Open, randomized, multi-center phase II study comparing efficacy and tolerability of Erlotinib vs. Carboplatin/Vinorelbin in elderly patients (>70 years of age) with untreated non-small cell lung cancer.

BACKGROUND: Targeting the epidermal-growth-factor-receptor (EGFR) in non-small cell lung cancer (NSCLC) is an established treatment option with less toxicity compared to conventional chemotherapy. This study was undertaken to determine whether Erlotinib is non-inferior compared to chemotherapy as a first-line therapy in unselected elderly patients. MATERIALS AND METHODS: Patients ≥ 70 years with untreated, metastatic NSCLC were randomized to Erlotinib (E), 150 mg/day or Carboplatin (AUC5) plus Vinorelbine (25mg/m(2) on days 1 and 8) every three weeks (CV). Primary endpoint was progression-free survival (PFS). After progression, crossover was strongly recommended. Secondary endpoints were duration of response, 1-year survival, overall survival (OS), response rate (RR), quality of life (FACT-L), assessment of comorbidities by simplified comorbidity score (SCS) and Charlsons' comorbidity score, safety and assessment of molecular markers. RESULTS: Between June 2006 and August 2008 284 pts were randomized to E (144) and CV (140). PFS was significantly inferior with E (median PFS 2.4 versus 4.6 months [HR 1.6, 75% CI 1.22-2.09, p: 0.0005]) as well as RR (7.8% v 28.3%, p: 0.0001). No significant difference in OS appeared (median E: 7.3 months versus CV: 8.4 months, HR: 1.24 [75% CI 0.9-1.71]). In never smokers PFS (median PFS: 3.7 v 4.3 m, E v CV, HR 0.72, 75% CI 0.35-1.48) and OS (median: 16.5 versus 17 months, HR 0.99 [75% CI 0.38-2.57]) were comparable. More skin toxicity and diarrhea was seen with E compared to more myelotoxicity, neurotoxicity and constipation with CV. Less severe adverse events were observed with E (81 v 102, E v CV). CONCLUSION: CV had an increased efficacy compared with E in an unselected population of elderly patients with advanced NSCLC.

[Epidemiology of lung cancer]. / Epidemiologie des Lungenkarzinoms.

In 2005 approximately 45,000 people contracted lung cancer in Germany and at the same time a total of 40,641 patients died from the disease, making lung carcinoma the most frequent cause of tumor death in men. The peak age for the disease is between 70 and 85 years. The main risk factor of inhaling tobacco smoke is responsible for 85% of the cases of lung cancer. There is a direct correlation between the number of cigarettes smoked and the risk of developing lung cancer. Screening programs, e.g., low-dose computed tomography, are currently undergoing clinical assessment worldwide, but at the present time are not yet being comprehensively established.

Influence of age and comorbidities on the chemotherapeutic management of lung cancer.

More than 60% of all patients with cancer are currently older than 65 years. Correspondingly, the peak of lung cancer incidence is reached in the age group between 75 and 80 years. As a consequence to this ageing patient population, three factors become of major importance for the chemotherapeutic management of lung cancer, namely functional status, age-specific phenomenon and the presence of comorbidities. While the functional status is dependent on physiological changes in organ function, ageing-specific phenomena include depression, alterations of mental status, reduced nutritional status and missing social support. Comorbidities frequently have a risk profile comparable to that of lung cancer. Clinical studies with a special focus on elderly patients are still rare. In small-cell lung cancer retrospective analyses have demonstrated that age alone is not a major prognostic factor compared to performance status, tumor stage or gender. Nevertheless elderly patients with lung cancer are still frequently excluded from clinical trials, and receive less optimal or even no chemotherapeutic treatment at all. Studies evaluating less aggressive treatment figured out that single agent therapy with etoposide is inferior compared to combination chemotherapy in patients with small cell lung cancer (SCLC). In elderly patients with non-small cell lung cancer (NSCLC), single agent treatment with vinorelbine plus 'Best Supportive Care' was significantly superior to 'Best Supportive Care (BSC)' alone; with respect to survival and symptom palliation.

[Intraoperative transesophageal versus preoperative transthoracic contrast echocardiography. A method for detection of patent foramen ovale in neurosurgical patients]. / Intraoperative transösophageale versus präoperative transthorakale Kontrast-Echokardiographie. Eine Methode zum Nachweis eines funktionell offenen Foramen ovale bei neurochirurgischen Patienten.

Preoperative detection of a patent foramen ovale (PFO) may be achieved employing either transthoracic echocardiography (TTE) with the Valsalva manoeuvre in the awake patient or trans-oesophageal echocardiography (TEE) in the anaesthesised patient. Our study was undertaken to validate these methods with regard to their efficacy in identifying patients at risk for paradoxical air embolism (PAE). METHODS. In 67 patients ranging from 28 to 70 years of age, TTE was performed utilising the Valsalva manoeuvre prior to surgery. The patients were informed about all procedures and agreed to take part in the study. After induction of anaesthesia the patients were evaluated with TEE in the supine and sitting positions. At end-inspiration 10 ml agitated gelatine solution (Gelafundin) was injected through a central venous catheter into the right atrium after airway pressure of 20 cm H2O had been maintained for 5 s. The injected bolus was observed throughout the ventilatory cycle, with special attention being given to early expiration and systole. A right-to-left shunt was assumed if five echo targets were observed in the left atrium. RESULTS. The prevalence of PFO detected by TTE/Valsalva was 9%. The diagnosis was confirmed by TEE in 2 patients in the supine and 1 in the sitting position. An echocardiogram in these patients showed bulging of the septum to the left, which was not seen in those patients in whom PFO was detected only by TTE. DISCUSSION. The reason for the lower incidence of PFO detected by TEE during airway pressure 20 cm H2O may have been an insufficient increase of pressure in the right atrium with a negative right-to-left atrial pressure gradient. A standardised ventilation manoeuvre with supra-atmospheric airway pressure of 20 cm H2O is not sufficient. Bulging of the intra-atrial septum from right to left during airway pressure is a possible indication of the efficacy of the manoeuvre, regardless of the influence of the breathing pattern.

Pharmacokinetics of loracarbef and interaction with acetylcysteine.

A study was conducted to evaluate the pharmacokinetics of loracarbef, a new synthetic oral carbacephem antibiotic, following administration of 400 mg in normal male volunteers. The influence of food and possible interaction with acetylcysteine, a commonly used mucolytic agent, was also studied. Twelve healthy volunteers participated in the study and randomly received an oral dose of 400 mg loracarbef in the fasting state, 400 mg loracarbef following a standard breakfast or 400 mg loracarbef together with 200 mg acetylcysteine in granular form. Serum and urine concentrations were determined over 24 h by means of a bioassay. Loracarbef was well tolerated. Four volunteers complained of mild, transient headache. The substance was well absorbed with a mean peak level of 19.21 +/- 3.94 mg/l in the fasting state; it was primarily excreted in active form via the kidneys (urine recovery/24 h: 86-92%). The elimination half-life ranged from 70.3 to 102.0 min. Acetylcysteine had no effect on the absorption of loracarbef. The intake together with food delayed the absorption time, but had no influence on the bioavailability.

Influence of ranitidine, pirenzepine, and aluminum magnesium hydroxide on the bioavailability of various antibiotics, including amoxicillin, cephalexin, doxycycline, and amoxicillin-clavulanic acid.

Two randomized double-blind crossover studies and one randomized crossover study were performed to document possible drug-drug interactions between antacids (aluminum magnesium hydroxide, 10 ml per dose for 10 doses), antimuscarinic drugs (pirenzepine, 50 mg per dose for 4 doses), and H2-blockers (ranitidine, 150 mg per dose for 3 doses) and amoxicillin (1,000 mg), cephalexin (1,000 mg), doxycycline (200 mg), and amoxicillin-clavulanic acid (625 mg). Ten healthy volunteers participated in each study. Concentrations in serum and urine were measured by bioassay, and pharmacokinetic parameters were calculated by the usual open one- or two-compartment models (statistics were determined by the Wilcoxon test). The antacid, pirenzepine, and ranitidine had no influence on the bioavailability of amoxicillin, cephalexin, and amoxicillin-clavulanic acid. Only small differences could be observed in the pharmacokinetic parameters, but they are not of therapeutic importance. However, the antacid caused a significant (P less than 0.01) reduction in the gastrointestinal absorption of doxycycline (area under the concentration-time curve, 38.6 +/- 22.7 mg.h/liter, fasting; 6.0 +/- 3.2 mg.h/liter, with antacid), resulting in subtherapeutic levels of doxycycline.