S-1 plus cisplatin combination chemotherapy in patients with advanced non-small cell lung cancer: a multi-institutional phase II trial.

PURPOSE: To evaluate the efficacy and toxicity of a novel combination chemotherapeutic regimen including cisplatin with an oral anticancer agent, S-1 that consisted of tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate, for non-small-cell lung cancer (NSCLC) patients. EXPERIMENTAL DESIGN: In this phase II trial, patients with locally advanced and metastatic NSCLC were treated with the oral administration of S-1 at 40 mg/m(2) twice a day for 21 consecutive days while cisplatin (60 mg/m(2)) was administered intravenously on day 8. This schedule was repeated every 5 weeks. RESULTS: Of 56 patients enrolled in the study, 55 patients were eligible and analyzed. The median number of cycles administered was 3 (range, 1-12 cycles). Among these 55 patients, one complete response and 25 partial responses were observed with an overall response rate of 47% (95% confidence interval, 34-61%). The median survival time was 11 months and the 1-year survival rate was 45%. Hematologic toxicities of grades 3 and 4 included neutropenia (29%) and anemia (22%). No grade 4 nonhematologic toxicity was observed. Grade 3 toxicity included anorexia (13%), vomiting (7%), or diarrhea (7%). CONCLUSIONS: S-1 plus cisplatin combination chemotherapy showed a promising effectiveness with acceptable toxicity rates in patients with advanced NSCLC. These results warrant further investigations of this regimen including a randomized controlled trial for its use as a first line treatment for NSCLC.

Uracil/tegafur plus cisplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer: a multi-institutional phase II trial.

PURPOSE: To evaluate the efficacy and toxicity of a novel combination treatment using concurrent radiotherapy with cisplatin plus UFT, which is comprised of uracil and tegafur, in locally advanced non-small cell lung cancer (NSCLC) patients. EXPERIMENTAL DESIGN: In this Phase II trial, patients with unresectable stage III NSCLC were treated with the oral administration of UFT (400 mg/m(2)/d tegafur) on days 1-14 and days 29-42 whereas 80 mg/m(2) cisplatin was administered i.v. on days 8 and 36. Radiotherapy, with a total dose of 60 Gy, was delivered in 30 fractions from day 1. RESULTS: Seventy patients were enrolled and eligible, as follows: 57 males/13 females; mean age 61 ranging from 36 to 74; performance status 0/1:45/25; stage IIIA/IIIB, 14/56. A complete response was observed in two patients and a partial response in 54 patients, and the overall response rate was 81% (95% confidence interval; 70-89%). The median survival, the 1- and 2-year survival rates were 16.5 months, 67% and 33%, respectively. Grade 3/4 leukopenia occurred in 14%/1% of the patients. Grades 3 non-hematological toxicities were only reported in three patients with nausea, two with esophagitis and one with pneumonitis whereas no grade 4 non-hematological toxicity was observed. CONCLUSIONS: UFT plus cisplatin with concurrent radiotherapy is considered to be a feasible and effective treatment for locally advanced NSCLC patients. Additional study of this concurrent chemoradiotherapy is warranted.

High level of vascular endothelial growth factor in hemorrhagic pleural effusion of cancer.

Angiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin, are candidates for the induction of pleural effusions because they have been implicated in the induction of neovascularization, vascular permeability, and hemorrhage both in the inflammatory process and in tumor progression. Thus, we hypothesized that these angiogenic factors in effusion might be involved in the clinical manifestation of malignant pleural disease. We measured the levels of VEGF, bFGF, and angiogenin in pleural effusions and sera from 40 patients. Pleural effusions due to malignancy (1,350 pg/ml) contained significantly higher levels of VEGF than effusions due to inflammatory diseases (102 pg/ml; p = 0.034). Furthermore, hemorrhagic effusions showed significantly higher VEGF levels (1,942 pg/ml) than non-hemorrhagic effusions (202 pg/ml; p = 0.016) in malignant patients. In contrast, neither bFGF nor angiogenin were correlated with any clinical manifestation of pleural effusion. Immunohistochemical study revealed that malignant cells in the pleura were stained with anti-VEGF antibody. Our data suggest that VEGF secreted from tumor cells may be involved in the accumulation of pleural effusion in malignancy, and that increased levels of VEGF may induce hemorrhagic effusion.

In vitro antimicrobial activity and penetration rate into sputum of gatifloxacin, a novel 6-fluoro-8-methoxy quinolone, and its therapeutic efficacy in respiratory infections.

The in vitro antimicrobial activity of gatifloxacin against clinical isolates of pathogenic bacteria was evaluated. Minimum inhibitory concentrations of gatifloxacin, ofloxacin, ciprofloxacin, tosufloxacin, sparfloxacin, and rifampicin against 20 strains each of methicillin-susceptible Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, and Pseudomonas aeruginosa, 18 strains of Enterobacter cloacae, 15 strains each of Streptococcus Pneumoniae and Moraxella catarrhalis, 12 strains of Haemophilus influenzae, 18 strains of Mycobacterium intracellulare, and 22 strains each of Mycobacterium tuberculosis and Mycobacterium avium were determined. The minimum inhibitory concentrations90's of gatifloxacin against the above species were 0.12, 8, <==0.06, 0.5, 2, 2, <==0.06, 0.39, 0.05, 0.013, 2, 0.5, and 4 &mgr;g/ml, respectively. Gatifloxacin was four times as active as ofloxacin against methicillin-susceptible and -resistant Staphylococcus aureus, and as active as ofloxacin against Enterobacteriaceae and Pseudomonas aeruginosa. Gatifloxacin was as active as tosufloxacin and sparfloxacin against Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae. The antimycobacterial activity of gatifloxacin was similar to that of sparfloxacin. Five patients with chronic respiratory infections and one patient with acute pneumonia received 100-400 mg/day of gatifloxacin orally for 5-12 days (mean, 8.17 days). The clinical effects were excellent in one patient and good in five. One strain of Haemophilus influenzae was eradicated and one strain of Pseudomonas aeruginosa persisted after therapy. Adverse reactions were mild and improved after completion of therapy. In one patient with chronic bronchitis, the maximum sputum concentrations 2-4 h after oral administration of 150 mg of gatifloxacin on days 1 and 6 were 0.88 and 1.45 &mgr;g/ml, respectively, and in serum the values were 0.84 and 1.24 &mgr;g/ml, respectively. Thus it was found that gatifloxacin possesses potent activity against respiratory pathogens (including Mycobacteriaceae), and shows good penetration rate into sputum, and that it can be used as the drug of first choice in the treatment of respiratory tract infections.

Comparative in vitro activity of carbapenem antibiotics against respiratory pathogens isolated in recent years.

We investigated the antibacterial activity of 12 antibiotics, including 4 carbapenems, against 200 strains of respiratory pathogens isolated in 1997, and compared the results with those obtained in 1993. The strains examined were 38 strains of methicillin-susceptible Staphylococcus aureus (MSSA), 32 strains of methicillin-resistant S. aureus (MRSA), 22 strains of penicillin-susceptible Streptococcus pneumoniae (PSSP), 10 strains of penicillin-resistant S. pneumoniae (PRSP), 53 strains of Pseudomonas aeruginosa, 19 strains of Moraxella catarrhalis, and 26 strains of Haemophilus influenzae. In 1993, 100 strains were examined. The minimal inhibitory concentration data of the present study showed that imipenem and panipenem were more active than the other agents against gram-positive bacteria, and that meropenem and biapenem were more active than the other agents against gram-negative bacteria. By comparing these results with those obtained in 1993, it was found that increase of resistance to carbapenem antibiotics was not observed against all the strains tested in this study. Thus, it can be stated that carbapenem antibiotics retain their position as the drug of first choice for severe infections.