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DOI: 10.1055/a-1023-4214
Anti-Tumor Activity and Safety of Multikinase Inhibitors in Advanced and/or Metastatic Thyroid Cancer: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials
Publication History
received 21 August 2019
accepted 01 October 2019
Publication Date:
30 October 2019 (online)
![](https://www.thieme-connect.de/media/hmr/202001/lookinside/thumbnails/2019-08-0268_10-1055-a-1023-4214-1.jpg)
Abstract
Many trials have demonstrated prime antitumor activity of novel, small molecule multikinase inhibitors (MKIs) in advanced and/or metastatic thyroid cancer (TC). In this work, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, and clinicaltrials.gov databases were searched. Quality/risk of bias were assessed using GRADE criteria. Randomized clinical trials (RCTs) comparing two or more systemic therapies in patients with advanced and/or metastatic thyroid cancer were assessed. A total of 1347 articles and 548 clinical trials in clinicaltrials.gov were screened. We included seven relevant RCTs comprising 1934 unique patients assigned to different MKIs. Two separate network meta-analyses included four RCTs in radioiodine refractory well-differentiated thyroid cancer (RR-WDTC) and three RCTs in medullary thyroid cancer (MTC), respectively; all with a low risk of bias. We identified three therapies for RR-WDTC: sorafenib [disease control rate (DCR) odds ratio (OR): 0.11 (95% CI: 0.03–0.40); progression-free survival (PFS) hazard ratio (HR): 1.99 (95% CI: 1.62–2.46)], vandetanib [DCR_OR:0.26 (95% CI: 0.06–1.24); PFS_HR: 0.99 (95% CI: 0.82–1.20)] and lenvatinib [DCR_OR: 0.26 (95% CI: 0.05–1.33); PFS_HR: 0.99 (95% CI: 0.81–1.22)]; and the following therapies for MTC: vandetanib 300 mg [objective response rate (ORR)_OR: 3.31 (95% CI: 0.68–16.22); vandetanib 150 mg ORR_OR: 0.60 (95% CI: 0.16–2.33)]; and cabozantinib [ORR_OR: 85.32 (95% CI: 5.22–1395.15)]. Serious side effect (SE) analysis per organ/system demonstrated a varying MKI SE profile across both RR-WDTC and MTC diagnoses, more commonly involving metabolic/nutritional disorders [OR: 2.07 [95% CI: 0.82–5.18)] and gastrointestinal SE [OR: 1.63 (95% CI: 1.0–2.66)]. This network meta-analysis on advanced and/or metastatic TC points towards a higher efficacy of lenvatinib in RR-WDTC. The included MKIs exhibit a varying SE profile across different organs/systems favoring a patient-tailored approach with the anticipated toxicities guiding clinicians’ decisions.
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References
- 1 Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet 2016; 388: 2783-2795
- 2 Bhaijee F, Nikiforov YE. Molecular analysis of thyroid tumors. Endocr Pathol 2011; 22: 126-133
- 3 Sherman SI. Early clinical studies of novel therapies for thyroid cancers. Endocrinol Metab Clin North Am 2008; 37: 511-524 xi
- 4 Abubaker J, Jehan Z, Bavi P. et al. Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population. J Clin Endocrinol Metab 2008; 93: 611-618
- 5 Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 2013; 13: 184-199
- 6 Elisei R, Ugolini C, Viola D. et al. BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: A 15-year median follow-up study. J Clin Endocrinol Metab 2008; 93: 3943-3949
- 7 Xing M, Alzahrani AS, Carson KA. et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 2013; 309: 1493-1501
- 8 Romei C, Fugazzola L, Puxeddu E. et al. Modifications in the papillary thyroid cancer gene profile over the last 15 years. J Clin Endocrinol Metab 2012; 97: E1758-E1765
- 9 Grubbs EG, Ng PK, Bui J. et al. RET fusion as a novel driver of medullary thyroid carcinoma. J Clin Endocrinol Metab 2015; 100: 788-793
- 10 Eng C, Clayton D, Schuffenecker I. et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996; 276: 1575-1579
- 11 Ji JH, Oh YL, Hong M. et al. Identification of driving ALK fusion genes and genomic landscape of medullary thyroid cancer. PLoS Genet 2015; 11: e1005467
- 12 Boichard A, Croux L, Al Ghuzlan A. et al. Somatic RAS mutations occur in a large proportion of sporadic RET-negative medullary thyroid carcinomas and extend to a previously unidentified exon. J Clin Endocrinol Metab 2012; 97: E2031-E2035
- 13 Papotti M, Olivero M, Volante M. et al. Expression of Hepatocyte Growth Factor (HGF) and its Receptor (MET) in Medullary Carcinoma of the Thyroid. Endocr Pathol 2000; 11: 19-30
- 14 Soh EY, Duh QY, Sobhi SA. et al. Vascular endothelial growth factor expression is higher in differentiated thyroid cancer than in normal or benign thyroid. J Clin Endocrinol Metab 1997; 82: 3741-3747
- 15 Brose MS, Nutting CM, Jarzab B. et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 2014; 384: 319-328
- 16 Leboulleux S, Bastholt L, Krause T. et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol 2012; 13: 897-905
- 17 Wells Jr SA, Robinson BG, Gagel RF. et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: A randomized, double-blind phase III trial. J Clin Oncol 2012; 30: 134-141
- 18 Schlumberger M, Tahara M, Wirth LJ. et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015; 372: 621-630
- 19 Schlumberger M, Elisei R, Muller S. et al. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol 2017; 28: 2813-2819
- 20 Higgins JPTGS. Cochrane Handbook for Systematic Reviews of Interventions. In: The Cochrane Collaboration. 2019
- 21 Moher D, Liberati A, Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann Intern Med 2009; 151: 264-269 W264
- 22 Liberati A, Altman DG, Tetzlaff J. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. Ann Intern Med 2009; 151: W65-W94
- 23 Hutton B, Salanti G, Caldwell DM. et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: Checklist and explanations. Ann Intern Med 2015; 162: 777-784
- 24 Puhan MA, Schunemann HJ, Murad MH. et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ 2014; 349: g5630
- 25 Brignardello-Petersen R, Bonner A, Alexander PE. et al. Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis. J Clin Epidemiol 2018; 93: 36-44
- 26 Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 2004; 23: 1351-1375
- 27 Borenstein M, Hedges LV, Higgins JP. et al. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods 2010; 1: 97-111
- 28 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539-1558
- 29 Chaimani A, Higgins JP, Mavridis D. et al. Graphical tools for network meta-analysis in STATA. PLoS One 2013; 8: e76654
- 30 White IR. ‘Network Meta-analysis’. Stata J 2015; 15: 951-985
- 31 Haugen BR, Alexander EK, Bible KC. et al. 2015 American Thyroid Association Management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016; 26:: 1-133
- 32 Wells Jr. SA, Asa SL, Dralle H. et al. American Thyroid Association guidelines task force on medullary Thyroid C. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25: 567-610
- 33 Schlumberger M, Bastholt L, Dralle H. et al. European Thyroid Association Task F. 2012 European thyroid association guidelines for metastatic medullary thyroid cancer. Eur Thyroid J 2012; 1: 5-14
- 34 Tsoukalas N, Tsapakidis K, Alexandraki KI. The role of palbociclib in thyroid carcinoma with BRAF mutation. Gland Surg 2018; 7: S82-S85
- 35 Schutz FA, Je Y, Richards CJ, Choueiri TK. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J Clin Oncol 2012; 30: 871-877