Fibrin sealants in soft tissue surgery of the head and neck: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Fibrin sealants (FS) are commercially available products used in surgical wounds as adjuncts to haemostasis and closure of dead space. The role of FS in soft tissue head and neck surgery has not been established. OBJECTIVES: To assess whether FS improves wound-related outcomes in patients undergoing soft tissue surgery of the head and neck anatomical region that would commonly require a drain. TYPE OF REVIEW: Systematic review and meta-analysis of randomised controlled trials (RCTs). SEARCH STRATEGY: MEDLINE (1946-2016), EMBASE (1974-2016), PubMed (2016), CENTRAL (2016), ClinicalTrials.gov (2016), WHO International Clinical Trials Registry and Platform (2016), Research Gate (2016). EVALUATION METHOD: Two independent reviewers screened and selected studies. Included studies were assessed for risk of bias and data extracted using a predetermined data collection form. RESULTS: Of the 421 studies that were screened, 11 RCTs met the inclusion criteria. There were two RCTs on thyroidectomy, three on "surgery involving neck dissection" (central or lateral), five on rhytidectomy and one on parotidectomy. There was a tendency for FS to reduce "mean total drainage volume" (mean difference -26.86 mL, 95% CI -43.41 to -10.31, I2 =97%, P=.001). Subgroup analysis of thyroidectomy (mean difference -36.36 mL, 95% CI -72.82 to 0.10, I2 =79%, P=.05), "surgery involving neck dissection" (mean difference -33.21 mL, 95% CI -70.01 to 3.59, I2 =94%, P=.08) and rhytidectomy (mean difference -13.79 mL, 95% CI -17.57 to -10.01, I2 =0%, P < .00001) concurred with the overall analysis. There was a suggestion that FS may reduce "mean retention time of drains" by 1.24 days (95% CI -3.32 to 0.85, I2 =99%, P=.25) and "hospital length of stay" by 2.09 days (95% CI -5.18 to 0.99, I2 =97%, P=.18), but this was not statistically significant. There was also a suggestion that FS may protect against adverse events (RR 0.69, 95% CI 0.35 to 1.38, I2 =0%, P=.29) and haematoma/seroma formation (RR 0.49, 95% CI 0.22 to 1.07, I2 =0%, P=0.07). CONCLUSIONS: There was considerable heterogeneity within the RCTs included in this study, thus restricting definitive conclusions. FS has however shown a definite benefit in rhytidectomy and potential benefit in other soft tissue head and neck surgical procedures. Further pragmatic trials are required particularly in the field of lateral neck dissection.

How should individual participant data (IPD) from publicly funded clinical trials be shared?

BACKGROUND: Individual participant data (IPD) from completed clinical trials should be responsibly shared to support efficient clinical research, generate new knowledge and bring benefit to patients. The Medical Research Council (MRC) Hubs for Trials Methodology Research (HTMR) has developed guidance to facilitate the sharing of IPD from publicly funded clinical trials. METHODS: Development of the guidance was completed over four phases which included a focussed review of policy documents, a web-based survey of the UK Clinical Research Collaboration (CRC) Registered Clinical Trials Units (CTU) Network, participation of an expert committee and an open consultation with the UKCRC Registered CTU Network. The project was funded by the MRC HTMR (MR/L004933/1-R39). RESULTS: Good practice principles include: (i) the use of a controlled access approach, using a transparent and robust system to review requests and provide secure data access; (ii) seeking consent for sharing IPD from trial participants in all future clinical trials with adequate assurance that patient privacy and confidentiality can be maintained; and (iii) establishing an approach to resource the sharing of IPD which would include support from trial funders, sponsor organisations and users of IPD. The guidance has been endorsed by Cancer Research UK, MRC Methodology Research Programme Advisory Group, Wellcome Trust and the Executive Group of the UKCRC Registered CTU Network. The National Institute for Health Research (NIHR) has confirmed it is supportive of the application of this guidance. CONCLUSIONS: Implementation of these principles will improve transparency, increase the coherent sharing of IPD from publicly funded trials, and help publicly funded trials to adhere to trial funder and journal requirements for data sharing.

Clinical effectiveness and cost-effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer: a systematic review and economic evaluation.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) has issued multiple guidance for the first-line management of patients with lung cancer and recommends different combinations of chemotherapy treatments. This review provides a synthesis of clinical effectiveness and cost-effectiveness evidence supporting current guidance. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of first-line chemotherapy currently licensed in Europe and recommended by NICE, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). DATA SOURCES: Three electronic databases (MEDLINE, EMBASE and The Cochrane Library) were searched from 2001 to August 2010. REVIEW METHODS: Trials that compared first-line chemotherapy currently licensed in Europe and recommended by NICE in chemotherapy-naive adult patients with locally advanced or metastatic NSCLC were included. Data on key outcomes including, but not limited to, overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were extracted. For the assessment of cost-effectiveness, outcomes included incremental cost per quality-adjusted life-year (QALY) gained. Analyses were performed for three NSCLC subpopulations: patients with predominantly squamous disease, patients with predominantly non-squamous disease and patients with epidermal growth factor receptor (EGFR) mutation-positive (M+) status. Meta-analysis and mixed-treatment comparison methodology were conducted where appropriate. RESULTS: Twenty-three trials involving > 11,000 patients in total met the inclusion criteria. The quality of the trials was poor. In the case of patients with squamous disease, there were no statistically significant differences in OS between treatment regimes. The mixed-treatment comparison demonstrated that, in patients with non-squamous disease, pemetrexed (Alimta®, Eli Lilly and Company; PEM) + platinum (PLAT) increases OS statistically significantly compared with gemcitabine (Gemzar®, Eli Lilly and Company; GEM) + PLAT [hazard ratio (HR) = 0.85; 95% confidence interval (CI) 0.74 to 0.98] and that paclitaxel (Abraxane®, Celgene Corporation; PAX) + PLAT increases OS statistically significantly compared with docetaxel (Taxotere®, Sanofi-aventis; DOC) + PLAT (HR = 0.79, 95% CI 0.66 to 0.93). None of the comparisons found any statistically significant differences in OS among patients with EGFR M+ status. Direct meta-analysis showed a statistically significant improvement in PFS with gefitinib (Iressa®, AstraZeneca; GEF) compared with DOC + PLAT and PAX + PLAT (HR = 0.49; 95% CI 0.33 to 0.73; and HR = 0.38; 95% CI 0.24 to 0.60, respectively). No papers related to UK decision-making were identified. A de novo economic model was developed. Using list prices (British National Formulary), cisplatin (CIS) doublets are preferable to carboplatin doublets, but this is reversed if electronic market information tool prices are used, in which case drug administration costs then become more important than drug acquisition costs. For patients with both squamous and non-squamous disease, moving from low to moderate willingness-to-pay thresholds, the preferred drugs are PAX → GEM → DOC. However, in patients with non-squamous disease, PEM + CIS resulted in increased OS and would be considered cost-effective up to £35,000 per QALY gained. For patients with EGFR M+, use of GEF compared with PAX or DOC yields very high incremental cost-effectiveness ratios. Vinorelbine (Navelbine®, Pierre Fabre Pharmaceutical Inc.) was not shown to be cost-effective in any comparison. LIMITATIONS: Poor trial quality and a lack of evidence for all drug comparisons complicated and limited the data analysis. Outcomes and adverse effects are not consistently combined across the trials. Few trials reported quality-of-life data despite their relevance to patients and clinicians. CONCLUSIONS: The results of this comprehensive review are unique to NSCLC and will assist clinicians to make decisions regarding the treatment of patients with advanced NSCLC. The design of future lung cancer trials needs to reflect the influence of factors such as histology, genetics and the new prognostic biomarkers that are currently being identified. In addition, trials will need to be adequately powered so as to be able to test for statistically significant clinical effectiveness differences within patient populations. New initiatives are in place to record detailed information on the precise chemotherapy (and targeted chemotherapy) regimens being used, together with data on age, cell type, stage of disease and performance status, allowing for very detailed observational audits of management and outcomes at a population level. It would be useful if these initiatives could be expanded to include the collection of health economics data. FUNDING: The National Institute for Health Research Health Technology Assessment.

Clinical effectiveness of first-line chemoradiation for adult patients with locally advanced non-small cell lung cancer: a systematic review.

BACKGROUND: The National Institute for Health and Clinical Excellence has issued guidelines on the treatment of non-small cell lung cancer (NSCLC) and recommends that patients with stage IIIA-IIIB disease who are not amenable to surgery be treated with potentially curative chemoradiation (CTX-RT). This review was conducted as part of a larger systematic review of all first-line chemotherapy (CTX) and CTX-RT treatments for patients with locally advanced or metastatic NSCLC. However, it was considered that patients with potentially curable disease (e.g. stage IIIA) are different from those with advanced disease, who are suitable for palliative treatment only, and therefore the results should be reported separately. OBJECTIVE: To evaluate the clinical effectiveness of first-line CTX in addition to radiotherapy (RT) (CTX-RT vs CTX-RT) for adult patients with locally advanced NSCLC who are suitable for potentially curative treatment. DATA SOURCES: Three electronic databases (MEDLINE, EMBASE and The Cochrane Library) were searched from January 1990 to September 2010. REVIEW METHODS: Inclusion criteria comprised adult patients with locally advanced NSCLC, trials that compared any first-line CTX-RT therapy (induction, sequential, concurrent and consolidation) and outcomes of overall survival (OS) and/or progression-free survival (PFS). The results of clinical data extraction and quality assessment were summarised in tables and with narrative description. Direct meta-analyses using OS data were undertaken where possible: sequential CTX-RT compared with concurrent CTX-RT; sequential CTX-RT compared with concurrent/consolidation CTX-RT; and sequential CTX-RT compared with concurrent CTX-RT with or without consolidation. There were not sufficient data to perform meta-analysis on PFS. RESULTS: Of the 240 potentially relevant studies that were published post 2000, 19 met the inclusion criteria and compared CTX-RT with CTX-RT. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT appear to show an OS advantage for concurrent CTX-RT arms over sequential arms; this result is not statistically significant [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.50 to 1.25)]. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent/consolidation CTX-RT appear to show a statistically significant OS advantage for concurrent/consolidation CTX-RT treatment over sequential treatment (HR 0.68; 95% CI 0.55 to 0.83). The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT with or without consolidation appear to show a statistically significant OS advantage for concurrent CTX-RT with or without consolidation over sequential treatment (HR 0.72; 95% CI 0.61 to 0.84). LIMITATIONS: This report provides a summary and critical appraisal of a comprehensive evidence base of CTX-RT trials; however, it is possible that additional trials have been reported since our last literature search. It is disappointing that the quality of the research in this area does not meet the accepted quality standards regarding trial design and reporting. CONCLUSIONS: This review identified that the research conducted in the area of CTX-RT was generally of poor quality and suffered from a lack of reporting of all important clinical findings, including OS. The 19 trials included in the systematic review were too disparate to form any conclusions as to the effectiveness of individual CTX agents or types of RT. The focus of primary research should be good methodological quality; appropriate allocation of concealment and randomisation, and comprehensive reporting of key outcomes, will enable meaningful synthesis and conclusions to be drawn. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer.

BACKGROUND: The potential prognostic value of several commonly investigated immunohistochemical markers in resected pancreatic cancer is variably reported. The objective of this study was to conduct a systematic review of literature evaluating p53, p16, smad4, bcl-2, bax, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression as prognostic factors in resected pancreatic adenocarcinoma and to conduct a subsequent meta-analysis to quantify the overall prognostic effect. METHODS: Relevant literature was identified using Medline, EMBASE and ISI Web of Science. The primary end point was overall survival assessed on univariate analysis. Only studies analysing resected pancreatic adenocarcinoma were eligible for inclusion and the summary log(e) hazard ratio (logHR) and variance were pooled using an inverse variance approach. Evidence of heterogeneity was evaluated using the χ(2) test for heterogeneity and its impact on the meta-analysis was assessed by the I(2) statisic. Hazard ratios greater than one reflect adverse survival associated with positive immunostaining. RESULTS: Vascular endothelial growth factor emerged as the most potentially informative prognostic marker (11 eligible studies, n=767, HR=1.51 (95% confidence interval, CI=1.18-1.92)) with no evidence of any significant publication bias (Egger's test, P=0.269). Bcl-2 (5 eligible studies, n=314, HR=0.51 (95% CI=0.38-0.68)), bax (5 studies, n=274, HR=0.63 (95% CI=0.48-0.83)) and p16 (3 studies, n=229, HR=0.63 (95% CI=0.43-0.92)) also returned significant overall survival differences, but in smaller patient series due to a lack of evaluable literature. Neither p53 (17 studies, n=925, HR=1.22 (95% CI=0.96-1.56)), smad4 (5 studies, n=540, HR=0.88 (95% CI=0.61-1.27)) nor EGFR (4 studies, n=250, HR=1.35 (95% CI=0.80-2.27)) was found to represent significant prognostic factors when analysing the pooled patient data. There was evidence of significant heterogeneity in four of the seven study groups. CONCLUSION: These results support the case for immunohistochemical expression of VEGF representing a significant and reproducible marker of adverse prognosis in resected pancreatic cancer.

Pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in accordance with the licensed indication, based upon the evidence submission from Eli Lilly Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The majority of the efficacy evidence described in the manufacturer's submission is derived from a phase III open-label randomised controlled trial (RCT) known as the JMDB trial. The trial achieved its primary objective to demonstrate non-inferiority of pemetrexed/cisplatin to gemcitabine/cisplatin for overall survival in all patients with NSCLC. Because no other studies were found comparing pemetrexed/cisplatin with any other relevant comparator, additional efficacy evidence was presented from two phase III RCTs comparing gemcitabine/cisplatin with gemcitabine/carboplatin and docetaxel/cisplatin. The manufacturer's submission reported from its indirect comparisons' analysis that median overall survival and progression-free survival and tumour response rates were more favourable for pemetrexed/cisplatin than for any other comparator. The manufacturer did not identify any published cost-effectiveness analyses of pemetrexed for the first-line treatment of patients with NSCLC. Therefore economic evidence was derived solely from a de novo economic model developed by the manufacturer. A Markov model was developed to evaluate the cost-effectiveness of pemetrexed/cisplatin compared to gemcitabine/cisplatin, docetaxel/cisplatin and gemcitabine/carboplatin. The clinical data used in the economic evaluation were primarily generated from the JMDB trial, with additional data from the two further trials used in the indirect comparisons analysis. The ERG identified a series of problems with this economic model. As a result, three different versions of the model were submitted to NICE and considered by the ERG. The ICERs estimated by this final version of the model ranged from 8056 pounds to 33,065 pounds per QALY, depending on the comparator, the population and the application of a continuation rule. The ERG considered that the model required extensive modification and redesign, and should be subjected to thorough validation against the JMDB trial results. A full quality audit was also required as it was likely that further model inconsistencies may be present that had not yet been identified. The manufacturer subsequently included evidence in the form of three cost effectiveness analyses (two models and an 'in-trial' analysis), stating that a thorough validation process had been followed according to the NICE request. The very short time available to the ERG to consider the new evidence precluded a comprehensive assessment. Instead, the ERG chose to present a simple exploratory analysis combining its own survival projections with key cost estimates obtained from the JMDB trial individual patient data. Compared to gemcitabine, this resulted in ICERs ranging from 17,162 pounds to 30,142 pounds per QALY, depending on the patient population, the maximum number of cycles of chemotherapy and whether a cycle based efficacy adjustment was applied or not. The guidance issued by NICE in September 2009 states that pemetrexed in combination with cisplatin is recommended as an option for the first-line treatment of patients with locally advanced or metastatic NSCLC only if the histology of the tumour has been confirmed as adenocarcinoma or large-cell carcinoma.

Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials.

The ESPAC-1, ESPAC-1 plus, and early ESPAC-3(v1) results (458 randomized patients; 364 deaths) were used to estimate the effectiveness of adjuvant 5FU/FA vs resection alone for pancreatic cancer using meta-analysis. The pooled hazard ratio of 0.70 (95% CI=0.55-0.88) P=0.003, and the median survival of 23.2 (95% CI=20.1-26.5) months with 5FU/FA vs 16.8 (95% CI=14.3-19.2) months with resection alone supports the use of adjuvant 5FU/FA in pancreatic cancer.

Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer: results of secondary end points analyses.

In advanced pancreatic cancer, level one evidence has established a significant survival advantage with chemotherapy, compared to best supportive care. The treatment-associated toxicity needs to be evaluated. This study examines the secondary outcome measures for chemotherapy in advanced pancreatic cancer using meta-analyses. A systematic review was undertaken employing Cochrane methodology, with search of databases, conference proceedings and trial registers. The secondary end points were progression-free survival (PFS)/time to progression (TTP) (summarised using the hazard ratio (HR)), response rate and toxicity (summarised using relative risk). There was no significant advantage of 5FU combinations vs 5FU alone for TTP (HR=1.02; 95% CI=0.85-1.23) and toxicity. Progression-free survival (HR 0.78; CI 0.70-0.88), TTP (HR=0.85; 95% CI=0.72-0.99) and overall response rate (RR=0.56; 95% CI=0.46-0.68) were significantly better for gemcitabine combination chemotherapy, but offset by the greater grade 3/4 toxicity thrombocytopenia (RR=1.94; 95% CI=1.32-2.84), leucopenia (RR=1.46; 95% CI=1.15-1.86), neutropenia (RR=1.48; 95% CI=1.07-2.05), nausea (RR=1.77; 95% CI=1.37-2.29), vomiting (RR=1.64; 95% CI=1.24-2.16) and diarrhoea (RR=2.73; 95% CI=1.87-3.98). There is no significant advantage on secondary end point analyses for administering 5FU in combination over 5FU alone. There is improved PFS/TTP and response rate, with gemcitabine-based combinations, although this comes with greater toxicity.

Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy.

There is no consensus on the management of locally advanced pancreatic cancer, with either chemotherapy or combined modality approaches being employed (Maheshwari and Moser, 2005). No published meta-analysis (Fung et al, 2003; Banu et al, 2005; Liang, 2005; Bria et al, 2006; Milella et al, 2006) has included randomised controlled trials employing radiation therapy. The aim of this systematic review was to compare the following: (i) chemoradiation followed by chemotherapy (combined modality therapy) vs best supportive care (ii) radiotherapy vs chemoradiation (iii) radiotherapy vs combined modality therapy (iv) chemotherapy vs combined modality therapy (v) 5FU-based combined modality treatment vs another-agent-based combined modality therapy. Relevant randomised controlled trials were identified by searching databases, trial registers and conference proceedings. The primary end point was overall survival and secondary end points were progression-free survival/time-to-progression, response rate and adverse events. Survival data were summarised using hazard ratio (HR) and response-rate/adverse-event data with relative risk. Eleven trials involving 794 patients met the inclusion criteria. Length of survival with chemoradiation was increased compared with radiotherapy alone (two trials, 168 patients, HR 0.69; 95% confidence interval (CI) 0.51-0.94), but chemoradiation followed by chemotherapy did not lead to a survival advantage over chemotherapy alone (two trials, 134 patients, HR 0.79; CI 0.32-1.95). Meta-analyses could not be performed for the other comparisons. A survival benefit was demonstrated for chemoradiation over radiotherapy alone. Chemoradiation followed by chemotherapy did not demonstrate any survival advantage over chemotherapy alone, but important clinical differences cannot be ruled out due to the wide CI.