A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03)

Background

EORTC study 08021/ILCP 01/03 evaluated the role of consolidation gefitinib, an oral tyrosine kinase inhibitor (TKI), administered in patients with advanced non-small cell lung cancer (NSCLC), not progressing following standard 1st-line chemotherapy.

Methods

Patients with advanced NSCLC, not-progressing after four cycles of platinum-based chemotherapy, were randomised to receive either gefitinib 250 mg/d or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival (OS). Secondary end-points were progression-free survival (PFS) and toxicity. The study was powered to detect a 28% increase in OS from a median of 11–14.1 months (HR = 0.78) and planned to randomise 598 patients to observe 514 deaths.

Results

After inclusion of 173 patients, the trial was prematurely closed due to low accrual. Baseline characteristics for gefitinib (n = 86) and placebo (n = 87) arms were well balanced. After a median follow up of 41 months, the difference in median OS in the gefitinib and placebo arms was not statistically significant (10.9 and 9.4 months, HR 0.83 [95% confidence interval (95% CI) 0.60–1.15]; p = 0.2). The difference in median PFS significantly favoured gefitinib (4.1 and 2.9 months, HR = 0.61, [95% CI 0.45, 0.83]), p = 0.0015). Adverse events reported in more than 10% of patients were rash (47% with gefitinib versus 13% with placebo) and diarrhoea (34% with gefitinib versus13% with placebo).

Conclusions

Despite its premature closure, this trial confirms previous evidence that consolidation gefitinib is safe and improves PFS. However, no difference in OS was observed in this study (NCT00091156).     

Cardiovascular risk factors in adult patients with multisystem Langerhans-cell histiocytosis: evidence of glucose metabolism abnormalities

BACKGROUND: Langerhans-cell histiocytosis (LCH) is a rare disease with features of chronic inflammation and it may also induce hypopituitarism, conditions associated with an increased risk of cardiovascular diseases. AIM: Cardiovascular and metabolic risk profile investigation in multisystem LCH patients with and without anterior pituitary deficiency. DESIGN: Prospective, observational study. METHODS: Fourteen adult patients with LCH, 7 with and 7 without anterior pituitary deficiency, and 42 controls matched for age, body mass index (BMI) and smoking. Cardiovascular risk factors were estimated in all subjects: glucose and lipid profile, mathematical indices of insulin resistance (IR), blood pressure, structural arterial and functional endothelial properties (intima-media thickness, brachial artery flow-mediated dilatation). Cardiovascular risk factors were estimated in the three groups studied; the effect of disease activity and/or treatment was also determined in patients with LCH. RESULTS: Ten patients had diabetes insipidus, and 7 anterior pituitary hormone deficiencies: 8 patients had active disease and 11 had received systemic treatment. No difference was observed between the study groups in vascular parameters, in lipid profile or in blood pressure. However, the insulin resistance index GIR was decreased in patients with LCH without anterior pituitary deficiency compared to controls (P = 0.033). Three patients had impaired glucose tolerance and one diabetes mellitus type 2. These patients were older and had active disease; there was no association with hypopituitarism and/or previous treatment. CONCLUSION: Adults patients with LCH have abnormalities of glucose metabolism that tend to occur in patients with active disease, and may be a consequence of the pro-inflammatory state.     

Autoimmune cholangitis presented as fever of unknown origin

Autoimmune cholangitis is a rare chronic cholestatic liver disease. Fever of unknown origin is defined as a temperature higher than 38.3 degrees C that lasts for more than 3 weeks with no obvious source despite appropriate investigation. We describe the case of a 62-year-old woman who presented with fever, fatigue and weight loss. The serum biochemical study showed an increase in alkaline phosphatase and gamma-glutamyl transpeptidase levels. Antinuclear, antimitochondrial, anti-smooth-muscle antibodies and antibodies against the cytoplasm of neutrophils were negative. Liver biopsy was compatible with autoimmune cholangitis. The patient was successfully treated with methylprednisolone and ursodeoxycholic acid. We describe here a rare case of fever as preceding and leading symptom of autoimmune cholangitis.     

Combined acute effects of red wine consumption and cigarette smoking on haemodynamics of young smokers

OBJECTIVE: Red wine seems to improve haemodynamic variables, while smoking provokes adverse effects. The haemodynamic effects of their combined use is unknown. The purpose of the present study was to examine the acute effects of red wine and its constituents, in combination with the smoking of one cigarette, on haemodynamic parameters, such as blood pressure and wave reflections, in a group of smokers. METHODS: Twenty smokers (12 males, eight females) participated in a double-blind, crossover study comprised of 3 study days. All subjects either smoked one cigarette, or smoked and drank 250 ml of red wine, or 250 ml of de-alcoholized red wine (containing the same type and similar concentration of antioxidants). Applanation tonometry and generalized transfer functions were used to estimate aortic pressure waveforms at baseline and 30, 60 and 90 min after each trial. The augmentation index (AIx) was used to express wave reflections. RESULTS: Smoking increased peripheral systolic blood pressure (P < 0.005) 30 min later, but simultaneous consumption of either type of red wine caused no such effect. Additionally, smoking caused no overall effect on AIx, while smoking and drinking either regular or de-alcoholized red wine reduced AIx (P < 0.001). The reduction of AIx after red wine consumption was significantly greater than the respective reduction after de-alcoholized red wine (P = 0.004). CONCLUSION: Antioxidant substances in red wine counteracted the smoking-induced increase in peripheral systolic blood pressure. Both alcohol and antioxidants in red wine decrease wave reflections in uncomplicated habitual smokers postprandially, indicating an additional favourable effect of red wine.