John Brodersen

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.

Long-Term Psychosocial Consequences of False-Positive Screening Mammography

PURPOSE Cancer screening programs have the potential of intended beneficial effects, but they also inevitably have unintended harmful effects. In the case of screening mammography, the most frequent harm is a false-positive result. Prior efforts to measure their psychosocial consequences have been limited by short-term follow-up, the use of generic survey instruments, and the lack of a relevant benchmark—women with breast cancer. METHODS In this cohort study with a 3-year follow-up, we recruited 454 women with abnormal findings in screening mammography over a 1-year period. For each woman with an abnormal finding on a screening mammogram (false and true positives), we recruited another 2 women with normal screening results who were screened the same day at the same clinic. These participants were asked to complete the Consequences of Screening in Breast Cancer—a validated questionnaire encompassing 12 psychosocial outcomes—at baseline, 1, 6, 18, and 36 months. RESULTS Six months after final diagnosis, women with false-positive findings reported changes in existential values and inner calmness as great as those reported by women with a diagnosis of breast cancer (Δ = 1.15; P = .015; and Δ = 0.13; P = .423, respectively). Three years after being declared free of cancer, women with false-positive results consistently reported greater negative psychosocial consequences compared with women who had normal findings in all 12 psychosocial outcomes (Δ >0 for 12 of 12 outcomes; P <.01 for 4 of 12 outcomes). CONCLUSION False-positive findings on screening mammography causes long-term psychosocial harm: 3 years after a false-positive finding, women experience psychosocial consequences that range between those experienced by women with a normal mammogram and those with a diagnosis of breast cancer.

Breast screening: the facts—or maybe not

Peter Gøtzsche and colleagues argue that women are still not given enough, nor correct, information about the harms of screening

To nudge or not to nudge: cancer screening programmes and the limits of libertarian paternalism

‘Nudging—and the underlying idea ‘libertarian paternalism’—to an increasing degree influences policy thinking in the healthcare sector. This article discusses the influence exerted upon a womans choice of participation in the Danish breast screening programme in light of ‘libertarian paternalism’. The basic tenet of ‘libertarian paternalism’ is outlined and the relationship between ‘libertarian paternalism’ and informed consent investigated. Key elements in the process of enrolling women into the Danish mammography screening programme are introduced. It is shown that for several reasons the influence exerted upon womens choices of participation cannot be justified within a welfare-enhancing libertarian paternalistic framework. The article suggests that screening programmes alternatively adopt a liberty-enhancing approach and considers the practical implications of this alternative.

Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling

RATIONALE As of April 2015, participants in the Danish Lung Cancer Screening Trial had been followed for at least 5 years since their last screening. OBJECTIVES Mortality, causes of death, and lung cancer findings are reported to explore the effect of computed tomography (CT) screening. METHODS A total of 4,104 participants aged 50-70 years at the time of inclusion and with a minimum 20 pack-years of smoking were randomized to have five annual low-dose CT scans (study group) or no screening (control group). MEASUREMENTS AND MAIN RESULTS Follow-up information regarding date and cause of death, lung cancer diagnosis, cancer stage, and histology was obtained from national registries. No differences between the two groups in lung cancer mortality (hazard ratio, 1.03; 95% confidence interval, 0.66-1.6; P = 0.888) or all-cause mortality (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27; P = 0.867) were observed. More cancers were found in the screening group than in the no-screening group (100 vs. 53, respectively; P < 0.001), particularly adenocarcinomas (58 vs. 18, respectively; P < 0.001). More early-stage cancers (stages I and II, 54 vs. 10, respectively; P < 0.001) and stage IIIa cancers (15 vs. 3, respectively; P = 0.009) were found in the screening group than in the control group. Stage IV cancers were nonsignificantly more frequent in the control group than in the screening group (32 vs. 23, respectively; P = 0.278). For the highest-stage cancers (T4N3M1, 21 vs. 8, respectively; P = 0.025), this difference was statistically significant, indicating an absolute stage shift. Older participants, those with chronic obstructive pulmonary disease, and those with more than 35 pack-years of smoking had a significantly increased risk of death due to lung cancer, with nonsignificantly fewer deaths in the screening group. CONCLUSIONS No statistically significant effects of CT screening on lung cancer mortality were found, but the results of post hoc high-risk subgroup analyses showed nonsignificant trends that seem to be in good agreement with the results of the National Lung Screening Trial. Clinical trial registered with www.clinicaltrials.gov (NCT00496977).

Quantification of harms in cancer screening trials: literature review

Objectives To assess how often harm is quantified in randomised trials of cancer screening. Design Two authors independently extracted data on harms from randomised cancer screening trials. Binary outcomes were described as proportions and continuous outcomes with medians and interquartile ranges. Data sources For cancer screening previously assessed in a Cochrane review, we identified trials from their reference lists and updated the search in CENTRAL. For cancer screening not assessed in a Cochrane review, we searched CENTRAL, Medline, and Embase. Eligibility criteria for selecting studies Randomised trials that assessed the efficacy of cancer screening for reducing incidence of cancer, cancer specific mortality, and/or all cause mortality. Data extraction Two reviewers independently assessed articles for eligibility. Two reviewers, who were blinded to the identity of the study’s authors, assessed whether absolute numbers or incidence rates of outcomes related to harm were provided separately for the screening and control groups. The outcomes were false positive findings, overdiagnosis, negative psychosocial consequences, somatic complications, invasive follow-up procedures, all cause mortality, and withdrawals because of adverse events. Results Out of 4590 articles assessed, 198 (57 trials, 10 screening technologies) matched the inclusion criteria. False positive findings were quantified in two of 57 trials (4%, 95% confidence interval 0% to 12%), overdiagnosis in four (7%, 2% to 18%), negative psychosocial consequences in five (9%, 3% to 20%), somatic complications in 11 (19%, 10% to 32%), use of invasive follow-up procedures in 27 (47%, 34% to 61%), all cause mortality in 34 (60%, 46% to 72%), and withdrawals because of adverse effects in one trial (2%, 0% to 11%). The median percentage of space in the results section that reported harms was 12% (interquartile range 2-19%). Conclusions Cancer screening trials seldom quantify the harms of screening. Of the 57 cancer screening trials examined, the most important harms of screening—overdiagnosis and false positive findings—were quantified in only 7% and 4%, respectively.

The Adequacy of Measurement of Short and Long-Term Consequences of False-Positive Screening Mammography

Objectives: The aim of this study is to review quantitative studies on womens experiences of consequences of false-positive screening mammography to assess the adequacy of the most frequently used instruments for measuring short-term and long-term psychological consequences. Methods: Relevant papers reporting quantitative studies on consequences of false-positive screening mammography were identified using MEDLlNE, CINAHL, EMBASE and PsycInfo databases. Articles citing development and psychometric properties of the most frequently used measures were also retrieved. Finally, the review focused on studies that had used at least one of the most frequently used measures. Results: Twenty-three relevant studies were identified. The most commonly used measures were the General Health Questionnaire (GHQ), the Hospital Anxiety and Depression Scale (HADS), the Psychological Consequences Questionnaire (PCQ) and the State-Trait Anxiety Inventory (STAI). One or more of these was used in 17 of the 23 studies. Conclusions: The GHQ, the HADS and the STAI have problems with language, content relevance, and content coverage in studies of false-positive screening mammography. These instruments should not be used to measure psychological consequences of any kind of cancer screening. The PCQ is an adequate questionnaire for measuring short-term consequences, and the PCQ is preferable to other measures because of its higher sensitivity. However, there is little evidence that the PCQ is able to adequately detect all long-term consequences of screening mammography. Given the inadequacy of the measurement instruments used, any current conclusions about the long-term consequences of false-positive results of screening mammography must remain tentative.

Rasch analysis of the Knee injury and Osteoarthritis Outcome Score (KOOS): a statistical re‐evaluation

The knee injury and Osteoarthritis Outcome Score (KOOS), based on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), is widely used to evaluate subjective outcome in anterior cruciate ligament (ACL) reconstructed patients. However, the validity of KOOS has not been assessed using Rasch analysis. The objective of this study was to evaluate the viability of KOOS as an outcome measure for ACL reconstruction using the partial credit Rasch model. Rasch analysis was applied to 200 KOOS questionnaires completed by patients consecutively tested 20 weeks after ACL reconstruction and subsequent rehabilitation. Rasch analysis showed that of the five proposed subscales in KOOS, only knee‐related quality of life (QoL) and sport and recreational related function (Sport/Rec) fulfilled the criteria of a unidimensional measurement scale when applied to these patients. The three subdomains in KOOS extracted from WOMAC did not fulfill these criteria. While the content of KOOS appears to be relevant for knee patients, the psychometric measurement properties of KOOS are insufficient for use on patients 20 weeks subsequent to ACL reconstruction. A new knee measure targeted for these patients could be developed based on the content of KOOS. This study demonstrates that knee measurement instruments constructed for a specific condition cannot necessarily be used on patients with other similar conditions.

No evidence of a clinically important effect of adding local infusion analgesia administrated through a catheter in pain treatment after total hip arthroplasty

Background and purpose Postoperative analgesia after primary total hip arthroplasty (THA) using opioids is associated with troublesome side effects such as nausea and dizziness, and epidural analgesic means delayed mobilization. Thus, local infiltration analgesia (LIA) during surgery prolonged with local infusion analgesia (LINFA) into the soft tissue in the hip region through a catheter in the first postoperative days has gained major interest in THA fast-track settings within a short period of time. LIA at the time of surgery is a validated treatment. We investigated the additional effect of giving postoperative LINFA after THA in patients already having LIA during surgery. Patients and methods 60 consecutive patients undergoing non-cemented THA were randomized into two groups in a double-blind and controlled study. During surgery, all patients received standardized pain treatment with LIA. Postoperatively, they were treated either with a solution of Ropivacain, Ketorolac, and Adrenaline (LINFA group) or placebo (placebo group) administered through a catheter to the hip 10 and 22 h after surgery. Pain score, opioid consumption, and length of stay (LOS) were evaluated. Results After adjustment for multiple testing, there was no statistically significant postoperative difference between the LINFA group and the placebo group regarding pain and tiredness. We found some evidence of a short-term effect on nausea and vomiting. Opioid consumption and length of stay were similar in the two groups. Interpretation We found some evidence of a short-term effect of LINFA on nausea and vomiting, but no evidence of an effect on postoperative pain and tiredness. Thus, LINFA cannot be recommended as a standard pain treatment in patients with THA.