Treatment of newly diagnosed glioblastoma in the elderly

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: 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 the different management strategies for newly diagnosed glioblastoma among adults aged over 70 years

Interventions for visual field defects in people with stroke

BACKGROUND:Visual field defects are estimated to affect 20% to 57% of people who have had a stroke. Visual field defects can affect functional ability in activities of daily living (commonly affecting mobility, reading and driving), quality of life, ability to participate in rehabilitation, and depression and anxiety following stroke. There are many interventions for visual field defects, which are proposed to work by restoring the visual field (restitution); compensating for the visual field defect by changing behaviour or activity (compensation); substituting for the visual field defect by using a device or extraneous modification (substitution); or ensuring appropriate diagnosis, referral and treatment prescription through standardised assessment or screening, or both. OBJECTIVES:To determine the effects of interventions for people with visual field defects after stroke. SEARCH METHODS:We searched the Cochrane Stroke Group Trials Register, the Cochrane Eyes and Vision Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, AMED, PsycINFO, and PDQT Databse, and clinical trials databases, including ClinicalTrials.gov and WHO Clinical Trials Registry, to May 2018. We also searched reference lists and trials registers, handsearched journals and conference proceedings, and contacted experts. SELECTION CRITERIA:Randomised trials in adults after stroke, where the intervention was specifically targeted at improving the visual field defect or improving the ability of the participant to cope with the visual field loss. The primary outcome was functional ability in activities of daily living and secondary outcomes included functional ability in extended activities of daily living, reading ability, visual field measures, balance, falls, depression and anxiety, discharge destination or residence after stroke, quality of life and social isolation, visual scanning, adverse events, and death. DATA COLLECTION AND ANALYSIS:Two review authors independently screened abstracts, extracted data and appraised trials. We undertook an assessment of methodological quality for allocation concealment, blinding of outcome assessors, method of dealing with missing data, and other potential sources of bias. We assessed the quality of evidence for each outcome using the GRADE approach. MAIN RESULTS:Twenty studies (732 randomised participants, with data for 547 participants with stroke) met the inclusion criteria for this review. However, only 10 of these studies compared the effect of an intervention with a placebo, control, or no treatment group, and eight had data which could be included in meta-analyses. Only two of these eight studies presented data relating to our primary outcome of functional abilities in activities of daily living. One study reported evidence relating to adverse events.Three studies (88 participants) compared a restitutive intervention with a control, but data were only available for one study (19 participants). There was very low-quality evidence that visual restitution therapy had no effect on visual field outcomes, and a statistically significant effect on quality of life, but limitations with these data mean that there is insufficient evidence to draw any conclusions about the effectiveness of restitutive interventions as compared to control.Four studies (193 participants) compared the effect of scanning (compensatory) training with a control or placebo intervention. There was low-quality evidence that scanning training was more beneficial than control or placebo on quality of life, measured using the Visual Function Questionnaire (VFQ-25) (two studies, 96 participants, mean difference (MD) 9.36, 95% confidence interval (CI) 3.10 to 15.62). However, there was low or very-low quality evidence of no effect on measures of visual field, extended activities of daily living, reading, and scanning ability. There was low-quality evidence of no significant increase in adverse events in people doing scanning training, as compared to no treatment.Three studies (166 participants) compared a substitutive intervention (a type of prism) with a control. There was low or very-low quality evidence that prisms did not have an effect on measures of activities of daily living, extended activities of daily living, reading, falls, or quality of life, and very low-quality evidence that they may have an effect on scanning ability (one study, 39 participants, MD 9.80, 95% CI 1.91 to 17.69). There was low-quality evidence of an increased odds of an adverse event (primarily headache) in people wearing prisms, as compared to no treatment.One study (39 participants) compared the effect of assessment by an orthoptist to standard care (no assessment) and found very low-quality evidence that there was no effect on measures of activities of daily living.Due to the quality and quantity of evidence, we remain uncertain about the benefits of assessment interventions. AUTHORS' CONCLUSIONS:There is a lack of evidence relating to the effect of interventions on our primary outcome of functional ability in activities of daily living. There is limited low-quality evidence that compensatory scanning training may be more beneficial than placebo or control at improving quality of life, but not other outcomes. There is insufficient evidence to reach any generalised conclusions about the effect of restitutive interventions or substitutive interventions (prisms) as compared to placebo, control, or no treatment. There is low-quality evidence that prisms may cause minor adverse events

Toric intraocular lens versus limbal relaxing incisions for corneal astigmatism after phacoemulsification.

BACKGROUND: Cataract is the leading cause of blindness in the world, and clinically significant astigmatism may affect up to approximately 20% of people undergoing cataract surgery. Pre-existing astigmatism in people undergoing cataract surgery may be treated, among other techniques, by placing corneal incisions near the limbus (limbal relaxing incisions or LRIs) or by toric intraocular lens (IOLs) specially designed to reduce or treat the effect of corneal astigmatism on unaided visual acuity. OBJECTIVES: To assess the effects of toric IOLs compared with LRIs in the management of astigmatism during phacoemulsification cataract surgery. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; 2019, Issue 9); Ovid MEDLINE; Ovid Embase and four other databases. The date of the search was 27 September 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing toric IOLs with LRIs during phacoemulsification cataract surgery.  DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. We graded the certainty of the evidence using GRADE. Our primary outcome was the proportion of participants with postoperative residual refractive astigmatism of less than 0.50 dioptres (D) six months or more after surgery. We also collected data on mean residual refractive astigmatism. Secondary outcomes included: uncorrected distance visual acuity, vision-related quality of life, spectacle independence and adverse effects including postoperative lens rotation requiring re-alignment. To supplement the main systematic review assessing the effects of toric IOLs compared with LRIs in the management of astigmatism during phacoemulsification cataract surgery, we sought to identify economic evaluations on the subject. MAIN RESULTS: We identified 10 relevant studies including 517 people (626 eyes). These studies took place in China (three studies), UK (three), Brazil (one), India (one), Italy (one) and Spain (one). The median age of participants was 71 years. The level of corneal astigmatism specified in the inclusion criteria of these studies ranged from 0.75 D to 3 D. A variety of toric IOLs were used in these studies, in all but one study, these were monofocal. Studies used three different nomograms to determine the size and placement of the LRI. Two studies did not specify this. None of the studies were at low risk of bias in all domains, but two studies were at low risk of bias in all domains except selective outcome reporting, which was unclear. The remaining studies were at a mixture of low, unclear or high risk of bias. People receiving toric IOLs were probably more likely to achieve a postoperative residual refractive astigmatism of less than 0.5 D six months or more after surgery (risk ratio (RR) 1.40, 95% confidence interval (CI) 1.10 to 1.78; 5 RCTs, 262 eyes). We judged this to be moderate-certainty evidence, downgrading for risk of bias. In the included studies, approximately 500 eyes per 1000 achieved postoperative astigmatism less than 0.5 D in the LRI group compared with 700 per 1000 in the toric IOLs group. There was a small difference in residual astigmatism between the two groups, favouring toric IOLs (mean difference (MD) -0.32 D, 95% CI -0.48 to -0.15 D; 10 RCTs, 620 eyes). Although all studies favoured toric IOLs, the results of individual studies were inconsistent (range of effects -0.02 D to -0.71 D; I² = 89%). We considered this to be low-certainty evidence, downgrading for risk of bias and inconsistency. People receiving a toric IOL probably have a small improvement in visual acuity at six months or more after surgery compared to people receiving LRI, but the difference is small and probably clinically insignificant (MD -0.04 logMAR, 95% CI -0.07 to -0.02; 8 RCTs, 474 eyes; moderate-certainty evidence). Low-certainty evidence from one study of 40 people suggested little difference in vision-related quality of life measured using the Visual Function Index (VF-14) (MD -3.01, 95% CI -8.56 to 2.54). Two studies reported spectacle independence and suggested that people receiving toric IOLs may be more likely to be spectacle independent (RR 1.56, 95% CI 1.14 to 2.15; 100 people; low-certainty evidence). There were no cases of lens rotation requiring surgery (very low-certainty evidence). Five studies (320 eyes) commented on a range of other adverse effects including corneal oedema, endophthalmitis and corneal ectasia. All these studies reported that there were no adverse events with the exception of one study (40 eyes) where one participant in the LRI group had a central de-epithelisation which recovered over 10 days. We found no economic studies that compared toric IOLs with LRIs. AUTHORS' CONCLUSIONS: Toric IOLs probably provide a higher chance of achieving astigmatism within 0.5 D after cataract surgery compared with LRIs. There may be a small mean difference in postoperative astigmatism, favouring toric IOLs, but this difference is likely to be clinically unimportant. There was no evidence of an important difference in postoperative visual acuity or quality of life between the techniques. Evidence on adverse effects was uncertain. The apparent shortage of relevant economic evaluations indicates that economic evidence regarding the costs and consequence of these two procedures is currently lacking

Long‐term neurocognitive and other side effects of radiotherapy, with or without chemotherapy, for glioma

Background: Gliomas are brain tumours arising from glial cells with an annual incidence of 4 to 11 people per 100,000. In this review we focus on gliomas with low aggressive potential in the short term, i.e. low‐grade gliomas. Most people with low‐grade gliomas are treated with surgery and may receive radiotherapy thereafter. However, there is concern about the possible long‐term effects of radiotherapy, especially on neurocognitive functioning. Objectives: To evaluate the long‐term neurocognitive and other side effects of radiotherapy (with or without chemotherapy) compared with no radiotherapy, or different types of radiotherapy, among people with glioma (where 'long‐term' is defined as at least two years after diagnosis); and to write a brief economic commentary. Search methods: We searched the following databases on 16 February 2018 and updated the search on 14 November 2018: Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 11) in the Cochrane Library; MEDLINE via Ovid; and Embase via Ovid. We also searched clinical trial registries and relevant conference proceedings from 2014 to 2018 to identify ongoing and unpublished studies. Selection criteria: Randomised and non‐randomised trials, and controlled before‐and‐after studies (CBAS). Participants were aged 16 years and older with cerebral glioma other than glioblastoma. We included studies where patients in at least one treatment arm received radiotherapy, with or without chemotherapy, and where neurocognitive outcomes were assessed two or more years after treatment. Data collection and analysis: Two review authors independently extracted data and assessed risk of bias. We assessed the certainty of findings using the GRADE approach. Main results: The review includes nine studies: seven studies were of low‐grade glioma and two were of grade 3 glioma. Altogether 2406 participants were involved but there was high sample attrition and outcome data were available for a minority of people at final study assessments. In seven of the nine studies, participants were recruited to randomised controlled trials (RCTs) in which longer‐term follow‐up was undertaken in a subset of people that had survived without disease progression. There was moderate to high risk of bias in studies due to lack of blinding and high attrition, and in two observational studies there was high risk of selection bias. Paucity of data and risk of bias meant that evidence was of low to very low certainty. We were unable to combine results in meta‐analysis due to diversity in interventions and outcomes. The studies examined the following five comparisons. Radiotherapy versus no adjuvant treatment Two observational studies contributed data. At the 12‐year follow‐up in one study, the risk of cognitive impairment (defined as cognitive disability deficits in at least five of 18 neuropsychological tests) was greater in the radiotherapy group (risk ratio (RR) 1.95, 95% confidence interval (CI) 1.02 to 3.71; n = 65); at five to six years the difference between groups did not reach statistical significance (RR 1.38, 95% CI 0.92 to 2.06; n = 195). In the other study, one subject in the radiotherapy group had cognitive impairment (defined as significant deterioration in eight of 12 neuropsychological tests) at two years compared with none in the control group (very low certainty evidence). With regard to neurocognitive scores, in one study the radiotherapy group was reported to have had significantly worse mean scores on some tests compared with no radiotherapy; however, the raw data were only given for significant findings. In the second study, there were no clear differences in any of the various cognitive outcomes at two years (n = 31) and four years (n = 15) (very low certainty evidence). Radiotherapy versus chemotherapy One RCT contributed data on cognitive impairment at up to three years with no clear difference between arms (RR 1.43, 95% CI 0.36 to 5.70, n = 117) (low‐certainty evidence). High‐dose radiotherapy versus low‐dose radiotherapy Only one of two studies reporting this comparison contributed data, and at two and five years there were no clear differences between high‐ and low‐dose radiotherapy arms (very low certainty evidence). Conventional radiotherapy versus stereotactic conformal radiotherapy One study involving younger people contributed limited data from the subgroup aged 16 to 25 years. The numbers of participants with neurocognitive impairment at five years after treatment were two out of 12 in the conventional arm versus none out of 11 in the stereotactic conformal radiotherapy arm (RR 4.62, 95% CI 0.25 to 86.72; n = 23; low‐certainty evidence). Chemoradiotherapy versus radiotherapy Two RCTs tested for cognitive impairment. One defined cognitive impairment as a decline of more than 3 points in MMSE score compared with baseline and reported data from 2‐year (110 participants), 3‐year (91 participants), and 5‐year (57 participants) follow‐up with no clear difference between the two arms at any time point. A second study did not report raw data but measured MMSE scores over five years in 126 participants at two years, 110 at three years, 69 at four years and 53 at five years. Authors concluded that there was no difference in MMSE scores between the two study arms (P = 0.4752) (low‐certainty evidence). Two RCTs reported quality of life (QoL) outcomes for this comparison. One reported no differences in Brain‐QoL scores between study arms over a 5‐year follow‐up period (P = 0.2767; no raw data were given and denominators were not stated). The other trial reported that the long‐term results of health‐related QoL showed no difference between the arms but did not give the raw data for overall HRQoL scores (low‐certainty evidence). We found no comparative data on endocrine dysfunction; we planned to develop a brief economic commentary but found no relevant economic studies for inclusion. Authors' conclusions: Radiotherapy for gliomas with a good prognosis may increase the risk of neurocognitive side effects in the long term; however the magnitude of the risk is uncertain. Evidence on long‐term neurocognitive side effects associated with chemoradiotherapy is also uncertain. Neurocognitive assessment should be an integral part of long‐term follow‐up in trials involving radiotherapy for lower‐grade gliomas to improve the certainty of evidence regarding long‐term neurocognitive effects. Such trials should also assess other potential long‐term effects, including endocrine dysfunction, and evaluate costs and cost effectiveness

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