Margaret Somerville

The harmful health effects of recreational ecstasy: a systematic review of observational evidence

OBJECTIVESnTo investigate the harmful health effects of taking ecstasy (3,4-methylenedioxymethamphetamine, MDMA) for recreational purposes.nnnDATA SOURCESnMEDLINE, EMBASE, PsycINFO and Web of Knowledge were searched. Additional information on deaths was collected from the General Mortality Register (GMR) and the Special Mortality Register collated by the National Programme on Substance Abuse Deaths (np-SAD).nnnREVIEW METHODSnStudies were categorised according to design, with systematic research syntheses (Level I evidence) the most valid and least open to bias. Where Level I evidence was not available, controlled observational studies (Level II evidence) were systematically reviewed. If neither Level I nor Level II evidence was available, uncontrolled case series and case reports (Level III evidence) were systematically surveyed. Data were extracted by one reviewer and a sample checked by a second. The heterogeneity of Level II evidence was addressed by undertaking stratified analyses for current and former ecstasy users and comparing them either with control groups using other illegal drugs but not ecstasy (polydrug controls) or with controls naïve to illegal drugs (drug-naïve controls). Statistical heterogeneity was minimised by using a random-effects model throughout and investigated using study-level regression analysis (metaregression).nnnRESULTSnFive Level I syntheses were identified; for each it was difficult to ascertain the exact methods adopted and evidence included. Small but significant deficits for ecstasy users compared to controls were reported in areas relating to attention, memory, psychomotor speed, executive systems functioning, and self-reported depressive symptoms. Data from Level II studies were directly pooled for seven individual outcomes, suggesting that ecstasy users performed worse than controls on common measures of immediate and delayed verbal recall (RAVLT, RBMT, digit span). No difference was seen in IQ (NART). The 915 outcome measures identified in Level II studies were analysed in broad domains: immediate and delayed verbal and visual memory, working memory, two measures of attention, three measures of executive function, perceptual organisation, self-rated depression, memory and anxiety, and impulsivity measured objectively and subjectively. Ecstasy users performed significantly worse than polydrug controls in 13/16 domains and significantly worse than drug-naïve controls in 7/12 domains for which sufficient data were available. The largest, most consistent exposure effects were seen in meta-analyses of memory (especially verbal and working memory, with less marked effects seen in visual memory). Former ecstasy users frequently showed deficits that matched or exceeded those seen amongst current users. At aggregate level, the effects do not appear to be dose-related, but are variably confounded by other drug use, particularly alcohol. Of Level III evidence, in the 10 years to 2006, the np-SAD and the GMR recorded an average of around 50 drug-related deaths per year involving ecstasy; it was the sole drug implicated in around 10 cases per year. Retrospective case series, based on hospital emergency department records, reported a death rate of 0-2% from emergency admissions related to ecstasy. Two major syndromes are most commonly reported as the immediate cause of death in fatal cases: hyperthermia and hyponatraemia.nnnCONCLUSIONSnA broad range of relatively low-quality literature suggests that recreational use of ecstasy is associated with significant deficits in neurocognitive function (particularly immediate and delayed verbal memory) and increased psychopathological symptoms. The clinical significance of the exposure effect in individual cases will be variable but, on average, deficits are likely to be relatively small. Ecstasy is associated with a range of acute harms but appears to be a rare cause of death in isolation.OBJECTIVESnTo provide an evidence-based perspective on the prognostic value of novel markers in localised prostate cancer and to identify the best prognostic model including the three classical markers and investigate whether models incorporating novel markers are better.nnnDATA SOURCESnEight electronic bibliographic databases were searched during March-April 2007. The reference lists of relevant articles were checked and various health services research-related resources consulted via the internet. The search was restricted to publications from 1970 onwards in the English language.nnnMETHODSnSelected studies were assessed, data extracted using a standard template, and quality assessed using an adaptation of published criteria. Because of the heterogeneity regarding populations, outcomes and study type, meta-analyses were not undertaken and the results are presented in tabulated format with a narrative synthesis of the results.nnnRESULTSnIn total 30 papers met the inclusion criteria, of which 28 reported on prognostic novel markers and five on prognostic models. A total of 21 novel markers were identified from the 28 novel marker studies. There was considerable variability in the results reported, the quality of the studies was generally poor and there was a shortage of studies in some categories. The marker with the strongest evidence for its prognostic significance was prostate-specific antigen (PSA) velocity (or doubling time). There was a particularly strong association between PSA velocity and prostate cancer death in both clinical and pathological models. In the clinical model the hazard ratio for death from prostate cancer was 9.8 (95% CI 2.8-34.3, p < 0.001) in men with an annual PSA velocity of more than 2 ng/ml versus an annual PSA velocity of 2 ng/ml or less; similarly, the hazard ratio was 12.8 (95% CI 3.7-43.7, p < 0.001) in the pathological model. The quality of the prognostic model studies was adequate and overall better than the quality of the prognostic marker studies. Two issues were poorly dealt with in most or all of the prognostic model studies: inclusion of established markers and consideration of the possible biases from study attrition. Given the heterogeneity of the models, they cannot be considered comparable. Only two models did not include a novel marker, and one of these included several demographic and co-morbidity variables to predict all-cause mortality. Only two models reported a measure of model performance, the C-statistic, and for neither was it calculated in an external data set. It was not possible to assess whether the models that included novel markers performed better than those without.nnnCONCLUSIONSnThis review highlighted the poor quality and heterogeneity of studies, which render much of the results inconclusive. It also pinpointed the small proportion of models reported in the literature that are based on patient cohorts with a mean or median follow-up of at least 5 years, thus making long-term predictions unreliable. PSA velocity, however, stood out in terms of the strength of the evidence supporting its prognostic value and the relatively high hazard ratios. There is great interest in PSA velocity as a monitoring tool for active surveillance but there is as yet no consensus on how it should be used and, in particular, what threshold should indicate the need for radical treatment.

Chemotherapy wafers for high grade glioma

BACKGROUNDnStandard treatment for high grade glioma (HGG) usually entails surgery (either biopsy or resection) followed by radiotherapy plus or minus temozolomide. Implanting wafers impregnated with chemotherapy agents into the resection cavity represents a novel means of delivering drugs directly to the resection cavity with potentially fewer systemic side effects. It is not clear how effective this modality is or whether it should be recommended as part of standard care for patients with HGG.nnnOBJECTIVESnTo estimate the clinical effectiveness of chemotherapy wafers for patients with HGG.nnnSEARCH STRATEGYnThe following databases were searched: CENTRAL (issue 4. 2010); MEDLINE and EMBASE. The original search strategy also included: Science Citation Index; Physician Data Query; and the meta-Register of Controlled Trials. Reference lists of all identified studies were searched. The Journal of Neuro-Oncology and Neuro-oncology were hand searched from 1999 to 2010, including all conference abstracts. Neuro-oncologists, trial authors and drug manufacturers were contacted regarding ongoing and unpublished trials.nnnSELECTION CRITERIAnPatients included those of all ages with a histologically proven diagnosis of HGG (using intra-operative analysis when undergoing first resection). Therapy could be instigated for either newly diagnosed disease (primary therapy) or at recurrence. Interventions included insertion of chemotherapy wafers to the resection cavity. Included studies had to be randomised controlled trials (RCTs).nnnDATA COLLECTION AND ANALYSISnTwo independent review authors assessed the search results for relevance and undertook critical appraisal according to pre-specified guidelines.nnnMAIN RESULTSnIn primary disease two RCTs assessing the effect of carmustine impregnated wafers (Gliadel®) and enrolling a total of 272 participants were identified. Survival was increased with Gliadel® compared to placebo (hazard ratio (HR) 0.65, 95% Confidence Interval (CI) 0.48 to 0.86, P = 0.003). In recurrent disease a single RCT was included comparing Gliadel® with placebo and enrolled 222 participants. It did not demonstrate a significant survival increase (HR 0.83, 95% CI 0.62 to 1.10, P = 0.2). There was no suitable data for any of the secondary outcome measures. Adverse events were not more common in either arm and are presented in a descriptive fashion.nnnAUTHORS CONCLUSIONSnCarmustine impregnated wafers (Gliadel®) result in improved survival without an increased incidence of adverse events over placebo wafers when used for primary disease therapy. There is no evidence of benefit for any other outcome measures. In recurrent disease Gliadel® does not appear to confer any additional benefit.

Chemotherapeutic wafers for High Grade Glioma

BACKGROUNDnStandard treatment for high grade glioma (HGG) usually entails biopsy or surgical resection where possible followed by radiotherapy. Systemic chemotherapy is usually only given in selected cases and its use is often limited by side effects. Implanting wafers impregnated with chemotherapy agents into the resection cavity represents a novel means of delivering drugs to the central nervous system (CNS) with fewer side effects. It is not clear how effective this modality is or whether it should be recommended as part of standard care for HGG.nnnOBJECTIVESnTo assess whether chemotherapeutic wafers have any advantage over conventional therapy for HGG.nnnSEARCH STRATEGYnThe following databases were searched: The Cochrane Central Register of Controlled Trials (CENTRAL), Issue 2, 2007, MEDLINE, EMBASE, SCIENCE CITATION INDEX, Physician Data Query and the meta-Register of Controlled Trials. Reference lists of all identified studies were searched. The Journal of Neuro-Oncology was hand searched from 1999 to 2007, including all conference abstracts. Neuro-oncologists were contacted regarding ongoing and unpublished trials.nnnSELECTION CRITERIAnPatients included those of all ages with a presumed diagnosis of malignant glioma from clinical examination and radiology. Interventions included insertion of chemotherapeutic wafers to the resection cavity at either primary surgery or for recurrent disease. Included studies had to be randomised controlled trials (RCTs).nnnDATA COLLECTION AND ANALYSISnQuality assessment and data extraction were undertaken by two review authors. Outcome measures included survival, time to progression, quality of life (QOL) and adverse events.nnnMAIN RESULTSnIn primary disease two RCTs assessing the effect of carmustine impregnated wafers (Gliadel(R)) and enrolling a total of 272 participants were identified. Survival was increased (hazard ratio (HR) 0.65 confidence interval (CI) 0.48 to 0.86 p = 0.003). In recurrent disease a single RCT was included assessing the effect of Gliadel(R) and enrolling 222 participants. It did not demonstrate a significant survival increase (HR 0.83 CI 0.62 to 1.10 p = 0.2). There was no suitable data for time to progression or QOL. Adverse events were not more common in either arm, and were presented in a descriptive fashion.nnnAUTHORS CONCLUSIONSnGliadel(R) results in a prolongation of survival without an increased incidence of adverse events when used as primary therapy. There is no evidence of enhanced progression free survival (PFS) or QOL. In recurrent disease, Gliadel(R) does not appear to confer any added benefit. These findings are based on the results of three RCTs with approximately 500 patients in total.

Surveillance of Barrett’s oesophagus: Is it worthwhile?

OBJECTIVEnTo assess the cost-effectiveness of surveillance of Barretts oesophagus.nnnDESIGNnCost-utility model.nnnSETTINGnUK NHS.nnnPATIENTSnOne thousand 55-year-old men with Barretts oesophagus.nnnINTERVENTIONnSurveillance programme: endoscopy and biopsy at 3 yearly intervals for non-dysplastic Barretts oesophagus; low-grade dysplasia yearly; high grade-dysplasia 3 monthly.nnnOUTCOME MEASURESnIncremental cost-effectiveness ratio, expected value of perfect information.nnnRESULTSnNon-surveillance dominated surveillance (i.e. cost less and conferred more benefit), but there was substantial uncertainty around many of the model inputs. Probabilistic analyses showed that non-surveillance cost less and conferred more benefit in 75% of model runs. Surveillance was cost-effective at usual levels of willingness to pay in 11% of runs. For people with Barretts oesophagus in England and Wales, a value of pound6.5 million is placed on acquiring perfect information about surveillance of Barretts oesophagus.nnnCONCLUSIONSnThe PenTAG cost-utility model suggests that surveillance programmes do more harm than good.

Carmustine implants for the treatment of newly diagnosed high-grade gliomas: a cost-utility analysis.

BackgroundHigh-grade gliomas are aggressive brain tumours that are extremely challenging to treat effectively. The intracranial implantation of carmustine wafers (BCNU-W), which delivers chemotherapy directly to the affected area, may prolong survival in this population. However, no attention has yet been paid to the economic implications of BCNU-W in this setting.ObjectiveTo investigate the cost effectiveness of BCNU-W as an adjunct to surgery followed by radiotherapy, compared with surgery plus radiotherapy alone. Newly diagnosed, operable grade III and IV gliomas in a population with a mean age of 55 years were considered.MethodsA Markov cost-utility model was developed in Microsoft® Excel, adopting a UK NHS perspective. Transition probabilities and cost data (year 2004 values) were obtained from published literature or expert opinion. The model incorporated utility values, obtained from members of the public, reflecting the quality of life associated with high-grade glioma. The effects of uncertainty were explored through extensive one-way and probabilistic sensitivity analysis.ResultsSurgery with the implantation of BCNU-W followed by radiotherapy costs £54 500 per additional QALY gained when compared with surgery plus radiotherapy alone. Probabilistic sensitivity analysis shows a <10% probability that BCNU-W would be considered cost effective at a willingness-to-pay threshold of £30 000 per QALY. Although model outputs were sensitive to alterations in several key parameters, the incremental cost effectiveness of the intervention remained above £30 000 per QALY in all analyses.ConclusionCompared with usual care for the treatment of newly diagnosed high-grade gliomas, BCNU-W is unlikely to be considered a cost-effective use of healthcare resources when judged by the standards commonly adopted in England and Wales. However, the dreadful prognosis of the condition and the paucity of alternative therapies are additional issues that healthcare commissioners may choose to take into account when considering an adoption decision.