Martin Døssing

The Danish Randomized Lung Cancer CT Screening Trial—Overall Design and Results of the Prevalence Round

Introduction: Lung cancer screening with low dose computed tomography (CT) has not yet been evaluated in randomized clinical trials, although several are underway. Methods: In The Danish Lung Cancer Screening Trial, 4104 smokers and previous smokers from 2004 to 2006 were randomized to either screening with annual low dose CT scans for 5 years or no screening. A history of cigarette smoking of at least 20 pack years was required. All participants have annual lung function tests, and questionnaires regarding health status, psychosocial consequences of screening, smoking habits, and smoking cessation. Baseline CT scans were performed in 2052 participants. Pulmonary nodules were classified according to size and morphology: (1) Nodules smaller than 5 mm and calcified (benign) nodules were tabulated, (2) Noncalcified nodules between 5 and 15 mm were rescanned after 3 months. If the nodule increased in size or was larger than 15 mm the participant was referred for diagnostic workup. Results: At baseline 179 persons showed noncalcified nodules larger than 5 mm, and most were rescanned after 3 months: The rate of false-positive diagnoses was 7.9%, and 17 individuals (0.8%) turned out to have lung cancer. Ten of these had stage I disease. Eleven of 17 lung cancers at baseline were treated surgically, eight of these by video assisted thoracic surgery resection. Conclusions: Screening may facilitate minimal invasive treatment and can be performed with a relatively low rate of false-positive screen results compared with previous studies on lung cancer screening.

CT screening for lung cancer brings forward early disease. The randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT

Background The effects of low-dose CT screening on disease stage shift, mortality and overdiagnosis are unclear. Lung cancer findings and mortality rates are reported at the end of screening in the Danish Lung Cancer Screening Trial. Methods 4104 men and women, healthy heavy smokers/former smokers were randomised to five annual low-dose CT screenings or no screening. Two experienced chest radiologists read all CT scans and registered the location, size and morphology of nodules. Nodules between 5 and 15 mm without benign characteristics were rescanned after 3 months. Growing nodules (>25% volume increase and/or volume doubling time<400 days) and nodules >15 mm were referred for diagnostic workup. In the control group, lung cancers were diagnosed and treated outside the study by the usual clinical practice. Results Participation rates were high in both groups (screening: 95.5%; control: 93.0%; p<0.001). Lung cancer detection rate was 0.83% at baseline and mean annual detection rate was 0.67% at incidence rounds (p=0.535). More lung cancers were diagnosed in the screening group (69 vs 24, p<0.001), and more were low stage (48 vs 21 stage I–IIB non-small cell lung cancer (NSCLC) and limited stage small cell lung cancer (SCLC), p=0.002), whereas frequencies of high-stage lung cancer were the same (21 vs 16 stage IIIA–IV NSCLC and extensive stage SCLC, p=0.509). At the end of screening, 61 patients died in the screening group and 42 in the control group (p=0.059). 15 and 11 died of lung cancer, respectively (p=0.428). Conclusion CT screening for lung cancer brings forward early disease, and at this point no stage shift or reduction in mortality was observed. More lung cancers were diagnosed in the screening group, indicating some degree of overdiagnosis and need for longer follow-up.

A simple method for determination of antipyrine clearance.

Antipyrine clearance (ClAP) is widely used for assessment of microsomal liver function. The usual procedure involves collection of 4 to 7 samples of plasma or saliva obtained during 24 to 48 hr. To determine whether this procedure could be simplified it was compared with one based on a single sample (sClAP) and an estimated volume of distribution (VD) in 142 persons. VD was estimated from body weight, in kilograms (BW), height, in centimeters (BH), age in years, and sex, or assumed to be 40 l. The agreement between values of ClAP and sClAP increased with the time of the single sample and the two clearance estimates were nearly identical in all cases when the sample was taken after 18 hr. The method used for assessment of VD had only a small influence on the agreement. It is suggested that antipyrine clearance (in ml/min) is estimated as , where D is the dose of antipyrine (in mg), ct the concentration of antipyrine (in mg/l) at sampling time t (in min), t should be about 1440 min (24 hr), and VD (in l) is calculated as 0.2363 x BW + 0.1962 X BH ‐0.0272 X age ‐ 10.26 (women) or 0.3625 × BW + 0.2239 X BH ‐0.1387 X age ‐14.47 (men). Little information is lost, however, if a fixed volume of 40 l is used. Then, if the dose is 1 gm, ct is expressed in milligrams per liter, and the sampling time is 24 hr, sClAP = (3.28 ‐ In ct) X 28 ml/min.

Effect of CT screening on smoking habits at 1-year follow-up in the Danish Lung Cancer Screening Trial (DLCST)

Background: The effect of low-dose CT screening for lung cancer on smoking habits has not been reported in large randomised controlled trials. Methods: This study evaluated the effect on smoking habits of screening with low-dose CT at 1-year follow up in the Danish Lung Cancer Screening Trial (DLCST), a 5-year randomised controlled trial comprising 4104 subjects; 2052 subjects received annual low-dose CT scan (CT group) and 2052 received no intervention (control group). Participants were healthy current and former smokers (>4 weeks since smoking cessation) with a tobacco consumption of >20 pack years. Smoking habits were determined at baseline and at annual screening. Smoking status was verified using exhaled carbon monoxide levels. Lung function tests, nicotine dependency and motivation to quit smoking were assessed. Quit rates and relapse rates were determined at 1-year follow-up for all subjects. Results: At 1 year the quit rates among smokers were 11.9% in the CT group and 11.8% in the control group (p = 0.95). Relapse rates for former smokers were 10.0% and 10.5% in the CT and control groups, respectively (p = 0.81). Significant predictors (p<0.05) for smoking cessation were: high motivation to quit, low dependency, low ratio of forced expiratory volume in 1 s to forced vital capacity, low pack years, higher age, longer period of abstinence and CT findings necessitating 3-month repeat CT scans. Conclusions: Overall, quit rates were similar in the CT and control group at 1-year follow-up, with a net quit rate of 6.0%. Quit rates were higher and relapse rate lower among subjects with initial CT findings that necessitated a repeat scan 3 months later.

Time course of phenobarbital and cimetidine mediated changes in hepatic drug metabolism

SummaryFour healthy subjects were investigated weekly for 14 weeks by the antipyrine one sample saliva test, the 48-h urinary excretion of major antipyrine metabolites and the 2-h aminopyrine breath test before, during and after stimulation and inhibition of drug metabolism with phenobarbital and cimetidine, respectively. The phenobarbital-induced enhancement of antipyrine clearance (1.33–2.03 times) and of the aminopyrine breath test (0.94–1.19 times) occurred one week after beginning drug administration and persisted for 10 days after its cessation. The cimetidine-related inhibition of antipyrine clearance (0.62–0.85 times) and of the aminopyrine breath test (0.52–0.93 times) was observed 24 h after beginning cimetidine administration and subsided within two days after the last dose. During enhancement and inhibition the clearance of antipyrine to 3-hydroxymethyl-, 4-hydroxy- and norantipyrine varied as the total antipyrine clearance. The intraindividual variation in antipyrine clearance was 6–8%, and the corresponding variation in urinary excretion of antipyrine metabolites was 10–20%. It is concluded that the influence of phenobarbital and cimetidine on hepatic microsomal enzyme activity can be monitored simply by measurement of the blood concentration of the drug. Whether this simple relationship applies to other microsomally mediated drug interactions requires further evaluation.

Increased Susceptibility to Liver Disease in Relation to Alcohol Consumption in Women

Sex-related differences were prospectively studied in patients with the first presentation of alcoholic liver disease. Among 42 patients the diagnosis was cirrhosis in 8 women and 15 men, alcoholic hepatitis in 4 women and 1 man, steatosis in 6 women and 6 men, and no histologic changes were found in the liver biopsy specimens from 2 men (p greater than 0.1). The median (range) antipyrine clearance was 14.6 (1.0-64) versus 17.2 (3.0-83) ml/min and the clinical score in accordance with the Pugh modification of the Child-Turcotte classification was 8 (5-13) versus 8 (5-11) in the women and men, respectively (p greater than 0.05). In 5 women and only 1 man the antipyrine clearance was less than 5 ml/min, indicating an almost total loss of functional liver mass (p less than 0.05), whereas the Pugh score was above 11 in 6 women, but not in any of the men (p less than 0.05). On an average, the men estimated their total lifetime consumption of alcohol to be 2.1 times greater and the number of days they had consumed more than 5 drinks 2.9 times higher than the women (p less than 0.05). These ratios are reduced to 1.4 and 1.7, respectively (p greater than 0.05), if the female alcohol intake is adjusted to the average male volume of distribution. The results support the concept that women may develop similar, and sometimes even more severe, liver disease after consumption of less alcohol than men. The apparent difference in susceptibility to alcohol may be partly explained by differences in volume of distribution.

Antipyrine clearance in pneumonia

Antipyrine clearance was estimated by a one‐sample technique in 14 patients with acute fever and clinical pneumonia. Antipyrine clearance during the acute illness was 31.4 ± 7.6 ml/min (X ± SD). Fourteen and 28 days later during convalescence, clearance values were higher (47.8 ± 18.9 and 49.2 ± 15.0 ml/ min, respectively). We conclude that microsomal hepatic drug metabolism in adults is impaired during pneumonia.

Drug-induced hepatic disorders : incidence, management and avoidance

SummaryDrug-induced liver injury has been associated with more than 800 different drugs, leading to hospital admission in 1 of 600 to 3500 admissions. This amounts to 2 to 3% of all hospitalisations due to adverse drug reactions, or about 3% of all jaundiced patients. The prognosis of clinically overt drug hepatotoxicity is relatively serious. The clinical picture is essentially nonspecific, with a highly variable latency period from days to years. Drug hepatotoxicity can mimic almost any kind of liver disease. A thorough drug history, a low threshold of suspicion and the exclusion of other causes of liver disease are important for the detection of drug-induced liver disorders.Treatment consists of discontinuation of suspected drug(s), acetylcysteine in the course of paracetamol (acetaminophen) toxicity, and liver transplantation in selected cases of fulminant liver failure.Guidelines regarding the use of selected drugs such as methotrexate and halothane should be followed. Potentially hepatotoxic drugs should be used cautiously in alcoholic patients with or without liver involvement. Patients with uncompensated liver disease should receive a reduced dose of drugs adjusted to the degree of liver function impairment.The general public should be warned against abuse of hepatotoxic drugs such as paracetamol and anabolic steroids.

Hepatic drug metabolism and physical fitness

Physical fitness, as expressed by maximal oxygen uptake (VO2max), was measured in 14 subjects before and during physical education consisting of 4 to 8 hr of daily physical training. Mean pulse rate during training was 115 bpm. After 3 mo of physical training, VO2max increased a mean 6% (range −5% to +23%). Corresponding mean increases in hepatic drug metabolism, as expressed by the metabolism of the model drugs antipyrine and aminopyrine, were 12% (range −12% to +59%) and 13% (range −21% to +47%). Changes in the two groups were still present 6 mo after physical education. There was only a moderately close but nonetheless significant correlation (r =0.7) between the extent of change in VO2max and the corresponding relative change in antipyrine metabolism during the 3‐mo period of this investigation. The correlation between oxygen uptake and aminopyrine metabolism (r =0.6) was slightly less and was not significant. Improved physical fitness associated with enhanced drug metabolism may lead to changes in drug efficacy and drug toxicity that may be clinically important in the case of drugs with low therapeutic indices.

Influence of dose and route of administration on disposition of metronidazole and its major metabolites

SummaryThe influence of dose and route of administration on the kinetics of metronidazole and its major metabolites has been investigated in 8 healthy volunteers given 0.5 and 2.0 g i.v. and p.o. Metronidazole elimination kinetics from plasma could be described by an open two-compartment model. The systemic oral bioavailability of both doses was approximately 1. The total systemic clearance of the intravenous 2.0 g dose was 9% lower than that of the 0.5 g dose (p<0.05). There were no significant dose-related differences in volume or rate of distribution. The elimination half-life was similar after the four treatments with metronidazole. The major elimination pathways, renal excretion and hepatic oxidation and glucuronidation, accounted for more than 2/3 of the total systemic clearance. Clearance both by hepatic oxidative metabolism and renal excretion was significantly lower after 2.0 than after 0.5 g i.v., whereas there was no significant difference after the oral doses. The results indicate that a high therapeutic dose of metronidazole may be eliminated at a reduced rate, but this is probably not of clinical importance. No single saturable elimination pathway was identified.