Jayne S. Wilson

A systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma.

The optimal use and effectiveness of (131)I-meta iodobenzylguanidine ((131)I-mIBG) molecular radiotherapy for neuroblastoma remain unclear despite extensive clinical experience. This systematic review aimed to improve understanding of the current data and define uncertainties for future clinical trials. Bibliographic databases were searched for neuroblastoma and (131)I-mIBG. Clinical trials and non-comparative case series of (131)I-mIBG therapy for neuroblastoma were included. Two reviewers assessed papers for inclusion using the title and abstract with consensus achieved by discussion. Data were extracted by one reviewer and checked by a second. Studies with multiple publications were reported as a single study. The searches yielded 1216 citations, of which 51 publications reporting 30 studies met our inclusion criteria. No randomised controlled trials (RCTs) were identified. In two studies (131)I-mIBG had been used as induction therapy and in one study it had been used as consolidation therapy. Twenty-seven studies for relapsed and refractory disease were identified. Publication dates ranged from 1987 to 2012. Total number of patients was 1121 with study sizes ranging from 10 to 164. There was a large amount of heterogeneity between the studies with regard to patient population, treatment schedule and response assessment. Study quality was highly variable. The objective tumour response rate reported in 25 studies ranged from 0% to 75%, mean 32%. We conclude that (131)I-mIBG is an active treatment for neuroblastoma, but its place in the management of neuroblastoma remains unclear. Prospective randomised trials are essential to strengthen the evidence base.

Surgical excision margins in primary cutaneous melanoma: A meta-analysis and Bayesian probability evaluation.

BACKGROUND Surgery is the only curative treatment for primary cutaneous melanoma, therefore it is important to determine excision margins that minimise risk of local recurrence, distant recurrence and death. METHODS MEDLINE, EMBASE and Cochrane CENTRAL were searched from 2009 to 2015. Inclusion criteria were: population/setting - patients with primary melanoma; comparison - narrow versus wide margins; outcomes - overall survival, melanoma-specific survival, recurrence-free survival, and loco-regional recurrence; design - randomized controlled trials (RCTs). Results were pooled using meta-analysis and data explored using likelihood Bayesian probability plots. RESULTS Six RCTs with 4233 patients were included. Narrow margins were defined as 1 or 2 cm of clinically normal skin around the melanoma; wide margins as 3, 4 or 5 cm. Hazard ratios (HR) were as follows (HR>1 indicates wide margin better): overall survival 1.09 (95% CI 0.98-1.22; p=0.1); melanoma-specific survival 1.17 (CI 1.03-1.34; p=0.02); recurrence-free survival 1.08 (CI 0.97-1.20; p=0.2); loco-regional recurrence 1.10 (CI 0.96-1.26; p=0.2), with no evidence of heterogeneity between trials for any end point or within subgroup analyses. There was an 94% probability that overall survival was worse with a narrow margin and a 43% probability that it was more than 10% worse in proportional terms (i.e. HR>1.1). Probabilities that narrow margins were worse were 99%, 92% and 92% for melanoma-specific survival, recurrence-free survival and loco-regional recurrence respectively. CONCLUSIONS Contrary to recommendations in several national guidelines that narrow margins are safe, this systematic review and meta-analysis provides evidence that a narrow margin may lead to a worse outcome than a wide margin.

Comparison of anticipated and actual control group outcomes in randomised trials in paediatric oncology provides evidence that historically controlled studies are biased in favour of the novel treatment

BackgroundHistorically controlled studies are commonly undertaken in paediatric oncology, despite their potential biases. Our aim was to compare the outcome of the control group in randomised controlled trials (RCTs) in paediatric oncology with those anticipated in the sample size calculations in the protocols. Our rationale was that, had these RCTs been performed as historical control studies instead, the available outcome data used to calculate the sample size in the RCT would have been used as the historical control outcome data.MethodsA systematic search was undertaken for published paediatric oncology RCTs using the Cochrane Central Register of Controlled Trials (CENTRAL) database from its inception up to July 2013. Data on sample size assumptions and observed outcomes (timetoevent and proportions) were extracted to calculate differences between randomised and historical control outcomes, and a one-sample t-test was employed to assess whether the difference between anticipated and observed control groups differed from zero.ResultsForty-eight randomised questions were included. The median year of publication was 2005, and the range was from 1976 to 2010. There were 31 superiority and 11 equivalence/noninferiority randomised questions with time-to-event outcomes. The median absolute difference between observed and anticipated control outcomes was 5.0% (range: -23 to +34), and the mean difference was 3.8% (95% CI: +0.57 to +7.0; P = 0.022).ConclusionsBecause the observed control group (that is, standard treatment arm) in RCTs performed better than anticipated, we found that historically controlled studies that used similar assumptions for the standard treatment were likely to overestimate the benefit of new treatments, potentially leading to children with cancer being given ineffective therapy that may have additional toxicity.

The effectiveness and safety of proton beam radiation therapy in children with malignant central nervous system (CNS) tumours: protocol for a systematic review

BackgroundThe aim of this study is to use a systematic review framework to identify and synthesise the evidence on the use of proton beam therapy (PBT) for the treatment of children with CNS tumours and where possible compare this to the use of photon radiotherapy (RT).MethodsStandard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Twelve electronic databases have been searched, and further citation, hand searching and reference checking will be employed. Studies assessing the effects of PBT used either alone or as part of a multimodality treatment regimen in children with CNS tumours will be included. Relevant economic evaluations will also be identified. The outcomes are survival (overall, progression-free, event-free, disease-free), local and regional control rates, short- and long-term adverse events, functional status measures and quality of survival. Two reviewers will independently screen and select studies for inclusion in the review. All interventional study designs will be eligible for inclusion in the review. However, initial scoping searches indicate the evidence base is likely to be limited to case series studies, with no studies of a higher quality being identified. Quality assessment will be undertaken using pre-specified criteria and tailored to study design if applicable. Studies will be combined using a narrative synthesis, with differences in results between studies highlighted and discussed in relation to the patient population, intervention and study quality. Where appropriate, if no studies of a comparative design are identified, outcomes will be compared against a range of estimates from the literature for similar populations and treatment regimens from the best available evidence from studies that include the use of advanced conventional photon therapy.DiscussionThe evidence base for the use of PBT in children with CNS tumours is likely to be relatively sparse, highly heterogeneous and potentially of a low quality with small sample sizes. Furthermore, selection and publication biases may limit the internal and external validity of studies. However, any tentative results from the review on potential treatment effects can be used to plan better quality research studies that are of a design appropriate for outcome comparison with conventional therapy.Systematic review registrationPROSPERO CRD42015029583

A Systematic Review of Treatments of Relapsed/Refractory Mantle Cell Lymphoma

Abstract A systematic review was conducted to evaluate the clinical effectiveness and safety of treatments for patients with relapsed/refractory mantle cell lymphoma (MCL) unsuitable for intensive treatment. The criteria for inclusion of the trials were established before the review. A search of Medline, Embase, and the Cochrane library databases was conducted to identify phase II or III randomized controlled trials (RCTs), reported from January 1, 1994 to May 29, 2016. Relevant conference abstracts, citation lists from the included articles, published guidelines, and on‐going clinical trial databases were also searched. Studies were included if they had evaluated any single agent or combination of treatments for adult patients with relapsed/refractory MCL who had received ≥ 1 previous line of therapy. Seven RCTs were identified. Only 1 treatment appeared in > 1 trial; therefore, the results from each trial could not be quantitatively pooled for meta‐analysis. The lack of common comparators, differences in baseline characteristics and inclusion and exclusion criteria, and variances in the response criteria used to measure outcomes made comparison of the results difficult. Although the direction of effect for progression‐free survival (PFS) and overall survival (OS) was in favor of the experimental drug in all trials, the difference in PFS was statistically significant in 5 and OS in 2. None showed statistical significance for both. A noticeable lack of RCTs evaluating treatments for patients with relapsed/refractory MCL made meaningful comparisons of effectiveness across trials rather difficult. This trend continues, because all, bar 1, of the 85 ongoing trials in this area are single‐arm studies. RCTs are required to enable better evaluation of the optimal treatment regimen for this group of patients.

The impact of routine surveillance screening with magnetic resonance imaging (MRI) to detect tumour recurrence in children with central nervous system (CNS) tumours: protocol for a systematic review and meta-analysis

BackgroundThe aim of this study is to assess the impact of routine MRI surveillance to detect tumour recurrence in children with no new neurological signs or symptoms compared with alternative follow-up practices, including periodic clinical and physical examinations and the use of non-routine imaging upon presentation with disease signs or symptoms.MethodsStandard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Ten electronic databases have been searched, and further citation searching and reference checking will be employed. Randomised and non-randomised controlled trials assessing the impact of routine surveillance MRI to detect tumour recurrence in children with no new neurological signs or symptoms compared to alternative follow-up schedules including imaging upon presentation with disease signs or symptoms will be included.The primary outcome is time to change in therapeutic intervention. Secondary outcomes include overall survival, surrogate survival outcomes, response rates, diagnostic yield per set of images, adverse events, quality of survival and validated measures of family psychological functioning and anxiety. Two reviewers will independently screen and select studies for inclusion. Quality assessment will be undertaken using the Cochrane Collaboration’s tools for assessing risk of bias. Where possible, data will be summarised using combined estimates of effect for time to treatment change, survival outcomes and response rates using assumption-free methods. Further sub-group analyses and meta-regression models will be specified and undertaken to explore potential sources of heterogeneity between studies within each tumour type if necessary.DiscussionAssessment of the impact of surveillance imaging in children with CNS tumours is methodologically complex. The evidence base is likely to be heterogeneous in terms of imaging protocols, definitions of radiological response and diagnostic accuracy of tumour recurrence due to changes in imaging technology over time. Furthermore, the delineation of tumour recurrence from either pseudo-progression or radiation necrosis after radiotherapy is potentially problematic and linked to the timing of follow-up assessments. However, given the current routine practice of MRI surveillance in the follow-up of children with CNS tumours in the UK and the resource implications, it is important to evaluate the cost-benefit profile of this practice.Systematic review registrationPROSPERO CRD42016036802

Reply to response to Wheatley et al., “Surgical excision margins in primary cutaneous melanoma: A meta-analysis and Bayesian probability evaluation” Cancer Treatment Reviews April 2016;45:76

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Does ‘mapping’ the evidence usefully inform the research question prioritisation process in systematic reviews?

Background Defining the research questions in systematic reviews is a very important first stage in the process, providing the framework for subsequent stages. With numerous questions and uncertainty regarding the strength and size of the evidence base for undertaking reviews on the effectiveness of interventions for children’s central nervous system (CNS) tumours a ‘map’ of the evidence was produced.

The role of high-dose myeloablative chemotherapy with haematopoietic stem cell transplantation (HSCT) in children with central nervous system (CNS) tumours: protocol for a systematic review and meta-analysis

ObjectivesThe objective of the study is to conduct a systematic review to compare the effects of high-dose chemotherapy (HDCT) with autologous haematopoietic stem cell transplantation (HSCT) versus standard-dose chemotherapy (SDCT) in children with malignant central nervous system (CNS) tumours.MethodsStandard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Ten electronic databases will be searched, along with citation searching and reference checking. Studies assessing the effects of HDCT with HSCT in children with CNS tumours will be included. The outcomes are survival (overall, progression-free, event-free, disease-free), response rates, short- and long-term adverse events and health-related quality of life (HRQoL). Two reviewers will independently screen and select randomised and non-randomised controlled trials and controlled and uncontrolled observational studies for inclusion. Quality assessment will be tailored to the different study designs. Where possible data will be summarised using combined estimates of effect for the hazard ratio for survival outcomes and the risk ratio for response rates. A fixed effect model will be used; sub-group analyses and meta-regression will be used to explore potential sources of heterogeneity between studies.DiscussionGiven the poor prognosis of malignant brain tumours in children in terms of survival and quality of life, this review will help guide clinical practice by summarising the current evidence on the use of high-dose myeloblative chemotherapy with stem cell support in children with CNS tumours.