Multicenter phase II trial of docetaxel and carboplatin in patients with stage IIIB and IV non-small-cell lung cancer.

PURPOSE: To evaluate the safety and efficacy of docetaxel and carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this multicenter, phase II trial, 33 patients with previously untreated stage IIIB (n = 8) or IV (n = 25) NSCLC received intravenous infusions of docetaxel 80 mg/m2 followed immediately by carboplatin dosed to AUC of 6 mg/ml/min (Calvert's formula) every three weeks. Patients also received dexamethasone 8 mg orally twice daily for three days beginning one day before each docetaxel treatment. Filgrastim was not allowed during the first cycle and was added only if a patient experienced febrile neutropenia or grade 4 neutropenia lasting > or = 7 days. RESULTS: There were 1 complete and 11 partial responses for an objective response rate of 43% (95% CI: 24%-63%) in 28 evaluable patients and 36% (95% CI: 20%-55%) in the intent-to-treat population. The median duration of response was 5.5 months (range 3.0-12.5 months). The median survival was 13.9 months (range 1-35+ months); one-year survival was 52%. The most common toxicity was hematologic, which included grade 4 neutropenia (79% of patients and 7% percent of cycles) and febrile neutropenia (15% of patients); there were no episodes of grade 3 or 4 infection. The most common severe nonhematologic toxicities were asthenia (24%) and myalgia (12%); there were no grade 3 or 4 neurologic effects. CONCLUSIONS: The combination of docetaxel and carboplatin has an acceptable toxicity profile and is active in the treatment of previously untreated patients with advanced NSCLC. This combination is being evaluated in a randomized phase III trial involving patients with advanced and metastatic NSCLC.

Urokinase receptor interacts with alpha(v)beta5 vitronectin receptor, promoting urokinase-dependent cell migration in breast cancer.

Perturbation of adhesive interactions at cell-substratum and cell-cell contact sites is a critical event in the multistep process of cancer invasion. Recent studies indicate that the urokinase receptor (uPAR) is associated in large molecular complexes with other molecules, such as integrins. To test the possibility that uPAR may physically and functionally interact with vitronectin (Vn) receptors, we determined the expression level of uPAR, alpha(v)beta3, and alpha(v)beta5 Vn receptors in 10 human breast carcinomas. Here, we show the ability of uPAR to physically associate with alpha(v)beta5 in the breast carcinomas examined. The functional effects of this interaction were studied using HT1080 human fibrosarcoma and MCF-7 human breast carcinoma cell lines, both exhibiting a urokinase-dependent physical association between uPAR and alpha(v)beta5. Both cell lines respond to urokinase or to its noncatalytic amino-terminal fragment by exhibiting remarkable cytoskeletal rearrangements that are mediated by alpha(v)beta5 and require protein kinase C activity. On the contrary, binding of Vn to alpha(v)beta5 results in the protein kinase C-independent formation of F-actin containing microspike-type structures. Furthermore, alpha(v)beta5 is required for urokinase-directed, receptor-dependent MCF-7 and HT1080 cell migration. These data show that uPAR association with alpha(v)beta5 leads to a functional interaction of these receptors and suggest that uPAR directs cytoskeletal rearrangements and cell migration by altering alpha(v)beta5 signaling specificity.

Phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose of paclitaxel with carboplatin with and without filgrastim support in patients with metastatic non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of paclitaxel and carboplatin and correlate these with the pharmacodynamic effects. PATIENTS AND METHODS: Thirty-six chemotherapy-naive patients with metastatic NSCLC were entered into this phase I dose-escalation and pharmacokinetic study. Paclitaxel was initially administered as a 24-hour infusion at a fixed dose of 135 mg/m2, and the carboplatin dose was escalated in cohorts of three patients, using Calvert's formula [dose(mg) = area under the concentration time curve (glomerular filtration rate + 25)], to target areas under the concentration time curve (AUCs) of 5, 7, 9, and 11 mg/mL x minute. A measured 24-hour urinary creatinine clearance was substituted for the glomerular filtration rate. Once the maximum-tolerated AUC (MTAUC) of carboplatin was reached, the paclitaxel dose was escalated to 175, 200, and 225 mg/m2. When the paclitaxel dose escalation began, the AUC of carboplatin was reduced to one level below the MTAUC. RESULTS: Myelosuppression was the major dose-limiting toxicity. Thrombocytopenia was observed at a carboplatin AUC of 11 mg/mL x minute after course 2 and thereafter. End-of-infusion plasma paclitaxel concentrations and median duration of time above 0.05 microM were similar in course 1 versus course 2 at the 135 and 175 mg/m2 dose levels. The neutropenia experienced by patients was consistent with that observed in patients who had received paclitaxel alone. Measured carboplatin AUCs were approximately 12% (20% v 3% with course 1 v course 2, respectively) below the desired target, with a standard deviation of 34% at all dose levels. A sigmoid-maximum effect model describing the relationship between relative thrombocytopenia and measured free platinum exposure indicated that patients who received the combination of carboplatin with paclitaxel experienced less severe thrombocytopenia than would be expected from carboplatin alone. Of the 36 patients entered onto the study, one experienced a complete response and 17 had partial responses, for an overall response rate of 50%. The recommended doses of paclitaxel (24-hour infusion) and carboplatin for future phase II studies of this combination are (1) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute without filgrastim support; (2) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 9 mg/mL x minute with filgrastim support; and (3) paclitaxel 225 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute with filgrastim support. CONCLUSION: The regimen of paclitaxel and carboplatin is well-tolerated and has promising activity in the treatment of NSCLC. There is no pharmacokinetic interaction between paclitaxel and carboplatin, but there is a pharmacodynamic, platelet-sparing effect on this dose-limiting toxicity of carboplatin.

Age, individuality, and context as factors in sustained visual attention during the preschool years.

In 3 studies, the authors explored age changes and individual differences in preschool children's sustained attention in several different contexts--watching a videotape, playing with toys, and performing reaction time tasks. Various indexes of attention increased from 30 months to 54 months, whereas inattention decreased. Changes tended to occur earlier for play and television viewing than for the reaction time task. Together, the results also provide evidence for individual differences in measures of attention and inattention through high internal consistency and stability over time within situations. Correlations across situations, however, were low to modest. These results suggest that children have stable tendencies to focus and sustain attention in particular contexts but that their attention varies with the demands of the task and their ability or interest in meeting those demands.