Efficacy and safety of targeted therapeutics for patients with radioiodine-refractory differentiated thyroid cancer: Systematic review and network meta-analysis

Abstract

Background: Multiple targeted therapeutics are available for radioiodine-refractory differentiated thyroid cancer (RAIR-DTC), but it remains unclear which treatment is optimal to achieve long-term survival. Methods: A systematic search of the PubMed, Embase, and ClinicalTrials.gov databases was conducted to identify eligible randomized controlled trials (RCTs) comparing the efficacy and safety of targeted treatments for patients with RAIR-DTC from inception to April, 2022. Data were extracted by following the recommendations of the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. We calculated the odds ratio (OR) or hazard ratio (HR), its corresponding 95% credible intervals (CrI), and the surface under the cumulative ranking curve (SUCRA) to indicate ranking probability using Bayesian network meta-analyses. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and grade 3 or higher adverse events. Results: A total of 12 eligible RCTs involved 1,959 patients and 13 treatments: apatinib, cabozantinib, anlotinib, nintedanib, lenvatinib, lenvatinib with low dose (LD), sorafenib, sorafenib plus everolimus, donafenib (200 mg), donafenib (300 mg), pazopanib (continuous), pazopanib (intermittent), and vandetanib. Pooled analyses indicated that targeted therapeutics significantly prolonged PFS and OS in patients with RAIR-DTC (0.31, 0.21-0.41; 0.69, 0.53-0.85, respectively) compared with placebo. Network meta-analyses indicated that lenvatinib showed the most favorable PFS, with significant differences versus sorafenib (0.33, 0.23-0.48), vandetanib (0.31, 0.20-0.49), nintedanib (0.30, 0.15-0.60), and placebo (0.19, 0.15-0.25), while apatinib was most likely to be ranked first for prolonging OS with a SUCRA of 0.90. Lenvatinib showed the highest ORR (66%, 61%-70%), followed by anlotinib (59%, 48%-70%) and apatinib (54%, 40%-69%). Lenvatinib caused the most adverse events of grade 3 or higher, followed by lenvatinib (LD) and apatinib. Different toxicity profiles of individual treatment were also revealed. Conclusion: This network meta-analysis suggests that lenvatinib and apatinib were associated with the best progression-free survival and overall survival benefits, respectively, for patients with RAIR-DTC, compared with other targeted therapeutics. Patients who received lenvatinib or apatinib also had more grade 3 or higher adverse events. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=302249], identifier [CRD42022302249].

Keywords: anlotinib; apatinib; cabozantinib; differentiated thyroid cancer; lenvatinib (LEN); radioiodine-refractory; sorafenib; targeted therapy.

FIGURE 1

Study selection flowchart.

FIGURE 2

Pairwise meta-analysis of a comparison of targeted therapy versus placebo on major outcomes in patients with radioiodine-refractory differentiated thyroid cancer. (A) Network diagrams of comparing progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and grade 3 or higher adverse events (⩾3 AEs). Each circular node represents a type of treatment. Each line represents a type of head-to-head comparison. Node size and line thickness are weighted according to the number of studies evaluating each treatment and direct comparison, respectively. The total number of patients receiving a treatment is shown in brackets. (B) Pooled hazard ratio (HR) of PFS and OS in comparison of targeted therapy versus placebo. (C) Objective response rate (ORR) and its 95% confidence interval (CI) for each treatment.

FIGURE 3

Network meta-analysis of a comparison of different treatments on PFS, OS, DCR, and ⩾3 AEs in patients with radioiodine-refractory differentiated thyroid cancer. (A) Pooled estimates of the network meta-analysis of progression-free survival (PFS) and overall survival (OS). Data on each cell is a hazard ratio (HR) (95% CrIs) for the comparison of row-defining treatment versus column-defining treatment. The HR less than 1 favors upper-row treatment. Significant results are highlighted in bold. (B) Reconstruction of the Kaplan–Meier curve of PFS for each treatment with median PFS. (C) Reconstruction of the Kaplan–Meier curve of OS for each treatment. (D) Pooled estimates of the network meta-analysis of the disease control rate (DCR) and grade 3 or higher adverse events (⩾3 AEs). Data on each cell is an odds ratio (OR) (95% CrIs) for the comparison of row-defining treatment versus column-defining treatment. The OR greater than 1 favors upper-row treatment. Significant results are highlighted in bold.

FIGURE 4

Profiles indicate the probability of each comparable treatment being ranked from first to last on overall survival, progression-free survival, disease control rate, and grade 3 or higher adverse events.