Valuing selected WAItE health states using the Time Trade-Off methodology: findings from an online interviewer-assisted remote survey.

PURPOSE: The Weight-Specific Adolescent Instrument for Economic Evaluation (WAItE) is a physical weight-specific patient reported outcome measure for use in adolescence. The purpose of this study was to use the Time Trade-Off (TTO) methodology, administered using an online interviewer-assisted remote survey, to obtain utility values for several health states from the WAItE descriptive system from a sample of the UK adult general population. METHODS: The adult sample was gathered using a market research company and a sample of local residents. All participants completed the same interviewer-assisted remote survey, which included rating WAItE states of varying impairment using the TTO. RESULTS: 42 adults completed the survey. Utility values were gathered for four health states, ranging from low impairment to the most severe health from the WAItE descriptive system (the Pits state). Consistent orderings of the WAItE health states were observed; the health state with the lowest level of impairment was valued highest and the Pits state was valued lowest. Several respondents (n = 7, 17%) considered the Pits state to be worse than death; however, the mean value of this health state was 0.23. CONCLUSIONS: The utility value of the Pits state relative to death generated from this study will be used to anchor latent values for WAItE health states generated from a Discrete Choice Experiment onto the 0 = death, 1 = full health Quality Adjusted Life Year (QALY) scale as part of a valuation study for the WAItE in the UK population. This study also provides further evidence that interviewer-assisted digital studies are feasible for collecting TTO data.

Evaluating high-cost technologies - no need to throw the baby out with the bathwater.

INTRODUCTION: Evidence generation for the health technology assessment (HTA) of a new technology is a long and expensive process with no guarantees that the health technology will be adopted and implemented into a health-care system. This would suggest that there is a greater risk of failure for a company developing a high-cost technology and therefore incentives (such as increasing the funding available for research or additional market exclusivity) may be needed to encourage development of such technologies as has been seen with many high-cost orphan drugs. AREAS COVERED: This paper discusses some of the key issues relating to the evaluation of high-cost technologies through the use of existing HTA processes and what the challenges will be going forward. EXPERT OPINION: We propose that while the current HTA process is robust, its evolution into accommodating the incorporation of real-world data and evidence alongside a life-cycle HTA approach should better enable developers to produce the evidence required on effectiveness and cost-effectiveness. This should lead to reduced decision uncertainty for HTA agencies to make adoption decisions in a more timely and efficient manner. Furthermore, budget impact analysis remains important in understanding the actual financial impact on health-care systems and budgets outside of the cost-effectiveness framework used to aid decision-making.

Incorporating economic methods into Cochrane systematic reviews: case studies in brain tumour research.

BACKGROUND: Cochrane systematic reviews have established methods for identifying and critically appraising empirical evidence in health. In addition to evidence regarding the clinical effectiveness of interventions, the resource implications of such interventions can have a huge impact on a decision maker's ability to adopt and implement them. In this paper, we present examples of the three approaches to include economic evidence in Cochrane reviews. METHODS: The Cochrane Handbook presents three different methods of integrating economic evidence into reviews: the Brief Economic Commentary (BEC), the Integrated Full Systematic Review of Economic Evaluations (IFSREE) and using an Economic Decision Model. Using the examples from three different systematic reviews in the field of brain cancer, we utilised each method to address three different research questions. A BEC was utilised in a review that evaluates the long-term side effects of radiotherapy (with or without chemotherapy). An IFSREE was utilised in a review comparing different treatment strategies for newly diagnosed glioblastoma in the elderly. Finally, an economic model was included in a review assessing diagnostic test accuracy for tests of codeletion of chromosomal arms in people with glioma. RESULTS: The BEC mirrored the results of the main review and found a paucity of quality evidence with regard to the side effects of radiotherapy in those with glioma. The IFSREE identified a single economic evaluation regarding glioblastoma in the elderly, but this study had a number of methodological issues. The economic model identified a number of potentially cost-effective strategies for tests for codeletion of chromosomal arms 1p and 19q in people with glioma. CONCLUSIONS: There are strengths and limitations of each approach for integrating economic evidence in Cochrane systematic reviews. The type of research question, resources available and study timeline should be considered when choosing which approach to use when integrating economic evidence.

Abemaciclib in Combination with Endocrine Therapy for Adjuvant Treatment of Hormone Receptor-Positive, HER2-Negative, Node-Positive Early Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Eli Lilly) of abemaciclib (Verzenios) to submit evidence for the clinical and cost effectiveness of this drug in combination with endocrine therapy (ET) for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive early breast cancer at high risk of recurrence, as part of the Institute's Single Technology Appraisal (STA) process. Kleijnen Systematic Reviews Ltd, in combination with Newcastle University, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarised the Company Submission (CS), presents the ERG's critical review of the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the Appraisal Committee. The ERG produced a critical review of the evidence for the clinical and cost-effectiveness evidence in the CS and also independently searched for relevant evidence and modified the manufacturer decision analytic model to examine the impact of altering some of the key assumptions. A systematic literature review identified the MonarchE trial, an ongoing, open-label, randomised, double blind trial involving 5637 people comparing abemaciclib in combination with ET versus ET alone. The trial included two cohorts that used different inclusion criteria to define high risk of recurrence. The ERG considered Cohort 1 as an adequate representation of this population and the AC concluded that Cohort 1 was generalisable to National Health Service clinical practice. Trial results showed improvements in invasive disease-free survival for the abemaciclib arm, which was considered an appropriate surrogate outcome. The ERG believed that the modelling structure presented in the de novo economic model by the company was appropriate but highlighted several areas of uncertainty that had the potential to have a significant impact on the resulting incremental cost-effectiveness ratio (ICER). Areas of uncertainty included the extrapolation of long-term survival curves, the duration of treatment effect and treatment waning, and the proportion of patients who receive other CDK4/6 treatments for metastatic disease after receiving abemaciclib. ICER estimates were £9164 per quality-adjusted life-year gained for the company's base-case and £17,810 for the ERG's base-case. NICE recommended abemaciclib with ET as an option for the adjuvant treatment of HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence.

Differences in health-related quality of life between the Roma community and the general population in Romania.

BACKGROUND: Previous research has shown that Roma people report worse health outcomes than the general population and suffer from a myriad of economic and social disadvantages. The objective of this study was to assess the differences in the health-related quality of life (HRQoL) between the Roma people and the Romanian general population. METHODS: Two cross-sectional surveys were conducted face-to-face in 2018 and 2019 in two nationally representative samples of both the general population and Roma communities, recruited from all regions of Romania. Both samples completed the EQ-5D-5L and EQ-VAS questionnaires, as well as a range of sociodemographic questions. Coarsened Exact Matching and several different regression models were used to assess the differences in HRQoL between the two groups. RESULTS: 2308 respondents were included in the matched sample: 1,621 general population individuals; 687 Roma people. Roma people had more problems with self-care, pain/discomfort, and anxiety/depression than the general population. They also reported a lower overall level of HRQoL than the general population of Romania, as reflected by the lower EQ-5D-5L and EQ-VAS scores. Our sensitivity analysis between Coarsened Exact Matching and other matching procedures showed consistent results across all regression models. CONCLUSIONS: In Romania, the Roma community has a lower level of HRQoL than the general population. Understanding the underlying causes of this inequality should be the focus of future research. Policies aimed at reducing the level of health inequality between the Roma and the general populations should be promoted locally.

Photobiomodulation in the management of oral mucositis for adult head and neck cancer patients receiving irradiation: the LiTEFORM RCT.

BACKGROUND: Oral mucositis is a debilitating and painful complication of head and neck cancer irradiation that is characterised by inflammation of the mucous membranes, erythema and ulceration. Oral mucositis affects 6000 head and neck cancer patients per year in England and Wales. Current treatments have not proven to be effective. International studies suggest that low-level laser therapy may be an effective treatment. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of low-level laser therapy in the management of oral mucositis in head and neck cancer irradiation. To identify barriers to and facilitators of implementing low-level laser therapy in routine care. DESIGN: Placebo-controlled, individually randomised, multicentre Phase III superiority trial, with an internal pilot and health economic and qualitative process evaluations. The participants, outcome assessors and therapists were blinded. SETTING: Nine NHS head and neck cancer sites in England and Wales. PARTICIPANTS: A total of 87 out of 380 participants were recruited who were aged ≥ 18 years and were undergoing head and neck cancer irradiation with ≥ 60 Gy. INTERVENTION: Random allocation (1 : 1 ratio) to either low-level laser therapy or sham low-level laser therapy three times per week for the duration of irradiation. The diode laser had the following specifications: wavelength 660 nm, power output 75 mW, beam area 1.5 cm2, irradiance 50 mW/cm2, exposure time 60 seconds and fluence 3 J/cm2. There were 20-30 spots per session. Sham low-level laser therapy was delivered in an identical manner. MAIN OUTCOME MEASURE: The mean Oral Mucositis Weekly Questionnaire-Head and Neck Cancer score at 6 weeks following the start of irradiation. Higher scores indicate a worse outcome. RESULTS: A total of 231 patients were screened and, of these, 87 were randomised (low-level laser therapy arm, n = 44; sham arm, n = 43). The mean age was 59.4 years (standard deviation 8.8 years) and 69 participants (79%) were male. The mean Oral Mucositis Weekly Questionnaire-Head and Neck Cancer score at 6 weeks was 33.2 (standard deviation 10) in the low-level laser therapy arm and 27.4 (standard deviation 13.8) in the sham arm. LIMITATIONS: The trial lacked statistical power because it did not meet the recruitment target. Staff and patients willingly participated in the trial and worked hard to make the LiTEFORM trial succeed. However, the task of introducing, embedding and sustaining new low-level laser therapy services into a complex care pathway proved challenging. Sites could deliver low-level laser therapy to only a small number of patients at a time. The administration of low-level laser therapy was viewed as straightforward, but also time-consuming and sometimes uncomfortable for both patients and staff, particularly those staff who were not used to working in a patient's mouth. CONCLUSIONS: This trial had a robust design but lacked power to be definitive. Low-level laser therapy is relatively inexpensive. In contrast with previous trials, some patients found low-level laser therapy sessions to be difficult. The duration of low-level laser therapy sessions is, therefore, an important consideration. Clinicians experienced in oral cavity work most readily adapt to delivering low-level laser therapy, although other allied health professionals can be trained. Blinding the clinicians delivering low-level laser therapy is feasible. There are important human resource, real estate and logistical considerations for those setting up low-level laser therapy services. FUTURE WORK: Further well-designed randomised controlled trials investigating low-level laser therapy in head and neck cancer irradiation are needed, with similar powered recruitment targets but addressing the recruitment challenges and logistical findings from this research. TRIAL REGISTRATION: This trial is registered as ISRCTN14224600. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 46. See the NIHR Journals Library website for further project information.

Around 9 out of 10 head and neck cancer patients undergoing treatment experience pain, swelling and sores in their mouth (oral mucositis). This can lead to weight loss, painful ulcers, difficulty talking, eating and drinking, and even hospitalisation. Current care includes helping patients to keep their mouth and teeth clean, encouraging them to have a healthy diet and prescribing mouthwashes, painkillers and mouth-coating gels. However, these treatments give limited help in preventing or treating this condition. The LiTEFORM trial looked at whether or not low-level laser therapy could be used to prevent and treat oral mucositis. Patients were allocated to one of two arms at random: active laser or fake (sham) laser. Neither the patients nor the hospital staff knew which laser was being used. Eighty-seven people joined the study during the time allowed (44 received low-level laser therapy and 43 received sham treatment); however, this was a smaller number than the planned target of 380 people. As a result, no meaningful conclusion can be drawn from the results about whether the therapy is beneficial or cost-effective. People receiving the low-level laser therapy reported slightly more soreness in their mouth than those receiving the sham laser, but this could be down to chance. The number of participants is too small to draw conclusions about whether or not the low-level laser is helpful. Some patients found the laser treatment sessions to be difficult. Setting up a new service delivering laser therapy at the same time as cancer treatments was more complicated than originally anticipated. Problems included the scheduling of appointments, finding suitable rooms and having enough trained staff with time to deliver laser therapy. However, this study has provided us with knowledge on how best to set up a laser therapy service in the NHS as part of the cancer treatment pathway and the costs involved. These findings could help future studies looking into low-level laser therapy for those with head and neck cancer.

Diagnostic test accuracy and cost-effectiveness of tests for codeletion of chromosomal arms 1p and 19q in people with glioma.

BACKGROUND: Complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), known as 1p/19q codeletion, is a mutation that can occur in gliomas. It occurs in a type of glioma known as oligodendroglioma and its higher grade counterpart known as anaplastic oligodendroglioma. Detection of 1p/19q codeletion in gliomas is important because, together with another mutation in an enzyme known as isocitrate dehydrogenase, it is needed to make the diagnosis of an oligodendroglioma. Presence of 1p/19q codeletion also informs patient prognosis and prediction of the best drug treatment. The main two tests in use are fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) assays (also known as PCR-based short tandem repeat or microsatellite analysis). Many other tests are available. None of the tests is perfect, although PCR-based LOH is expected to have very high sensitivity. OBJECTIVES: To estimate the sensitivity and specificity and cost-effectiveness of different deoxyribonucleic acid (DNA)-based techniques for determining 1p/19q codeletion status in glioma. SEARCH METHODS: We searched MEDLINE, Embase and BIOSIS up to July 2019. There were no restrictions based on language or date of publication. We sought economic evaluation studies from the results of this search and using the National Health Service Economic Evaluation Database. SELECTION CRITERIA: We included cross-sectional studies in adults with glioma or any subtype of glioma, presenting raw data or cross-tabulations of two or more DNA-based tests for 1p/19q codeletion. We also sought economic evaluations of these tests. DATA COLLECTION AND ANALYSIS: We followed procedures outlined in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. Two review authors independently screened titles/abstracts/full texts, performed data extraction, and undertook applicability and risk of bias assessments using QUADAS-2. Meta-analyses used the hierarchical summary ROC model to estimate and compare test accuracy. We used FISH and PCR-based LOH as alternate reference standards to examine how tests compared with those in common use, and conducted a latent class analysis comparing FISH and PCR-based LOH. We constructed an economic model to evaluate cost-effectiveness. MAIN RESULTS: We included 53 studies examining: PCR-based LOH, FISH, single nucleotide polymorphism (SNP) array, next-generation sequencing (NGS), comparative genomic hybridisation (CGH), array comparative genomic hybridisation (aCGH), multiplex-ligation-dependent probe amplification (MLPA), real-time PCR, chromogenic in situ hybridisation (CISH), mass spectrometry (MS), restriction fragment length polymorphism (RFLP) analysis, G-banding, methylation array and NanoString. Risk of bias was low for only one study; most gave us concerns about how patients were selected or about missing data. We had applicability concerns about many of the studies because only patients with specific subtypes of glioma were included. 1520 participants contributed to analyses using FISH as the reference, 1304 participants to analyses involving PCR-based LOH as the reference and 262 participants to analyses of comparisons between methods from studies not including FISH or PCR-based LOH. Most evidence was available for comparison of FISH with PCR-based LOH (15 studies, 915 participants): PCR-based LOH detected 94% of FISH-determined codeletions (95% credible interval (CrI) 83% to 98%) and FISH detected 91% of codeletions determined by PCR-based LOH (CrI 78% to 97%). Of tumours determined not to have a deletion by FISH, 94% (CrI 87% to 98%) had a deletion detected by PCR-based LOH, and of those determined not to have a deletion by PCR-based LOH, 96% (CrI 90% to 99%) had a deletion detected by FISH. The latent class analysis suggested that PCR-based LOH may be slightly more accurate than FISH. Most other techniques appeared to have high sensitivity (i.e. produced few false-negative results) for detection of 1p/19q codeletion when either FISH or PCR-based LOH was considered as the reference standard, although there was limited evidence. There was some indication of differences in specificity (false-positive rate) with some techniques. Both NGS and SNP array had high specificity when considered against FISH as the reference standard (NGS: 6 studies, 243 participants; SNP: 6 studies, 111 participants), although we rated certainty in the evidence as low or very low. NGS and SNP array also had high specificity when PCR-based LOH was considered the reference standard, although with much more uncertainty as these results were based on fewer studies (just one study with 49 participants for NGS and two studies with 33 participants for SNP array). G-banding had low sensitivity and specificity when PCR-based LOH was the reference standard. Although MS had very high sensitivity and specificity when both FISH and PCR-based LOH were considered the reference standard, these results were based on only one study with a small number of participants. Real-time PCR also showed high specificity with FISH as a reference standard, although there were only two studies including 40 participants. We found no relevant economic evaluations. Our economic model using FISH as the reference standard suggested that the resource-optimising test depends on which measure of diagnostic accuracy is most important. With FISH as the reference standard, MLPA is likely to be cost-effective if society was willing to pay GBP 1000 or less for a true positive detected. However, as the value placed on a true positive increased, CISH was most cost-effective. Findings differed when the outcome measure changed to either true negative detected or correct diagnosis. When PCR-based LOH was used as the reference standard, MLPA was likely to be cost-effective for all measures of diagnostic accuracy at lower threshold values for willingness to pay. However, as the threshold values increased, none of the tests were clearly more likely to be considered cost-effective. AUTHORS' CONCLUSIONS: In our review, most techniques (except G-banding) appeared to have good sensitivity (few false negatives) for detection of 1p/19q codeletions in glioma against both FISH and PCR-based LOH as a reference standard. However, we judged the certainty of the evidence low or very low for all the tests. There are possible differences in specificity, with both NGS and SNP array having high specificity (fewer false positives) for 1p/19q codeletion when considered against FISH as the reference standard. The economic analysis should be interpreted with caution due to the small number of studies.

Diagnostic accuracy of 1p/19q codeletion tests in oligodendroglioma: A comprehensive meta-analysis based on a Cochrane systematic review.

Codeletion of chromosomal arms 1p and 19q, in conjunction with a mutation in the isocitrate dehydrogenase 1 or 2 gene, is the molecular diagnostic criterion for oligodendroglioma, IDH mutant and 1p/19q codeleted. 1p/19q codeletion is a diagnostic marker and allows prognostication and prediction of the best drug response within IDH-mutant tumours. We performed a Cochrane review and simple economic analysis to establish the most sensitive, specific and cost-effective techniques for determining 1p/19q codeletion status. Fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) test methods were considered as reference standard. Most techniques (FISH, chromogenic in situ hybridisation [CISH], PCR, real-time PCR, multiplex ligation-dependent probe amplification [MLPA], single nucleotide polymorphism [SNP] array, comparative genomic hybridisation [CGH], array CGH, next-generation sequencing [NGS], mass spectrometry and NanoString) showed good sensitivity (few false negatives) for detection of 1p/19q codeletions in glioma, irrespective of whether FISH or PCR-based LOH was used as the reference standard. Both NGS and SNP array had a high specificity (fewer false positives) for 1p/19q codeletion when considered against FISH as the reference standard. Our findings suggest that G banding is not a suitable test for 1p/19q analysis. Within these limits, considering cost per diagnosis and using FISH as a reference, MLPA was marginally more cost-effective than other tests, although these economic analyses were limited by the range of available parameters, time horizon and data from multiple healthcare organisations.

Developing a preference-based measure for weight-specific health-related quality of life in adolescence: the WAItE UK valuation study protocol.

INTRODUCTION: Adolescent obesity is a public health problem in the UK. The Weight-Specific Adolescent Instrument for Economic Evaluation (WAItE) has been developed as the first weight-specific health-related quality of life measure appropriate for economic evaluation, but currently cannot be used to generate quality-adjusted life years (QALYs), which are the basis of cost-utility analysis. Generic measures (such as the EQ-5D-Y or CHU-9D) may be insensitive to small but important health changes in overweight or obese adolescents. This study aims to generate a preference-based scoring algorithm for the WAItE. METHODS AND ANALYSIS: A discrete choice experiment (DCE) will be administered to value health states described by the WAItE classification system. These health states will be presented to members of the adult general population of the UK via an online survey. A range of regression models will be used to produce the utility algorithm for the WAItE. The DCE-visual analogue scale and time trade-off (TTO) anchoring methods will be used anchor the value set on to the 0-1 QALY scale. ETHICS AND DISSEMINATION: The Newcastle University Medical School Ethics Committee approved the study (references 4772/2020 (DCE) and 9978/2020 (TTO)). The developed algorithm can be applied to future economic evaluations of weight management interventions and treatments for adolescents.

Treatment options for progression or recurrence of glioblastoma: a network meta-analysis.

BACKGROUND: Glioblastoma (GBM) is a highly malignant brain tumour that almost inevitably progresses or recurs after first line standard of care. There is no consensus regarding the best treatment/s to offer people upon disease progression or recurrence. For the purposes of this review, progression and recurrence are considered as one entity. OBJECTIVES: To evaluate the effectiveness of further treatment/s for first and subsequent progression or recurrence of glioblastoma (GBM) among people who have received the standard of care (Stupp protocol) for primary treatment of the disease; and to prepare a brief economic commentary on the available evidence. SEARCH METHODS: We searched MEDLINE and Embase electronic databases from 2005 to December 2019 and the Cochrane Central Register of Controlled Trials (CENTRAL, in the Cochrane Library; Issue 12, 2019). Economic searches included the National Health Service Economic Evaluation Database (NHS EED) up to 2015 (database closure) and MEDLINE and Embase from 2015 to December 2019. SELECTION CRITERIA: Randomised controlled trials (RCTs) and comparative non-randomised studies (NRSs) evaluating effectiveness of treatments for progressive/recurrent GBM. Eligible studies included people with progressive or recurrent GBM who had received first line radiotherapy with concomitant and adjuvant temozolomide (TMZ). DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data to a pre-designed data extraction form. We conducted network meta-analyses (NMA) and ranked treatments according to effectiveness for each outcome using the random-effects model and Stata software (version 15). We rated the certainty of evidence using the GRADE approach. MAIN RESULTS: We included 42 studies: these comprised 34 randomised controlled trials (RCTs) and 8 non-randomised studies (NRSs) involving 5236 participants. We judged most RCTs to be at a low risk of bias and NRSs at high risk of bias. Interventions included chemotherapy, re-operation, re-irradiation and novel therapies either used alone or in combination. For first recurrence, we included 11 interventions in the network meta-analysis (NMA) for overall survival (OS), and eight in the NMA for progression-free survival (PFS). Lomustine (LOM; also known as CCNU) was the most common comparator and was used as the reference treatment. No studies in the NMA evaluated surgery, re-irradiation, PCV (procarbazine, lomustine, vincristine), TMZ re-challenge or best supportive care. We could not perform NMA for second or later recurrence due to insufficient data. Quality-of-life data were sparse. First recurrence (NMA findings) Median OS across included studies in the NMA ranged from 5.5 to 12.6 months and median progression-free survival (PFS) ranged from 1.5 months to 4.2 months. We found no high-certainty evidence that any treatments tested were better than lomustine. These treatments included the following. Bevacizumab plus lomustine: Evidence suggested probably little or no difference in OS between bevacizumab (BEV) combined with lomustine (LOM) and LOM monotherapy (hazard ratio (HR) 0.91, 0.75 to 1.10; moderate-certainty evidence), although BEV + LOM may improve PFS (HR 0.57, 95% confidence interval (CI) 0.44 to 0.74; low-certainty evidence). Bevacizumab monotherapy: Low-certainty evidence suggested there may be little or no difference in OS (HR 1.22, 95% CI 0.84 to 1.76) and PFS (HR 0.90, 95% CI 0.58 to 1.38; low-certainty evidence) between BEV and LOM monotherapies; more evidence on BEV is needed. Regorafenib (REG): REG may improve OS compared with LOM (HR 0.50, 95% CI 0.33 to 0.76; low-certainty evidence). Evidence on PFS was very low certainty and more evidence on REG is needed. Temozolomide (TMZ) plus Depatux-M (ABT414): For OS, low-certainty evidence suggested that TMZ plus ABT414 may be more effective than LOM (HR 0.66, 95% CI 0.47 to 0.92) and may be more effective than BEV (HR 0.54, 95% CI 0.33 to 0.89; low-certainty evidence). This may be due to the TMZ component only and more evidence is needed. Fotemustine (FOM): FOM and LOM may have similar effects on OS (HR 0.89, 95% CI 0.51 to 1.57, low-certainty evidence). Bevacizumab and irinotecan (IRI): Evidence on BEV + irinotecan (IRI) versus LOM for both OS and PFS is very uncertain and there is probably little or no difference between BEV + IRI versus BEV monotherapy (OS: HR 0.95, 95% CI 0.70 to 1.30; moderate-certainty evidence). When treatments were ranked for OS, FOM ranked first, BEV + LOM second, LOM third, BEV + IRI fourth, and BEV fifth. Ranking does not take into account the certainty of the evidence, which also suggests there may be little or no difference between FOM and LOM. Other treatments Three studies evaluated re-operation versus no re-operation, with or without re-irradiation and chemotherapy, and these suggested possible survival advantages with re-operation within the context of being able to select suitable candidates for re-operation. A cannabinoid treatment in the early stages of evaluation, in combination with TMZ, merits further evaluation. Second or later recurrence Limited evidence from three heterogeneous studies suggested that radiotherapy with or without BEV may have a beneficial effect on survival but more evidence is needed. Evidence was insufficient to draw conclusions about the best radiotherapy dosage. Other evidence suggested that there may be little difference in survival with tumour-treating fields compared with physician's best choice of treatment. We found no reliable evidence on best supportive care. Severe adverse events (SAEs) The BEV+LOM combination was associated with significantly greater risk of SAEs than LOM monotherapy (RR 2.51, 95% CI 1.72 to 3.66, high-certainty evidence), and ranked joint worst with cediranib + LOM (RR 2.51, 95% CI 1.29 to 4.90; high-certainty evidence). LOM ranked best and REG ranked second best. Adding novel treatments to BEV was generally associated with a higher risk of severe adverse events compared with BEV alone. AUTHORS' CONCLUSIONS: For treatment of first recurrence of GBM, among people previously treated with surgery and standard chemoradiotherapy, the combination treatments evaluated did not improve overall survival compared with LOM monotherapy and were often associated with a higher risk of severe adverse events. Limited evidence suggested that re-operation with or without re-irradiation and chemotherapy may be suitable for selected candidates. Evidence on second recurrence is sparse. Re-irradiation with or without bevacizumab may be of value in selected individuals, but more evidence is needed.

ANTECEDENTES: El glioblastoma (GBM) es un tumor cerebral altamente maligno que casi inevitablemente progresa o recidiva después de un tratamiento de primera línea. No hay consenso sobre el mejor o los mejores tratamientos que se pueden ofrecer a las personas que presentan progresión o recidiva de la enfermedad. A los efectos de la presente revisión, la progresión y la recidiva se consideran como una sola entidad. OBJETIVOS: Evaluar la efectividad de los tratamientos adicionales para la primera y subsiguiente progresión o recidiva del glioblastoma (GBM) entre las personas que han recibido atención estándar (protocolo Stupp) para el tratamiento primario de la enfermedad, así como preparar un breve comentario económico sobre la evidencia disponible. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en las bases de datos electrónicas de MEDLINE y Embase desde 2005 hasta diciembre de 2019 y en el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials) (CENTRAL, en la Cochrane Library; Número 12, 2019). Las búsquedas económicas incluyeron la National Health Service Economic Evaluation Database (NHS EED) hasta 2015 (cierre de la base de datos) y MEDLINE y Embase desde 2015 hasta diciembre de 2019. CRITERIOS DE SELECCIÓN: Ensayos controlados aleatorizados (ECA) y estudios comparativos no aleatorizados (no ECA) que evaluaron la efectividad de los tratamientos para el GBM progresivo/recidivante. Los estudios elegibles incluyeron personas con GBM progresivo o recidivante que habían recibido radioterapia de primera línea con temozolomida (TMZ) concomitante y adyuvante. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión de forma independiente seleccionaron los estudios y extrajeron los datos en un formulario de extracción de datos prediseñado. Se realizaron metanálisis en red (MAR) y los tratamientos se clasificaron según la efectividad de cada desenlace, mediante el modelo de efectos aleatorios y el software Stata (versión 15). La certeza de la evidencia se evaluó mediante los criterios GRADE. RESULTADOS PRINCIPALES: Se incluyeron 42 estudios, que comprendieron 34 ensayos controlados aleatorizados (ECA) y ocho estudios no aleatorizados (no ECA), con 5236 participantes. Se consideró que la mayoría de los ECA tuvieron bajo riesgo de sesgo y que los no ECA tuvieron alto riesgo de sesgo. Las intervenciones incluyeron quimioterapia, reoperación, reirradiación y tratamientos nuevos, ya sea utilizadas solos o en combinación. Para la primera recidiva se incluyeron 11 intervenciones en el metanálisis en red (MAR) para la supervivencia general (SG), y ocho para la supervivencia sin progresión (SSP). La lomustina (LOM; también conocida como CCNU) fue el comparador más frecuente y se utilizó como tratamiento de referencia. Ningún estudio en el MAR evaluó la cirugía, la reirradiación, la PCV (procarbazina, lomustina, vincristina), la reexposición a TMZ o el mejor tratamiento de apoyo. No fue posible realizar un MAR para una segunda o posterior recidiva debido a que los datos no fueron suficientes. Los datos de calidad de vida fueron escasos. Primera recidiva (hallazgos del MAR) La mediana de la SG en los estudios incluidos en el MAR varió entre 5,5 y 12,6 meses y la mediana de la supervivencia sin progresión (SSP) varió entre 1,5 y 4,2 meses. No se encontró evidencia de certeza alta de que los tratamientos probados fueran mejores que la lomustina. Estos tratamientos incluyeron los siguientes. Bevacizumab más lomustina: La evidencia indicó probablemente poca o ninguna diferencia en la SG entre el bevacizumab (BEV) combinado con lomustina (LOM) y la monoterapia con LOM (cociente de riesgos instantáneo [CRI] 0,91; 0,75 a 1,10; evidencia de certeza moderada), aunque BEV + LOM puede mejorar la SSP (CRI 0,57; intervalo de confianza [IC] del 95%: 0,44 a 0,74; evidencia de certeza baja). Monoterapia con bevacizumab: La evidencia de certeza baja indicó que puede haber poca o ninguna diferencia en la SG (CRI 1,22; IC del 95%: 0,84 a 1,76) y la SSP (CRI 0,90; IC del 95%: 0,58 a 1,38; evidencia de certeza baja) entre las monoterapias con BEV y LOM; se necesita más evidencia sobre el BEV. Regorafenib (REG): El REG puede mejorar la SG en comparación con la LOM (CRI 0,50; IC del 95%: 0,33 a 0,76; evidencia de certeza baja). La evidencia sobre la SSP fue de certeza muy baja y se necesita más evidencia sobre el REG. Temozolomida (TMZ) más Depatux­M (ABT414): En cuanto a la SG, evidencia de certeza baja indicó que TMZ más ABT414 puede ser más efectiva que LOM (CRI 0,66; IC del 95%: 0,47 a 0,92) y puede ser más efectiva que BEV (CRI 0,54; IC del 95%: 0,33 a 0,89; evidencia de certeza baja). Lo anterior se puede deber solamente al componente de TMZ, y se necesita más evidencia. Fotemustina (FOM): FOM y LOM pueden tener efectos similares sobre la SG (CRI 0,89; IC del 95%: 0,51 a 1,57, evidencia de certeza baja). Bevacizumab e irinotecan (IRI): La evidencia sobre BEV + irinotecan (IRI) versus LOM para la SG y la SSP no está clara y probablemente hay poca o ninguna diferencia entre BEV + IRI versus la monoterapia con BEV (SG: CRI 0,95; IC del 95%: 0,70 a 1,30; evidencia de certeza moderada). Cuando los tratamientos se clasificaron según la SG, FOM se clasificó primero, BEV + LOM segundo, LOM tercero, BEV + IRI cuarto, y BEV quinto. La clasificación no tiene en cuenta la certeza de la evidencia, lo que también indica que puede haber poca o ninguna diferencia entre FOM y LOM. Otros tratamientos Tres estudios evaluaron la reoperación versus ninguna reoperación, con o sin reirradiación y quimioterapia, e indicaron posibles ventajas en la supervivencia con la reoperación, en el contexto de poder seleccionar candidatos adecuados para esta intervención. Un tratamiento con cannabinoides en las primeras etapas de evaluación, en combinación con TMZ, merece evaluación adicional. Segunda o posterior recidiva La evidencia limitada de tres estudios heterogéneos indicó que la radioterapia con o sin BEV puede tener un efecto beneficioso sobre la supervivencia, pero se necesita más evidencia. La evidencia no fue suficiente para establecer conclusiones sobre la mejor dosis de radioterapia. Otra evidencia indicó que puede haber poca diferencia en la supervivencia con los campos de tratamiento del tumor en comparación con la mejor opción de tratamiento del médico. No se encontró evidencia fiable sobre el mejor tratamiento de apoyo. Eventos adversos graves (EAG) La combinación BEV + LOM se asoció con un riesgo significativamente mayor de EAG que la monoterapia con LOM (RR 2,51; IC del 95%: 1,72 a 3,66; evidencia de certeza alta), y se clasificó peor junto con cediranib + LOM (RR 2,51; IC del 95%: 1,29 a 4,90; evidencia de certeza alta). LOM se clasificó como el mejor y REG como el segundo mejor. Agregar nuevos tratamientos al BEV se asoció generalmente con un mayor riesgo de eventos adversos graves, en comparación con BEV solo. CONCLUSIONES DE LOS AUTORES: Para el tratamiento de la primera recidiva del GBM en personas tratadas previamente con cirugía y quimiorradioterapia estándar, los tratamientos combinados evaluados no mejoraron la supervivencia general en comparación con la monoterapia con LOM, y a menudo se asociaron con un mayor riesgo de eventos adversos graves. Hay evidencia limitada que indica que la reoperación con o sin reirradiación y quimioterapia puede ser adecuada para candidatos seleccionados. La evidencia sobre la segunda recidiva es escasa. La reirradiación con o sin bevacizumab puede ser de valor en determinados individuos, pero se necesita más evidencia.

Prognostic value of test(s) for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide.

BACKGROUND: Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a particular modification to their DNA (called methylation) in a particular region (the O6-methylguanine-DNA methyltransferase (MGMT) promoter) respond better to treatment with chemotherapy using a drug called temozolomide. OBJECTIVES: To determine which method for assessing MGMT methylation status best predicts overall survival in people diagnosed with glioblastoma who are treated with temozolomide. SEARCH METHODS: We searched MEDLINE, Embase, BIOSIS, Web of Science Conference Proceedings Citation Index to December 2018, and examined reference lists. For economic evaluation studies, we additionally searched NHS Economic Evaluation Database (EED) up to December 2014. SELECTION CRITERIA: Eligible studies were longitudinal (cohort) studies of adults with diagnosed glioblastoma treated with temozolomide with/without radiotherapy/surgery. Studies had to have related MGMT status in tumour tissue (assessed by one or more method) with overall survival and presented results as hazard ratios or with sufficient information (e.g. Kaplan-Meier curves) for us to estimate hazard ratios. We focused mainly on studies comparing two or more methods, and listed brief details of articles that examined a single method of measuring MGMT promoter methylation. We also sought economic evaluations conducted alongside trials, modelling studies and cost analysis. DATA COLLECTION AND ANALYSIS: Two review authors independently undertook all steps of the identification and data extraction process for multiple-method studies. We assessed risk of bias and applicability using our own modified and extended version of the QUality In Prognosis Studies (QUIPS) tool. We compared different techniques, exact promoter regions (5'-cytosine-phosphate-guanine-3' (CpG) sites) and thresholds for interpretation within studies by examining hazard ratios. We performed meta-analyses for comparisons of the three most commonly examined methods (immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ)), with ratios of hazard ratios (RHR), using an imputed value of the correlation between results based on the same individuals. MAIN RESULTS: We included 32 independent cohorts involving 3474 people that compared two or more methods. We found evidence that MSP (CpG sites 76 to 80 and 84 to 87) is more prognostic than IHC for MGMT protein at varying thresholds (RHR 1.31, 95% confidence interval (CI) 1.01 to 1.71). We also found evidence that PSQ is more prognostic than IHC for MGMT protein at various thresholds (RHR 1.36, 95% CI 1.01 to 1.84). The data suggest that PSQ (mainly at CpG sites 74 to 78, using various thresholds) is slightly more prognostic than MSP at sites 76 to 80 and 84 to 87 (RHR 1.14, 95% CI 0.87 to 1.48). Many variants of PSQ have been compared, although we did not see any strong and consistent messages from the results. Targeting multiple CpG sites is likely to be more prognostic than targeting just one. In addition, we identified and summarised 190 articles describing a single method for measuring MGMT promoter methylation status. AUTHORS' CONCLUSIONS: PSQ and MSP appear more prognostic for overall survival than IHC. Strong evidence is not available to draw conclusions with confidence about the best CpG sites or thresholds for quantitative methods. MSP has been studied mainly for CpG sites 76 to 80 and 84 to 87 and PSQ at CpG sites ranging from 72 to 95. A threshold of 9% for CpG sites 74 to 78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies making such comparisons.

Exploration of the costs of accessing health services: data from a longitudinal study of young people in transition from paediatric to adult services.

BACKGROUND: Economic evaluations that include the patient perspective often base their estimates of patient time and travel costs on data collected at a single point in time. This, however, may be inaccurate if the costs of accessing care change substantially over time, as may be the case for young people in transition from paediatric to adult health services. AIMS: The aim of this study was to explore the differences in these time and travel costs between two data collection points for young individuals in transition between health care services, and thus to provide an insight of whether such costs should be collected more than once. METHODS: Descriptive statistics and regression modelling were used to estimate the average difference in costs between the two points of data collection, as well as the potential drivers of those cost differences. RESULTS: We found a small difference in costs between the two time points, equal to -£45.78 [95% CI: - 89.70 to - 1.86]. The results were largely driven by changes in the unit cost of visits and in the number of attendances. CONCLUSIONS: A simple and common assumption that patient costs could be collected at a single time point cannot be made in the context of our study. When deciding on the frequency of elicitation of patient costs, future studies should consider the relative impacts of additional data collection on the estimates of efficiency, inequalities and resource implications for collecting new data.

Interventions to reduce the time to diagnosis of brain tumours.

BACKGROUND: Brain tumours are recognised as one of the most difficult cancers to diagnose because presenting symptoms, such as headache, cognitive symptoms, and seizures, may be more commonly attributable to other, more benign conditions. Interventions to reduce the time to diagnosis of brain tumours include national awareness initiatives, expedited pathways, and protocols to diagnose brain tumours, based on a person's presenting symptoms and signs; and interventions to reduce waiting times for brain imaging pathways. If such interventions reduce the time to diagnosis, it may make it less likely that people experience clinical deterioration, and different treatment options may be available. OBJECTIVES: To systematically evaluate evidence on the effectiveness of interventions that may influence: symptomatic participants to present early (shortening the patient interval), thresholds for primary care referral (shortening the primary care interval), and time to imaging diagnosis (shortening the secondary care interval and diagnostic interval). To produce a brief economic commentary, summarising the economic evaluations relevant to these interventions. SEARCH METHODS: For evidence on effectiveness, we searched CENTRAL, MEDLINE, and Embase from January 2000 to January 2020; Clinicaltrials.gov to May 2020, and conference proceedings from 2014 to 2018. For economic evidence, we searched the UK National Health Services Economic Evaluation Database from 2000 to December 2014. SELECTION CRITERIA: We planned to include studies evaluating any active intervention that may influence the diagnostic pathway, e.g. clinical guidelines, direct access imaging, public health campaigns, educational initiatives, and other interventions that might lead to early identification of primary brain tumours. We planned to include randomised and non-randomised comparative studies. Included studies would include people of any age, with a presentation that might suggest a brain tumour. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed titles identified by the search strategy, and the full texts of potentially eligible studies. We resolved discrepancies through discussion or, if required, by consulting another review author. MAIN RESULTS: We did not identify any studies for inclusion in this review. We excluded 115 studies. The main reason for exclusion of potentially eligible intervention studies was their study design, due to a lack of control groups. We found no economic evidence to inform a brief economic commentary on this topic. AUTHORS' CONCLUSIONS: In this version of the review, we did not identify any studies that met the review inclusion criteria for either effectiveness or cost-effectiveness. Therefore, there is no evidence from good quality studies on the best strategies to reduce the time to diagnosis of brain tumours, despite the prioritisation of research on early diagnosis by the James Lind Alliance in 2015. This review highlights the need for research in this area.

An examination of trends in antibiotic prescribing in primary care and the association with area-level deprivation in England.

BACKGROUND: Internationally, there are growing concerns about antimicrobial resistance. This has resulted in increased scrutiny of antibiotic prescribing trends - particularly in primary care where the majority of prescribing occurs. In England, antibiotic prescribing targets are set nationally but little is known about the local context of antibiotic prescribing. This study aimed to examine trends in antibiotic prescribing (including broad-spectrum), and the association with area-level deprivation and region in England. METHODS: Antibiotic prescribing data by GP surgery in England were obtained from NHS Business Service Authority for the years 2014-2018. These data were matched with the Index of Multiple Deprivation (IMD) 2015 at the Lower Layer Super Output Area level Lower Layer Super Output Area (LSOA) level. Linear regression methods were employed to explore the relationship between antibiotic use and area-level deprivation as well as region, after controlling for a range of other confounding variables, including health need, rurality, and ethnicity. RESULTS: Over time, the amount of antibiotic prescribing significantly reduced from 1.11 items per STAR-PU to 0.96 items per STAR-PU - a reduction of 13.6%. The adjusted models found that, at LSOA level, the most deprived areas of England had the highest levels of antibiotic prescribing (0.03 items per STAR-PU higher). However, broad spectrum antibiotic prescribing exceeding 10% of all antibiotic prescribing within a GP practice was higher in more affluent areas. There were also significant regional differences - with the North East and the East of England having the highest levels of antibiotic prescribing (by 0.16 items per STAR-PU). CONCLUSION: Although antibiotic prescribing has reduced over time, there remains significant variation in by area-level deprivation and region in England - with higher antibiotic prescribing in more deprived areas. Future prescribing targets should account for local factors to ensure the most deprived communities are not inappropriately penalised.

Treatment of newly diagnosed glioblastoma in the elderly: a network meta-analysis.

BACKGROUND: A glioblastoma is a fatal type of brain tumour for which the standard of care is maximum surgical resection followed by chemoradiotherapy, when possible. Age is an important consideration in this disease, as older age is associated with shorter survival and a higher risk of treatment-related toxicity. OBJECTIVES: To determine the most effective and best-tolerated approaches for the treatment of elderly people with newly diagnosed glioblastoma. To summarise current evidence for the incremental resource use, utilities, costs and cost-effectiveness associated with these approaches. SEARCH METHODS: We searched electronic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase to 3 April 2019, and the NHS Economic Evaluation Database (EED) up to database closure. We handsearched clinical trial registries and selected neuro-oncology society conference proceedings from the past five years. SELECTION CRITERIA: Randomised trials (RCTs) of treatments for glioblastoma in elderly people. We defined 'elderly' as 70+ years but included studies defining 'elderly' as over 65+ years if so reported. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for study selection and data extraction. Where sufficient data were available, treatment options were compared in a network meta-analysis (NMA) using Stata software (version 15.1). For outcomes with insufficient data for NMA, pairwise meta-analysis were conducted in RevMan. The GRADE approach was used to grade the evidence. MAIN RESULTS: We included 12 RCTs involving approximately 1818 participants. Six were conducted exclusively among elderly people (either defined as 65 years or older or 70 years or older) with newly diagnosed glioblastoma, the other six reported data for an elderly subgroup among a broader age range of participants. Most participants were capable of self-care. Study quality was commonly undermined by lack of outcome assessor blinding and attrition. NMA was only possible for overall survival; other analyses were pair-wise meta-analyses or narrative syntheses. Seven trials contributed to the NMA for overall survival, with interventions including supportive care only (one trial arm); hypofractionated radiotherapy (RT40; four trial arms); standard radiotherapy (RT60; five trial arms); temozolomide (TMZ; three trial arms); chemoradiotherapy (CRT; three trial arms); bevacizumab with chemoradiotherapy (BEV_CRT; one trial arm); and bevacizumab with radiotherapy (BEV_RT). Compared with supportive care only, NMA evidence suggested that all treatments apart from BEV_RT prolonged survival to some extent. Overall survival High-certainty evidence shows that CRT prolongs overall survival (OS) compared with RT40 (hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.56 to 0.80) and low-certainty evidence suggests that CRT may prolong overall survival compared with TMZ (TMZ versus CRT: HR 1.42, 95% CI 1.01 to 1.98). Low-certainty evidence also suggests that adding BEV to CRT may make little or no difference (BEV_CRT versus CRT: HR 0.83, 95% CrI 0.48 to 1.44). We could not compare the survival effects of CRT with different radiotherapy fractionation schedules (60 Gy/30 fractions and 40 Gy/15 fractions) due to a lack of data. When treatments were ranked according to their effects on OS, CRT ranked higher than TMZ, RT and supportive care only, with the latter ranked last. BEV plus RT was the only treatment for which there was no clear benefit in OS over supportive care only.   One trial comparing tumour treating fields (TTF) plus adjuvant chemotherapy (TTF_AC) with adjuvant chemotherapy alone could not be included in the NMA as participants were randomised after receiving concomitant chemoradiotherapy, not before. Findings from the trial suggest that the intervention probably improves overall survival in this selected patient population. We were unable to perform NMA for other outcomes due to insufficient data. Pairwise analyses were conducted for the following. Quality of life Moderate-certainty narrative evidence suggests that overall, there may be little difference in QoL between TMZ and RT, except for discomfort from communication deficits, which are probably more common with RT (1 study, 306 participants, P = 0.002). Data on QoL for other comparisons were sparse, partly due to high dropout rates, and the certainty of the evidence tended to be low or very low. Progression-free survival High-certainty evidence shows that CRT increases time to disease progression compared with RT40 (HR 0.50, 95% CI 0.41 to 0.61); moderate-certainty evidence suggests that RT60 probably increases time to disease progression compared with supportive care only (HR 0.28, 95% CI 0.17 to 0.46), and that BEV_RT probably increases time to disease progression compared with RT40 alone (HR 0.46, 95% CI 0.27 to 0.78). Evidence for other treatment comparisons was of low- or very low-certainty. Severe adverse events Moderate-certainty evidence suggests that TMZ probably increases the risk of grade 3+ thromboembolic events compared with RT60 (risk ratio (RR) 2.74, 95% CI 1.26 to 5.94; participants = 373; studies = 1) and also the risk of grade 3+ neutropenia, lymphopenia, and thrombocytopenia. Moderate-certainty evidence also suggests that CRT probably increases the risk of grade 3+ neutropenia, leucopenia and thrombocytopenia compared with hypofractionated RT alone. Adding BEV to CRT probably increases the risk of thromboembolism (RR 16.63, 95% CI 1.00 to 275.42; moderate-certainty evidence). Economic evidence There is a paucity of economic evidence regarding the management of newly diagnosed glioblastoma in the elderly. Only one economic evaluation on two short course radiotherapy regimen (25 Gy versus 40 Gy) was identified and its findings were considered unreliable. AUTHORS' CONCLUSIONS: For elderly people with glioblastoma who are self-caring, evidence suggests that CRT prolongs survival compared with RT and may prolong overall survival compared with TMZ alone. For those undergoing RT or TMZ therapy, there is probably little difference in QoL overall. Systemic anti-cancer treatments TMZ and BEV carry a higher risk of severe haematological and thromboembolic events and CRT is probably associated with a higher risk of these events. Current evidence provides little justification for using BEV in elderly patients outside a clinical trial setting. Whilst the novel TTF device appears promising, evidence on QoL and tolerability is needed in an elderly population. QoL and economic assessments of CRT versus TMZ and RT are needed. More high-quality economic evaluations are needed, in which a broader scope of costs (both direct and indirect) and outcomes should be included.

The impact of New Labour's English health inequalities strategy on geographical inequalities in infant mortality: a time-trend analysis.

BACKGROUND: The English health inequalities strategy (1999-2010) aimed to reduce health inequalities between the most deprived local authorities and the rest of England. The multifaceted strategy included increased investment in healthcare, the early years, education and neighbourhood renewal. The objective of this study was to investigate whether the strategy was associated with a reduction in geographical inequalities in the infant mortality rate (IMR). METHODS: We used segmented regression analysis to measure inequalities in the IMR between the most deprived local authorities and the rest of England before, during and after the health inequalities strategy period. RESULTS: Before the strategy was implemented (1983-1998), absolute inequalities in the IMR increased between the most deprived local authorities and the rest of England at a rate of 0.034 annually (95% CI 0.001 to 0.067). Once the strategy had been implemented (1999-2010), absolute inequalities decreased at a rate of -0.116 annually (95% CI -0.178 to -0.053). After the strategy period ended (2011-2017), absolute inequalities increased at a rate of 0.042 annually (95% CI -0.042 to 0.125). Relative inequalities also marginally decreased during the strategy period. CONCLUSION: The English health inequalities strategy period was associated with a decline in geographical inequalities in the IMR. This research adds to the evidence base suggesting that the English health inequalities strategy was at least partially effective in reducing health inequalities, and that current austerity policies may undermine these gains.

Estimating CHU-9D Utility Scores from the WAItE: A Mapping Algorithm for Economic Evaluation.

BACKGROUND: The Weight-Specific Adolescent Instrument for Economic Evaluation (WAItE) is a new condition-specific patient reported outcome measure that incorporates the views of adolescents in assessing the impact of above healthy weight status on key aspects of their lives. Presently it is not possible to use the WAItE to calculate quality adjusted life years (QALYs) for cost-utility analysis (CUA), given that utility scores are not available for health states described by the WAItE. OBJECTIVE: This paper examines different regression models for estimating Child Health Utility 9 Dimension (CHU-9D) utility scores from the WAItE for the purpose of calculating QALYs to inform CUA. METHODS: The WAItE and CHU-9D were completed by a sample of 975 adolescents. Nine regression models were estimated: ordinary least squares, Tobit, censored least absolute deviations, two-part, generalized linear model, robust MM-estimator, beta-binomial, finite mixture models, and ordered logistic regression. The mean absolute error (MAE) and mean squared error (MSE) were used to assess the predictive ability of the models. RESULTS: The robust MM-estimator with stepwise-selected WAItE item scores as explanatory variables had the best predictive accuracy. CONCLUSIONS: Condition-specific tools have been shown to be more sensitive to changes that are important to the population for which they have been developed for. The mapping algorithm developed in this study facilitates the estimation of health-state utilities necessary for undertaking CUA within clinical studies that have only collected the WAItE.