Cochrane Qualitative and Implementation Methods Group guidance paper 6:Methods for question formulation, searching, and protocol development for qualitative evidence synthesis

This paper updates previous Cochrane guidance on question formulation, searching, and protocol development, reflecting recent developments in methods for conducting qualitative evidence syntheses to inform Cochrane intervention reviews. Examples are used to illustrate how decisions about boundaries for a review are formed via an iterative process of constructing lines of inquiry and mapping the available information to ascertain whether evidence exists to answer questions related to effectiveness, implementation, feasibility, appropriateness, economic evidence, and equity. The process of question formulation allows reviewers to situate the topic in relation to how it informs and explains effectiveness, using the criterion of meaningfulness, appropriateness, feasibility, and implementation. Questions related to complex questions and interventions can be structured by drawing on an increasingly wide range of question frameworks. Logic models and theoretical frameworks are useful tools for conceptually mapping the literature to illustrate the complexity of the phenomenon of interest. Furthermore, protocol development may require iterative question formulation and searching. Consequently, the final protocol may function as a guide rather than a prescriptive route map, particularly in qualitative reviews that ask more exploratory and open-ended questions

Upregulated Glucose Metabolism Correlates Inversely with CD8(+) T-cell Infiltration and Survival in Squamous Cell Carcinoma

Antibodies that block T-cell–regulatory checkpoints have recently emerged as a transformative approach to cancer treatment. However, the clinical efficacy of checkpoint blockade depends upon inherent tumor immunogenicity, with variation in infiltrating T cells contributing to differences in objective response rates. Here, we sought to understand the molecular correlates of tumor-infiltrating T lymphocytes (TIL) in squamous cell carcinoma (SCC), using a systems biologic approach to integrate publicly available omics datasets with histopathologic features. We provide evidence that links TIL abundance and therapeutic outcome to the regulation of tumor glycolysis by EGFR and HIF, both of which are attractive molecular targets for use in combination with immunotherapeutics

Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Small-Cell Lung Cancer (LUNGSTAR)

Purpose Treating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies show that statins exert additive effects with agents, such as cisplatin, to impair tumor growth, and observational studies suggest that statins combined with anticancer therapies delay relapse and prolong life in several cancer types. To our knowledge, we report the first large, randomized, placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer, specifically SCLC. Patients and Methods Patients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 were randomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles of etoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerable toxicity. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, and toxicity. Results Eight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups. Conclusion Pravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients. Our conclusions are the same as those found in all four much smaller, randomized, placebo-controlled trials specifically designed to evaluate statin therapy in patients with cancer

Cochrane Qualitative and Implementation Methods Group Guidance paper 2: Methods for assessing methodological limitations, data extraction and synthesis, and confidence in synthesized qualitative findings

The Cochrane Qualitative and Implementation Methods Group develop and publish guidance on the synthesis of qualitative and mixed-method implementation evidence. Choice of appropriate methodologies, methods and tools is essential when developing a rigorous protocol and conducting the synthesis. Cochrane authors who conduct qualitative evidence syntheses have thus far used a small number of relatively simple methods to address similarly written questions. Cochrane has invested in methodological work to develop new tools and to encourage the production of exemplar reviews to show the value of more innovative methods that address a wider range of questions. In this paper in the series we report updated guidance on the selection of tools to assess methodological limitations in qualitative studies, and methods to extract and synthesise qualitative evidence. We recommend application of GRADE-CERQual to assess confidence in qualitative synthesised findings. This guidance aims to support review authors to undertake a qualitative evidence synthesis that is intended to be integrated subsequently with the findings of one or more Cochrane reviews of the effects of similar interventions. The review of intervention effects may be undertaken concurrently with or separate to the qualitative evidence synthesis. We encourage further development through reflection and formal testing

Cochrane Qualitative and Implementation Methods Group Guidance Paper 5: Reporting guidelines for qualitative, implementation and process evaluation evidence syntheses

OBJECTIVE: To outline contemporary and novel developments for presentation and reporting of syntheses of qualitative, implementation and process evaluation evidence, and provide recommendations for use of reporting guidelines. STUDY DESIGN AND SETTING: An overview of reporting guidelines for qualitative, implementation and process evaluation evidence syntheses drawing on current international literature and the collective expert knowledge of the Cochrane Qualitative and Implementation Methods Group. RESULTS AND CONCLUSION: Several reporting guidelines exist that can be used or adapted to report syntheses of qualitative, implementation and process evaluation evidence. Methods to develop individual guidance varied. The use of a relevant reporting guideline can enhance the transparency, consistency and quality of reporting. Guidelines exist that are: generic; method specific; and for particular aspects of the reviewing process eg searching. Caution is expressed over the potential for reporting guidelines to produce a mechanistic approach moving the focus away from the content and towards the procedural aspects of the review. The use of a reporting guideline is recommended and a five-step decision flowchart to guide the choice of reporting guideline is provided. Gaps remain in method specific reporting guidelines such as mixed-study, implementation and process evaluation evidence syntheses

Cochrane Qualitative and Implementation Methods Group Guidance Paper 5: Reporting guidelines for qualitative, implementation and process evaluation evidence syntheses

OBJECTIVE: To outline contemporary and novel developments for presentation and reporting of syntheses of qualitative, implementation and process evaluation evidence, and provide recommendations for use of reporting guidelines. STUDY DESIGN AND SETTING: An overview of reporting guidelines for qualitative, implementation and process evaluation evidence syntheses drawing on current international literature and the collective expert knowledge of the Cochrane Qualitative and Implementation Methods Group. RESULTS AND CONCLUSION: Several reporting guidelines exist that can be used or adapted to report syntheses of qualitative, implementation and process evaluation evidence. Methods to develop individual guidance varied. The use of a relevant reporting guideline can enhance the transparency, consistency and quality of reporting. Guidelines exist that are: generic; method specific; and for particular aspects of the reviewing process eg searching. Caution is expressed over the potential for reporting guidelines to produce a mechanistic approach moving the focus away from the content and towards the procedural aspects of the review. The use of a reporting guideline is recommended and a five-step decision flowchart to guide the choice of reporting guideline is provided. Gaps remain in method specific reporting guidelines such as mixed-study, implementation and process evaluation evidence syntheses

Cochrane Qualitative and Implementation Methods Group Guidance Series - paper 1: Introduction

Cochrane Reviews are systematic reviews of primary research in human health care and health policy, and are internationally recognized health c are resources for use in a decision-making process. 1 Cochrane works collaboratively with contributors around the world to produce authoritative, relevant, and reliable reviews. Coch rane reviews are commonly used in a guideline development process to determine recommendations fo r practice. The Cochrane Qualitative and Implementation Methods Group provide methodolog ical advice and guidance to Cochrane as well as leading methodological developm ent to benefit the wider qualitative evidence synthesis community. In this introductory paper 1 we briefly outline the evolution of qualitative and mixed-method synthesis methods, the role of qualitative and mixed- method syntheses in a decision-making process, and the contribution of qualitative and mixed-method syntheses to understanding complexity in complex intervention reviews. We then introduce a series of papers that provide Coch rane guidance on conducting qualitative and mixed-method evidence syntheses for a decision- making context

Cochrane Qualitative and Implementation Methods Group Guidance Paper 5: Methods for integrating qualitative and implementation evidence within intervention effectiveness reviews

The Cochrane Qualitative and Implementation Methods Group (CQIMG) develops and publishes guidance on the synthesis of qualitative and mixed-method evidence from process evaluations. Despite a proliferation of methods for the synthesis of qualitative research, less attention has focused on how to integrate these syntheses within intervention effectiveness reviews. In this paper we report updated guidance from the group on approaches, methods and tools which can be used to integrate the findings from quantitative studies evaluating intervention effectiveness with those from qualitative studies and process evaluations. We draw on conceptual analyses of mixed methods systematic review designs and the range of methods and tools that have been used in published reviews that have successfully integrated different types of evidence. We outline five key methods and tools as devices for integration which vary in terms of the levels at which integration takes place; the specialist skills and expertise required within the review team; and their appropriateness in the context of limited evidence. In situations where the requirement is the integration of qualitative and process evidence within intervention effectiveness reviews, we recommend the use of a sequential approach. Here evidence from each tradition is synthesised separately using methods consistent with each tradition before integration takes place using a common framework. Reviews which integrate qualitative and process evaluation evidence alongside quantitative evidence on intervention effectiveness in a systematic way are rare. This guidance aims to support review teams to achieve integration and we encourage further development through reflection and formal testing

Cochrane Qualitative and Implementation Methods Group Guidance paper 2: Methods for assessing methodological limitations, data extraction and synthesis, and confidence in synthesized qualitative findings

The Cochrane Qualitative and Implementation Methods Group develop and publish guidance on the synthesis of qualitative and mixed-method implementation evidence. Choice of appropriate methodologies, methods and tools is essential when developing a rigorous protocol and conducting the synthesis. Cochrane authors who conduct qualitative evidence syntheses have thus far used a small number of relatively simple methods to address similarly written questions. Cochrane has invested in methodological work to develop new tools and to encourage the production of exemplar reviews to show the value of more innovative methods that address a wider range of questions. In this paper in the series we report updated guidance on the selection of tools to assess methodological limitations in qualitative studies, and methods to extract and synthesise qualitative evidence. We recommend application of GRADE-CERQual to assess confidence in qualitative synthesised findings. This guidance aims to support review authors to undertake a qualitative evidence synthesis that is intended to be integrated subsequently with the findings of one or more Cochrane reviews of the effects of similar interventions. The review of intervention effects may be undertaken concurrently with or separate to the qualitative evidence synthesis. We encourage further development through reflection and formal testing