Neoadjuvant systemic therapy for inoperable differentiated thyroid cancers: Impact on tumor resectability.

Background: Limited treatment options exist for inoperable thyroid cancers. We evaluated whether neoadjuvant use of systemic tyrosine kinase inhibitors facilitates surgery of differentiated thyroid cancers in this challenging context.

Methods: A single-institution experience of 42 patients receiving tyrosine kinase inhibitors for papillary, follicular and anaplastic thyroid carcinomas between 2018 and 2023 was reviewed to identify differentiated thyroid cancers treated with neoadjuvant tyrosine kinase inhibitors (dabrafenib/trametinib, lenvatinib/pembrolizumab, or lenvatinib alone) via multidisciplinary protocols.

Results: Nine patients with differentiated thyroid cancers (age 49 years, range 19-80, 5 women, 4 men) received neoadjuvant tyrosine kinase inhibitors with intent to improve resectability of primary or recurrent/residual tumors. All had locoregionally advanced disease deemed either unresectable or resectable with unacceptable morbidities. Six exhibited distant metastases (6 lungs, 6 vertebral/axial bones, 1 sternum). Tumors had BRAF V600E (6 papillary thyroid carcinoma) or RAS/TERT (2 follicular thyroid carcinoma) mutations or NCOA4-RET fusion. Most received neoadjuvant tyrosine kinase inhibitors for <6 months with visible results within weeks, radiologically and by examination. All patients completing surgery achieved R0 resection without major surgical complications or aerodigestive structure resection. Neoadjuvant tyrosine kinase inhibitors were generally well-tolerated (4 minor, 1 major toxicity that halted therapy but not surgery). Unique patients with distant metastases continued to receive adjuvant tyrosine kinase inhibitors. At median postoperative follow-up of 2 years, all patients are alive without new locoregional recurrence.

Conclusion: Neoadjuvant use of tyrosine kinase inhibitors seems extremely effective in downstaging surgically unresectable differentiated thyroid cancers to achieve R0 resection while avoiding unnecessary surgical morbidities. A multidisciplinary approach with early genomic profiling to guide personalized neoadjuvant use of tyrosine kinase inhibitors is essential. Prospective studies are urgently needed to define the potential role of neoadjuvant tyrosine kinase inhibitors in advanced thyroid cancer management.