Do we know enough about the effect of low-dose computed tomography screening for lung cancer on mortality to act? An updated systematic review, meta-analysis and network meta-analysis of randomised controlled trials 2017 to 2021.

BACKGROUND: For people at high risk of lung cancer, low-dose computed tomography (LDCT) is proposed as a method to reduce mortality. METHODS: Our objective was to estimate the effect of LDCT lung cancer screening on mortality in high-risk populations. A systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programme (such as chest X-ray (CXR)) was conducted. RCTs of CXR screening were additionally included in the network meta-analyses. Bibliographic sources including MEDLINE, Embase, Web of Science and the Cochrane Library were searched to January 2017, and then further extended to November 2021. All key review steps were done by two persons. Quality assessment used the Cochrane Risk of Bias tool. Meta-analyses were performed. RESULTS: Nine RCTs, with up to 12.3 years of follow-up from randomisation, were included in the direct meta-analysis, which showed that LDCT screening was associated with a statistically significant decrease in lung cancer mortality (pooled relative risk (RR) 0.86, 95% confidence interval [CI] 0.77 to 0.96). There was a statistically non-significant decrease in all-cause mortality (pooled RR 0.98, 95% CI 0.95 to 1.01). The statistical heterogeneity for both outcomes was minimal. Network meta-analysis including the nine RCTs in the direct meta-analysis plus two further RCTs comparing CXR with usual care confirmed the size of the effect of LDCT on lung cancer mortality and that this was very similar irrespective of whether the comparator was usual care or CXR screening. CONCLUSIONS: LDCT screening is effective in reducing lung cancer mortality in high-risk populations. The uncertainty of its effect on lung cancer mortality observed in 2018 has been much reduced with new trial results and updates to existing trials, emphasising the importance of updating systematic reviews. Although there are still a number of RCTs unreported or in progress, we predict that further evolution of summary mortality estimates is unlikely. The focus for debate now moves to resolving uncertainty about the cost-effectiveness of LDCT screening taking into account the balance between benefits and harms which occur in all screening programmes.

Pre-Navigation via Interactive Audio Tactile Maps to Promote the Wellbeing of Visually Impaired People.

BACKGROUND: Pre-navigational tools can assist visually impaired people when navigating unfamiliar environments. Assistive technology products (eg tactile maps or auditory simulations) can stimulate cognitive mapping processes to provide navigational assistance in these people. OBJECTIVES: We compared how well blind and visually impaired people could learn a map presented via a tablet computer auditory tactile map (ATM) in contrast to a conventional tactile map accompanied by a text description objectives. METHODS: Performance was assessed with a multiple choice test that quizzed participants on orientation and spatial awareness. Semi-structured interviews explored participant experiences and preferences. RESULTS: A statistically significant difference was found between the conditions with participants using the ATM performing much better than those who used a conventional tactile map and text description. Participants preferred the flexibility of learning of the ATM. CONCLUSION: This computer-based ATM provided an effective, easy to use and cost-effective way of enabling blind and partially sighted people learn a cognitive map and enhance their wellbeing.

Do we know enough about the effect of low-dose computed tomography screening for lung cancer on survival to act? A systematic review, meta-analysis and network meta-analysis of randomised controlled trials.

BACKGROUND: Diagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early. METHODS: Our objective was to estimate the effect of LDCT lung cancer screening on mortality in high-risk populations. A systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programme (such as chest X-ray (CXR)) was conducted. RCTs of CXR screening were additionally included in the network meta-analysis. Bibliographic sources including MEDLINE, Embase, Web of Science and the Cochrane Library were searched to January 2017. All key review steps were done by two persons. Quality assessment used the Cochrane Risk of Bias tool. Meta-analyses were performed. RESULTS: Four RCTs were included. More will provide data in the future. Meta-analysis demonstrated that LDCT screening with up to 9.80 years of follow-up was associated with a statistically non-significant decrease in lung cancer mortality (pooled relative risk (RR) 0.94, 95% confidence interval (CI) 0.74 to 1.19; p = 0.62). There was a statistically non-significant increase in all-cause mortality. Given the considerable heterogeneity for both outcomes, the results should be treated with caution.Network meta-analysis including the four original RCTs plus two further RCTs assessed the relative effectiveness of LDCT, CXR and usual care. The results showed that in terms of lung cancer mortality reduction LDCT was ranked as the best screening strategy, CXR screening as the worst strategy and usual care intermediate. CONCLUSIONS: LDCT screening may be effective in reducing lung cancer mortality but there is considerable uncertainty: the largest of the RCTs compared LDCT with CXR screening rather than no screening; there is imprecision of the estimates; and there is important heterogeneity between the included study results. The uncertainty about the effect on all-cause mortality is even greater. Maturing trials may resolve the uncertainty.

Low-dose computed tomography for lung cancer screening in high-risk populations: a systematic review and economic evaluation.

BACKGROUND: Diagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early. OBJECTIVES: To estimate the clinical effectiveness and cost-effectiveness of LDCT lung cancer screening in high-risk populations. DATA SOURCES: Bibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library. METHODS: Clinical effectiveness - a systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programmes [such as chest X-ray (CXR)] was conducted. Bibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library. Meta-analyses, including network meta-analyses, were performed. Cost-effectiveness - an independent economic model employing discrete event simulation and using a natural history model calibrated to results from a large RCT was developed. There were 12 different population eligibility criteria and four intervention frequencies [(1) single screen, (2) triple screen, (3) annual screening and (4) biennial screening] and a no-screening control arm. RESULTS: Clinical effectiveness - 12 RCTs were included, four of which currently contribute evidence on mortality. Meta-analysis of these demonstrated that LDCT, with ≤ 9.80 years of follow-up, was associated with a non-statistically significant decrease in lung cancer mortality (pooled relative risk 0.94, 95% confidence interval 0.74 to 1.19). The findings also showed that LDCT screening demonstrated a non-statistically significant increase in all-cause mortality. Given the considerable heterogeneity detected between studies for both outcomes, the results should be treated with caution. Network meta-analysis, including six RCTs, was performed to assess the relative clinical effectiveness of LDCT, CXR and usual care. The results showed that LDCT was ranked as the best screening strategy in terms of lung cancer mortality reduction. CXR had a 99.7% probability of being the worst intervention and usual care was ranked second. Cost-effectiveness - screening programmes are predicted to be more effective than no screening, reduce lung cancer mortality and result in more lung cancer diagnoses. Screening programmes also increase costs. Screening for lung cancer is unlikely to be cost-effective at a threshold of £20,000/quality-adjusted life-year (QALY), but may be cost-effective at a threshold of £30,000/QALY. The incremental cost-effectiveness ratio for a single screen in smokers aged 60-75 years with at least a 3% risk of lung cancer is £28,169 per QALY. Sensitivity and scenario analyses were conducted. Screening was only cost-effective at a threshold of £20,000/QALY in only a minority of analyses. LIMITATIONS: Clinical effectiveness - the largest of the included RCTs compared LDCT with CXR screening rather than no screening. Cost-effectiveness - a representative cost to the NHS of lung cancer has not been recently estimated according to key variables such as stage at diagnosis. Certain costs associated with running a screening programme have not been included. CONCLUSIONS: LDCT screening may be clinically effective in reducing lung cancer mortality, but there is considerable uncertainty. There is evidence that a single round of screening could be considered cost-effective at conventional thresholds, but there is significant uncertainty about the effect on costs and the magnitude of benefits. FUTURE WORK: Clinical effectiveness and cost-effectiveness estimates should be updated with the anticipated results from several ongoing RCTs [particularly the NEderlands Leuvens Longkanker Screenings ONderzoek (NELSON) screening trial]. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016048530. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Everolimus, lutetium-177 DOTATATE and sunitinib for advanced, unresectable or metastatic neuroendocrine tumours with disease progression: a systematic review and cost-effectiveness analysis.

BACKGROUND: Neuroendocrine tumours (NETs) are a group of heterogeneous cancers that develop in cells in the diffuse neuroendocrine system. OBJECTIVES: To estimate the clinical effectiveness of three interventions [everolimus (Afinitor®; Novartis International AG, Basel, Switzerland), lutetium-177 DOTATATE (177Lu-DOTATATE) (Lutathera®; Imaging Equipment Ltd, Radstock, UK) and sunitinib (Sutent®; Pfizer Inc., New York, NY, USA)] for treating unresectable or metastatic NETs with disease progression and establish the cost-effectiveness of these interventions. DATA SOURCES: The following databases were searched from inception to May 2016: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Daily, Epub Ahead of Print, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science. REVIEW METHODS: We systematically reviewed the clinical effectiveness and cost-effectiveness literature on everolimus, 177Lu-DOTATATE and sunitinib for treating advanced, unresectable or metastatic progressive NETs. The following NET locations were considered separately: pancreas, gastrointestinal (GI) tract and lung, and GI tract (midgut only). We wrote a survival partition cohort-based economic evaluation in Microsoft Excel® 2013 (Microsoft Corporation, Redmond, WA, USA) from the UK NHS and Personal Social Services perspective. This comprised three health states: (1) progression-free survival (PFS), (2) progressed disease and (3) death. RESULTS: Three randomised controlled trials (RCTs), RADIANT-3 [RAD001 in Advanced Neuroendocrine Tumors, Third Trial; pancreatic NETs (pNETs): everolimus vs. best supportive care (BSC)], A6181111 (pNETs: sunitinib vs. BSC) and RADIANT-4 (RAD001 in Advanced Neuroendocrine Tumors, Fourth Trial; GI and lung NETs: everolimus vs. BSC), met the inclusion criteria for the clinical effectiveness systematic review. The risk of bias was low. Although the NETTER-1 (Neuroendocrine Tumors Therapy) RCT, of 177Lu-DOTATATE plus 30 mg of octreotide (Sandostatin®, Novartis) compared with 60 mg of octreotide, was excluded from the review, we nonetheless present the results of this trial, as it informs our estimate of the cost-effectiveness of 177Lu-DOTATATE. The pNETs trials consistently found that the interventions improved PFS and overall survival (OS) compared with BSC. Our indirect comparison found no significant difference in PFS between everolimus and sunitinib. Estimates of OS gain were confounded because of high rates of treatment switching. After adjustment, our indirect comparison suggested a lower, but non-significant, hazard of death for sunitinib compared with everolimus. In GI and lung NETs, everolimus significantly improved PFS compared with BSC and showed a non-significant trend towards improved OS compared with BSC. Adverse events were more commonly reported following treatment with targeted interventions than after treatment with BSC. In the base case for pNETs, assuming list prices, we estimated incremental cost-effectiveness ratios (ICERs) for everolimus compared with BSC of £45,493 per quality-adjusted life-year (QALY) and for sunitinib compared with BSC of £20,717 per QALY. These ICERs increased substantially without the adjustment for treatment switching. For GI and lung NETs, we estimated an ICER for everolimus compared with BSC of £44,557 per QALY. For GI (midgut) NETs, the ICERs were £199,233 per QALY for everolimus compared with BSC and £62,158 per QALY for a scenario analysis comparing 177Lu-DOTATATE with BSC. We judge that no treatment meets the National Institute for Health and Care Excellence's (NICE) end-of-life criteria, although we cannot rule out that sunitinib in the A6181111 trial does. LIMITATIONS: A RCT with included comparators was not identified for 177Lu-DOTATATE. The indirect treatment comparison that our economic analysis was based on was of a simple Bucher type, unadjusted for any differences in the baseline characteristics across the two trials. CONCLUSIONS: Given NICE's current stated range of £20,000-30,000 per QALY for the cost-effectiveness threshold, based on list prices, only sunitinib might be considered good value for money in England and Wales. FUTURE WORK: Further analysis of individual patient data from RADIANT-3 would allow assessment of the robustness of our findings. The data were not made available to us by the company sponsoring the trial. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016041303. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Impact of missed treatment opportunities on outcomes in hospitalised patients with heart failure.

Objective: Many patients with heart failure (HF) do not receive recommended treatments, resulting in suboptimal outcomes. We aimed to investigate the impact of implementing recommended HF therapies on health outcomes, and the costs and effectiveness of interventions for improving adherence. Methods: The health benefits of ACE inhibitor (ACEi), beta blockers and optimal therapy (ACEi and beta blockers if not contraindicated) following hospitalisation for HF were combined with evidence on uptake. The aim was to examine how much health was lost as a result of failure to follow guidelines, and how much could be gained using strategies to promote uptake.The net health benefits of different treatments (measured in quality-adjusted life-years (QALY)) were estimated using a decision-analytic model and treatment effectiveness from the literature. Data on the number of patients who would have benefitted from the additional treatments were estimated from 2010 to 2013 using the National Heart Failure Audit. Results: Each recommended treatment was associated with positive net health benefit. In 2010, up to 4019 (38.3%) patients would have benefitted from additional treatments rising to 4886 patients in 2013 (although falling to 25.2% of patients). Failure to follow guidelines resulted in large health losses. In 2010, if all patients had received optimal therapy, 1569 QALYs would have been gained, implying a maximum justifiable investment in interventions to promote uptake of £31.4 million. Conclusion: Current gaps in translation of evidence to practise in hospitals are associated with significant health losses. Strategies to encourage uptake of guidelines could be effective and cost-effective.

The effect of spatial barriers on realised accessibility to heath services after a natural disaster.

The closure of the Manawatu Gorge in New Zealand in August 2011 caused a change in the travel time for patients living in the east of the MidCentral Health District to their health services located in Palmerston North. This presented an opportunity to study the effect a change in spatial access had on a population before and after such an event. We used a retrospective cohort design with routinely collected data from general practice and hospital services. Realised accessibility was calculated for 101,456 patients over 3.5 years. General practice utilization appeared to be the only service affected negatively during the gorge closure (rate ratio 1.106). Outpatient attendances had an increase in use by those with increased travel time (rate ratio 0.922). There was evidence of other unidentified factors that impacted the use of services across both intervention and control groups between the gorge open and closed periods. These results were more conservative than those produced by a traditional uncontrolled travel time category analysis which suggested a correlation in non-urgent ED attendance and general practice and boundary effects in all ED attendances and hospital admissions.