapted to the "hospital demand" and its validity confirmed by an experience that now belongs to the past.

[Pulmonary surfactants. Generalities]. / Le surfactant pulmonaire. Généralités

The alveolar wall on contact with air can be compared with a biological air-liquide interface. As with all interfaces, there are therefore superficial forces which tend to reduce the surface to a minimum. In the case of a pulmonary alveolus with a spherical surface, these forces are at the origin of an internal pressure excess dependent on the radius of the alveolus and on the superficial tension related to the nature of the interface. Owing to the disparity in the alveolar radii, under these conditions the smaller alveoli would collapse to the benefit of a larger one, the pressure being lower and lower in the latter. In addition, at any time in the respiratory cycles, this surpression must be negligible in order to avoid rupture of the equilibrium of the forces exerted on the alveolar wall. Consequently, it is necessary that this air-alveolar wall interface should have a superficial tension on the one hand variable with the surface, and on the other hand always very low. Owing to the demonstration of large concentrations of phospholipid in this area, it can be thought that a superficial film is substituted at the air-biological liquid interface and owing to this fact effectively has superficial properties necessary for alveolar stability. The "surface-tensio-active" effect of this film lead to the giving of the name of "surfactant" to these constituents as a whole.