The efficacy and safety of tyrosine kinase inhibitors in advanced and metastatic thyroid cancer: Study Protocol for a systematic review and meta-analysis of Phase III and IV randomised controlled trials

Background and AimsTyrosine kinase inhibitors (TKIs) are now readily considered in the management of advanced and metastatic thyroid cancer. However, a key limiting factor are their adverse events (AEs), which can impair quality of life and influence patient acceptance of treatment. Prior systematic reviews have assessed the efficacy and safety of TKIs by reviewing both retrospective and prospective studies and further Phase III randomised controlled trials (RCTs) have since been published. We therefore plan to conduct a systematic review and meta-analysis of only prospective phase III and IV RCTs including the most recently published trials to investigate the efficacy and AEs of TKIs in patients with advanced and metastatic thyroid cancer compared to placebo. Review methodsThe Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, OVID Medline, Embase and PubMed databases will be electronically searched. Grey literature will be searched through Clinicaltrials.gov and www.ISRCTN.com. Expert informants will be contacted. We will include Phase III and IV randomised controlled trials that investigate the efficacy and AEs of TKIs in adults with advanced or metastatic thyroid cancer compared to placebo. Two authors will extract and assess for risk of bias using the Cochrane Risk of Bias Tool. Data extraction will include outcomes for objective response rate (ORR), progression free survival (PFS) and AEs, including diarrhoea, nausea, hypertension, proteinuria, palmar-plantar erythrodysaesthesia (PPE) and grade 3+ AEs, with a subgroup analysis on medullary vs differentiated thyroid cancer, TKI type and history of prior TKI or other systemic therapy. Pooled effect sizes will be meta-analysed using Review Manager 5 software through a random effects model. The study will be reported in line with the PRISMA guidelines. DiscussionThis will be the first systematic review to be conducted on the safety and efficacy of TKIs in advanced or metastatic thyroid cancer to meta-analyse phase III and IV RCT level data and include the most recently published trials. This review aims to highlight the balance between the therapeutic effect and toxicity of TKIs, and guide future studies that may be required in exploring different dosing and timing of TKI therapy.