House modifications for preventing malaria.

BACKGROUND: Malaria remains an important public health problem. Research in 1900 suggested house modifications may reduce malaria transmission. A previous version of this review concluded that house screening may be effective in reducing malaria. This update includes data from five new studies. OBJECTIVES: To assess the effects of house modifications that aim to reduce exposure to mosquitoes on malaria disease and transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (OVID); Centre for Agriculture and Bioscience International (CAB) Abstracts (Web of Science); and the Latin American and Caribbean Health Science Information database (LILACS) up to 25 May 2022. We also searched the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and the ISRCTN registry to identify ongoing trials up to 25 May 2022. SELECTION CRITERIA: Randomized controlled trials, including cluster-randomized controlled trials (cRCTs), cross-over studies, and stepped-wedge designs were eligible, as were quasi-experimental trials, including controlled before-and-after studies, controlled interrupted time series, and non-randomized cross-over studies. We sought studies investigating primary construction and house modifications to existing homes reporting epidemiological outcomes (malaria case incidence, malaria infection incidence or parasite prevalence). We extracted any entomological outcomes that were also reported in these studies. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, extracted data, and assessed the risk of bias. We used risk ratios (RR) to compare the effect of the intervention with the control for dichotomous data. For continuous data, we presented the mean difference; and for count and rate data, we used rate ratios. We presented all results with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: One RCT and six cRCTs met our inclusion criteria, with an additional six ongoing RCTs. We did not identify any eligible non-randomized studies. All included trials were conducted in sub-Saharan Africa since 2009; two randomized by household and four at the block or village level. All trials assessed screening of windows, doors, eaves, ceilings, or any combination of these; this was either alone, or in combination with roof modification or eave tube installation (an insecticidal "lure and kill" device that reduces mosquito entry whilst maintaining some airflow). In one trial, the screening material was treated with 2% permethrin insecticide. In five trials, the researchers implemented the interventions. A community-based approach was adopted in the other trial. Overall, the implementation of house modifications probably reduced malaria parasite prevalence (RR 0.68, 95% CI 0.57 to 0.82; 5 trials, 5183 participants; moderate-certainty evidence), although an inconsistent effect was observed in a subpopulation of children in one study. House modifications reduced moderate to severe anaemia prevalence (RR 0.70, 95% CI 0.55 to 0.89; 3 trials, 3643 participants; high-certainty evidence). There was no consistent effect on clinical malaria incidence, with rate ratios ranging from 0.38 to 1.62 (3 trials, 3365 participants, 4126.6 person-years). House modifications may reduce indoor mosquito density (rate ratio 0.63, 95% CI 0.30 to 1.30; 4 trials, 9894 household-nights; low-certainty evidence), although two studies showed little effect on this parameter. AUTHORS' CONCLUSIONS: House modifications - largely screening, sometimes combined with insecticide and lure and kill devices - were associated with a reduction in malaria parasite prevalence and a reduction in people with anaemia. Findings on malaria incidence were mixed. Modifications were also associated with lower indoor adult mosquito density, but this effect was not present in some studies.

House modifications for preventing malaria.

BACKGROUND: Despite being preventable, malaria remains an important public health problem. The World Health Organization (WHO) reports that overall progress in malaria control has plateaued for the first time since the turn of the century. Researchers and policymakers are therefore exploring alternative and supplementary malaria vector control tools. Research in 1900 indicated that modification of houses may be effective in reducing malaria: this is now being revisited, with new research now examining blocking house mosquito entry points or modifying house construction materials to reduce exposure of inhabitants to infectious bites. OBJECTIVES: To assess the effects of house modifications on malaria disease and transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (OVID); Centre for Agriculture and Bioscience International (CAB) Abstracts (Web of Science); and the Latin American and Caribbean Health Science Information database (LILACS), up to 1 November 2019. We also searched the WHO International Clinical Trials Registry Platform (www.who.int/ictrp/search/en/), ClinicalTrials.gov (www.clinicaltrials.gov), and the ISRCTN registry (www.isrctn.com/) to identify ongoing trials up to the same date. SELECTION CRITERIA: Randomized controlled trials, including cluster-randomized controlled trials (cRCTs), cross-over studies, and stepped-wedge designs were eligible, as were quasi-experimental trials, including controlled before-and-after studies, controlled interrupted time series, and non-randomized cross-over studies. We only considered studies reporting epidemiological outcomes (malaria case incidence, malaria infection incidence or parasite prevalence). We also summarised qualitative studies conducted alongside included studies. DATA COLLECTION AND ANALYSIS: Two review authors selected eligible studies, extracted data, and assessed the risk of bias. We used risk ratios (RR) to compare the effect of the intervention with the control for dichotomous data. For continuous data, we presented the mean difference; and for count and rate data, we used rate ratios. We presented all results with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: Six cRCTs met our inclusion criteria, all conducted in sub-Saharan Africa; three randomized by household, two by village, and one at the community level. All trials assessed screening of windows, doors, eaves, ceilings or any combination of these; this was either alone, or in combination with eave closure, roof modification or eave tube installation (a "lure and kill" device that reduces mosquito entry whilst maintaining some airflow). In two trials, the interventions were insecticide-based. In five trials, the researchers implemented the interventions. The community implemented the interventions in the sixth trial. At the time of writing the review, two of the six trials had published results, both of which compared screened houses (without insecticide) to unscreened houses. One trial in Ethiopia assessed screening of windows and doors. Another trial in the Gambia assessed full screening (screening of eaves, doors and windows), as well as screening of ceilings only. Screening may reduce clinical malaria incidence caused by Plasmodium falciparum (rate ratio 0.38, 95% CI 0.18 to 0.82; 1 trial, 184 participants, 219.3 person-years; low-certainty evidence; Ethiopian study). For malaria parasite prevalence, the point estimate, derived from The Gambia study, was smaller (RR 0.84, 95% CI 0.60 to 1.17; 713 participants, 1 trial; low-certainty evidence), and showed an effect on anaemia (RR 0.61, 95% CI 0.42, 0.89; 705 participants; 1 trial, moderate-certainty evidence). Screening may reduce the entomological inoculation rate (EIR): both trials showed lower estimates in the intervention arm. In the Gambian trial, there was a mean difference in EIR between the control houses and treatment houses ranging from 0.45 to 1.50 (CIs ranged from -0.46 to 2.41; low-certainty evidence), depending on the study year and treatment arm. The Ethiopian trial reported a mean difference in EIR of 4.57, favouring screening (95% CI 3.81 to 5.33; low-certainty evidence). Pooled analysis of the trials showed that individuals living in fully screened houses were slightly less likely to sleep under a bed net (RR 0.84, 95% CI 0.65 to 1.09; 2 trials, 203 participants). In one trial, bed net usage was also lower in individuals living in houses with screened ceilings (RR 0.69, 95% CI 0.50 to 0.95; 1 trial, 135 participants). AUTHORS' CONCLUSIONS: Based on the two trials published to date, there is some evidence that screening may reduce malaria transmission and malaria infection in people living in the house. The four trials awaiting publication are likely to enrich the current evidence base, and we will add these to this review when they become available.

House modifications for preventing malaria.

BACKGROUND: Despite being preventable, malaria remains an important public health problem. The World Health Organization (WHO) reports that overall progress in malaria control has plateaued for the first time since the turn of the century. Researchers and policymakers are therefore exploring alternative and supplementary malaria vector control tools. Research in 1900 indicated that modification of houses may be effective in reducing malaria: this is now being revisited, with new research now examining blocking house mosquito entry points or modifying house construction materials to reduce exposure of inhabitants to infectious bites. OBJECTIVES: To assess the effects of house modifications on malaria disease and transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (OVID); Centre for Agriculture and Bioscience International (CAB) Abstracts (Web of Science); and the Latin American and Caribbean Health Science Information database (LILACS), up to 1 November 2019. We also searched the WHO International Clinical Trials Registry Platform (www.who.int/ictrp/search/en/), ClinicalTrials.gov (www.clinicaltrials.gov), and the ISRCTN registry (www.isrctn.com/) to identify ongoing trials up to the same date. SELECTION CRITERIA: Randomized controlled trials, including cluster-randomized controlled trials (cRCTs), cross-over studies, and stepped-wedge designs were eligible, as were quasi-experimental trials, including controlled before-and-after studies, controlled interrupted time series, and non-randomized cross-over studies. We only considered studies reporting epidemiological outcomes (malaria case incidence, malaria infection incidence or parasite prevalence). We also summarised qualitative studies conducted alongside included studies. DATA COLLECTION AND ANALYSIS: Two review authors selected eligible studies, extracted data, and assessed the risk of bias. We used risk ratios (RR) to compare the effect of the intervention with the control for dichotomous data. For continuous data, we presented the mean difference; and for count and rate data, we used rate ratios. We presented all results with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: Six cRCTs met our inclusion criteria, all conducted in sub-Saharan Africa; three randomized by household, two by village, and one at the community level. All trials assessed screening of windows, doors, eaves, ceilings or any combination of these; this was either alone, or in combination with eave closure, roof modification or eave tube installation (a "lure and kill" device that reduces mosquito entry whilst maintaining some airflow). In two trials, the interventions were insecticide-based. In five trials, the researchers implemented the interventions. The community implemented the interventions in the sixth trial. At the time of writing the review, two of the six trials had published results, both of which compared screened houses (without insecticide) to unscreened houses. One trial in Ethiopia assessed screening of windows and doors. Another trial in the Gambia assessed full screening (screening of eaves, doors and windows), as well as screening of ceilings only. Screening may reduce clinical malaria incidence caused by Plasmodium falciparum (rate ratio 0.38, 95% CI 0.18 to 0.82; 1 trial, 184 participants, 219.3 person-years; low-certainty evidence; Ethiopian study). For malaria parasite prevalence, the point estimate, derived from The Gambia study, was smaller (RR 0.84, 95% CI 0.60 to 1.17; 713 participants, 1 trial; moderate-certainty evidence), and showed an effect on anaemia (RR 0.61, 95% CI 0.42, 0.89; 705 participants; 1 trial, moderate-certainty evidence). Screening may reduce the entomological inoculation rate (EIR): both trials showed lower estimates in the intervention arm. In the Gambian trial, there was a mean difference in EIR between the control houses and treatment houses ranging from 0.45 to 1.50 (CIs ranged from -0.46 to 2.41; low-certainty evidence), depending on the study year and treatment arm. The Ethiopian trial reported a mean difference in EIR of 4.57, favouring screening (95% CI 3.81 to 5.33; low-certainty evidence). Pooled analysis of the trials showed that individuals living in fully screened houses were slightly less likely to sleep under a bed net (RR 0.84, 95% CI 0.65 to 1.09; 2 trials, 203 participants). In one trial, bed net usage was also lower in individuals living in houses with screened ceilings (RR 0.69, 95% CI 0.50 to 0.95; 1 trial, 135 participants). AUTHORS' CONCLUSIONS: Based on the two trials published to date, there is some evidence that screening may reduce malaria transmission and malaria infection in people living in the house. The four trials awaiting publication are likely to enrich the current evidence base, and we will add these to this review when they become available.

Health Care Resource Utilization and Exacerbation Rates in Patients with COPD Stratified by Disease Severity in a Commercially Insured Population.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and is associated with substantial economic burden. There is a lack of data regarding COPD outcomes and costs in a real-world setting, particularly by Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity. OBJECTIVES: To (a) characterize a commercially insured U.S. population with COPD and (b) assess prevalence of exacerbations, health care resource utilization (HCRU), costs, and treatment patterns in a cohort of patients with confirmed COPD, overall and stratified by GOLD stage. METHODS: This retrospective observational cohort study used administrative claims data from the HealthCore Integrated Research Database to identify patients with ≥ 1 inpatient, emergency room (ER), or office visit claim for COPD between January 1, 2012, and November 30, 2013, and continuous enrollment for 1 year before and 2 years after the first COPD diagnosis date. Patients with a spirometry claim within 12 months were eligible for medical record abstraction to confirm COPD diagnosis (forced expiratory volume in 1 second [FEV1]/forced vital capacity ratio < 0.7) and GOLD 1-4 classification (based on postbronchodilator FEV1 percent predicted). HCRU, costs, treatment patterns, and rate of moderate/severe exacerbation were identified from diagnosis up to 24 months. Outcomes were analyzed by univariate analysis stratified by GOLD classification. Multivariable analysis was conducted to assess associations between GOLD classification and outcomes of interest. RESULTS: 53,484 patients newly diagnosed with COPD were identified who met initial inclusion criteria: 14,293 (27%) had a qualifying spirometry claim, and 1,505 had confirmed COPD (GOLD 1, 333 [22%]; GOLD 2, 823 [55%]; GOLD 3, 317 [21%]; GOLD 4, 32 [2%]). Patients with greater disease severity had higher rates of moderate/severe COPD exacerbations (GOLD 1 and 2, 40.4 and 48.9 per 100 person-years, respectively; GOLD 3 and 4, 83.6 and 89.1 per 100 person-years, respectively). All-cause and COPD-related inpatient admissions, COPD-related office visits, and COPD-related ER visits were more prevalent with more severe GOLD classification. Mean annual COPD-related medical costs increased with GOLD classification ($5,945 for GOLD 1 patients, $18,070 for GOLD 4). COPD maintenance medication was filled by 42%, 56%, 73%, and 75% of patients in GOLD 1-4 (57% overall), respectively; combination corticosteroid/long-acting beta2-agonist inhalers were the most commonly used medication, regardless of GOLD classification. Patients with more severe disease had greater adherence (range 44%-68% of days covered for GOLD 1-4) and persistence (range 107-209 days for GOLD 1-4). CONCLUSIONS: Trends toward increases in exacerbations, HCRU, and costs were observed as airflow limitation worsened. Adherence and persistence with COPD maintenance therapy was suboptimal even with severe disease. DISCLOSURES: This study was supported by Boehringer Ingelheim Pharmaceuticals (Ridgefield, CT), which was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations. Willey and Singer are employees of HealthCore (parent company Anthem), which received funding from Boehringer Ingelheim to complete this study. Wallace and Shinde were employed by HealthCore at the time of this study. Wallace and Singer report stock ownership in Anthem. Napier is an employee of Anthem. Kaila, Bayer, and Shaikh are employees of Boehringer Ingelheim Pharmaceuticsls. Portions of this research were presented at the following conferences: (a) A. Wallace, S. Kaila, V. Zubek, A. Shaikh, M. Shinde, V. Willey, M. Napier, and J. Singer, Healthcare resource utilization, costs, and exacerbation rates in patients with COPD stratified by GOLD airflow limitation classification in a US commercially insured population, presented at AMCP Nexus 2017; October 16-19, 2017; Dallas, TX; and (b) A.E. Wallace, V. Zubek, S. Kaila, A. Shaikh, M. Shinde, V. Willey, M.B. Napier, and J.R. Singer, Real-world treatment patterns among newly diagnosed COPD patients according to GOLD airflow limitation severity classification in a U.S. commercially insured/Medicare Advantage population, presented at CHEST 2017 Annual Meeting; October 28-November 1, 2017; Toronto, Ontario, Canada.

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.

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England.

BACKGROUND: Combination therapies with cetuximab (Erbitux®; Merck Serono UK Ltd) and panitumumab (Vectibix®; Amgen UK Ltd) are shown to be less effective in adults with metastatic colorectal cancer who have mutations in exons 2, 3 and 4 of KRAS and NRAS oncogenes from the rat sarcoma (RAS) family. OBJECTIVE: The objective of the study was to estimate the cost effectiveness of these drugs in patients with previously untreated RAS wild-type (i.e. non-mutated) metastatic colorectal cancer, not eligible for liver resection at baseline, from the UK National Health Service and Personal Social Services perspective. METHODS: We constructed a partitioned survival model to evaluate the long-term costs and benefits of cetuximab and panitumumab combined with either FOLFOX (folinic acid, fluorouracil and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil and irinotecan) vs. FOLFOX or FOLFIRI alone. The economic analysis was based on three randomised controlled trials. Costs and quality-adjusted life-years were discounted at 3.5% per annum. RESULTS: Based on the evidence available, both drugs fulfil the National Institute for Health and Care Excellence's end-of-life criteria. In the analysis, assuming discount prices for the drugs from patient access schemes agreed by the drug manufacturers with the Department of Health, predicted mean incremental cost-effectiveness ratios for cetuximab + FOLFOX, panitumumab + FOLFOX and cetuximab + FOLFIRI compared with chemotherapy alone appeared cost-effective at the National Institute for Health and Care Excellence's threshold of £50,000 per quality-adjusted life-year gained, applicable to end-of-life treatments. CONCLUSION: Cetuximab and panitumumab were recommended by the National Institute for Health and Care Excellence for patients with previously untreated RAS wild-type metastatic colorectal cancer, not eligible for liver resection at baseline, for use within the National Health Service in England. Both treatments are available via the UK Cancer Drugs Fund.

Complications of long and intermediate term venous catheters in cystic fibrosis patients: A multicenter study.

BACKGROUND: Totally implantable venous access devices (TIVADs) or peripherally inserted central venous catheters (PICCs) are commonly used in the care of patients with cystic fibrosis (CF), but they are associated with various complications, including thrombosis, infection, and insertion site symptoms. METHODS: We conducted a retrospective review of PICC and TIVAD use in adults and children with CF over an 8-year period at 3 accredited care centers. Patient attributes included CFTR genotype, comorbidities, lung function, body mass index, use of anticoagulation, and respiratory tract microbiology. Catheter data included line type, caliber, and lumen number. We assessed practice variation by surveying physicians. RESULTS: In a population of 592 CF patients, 851 PICC and 61 TIVADs were placed between January 1, 2003 and July 1, 2011. Larger catheter caliber and increased lumen number were risk factors for PICC complications in adults. Patient-related risk factors for PICC complications included poor nutritional status, infection with Burkholderia cepacia spp., and having ≥5 lines inserted during the study period. The probability of a PICC complication varied across centers (2.6% to 14.1%, p=0.001) and remained significant after adjustment for patient-and line-related risk factors. The median complication-free survival of TIVADs, however, did not vary significantly by center (p=0.85). CONCLUSIONS: This is the first longitudinal, multicenter assessment of complication rates for PICCs and TIVADs in a large cohort of adults and children with CF. Specific patient- and catheter-related characteristics were associated with increased risk of complications. Center effects on complication rates were observed for PICCs.

The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation.

BACKGROUND: Colorectal cancer is the fourth most commonly diagnosed cancer in the UK after breast, lung and prostate cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Targeted agents are available, including the antiepidermal growth factor receptor (EGFR) agents cetuximab (Erbitux®, Merck Serono UK Ltd, Feltham, UK) and panitumumab (Vecitibix®, Amgen UK Ltd, Cambridge, UK). OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of panitumumab in combination with chemotherapy and cetuximab in combination with chemotherapy for rat sarcoma (RAS) wild-type (WT) patients for the first-line treatment of metastatic colorectal cancer. DATA SOURCES: The assessment included a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions, and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted up to 27 April 2015 in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library. REVIEW METHODS: Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab or panitumumab in participants with previously untreated metastatic colorectal cancer with RAS WT status. All steps in the review were performed by one reviewer and checked independently by a second. Narrative synthesis and network meta-analyses (NMAs) were conducted for outcomes of interest. An economic model was developed focusing on first-line treatment and using a 30-year time horizon to capture costs and benefits. Costs and benefits were discounted at 3.5% per annum. Scenario analyses and probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS: The searches identified 2811 titles and abstracts, of which five clinical trials were included. Additional data from these trials were provided by the manufacturers. No data were available for panitumumab plus irinotecan-based chemotherapy (folinic acid + 5-fluorouracil + irinotecan) (FOLFIRI) in previously untreated patients. Studies reported results for RAS WT subgroups. First-line treatment with anti-EGFR therapies in combination with chemotherapy appeared to have statistically significant benefits for patients who are RAS WT. For the independent economic evaluation, the base-case incremental cost-effectiveness ratio (ICER) for RAS WT patients for cetuximab plus oxaliplatin-based chemotherapy (folinic acid + 5-fluorouracil + oxaliplatin) (FOLFOX) compared with FOLFOX was £104,205 per quality-adjusted life-year (QALY) gained; for panitumumab plus FOLFOX compared with FOLFOX was £204,103 per QALY gained; and for cetuximab plus FOLFIRI compared with FOLFIRI was £122,554 per QALY gained. The ICERs were sensitive to treatment duration, progression-free survival, overall survival (resected patients only) and resection rates. LIMITATIONS: The trials included RAS WT populations only as subgroups. No evidence was available for panitumumab plus FOLFIRI. Two networks were used for the NMA and model, based on the different chemotherapies (FOLFOX and FOLFIRI), as insufficient evidence was available to the assessment group to connect these networks. CONCLUSIONS: Although cetuximab and panitumumab in combination with chemotherapy appear to be clinically beneficial for RAS WT patients compared with chemotherapy alone, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK. It would be useful to conduct a RCT in patients with RAS WT. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015016111. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Randomized Prospective Biomarker Trial of ERCC1 for Comparing Platinum and Nonplatinum Therapy in Advanced Non-Small-Cell Lung Cancer: ERCC1 Trial (ET).

Purpose Retrospective studies indicate that expression of excision repair cross complementing group 1 (ERCC1) protein is associated with platinum resistance and survival in non-small-cell lung cancer (NSCLC). We conducted the first randomized trial, to our knowledge, to evaluate ERCC1 prospectively and to assess the superiority of nonplatinum therapy over platinum doublet therapy for ERCC1-positive NSCLC as well as noninferiority for ERCC1-negative NSCLC. Patients and Methods This trial had a marker-by-treatment interaction phase III design, with ERCC1 (8F1 antibody) status as a randomization stratification factor. Chemonaïve patients with NSCLC (stage IIIB and IV) were eligible. Patients with squamous histology were randomly assigned to cisplatin and gemcitabine or paclitaxel and gemcitabine; nonsquamous patients received cisplatin and pemetrexed or paclitaxel and pemetrexed. Primary end point was overall survival (OS). We also evaluated an antibody specific for XPF (clone 3F2). The target hazard ratio (HR) for patients with ERCC1-positive NSCLC was ≤ 0.78. Results Of patients, 648 were recruited (177 squamous, 471 nonsquamous). ERCC1-positive rates were 54.5% and 76.7% in nonsquamous and squamous patients, respectively, and the corresponding XPF-positive rates were 70.5% and 68.5%. Accrual stopped early in 2012 for squamous patients because OS for nonplatinum therapy was inferior to platinum therapy (median OS, 7.6 months [paclitaxel and gemcitabine] v 10.7 months [cisplatin and gemcitabine]; HR, 1.46; P = .02). Accrual for nonsquamous patients halted in 2013. Median OS was 8.0 (paclitaxel and pemetrexed) versus 9.6 (cisplatin and pemetrexed) months for ERCC1-positive patients (HR, 1.11; 95% CI, 0.85 to 1.44), and 10.3 (paclitaxel and pemetrexed) versus 11.6 (cisplatin and pemetrexed) months for ERCC1-negative patients (HR, 0.99; 95% CI, 0.73 to 1.33; interaction P = .64). OS HR was 1.09 (95% CI, 0.83 to 1.44) for XPF-positive patients, and 1.39 (95% CI, 0.90 to 2.15) for XPF-negative patients (interaction P = .35). Neither ERCC1 nor XPF were prognostic: among nonsquamous patients, OS HRs for positive versus negative were ERCC1, 1.11 ( P = .32), and XPF, 1.08 ( P = .55). Conclusion Superior outcomes were observed for patients with squamous histology who received platinum therapy compared with nonplatinum chemotherapy; however, selecting chemotherapy by using commercially available ERCC1 or XPF antibodies did not confer any extra survival benefit.

The effectiveness and cost-effectiveness of erythropoiesis-stimulating agents (epoetin and darbepoetin) for treating cancer treatment-induced anaemia (including review of technology appraisal no. 142): a systematic review and economic model.

BACKGROUND: Anaemia is a common side effect of cancer treatments and can lead to a reduction in quality of life. Erythropoiesis-stimulating agents (ESAs) are licensed for use in conjunction with red blood cell transfusions to improve cancer treatment-induced anaemia (CIA). OBJECTIVE: To investigate the effectiveness and cost-effectiveness of ESAs in anaemia associated with cancer treatment (specifically chemotherapy). DATA SOURCES: The following databases were searched from 2004 to 2013: The Cochrane Library, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health Literature, British Nursing Index, Health Management Information Consortium, Current Controlled Trials and ClinicalTrials.gov. The US Food and Drug Administration and European Medicines Agency websites were also searched. Bibliographies of included papers were scrutinised for further potentially includable studies. REVIEW METHODS: The clinical effectiveness review followed principles published by the NHS Centre for Reviews and Dissemination. Randomised controlled trials (RCTs), or systematic reviews of RCTs, of ESAs (epoetin or darbepoetin) for treating people with CIA were eligible for inclusion in the review. Comparators were best supportive care, placebo or other ESAs. Anaemia- and malignancy-related outcomes, health-related quality of life (HRQoL) and adverse events (AEs) were evaluated. When appropriate, data were pooled using meta-analysis. An empirical health economic model was developed comparing ESA treatment with no ESA treatment. The model comprised two components: one evaluating short-term costs and quality-adjusted life-years (QALYs) (while patients are anaemic) and one evaluating long-term QALYs. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS: Of 1457 titles and abstracts screened, 23 studies assessing ESAs within their licensed indication (based on start dose administered) were included in the review. None of the RCTs were completely aligned with current European Union licenses. The results suggest a clinical benefit from ESAs for anaemia-related outcomes and an improvement in HRQoL scores. The impact of ESAs on AEs and survival remains highly uncertain, although point estimates are lower, confidence intervals are wide and not statistically significant. Base-case incremental cost-effectiveness ratios (ICERs) for ESA treatment compared with no ESA treatment ranged from £ 19,429 to £ 35,018 per QALY gained, but sensitivity and scenario analyses demonstrate considerable uncertainty in these ICERs, including the possibility of overall health disbenefit. All ICERs were sensitive to survival and cost. LIMITATIONS: The relative effectiveness of ESAs was not addressed; all ESAs were assumed to have equivalent efficacy. No studies were completely aligned with their European labelling beyond the starting dose evaluated. There is questionable generalisability given that the included trials were published >20 years ago and there have been many changes to chemotherapy as well as to the quality of supportive treatment. Trial quality was moderate or poor and there was considerable unexplained heterogeneity for a number of outcomes, particularly survival, and evidence of publication bias. Adjustments were not made to account for multiple testing. CONCLUSIONS: ESAs could be cost-effective when used closer to licence, but there is considerable uncertainty, mainly because of unknown impacts on overall survival. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005812. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Pneumocystis jerovecii pneumonia in a patient with untreated chronic lymphocytic leukaemia: a novel case and postulations concerning the mechanism.

Chronic lymphocytic leukaemia (CLL), even when severe, is not directly associated with opportunistic infections. Opportunistic infections that occur with CLL are almost exclusively related to immunosuppression caused by chemotherapeutic drugs used to treat CLL. We report a case of Pneumocystis jirovecii (PJ) pneumonia that occurred in a patient with untreated CLL with pulmonary involvement. We suspect that PJ pneumonia resulted from an inadequate immune response in the lung parenchyma resulting from excessive local accumulation of CLL cells.

Cost-effectiveness of cetuximab, cetuximab plus irinotecan, and panitumumab for third and further lines of treatment for KRAS wild-type patients with metastatic colorectal cancer.

OBJECTIVES: To estimate the cost-effectiveness of cetuximab monotherapy, cetuximab plus irinotecan, and panitumumab monotherapy compared with best supportive care (BSC) for the third and subsequent lines of treatment of patients with Kirsten rat sarcoma wild-type metastatic colorectal cancer from the perspective of the UK National Health Service. METHODS: An "an area under the curve" cost-effectiveness model was developed. The clinical effectiveness evidence for both cetuximab and panitumumab was taken from a single randomized controlled trial (RCT) in each case and for cetuximab plus irinotecan from several sources. RESULTS: Patients are predicted to survive for approximately 6 months on BSC, 8.5 months on panitumumab, 10 months on cetuximab, and 16.5 months on cetuximab plus irinotecan. Panitumumab is dominated, and cetuximab is extended dominated. An incremental cost-effectiveness ratio (ICER) of £95,000 per quality-adjusted life-year (QALY) was estimated for cetuximab versus BSC and is likely to be relatively accurate, because the relevant clinical evidence is taken from a high-quality RCT. The estimated ICER for panitumumab versus BSC, at £187,000 per QALY, is less certain due to assumptions in the adjustment for the substantial crossing-over of patients in the RCT. The ICER for cetuximab plus irinotecan versus BSC, at £88,000 per QALY, is least certain due to substantial uncertainty about progression-free survival, treatment duration, and overall survival. Nonetheless, when key parameters are varied within plausible ranges, all three treatments always remain poor value for money. CONCLUSIONS: All three treatments are highly unlikely to be considered cost-effective in this patient population in the United Kingdom. We explain how the reader can adapt the model for other countries.

A randomized prospective trial of the utility of rapid on-site evaluation of transbronchial needle aspirate specimens.

BACKGROUND: Previous studies have suggested an increased diagnostic yield for flexible bronchoscopic transbronchial needle aspirate (TBNA) specimens from lymph nodes when using rapid on-site evaluation by cytopathology but were limited by a lack of randomization, suggesting that selection bias may have contributed to its higher reported yield with TBNA. OBJECTIVES: The purpose of our study was to determine the effect of rapid on-site evaluation (ROSE) on the diagnostic power of TBNA. METHODS: The study is a prospective randomized controlled trial. Diagnoses made by procedures were recorded prospectively. The primary endpoint was diagnostic yield. RESULTS: Thirty-four patients were randomized to the ROSE group and 34 patients to the no-ROSE group. Specimen adequacy was 94% in the ROSE group and 88% in the no-ROSE group (P=0.67). The TBNA diagnostic yield was similar in both groups: ROSE, 55%; no-ROSE, 53% (P=1.000). Neoplastic diagnoses were made in 59% and 50% of ROSE and no-ROSE patients, respectively (P=0.63). There were no significant differences in the number of needle passes, procedure duration, or amount of sedatives used. There was a trend toward a decrease in the number of transbronchial biopsies needed in the ROSE group. CONCLUSIONS: Previous reports of increased diagnostic yield of ROSE were subject to selection bias. Routine use of ROSE in all TBNA procedures was not associated with a reduced procedure time or sedative use. ROSE may be beneficial by decreasing the need for transbronchial biopsy and the associated risk or if the probability of malignancy is likely. We recommend ROSE in selected patients over all TBNA procedures.

The decision to operate: role of integrated computed tomography positron emission tomography in staging oesophageal and oesophagogastric junction cancer by the multidisciplinary team.

OBJECTIVE: Our objective was to assess the role of fusion positron emission tomography-computed tomography (PET-CT) in staging patients for minimally invasive oesophagectomy (MIO) with potentially resectable disease from the perspective of a multidisciplinary team (MDT) deciding on operability with conventional staging investigations. METHODS: Fifty consecutive patients presenting with potentially operable oesophageal or oesophagogastric junctional tumours were staged with computed tomography (CT) and endoluminal ultrasound (EUS). The MDT categorised patients as group A (n=33; CT N0M0) or group B (n=17; CT N1/possible M1). All patients underwent FDG PET-CT. Patients with localised disease (at T3), including single level N1 disease on PET-CT, were deemed suitable for induction chemotherapy followed by surgery. RESULTS: PET-CT re-categorised 12% of patients as inoperable on grounds of distant metastases (four in group A, two in group B). Five patients did not proceed to resection for other reasons. Two had metastatic disease at thoracoscopy. Resection specimens (n=37) contained 24 nodes (median). Compared with pN status, positive predictive value of PET-CT was 40% and negative predictive value was 43%. The expected PET-CT N1 group had the highest mean number of involved nodes. Median survival for all patients (n=50) was 31.9 months for group A compared with 17.3 months for group B (not statistically significant). There was no significant difference between patients who were PET-CT N0 or N1 in survival or disease-free survival in patients undergoing surgery (n=37). CONCLUSIONS: PET-CT informs the MDT decision to operate in avoiding futile surgery in stage IV disease or widespread nodal disease. In this study, overall PET-CT N1 status has low positive and negative predictive value for overall pN status.