Rebecca Stowe

Systematic review of levodopa dose equivalency reporting in Parkinson's disease.

Interpretation of clinical trials comparing different drug regimens for Parkinsons disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce better symptomatic control but more late complications. To address this problem, conversion factors have been calculated for antiparkinsonian drugs that yield a total daily levodopa equivalent dose (LED). LED estimates vary, so we undertook a systematic review of studies reporting LEDs to provide standardized formulae. Electronic database and hand searching of references identified 56 primary reports of LED estimates. Data were extracted and the mean and modal LEDs calculated. This yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale. Using these conversion formulae to report LEDs would improve the consistency of reporting and assist the interpretation of clinical trials comparing different PD medications.

Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials

BACKGROUND At least 28 randomised, controlled trials have compared outcomes of surgery for rectal cancer combined with preoperative or postoperative radiotherapy with those of surgery alone. We have done a collaborative meta-analysis of these results to give a more balanced view of the total evidence and to increase statistical precision. METHODS We centrally checked and analysed individual patient data from 22 randomised comparisons between preoperative (6,350 patients in 14 trials) or postoperative (2157 in eight trials) radiotherapy and no radiotherapy for rectal cancer. FINDINGS Overall survival was only marginally better in patients who were allocated to radiotherapy than in those allocated to surgery alone (62% vs 63% died; p=0.06). Rates of apparently curative resection were not improved by preoperative radiotherapy (85% radiotherapy vs 86% control). Yearly risk of local recurrence was 46% (SE 6) lower in those who had preoperative radiotherapy than in those who had surgery alone (p=0.00001), and 37% (10) lower in those who had postoperative treatment than those who had surgery alone (p=0.002). Fewer patients who had preoperative radiotherapy died from rectal cancer than did those who had surgery alone (45% vs 50%, respectively, p=0.0003), but early (</=1 year after treatment) deaths from other causes increased (8% vs 4% died, p<0.0001). INTERPRETATION Preoperative radiotherapy (at biologically effective doses >/=30 Gy) reduces risk of local recurrence and death from rectal cancer. If safety can be improved without compromising effectiveness, then overall survival would be moderately improved by use of preoperative radiotherapy, especially for young, high risk patients. Postoperative radiotherapy also reduces local recurrence, but short preoperative radiation schedules seem to be at least as effective as longer schedules.BACKGROUND: At least 28 randomised, controlled trials have compared outcomes of surgery for rectal cancer combined with preoperative or postoperative radiotherapy with those of surgery alone. We have done a collaborative meta-analysis of these results to give a more balanced view of the total evidence and to increase statistical precision. METHODS: We centrally checked and analysed individual patient data from 22 randomised comparisons between preoperative (6,350 patients in 14 trials) or postoperative (2157 in eight trials) radiotherapy and no radiotherapy for rectal cancer. FINDINGS: Overall survival was only marginally better in patients who were allocated to radiotherapy than in those allocated to surgery alone (62% vs 63% died; p=0.06). Rates of apparently curative resection were not improved by preoperative radiotherapy (85% radiotherapy vs 86% control). Yearly risk of local recurrence was 46% (SE 6) lower in those who had preoperative radiotherapy than in those who had surgery alone (p=0.00001), and 37% (10) lower in those who had postoperative treatment than those who had surgery alone (p=0.002). Fewer patients who had preoperative radiotherapy died from rectal cancer than did those who had surgery alone (45% vs 50%, respectively, p=0.0003), but early (</=1 year after treatment) deaths from other causes increased (8% vs 4% died, p<0.0001). INTERPRETATION: Preoperative radiotherapy (at biologically effective doses >/=30 Gy) reduces risk of local recurrence and death from rectal cancer. If safety can be improved without compromising effectiveness, then overall survival would be moderately improved by use of preoperative radiotherapy, especially for young, high risk patients. Postoperative radiotherapy also reduces local recurrence, but short preoperative radiation schedules seem to be at least as effective as longer schedules.

Chemotherapy Compared With Biochemotherapy for the Treatment of Metastatic Melanoma: A Meta-Analysis of 18 Trials Involving 2,621 Patients

PURPOSE To assess the effect of adding interferon-alpha (IFN) +/- interleukin-2 (IL-2) to chemotherapy in patients with metastatic melanoma. METHODS A published data meta-analysis of trials of biochemotherapy versus chemotherapy in patients with metastatic melanoma was undertaken. End points evaluated were rates of partial response (PR), complete response (CR) and overall (partial + complete) response (OR); response duration; progression-free survival; overall survival (OS); and toxicity. The only subgroup analysis performed was by type of immunotherapy, with trials divided according to whether IFN only or IFN and IL-2 were administered in the biochemotherapy arm. RESULTS Eighteen randomized trials were identified: 11 trials of chemotherapy +/- IFN and seven trials of chemotherapy +/- IFN and IL-2. More than 2,600 patients were entered onto the trials, with 555 responses and 2,039 deaths. There was a clear benefit for biochemotherapy for PR (odds ratio = 0.66; 95% CI, 0.53 to 0.82; P = .0001), CR (odds ratio = 0.50; 95% CI, 0.35 to 0.73; P = .0003) and OR (odds ratio = 0.59; 95% CI, 0.49 to 0.72; P < .00001). For OR, these benefits were significant for both the IFN (odds ratio = 0.60; 95% CI, 0.46 to 0.79; P = .0002) and IFN + IL-2 (odds ratio = 0.58; 95% CI, 0.44 to 0.77; P = .0001) subgroups. In contrast, there was no benefit overall in OS (odds ratio = 0.99; 95% CI, 0.91 to 1.08; P = .9), but there was evidence of heterogeneity of treatment effect between the individual trials (P = .006). CONCLUSION This meta-analysis provides a comprehensive summary of all the data currently available, and shows that although biochemotherapy clearly improves response rates, this does not appear to translate into a survival benefit.

Physiotherapy intervention in Parkinson’s disease: systematic review and meta-analysis

Objective To assess the effectiveness of physiotherapy compared with no intervention in patients with Parkinson’s disease. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Literature databases, trial registries, journals, abstract books, and conference proceedings, and reference lists, searched up to the end of January 2012. Review methods Randomised controlled trials comparing physiotherapy with no intervention in patients with Parkinson’s disease were eligible. Two authors independently abstracted data from each trial. Standard meta-analysis methods were used to assess the effectiveness of physiotherapy compared with no intervention. Tests for heterogeneity were used to assess for differences in treatment effect across different physiotherapy interventions used. Outcome measures were gait, functional mobility and balance, falls, clinician rated impairment and disability measures, patient rated quality of life, adverse events, compliance, and economic analysis outcomes. Results 39 trials of 1827 participants met the inclusion criteria, of which 29 trials provided data for the meta-analyses. Significant benefit from physiotherapy was reported for nine of 18 outcomes assessed. Outcomes which may be clinically significant were speed (0.04 m/s, 95% confidence interval 0.02 to 0.06, P<0.001), Berg balance scale (3.71 points, 2.30 to 5.11, P<0.001), and scores on the unified Parkinson’s disease rating scale (total score −6.15 points, −8.57 to −3.73, P<0.001; activities of daily living subscore −1.36, −2.41 to −0.30, P=0.01; motor subscore −5.01, −6.30 to −3.72, P<0.001). Indirect comparisons of the different physiotherapy interventions found no evidence that the treatment effect differed across the interventions for any outcomes assessed, apart from motor subscores on the unified Parkinson’s disease rating scale (in which one trial was found to be the cause of the heterogeneity). Conclusions Physiotherapy has short term benefits in Parkinson’s disease. A wide range of physiotherapy techniques are currently used to treat Parkinson’s disease, with little difference in treatment effects. Large, well designed, randomised controlled trials with improved methodology and reporting are needed to assess the efficacy and cost effectiveness of physiotherapy for treating Parkinson’s disease in the longer term.

Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomised trials involving 3525 patients

Abstract Objective To quantify more reliably the benefits and risks of monoamine oxidase type B inhibitors (MAOBIs) in early Parkinsons disease. Data sources Searches of the Cochrane Library, Medline, Embase, PubMed, and Web of Science for years 1966-2003, plus major journals in the field, abstract books, and proceedings of meetings, for randomised trials comparing MAOBIs with placebo or levodopa. Data extraction Available data on mortality, motor complications, side effects, treatment compliance, and clinician rated disability (for example, unified Parkinsons disease rating scale) were extracted from 17 trials and combined using standard meta-analytic methods. Results No significant difference in mortality existed between patients on MAOBIs and control patients (odds ratio 1.13, 95% confidence interval 0.94 to 1.34; P = 0.2). Patients randomised to MAOBIs had significantly better total scores, motor scores, and activities of daily living scores on the unified Parkinsons disease rating scale at three months compared with patients taking placebo; they were also less likely to need additional levodopa (0.57, 0.48 to 0.67; P < 0.00001) or to develop motor fluctuations (0.75, 0.59 to 0.95; P = 0.02). No difference existed between the two groups in the incidence of side effects or withdrawal of patients. Conclusions MAOBIs reduce disability, the need for levodopa, and the incidence of motor fluctuations, without substantial side effects or increased mortality. However, because few trials have compared MAOBIs with other antiparkinsonian drugs, uncertainty remains about the relative benefits and risks of MAOBIs. Further large, long term comparative trials that include patient rated quality of life measures are needed.

Ability of 5‐HT4 receptor ligands to modulate rat striatal dopamine release in vitro and in vivo

1 The ability of 5‐HT4 (5‐hydroxytryptamine4) receptor ligands to modify dopamine release from rat striatal slices in vitro and in the striatum of freely moving rats was assessed by the microdialysis technique. 2 The release of dopamine from slices of rat striatum continually perfused with Krebs buffer was enhanced by 5‐HT4 receptor agonists; 5‐HT (10 μm), 5‐methoxytryptamine (5‐MeOT; 10 μm), renzapride (10 μm) and (S)‐zacopride (10 μm) maximally increased dopamine release by 133 ± 5, 214 ± 25, 232 ± 29 and 264 ± 69%, respectively (mean ± s.e.mean, n = 3–8). The drug‐induced responses were maximal within the first 2 min of drug application, and subsequently declined. The non‐selective 5‐HT3/5‐HT4 receptor antagonist, SDZ205‐557 (10 μm), failed to modify basal dopamine release from striatal slices but completely antagonized the (S)‐zacopride (10 μm)‐induced increase in dopamine release. 3 To allow faster drug application, the modulation of dopamine release from rat striatal slices in a static release preparation was also investigated. The 5‐HT4 receptor agonist, renzapride (10 μm) also enhanced dopamine release in this preparation (maximal increase = 214 ± 35%, mean ± s.e.mean, n = 14), whilst a lower concentration of renzapride (3 μm) was less effective. The renzapride‐induced response was maximal within the first 2 min of drug application, before declining. In this preparation, the stimulation of dopamine release by renzapride (10 μm), was completely antagonized by the selective 5‐HT4 receptor antagonist, GR113808 (100 nM). In addition, both the Na+ channel blocker, tetrodotoxin (100 nM) and the non‐selective protein kinase A inhibitor, H7 (100 nM) completely prevented the stimulation of dopamine release induced by renzapride (10 μm). 4 In vivo microdialysis studies demonstrated that the 5‐HT4 receptor agonists, 5‐MeOT (10 μm), renzapride (100 μm) and (S)‐zacopride (100 μm) maximally elevated extracellular levels of dopamine in the striatum by 220 ± 20, 161 ± 10 and 189 ± 53%, respectively (mean ± s.e.mean, n = 5–9). A lower concentration of renzapride (10 μm) was less effective. The elevation of extracellular striatal dopamine levels induced by either renzapride (100 μm) or (S)‐zacopride (100 μm) were completely antagonized by the non‐selective 5‐HT3/5‐HT4 receptor antagonist, SDZ205‐557 (100 μm). In addition, the elevation of extracellular levels of dopamine induced by either 5‐MeOT (10 μm) or renzapride (100 μm) was completely prevented by the selective 5‐HT4 receptor antagonist, GR113808 (1 μm) and the renzapride (100 μm)‐induced response was also completely prevented by the non‐selective protein kinase A inhibitor, H7 (1 μm). In this in vivo preparation, both GR113808 (1 μm) and H7 (1 μm), when perfused alone, reduced extracellular levels of dopamine. 5 In conclusion, the present study provides evidence that the 5‐HT4 receptor facilitates rat striatal dopamine release in vitro and in vivo.

Selective labelling of 5-HT7 receptor recognition sites in rat brain using [3H]5-carboxamidotryptamine.

The aim of the present study was to establish a radioligand binding assay to selectively label the native 5-HT7 receptor expressed in rat brain. In rat whole brain (minus cerebellum and striatum) homogenate, (+/-)-pindolol (10 microM)-insensitive [3H]5-CT ([3H]5-carboxamidotryptamine; 0.5 nM) specific binding (defined by 5-HT, 10 microM) displayed a pharmacological profile similar to the recombinant 5-HT7 receptor, although the Hill coefficients for competition curves generated by methiothepin, ritanserin, sumatriptan, clozapine and pimozide were significantly less than unity. In homogenates of rat hypothalamus, (+/-)-pindolol (10 microM)-insensitive [3H]5-CT recognition sites also resembled, pharmacologically, the 5-HT7 receptor, although pimozide still generated Hill coefficients significantly less than unity. Subsequent studies were performed in the additional presence of WAY100635 (100 nM) to prevent [3H]5-CT binding to residual, possibly, 5-HT1A sites. Competition for this [3H]5-CT binding indicated the labelling in whole rat brain homogenate of a homogenous population of sites with the pharmacological profile of the 5-HT7 receptor. Saturation studies also indicated that (+/-)-pindolol (10 microM)/WAY 100635 (100 nM)-insensitive [3H]5-CT binding to homogenates of whole rat brain was saturable and to an apparently homogenous population of sites which were labelled with nanomolar affinity (Bmax=33.2+/-0.7 fmol mg(-1) protein, pKd=8.78+/-0.05, mean+/-S.E.M., n=3). The development of this 5-HT7 receptor binding assay will aid investigation of the rat native 5-HT7 receptor.

Meta-analysis of the comparative efficacy and safety of adjuvant treatment to levodopa in later Parkinson's disease.

Levodopa initially provides good symptomatic control of the symptoms of Parkinsons disease, but motor complications often develop after long‐term use. Other classes of antiparkinsonian drugs including dopamine agonists, catechol‐O‐methyl transferase inhibitors, or monoamine oxidase type B inhibitors are then added as adjuvant therapy. It is unclear whether one class of drug is more effective than another. This meta‐analysis evaluates the comparative benefits and risks of these agents as adjuvant treatment in Parkinsons disease patients with motor complications.

Evaluating drug treatments for Parkinson's disease: how good are the trials?

Keith Wheatley and colleagues make the case that most trials of drug treatment for Parkinsons disease have crucial methodological faults—and provide little reliable evidence on differences between classes of drugs Parkinsons disease is one of the commonest causes of disability in older people, with over 100 000 patients in the United Kingdom and at least 8000 new cases diagnosed annually. Prevalence and incidence will both increase with the ageing population and the reduction in competing causes of mortality such as stroke and coronary heart disease.1 No cure currently exists, and medical treatment is directed towards alleviating symptoms.2 Levodopa relieves symptoms in most patients with Parkinsons disease, but long term use of levodopa is associated with motor complications such as involuntary movements (dyskinesias), along with a shortened response to each dose (wearing-off phenomenon) and unpredictable “on-off” fluctuations. A number of other drugs have been used,3 either alone or with reduced doses of levodopa, in an attempt to delay the onset of motor complications in early Parkinsons disease or to control complications once they have developed. These agents have primarily been from three classes of drug: dopamine agonists, monoamine oxidase type B inhibitors, and catechol- O -methyltransferase inhibitors. Many randomised controlled trials have evaluated these drugs, but uncertainty about their relative effectiveness remains. This review assesses the methods used in these trials to reveal the quality of the existing evidence base. #### Summary points The prevalence of Parkinsons disease will increase as the population ages, making it important to identify reliably the most effective drug therapy Although many randomised controlled trials have evaluated the efficacy of different classes of drugs in both early and later Parkinsons disease, uncertainty about best treatment remains because of small numbers, inadequate follow up, and inappropriate end points Much larger trials are needed with long term follow …

Surgery for Parkinson's disease: lack of reliable clinical trial evidence.

There has been a striking resurgence of interest in surgery for Parkinson’s disease (PD) with new targets identified and new procedures developed. This systematic review identified over 500 studies of surgery for PD published since 1990, including over 10 000 patients. However, the authors were unable to assess the value of PD surgery reliably because only seven randomised trials were identified including just 196 patients. Studies of surgery for PD have generally been of poor quality with too few patients, too short follow up, inappropriate choice of outcome measures, and lack of control groups. Much larger, randomised, controlled trials are needed to assess the longer term effects of surgery on patient rated quality of life and cost effectiveness.