Comparison of inhaled antibiotics for the treatment of chronic Pseudomonas aeruginosa lung infection in patients with cystic fibrosis: systematic literature review and network meta-analysis

PURPOSE: In Europe, 4 inhaled antibiotics (tobramycin, colistimethate sodium, aztreonam, and levofloxacin) are currently approved for the treatment of chronic Pseudomonas aeruginosa lung infection in patients with cystic fibrosis (CF). Levofloxacin inhalation solution (LIS) is the most recently approved inhaled antibiotic for adult patients with CF. A systematic literature review and Bayesian network meta-analysis (NMA) was conducted to compare the relative short-term (4 weeks) and long-term (24 weeks) outcomes of these inhaled antibiotics versus LIS. METHODS: A systematic literature search was conducted on February 16, 2016, using EMBASE and Medline via OvidSP. All randomized controlled trials comparing any of the aforementioned inhaled antibiotics with 4 or 24 weeks of follow-up were evaluated. NMA was performed for the following outcomes: relative and absolute percent changes from baseline in forced expiratory volume in 1 second (FEV1%) predicted, change in P aeruginosa sputum density, respiratory symptoms score from the CF questionnaire-revised, hospitalization, additional antibiotics use, and study withdrawal rates. RESULTS: Of the 685 articles identified, 7 unique studies were included in the 4 weeks' NMA and 9 unique studies were included in the 24 weeks' NMA. Aztreonam was predicted to result in the greatest numerically increase in FEV1% predicted at 4 weeks, whereas LIS were predicted to be numerically greater than colistimethate sodium, tobramycin inhaled solution (TIS), and tobramycin inhaled powder (TIP). However, all of the 95% credibility intervals (CrIs) of these comparisons included zero. At 24 weeks, none of the treatments was significantly more effective than LIS. The estimates for the mean change from baseline to 24 weeks in relative FEV1% versus LIS was -0.55 (95% CrI, -3.91 to 2.80) for TIS, -2.36 (95% CrI, -7.32 to 2.63) for aztreonam, -2.95 (95% CrI, -10.44 to 4.51) for TIP, and -9.66 (95% CrI, -15.01 to -4.33) for placebo. Compared with LIS, the odds ratio for hospitalization at 24 weeks was 1.92 (95% CrI, 1.01-3.30) for TIS, 2.25 (95% CrI, 1.01-4.34) for TIP, and 3.16 (95% CrI, 1.53-5.78) for placebo, all statistically worse than LIS. P aeruginosa sputum density scores, additional use of antipseudomonal antibiotics, and study withdrawal rates were comparable among all inhaled antibiotics at all times. IMPLICATIONS: Based on this NMA, the analyses for many of the outcomes did not provide significant evidence to indicate that the other approved inhaled antibiotics were more effective than LIS for the treatment of chronic P aeruginosa lung infection in patients with CF. Study withdrawal rates seemed to be comparable among these inhaled antibiotics

Synchronous and metachronous head and neck carcinomas

BACKGROUND. The incidence of head and neck cancer is increasing. To improve the survival of head and neck cancer patients, an effective program of screening and/or chemoprevention of second malignancies is essential. An analysis of the incidence, time to development, and risk factors of second malignant tumors in head and neck cancer patients can contribute to the design of effective screening and chemoprevention programs. METHODS. Eight hundred, fifty-one patients with initial squamous cell carcinoma of the larynx (n = 224), tonsils (n = 189), pyriform sinus (n = 165), oral cavity (n = 129), mobile tongue (n = 72), and base of tongue (n = 72) treated from 1978 to 1990 were analyzed for the presence of a second malignancy after initial therapy. Of these 851 patients, 544 (64%) were documented smokers and 35 (4%) were nonsmokers. No smoking information was available for 272 patients. Four hundred, fifty-four patients (53%) were consumers of alcohol and 64 patients (8%) were nondrinkers. Alcohol consumption information was not available for 333 patients. RESULTS. One hundred, sixty-two (19%) second head and neck carcinomas occurred in the original 851 patients. Sixty-six patients (41%) had synchronous tumors, and 96 patients (59%) had metachronous tumors. The probability of developing a second metachronous cancer 5-years after undergoing treatment for the initial head and neck cancer was 22%. Borderline statistical significance was observed in the 5-year second cancer incidence based on the site of the initial primary cancer (46% for the base of tongue, 34% for the pyriform sinus, 23% for the larynx, 18% for the oral cavity, 15% for the tonsils, and 10% for the mobile tongue). Tobacco smoking (3% for nonsmokers vs. 26% for < or = 20 pack-years vs. 42% for > 20 and < or = 40 packs/year vs. 30% for > 40 packs/year of smoking) and the consumption of alcohol (5% for non-drinkers vs. 32% for drinkers) were both statistically significant in predicting the likelihood of developing a second malignancy. Multivariate analysis revealed that the two independent variables that influenced the occurrence of a second metachronous cancer were the anatomic site of the original primary cancer and patient age. The survival rate after the second cancer was influenced significantly by the site of the second cancer (20% for a second head or neck cancer, 3% for a second esophageal cancer, and 2% for a second lung cancer). Continued smoking (20% for non-smokers vs. 5% for smokers) and continued alcohol consumption (27% for nondrinkers vs. 6% for drinkers) also adversely influenced the survival after the occurrence of a second cancer. CONCLUSIONS. This study confirms the high rate of second cancers in patients with initial head and neck malignancies. The development of a second malignancy is almost always fatal. Screening programs and chemoprevention trials should be directed toward cancer patients with initial head and neck cancers. Only the small subset of nonsmokers and nondrinkers should be excluded from such trials