A combination of gemcitabine and 5-fluorouracil in advanced pancreatic cancer, a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)

In a randomized clinical trial, gemcitabine (GEM) was more effective than 5-fluorouracil (5-FU) in advanced pancreatic cancer patients. GEM and 5-FU have different mechanisms of action and their combination, from a theoretical point of view, could result in a higher activity. To test activity and feasibility of such a combination, a multi-institutional phase II study was initiated in November 1996 by the Italian Group for the study of Digestive Tract Cancer (GISCAD). Primary objectives of this study were to determine the activity in terms of response rate and clinical benefit, while the secondary objective was toxicity. According to the optimal two-stage phase II design, 54 patients were enrolled. Schedule was: GEM 1000 mg m(-2) intravenous (i.v.), and 5-FU 600 mg m(-2) bolus i.v. weekly for 3 weeks out of every 4. All the 54 patients were symptomatic (pain, weight loss, dyspepsia). A clinical benefit was obtained in 28 patients (51\%) (95\% confidence interval (CI) 38-64\%). Two patients achieved a partial response and 34 a stable disease. Median survival for all the patients was 7 months. Side-effects were mild: no gastrointestinal or haematological grade 3-4 toxicity (WHO) were recorded. We observed only six episodes of grade 2 (WHO) leukopenia and seven episodes of thrombocytopenia. Although the non-randomized design of this study suggests caution in the interpretation of these data, in consideration of the low incidence of toxicity and the favourable results obtained in terms of clinical benefit, it may be worthwhile to test more active schedules of 5-FU (continuous infusion) in combination with gemcitabine

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events