Non-Surgical Management of Thyroid Cancer
For patients with advanced, progressive, radioactive iodine-refractory differentiated thyroid cancer, lenvatinib is the first-line systemic therapy, while TSH suppression with levothyroxine remains the cornerstone non-surgical treatment across all stages of thyroid cancer. 1, 2
TSH Suppression Therapy with Levothyroxine
All thyroid cancer patients require TSH suppression as a fundamental non-surgical treatment modality. 1
Target TSH Levels by Risk Category:
- Low-risk patients with excellent response to treatment: Maintain TSH in low-normal range (0.5–2 μIU/ml) 1
- Intermediate to high-risk patients with biochemical incomplete or indeterminate response: Maintain mild TSH suppression (0.1–0.5 μIU/ml) 1
- Patients with persistent structural disease: Maintain TSH <0.1 μIU/ml unless specific contraindications exist 1
- High-risk patients free of disease after initial treatment: Continue suppressive doses (TSH <0.1 μIU/ml) for 3–5 years before considering transition to replacement therapy 1
This approach reduces progression rates, recurrence rates, and cancer-related mortality in high-risk patients, though low-risk patients show no significant benefit from aggressive suppression. 1
Radioactive Iodine (RAI) Therapy
RAI therapy is the primary non-surgical treatment for metastatic disease in iodine-avid tumors. 1
Indications and Dosing:
- Distant metastases with RAI uptake: Administer 100–200 mCi (3.7–7.4 GBq) after TSH stimulation 1
- Small lung metastases (not visible on X-ray): Most successfully treated with RAI, with potential for cure 1
- Lung macro-nodules: May benefit from RAI but definitive cure rate is very low 1
- Bone metastases: Worst prognosis even with aggressive RAI combined with external beam radiotherapy 1
RAI-Refractory Disease Definition:
Lesions are considered RAI-refractory when they are non-RAI-avid, lose their ability to concentrate RAI, or progress despite RAI avidity. 1 Approximately 60% of patients with aggressive metastatic DTC develop RAI resistance. 3
Systemic Therapy for RAI-Refractory Disease
For clinically progressive or symptomatic RAI-refractory differentiated thyroid cancer, lenvatinib and sorafenib are the standard first-line systemic therapies. 1
First-Line Multikinase Inhibitors:
- Lenvatinib: FDA-approved at 24 mg orally once daily for locally recurrent or metastatic, progressive, RAI-refractory DTC 2
- Sorafenib: Alternative first-line option 1
- ESMO-MCBS score: 2 1
Critical caveat: These agents prolong progression-free survival but do not consistently prolong overall survival, and disease often continues to progress. 3 Decisions must be based on patient preference after careful discussion of expected benefits versus risks. 1
Targeted Therapy for Specific Mutations:
- BRAF V600E-positive malignancies: Dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) 1, 4
- RET, NTRK, MEK mutations: Selpercatinib and other targeted therapies are increasingly used 4
Medullary Thyroid Cancer (MTC):
- First-line systemic therapy: Cabozantinib or vandetanib for progressive, metastatic MTC 1
Locoregional Non-Surgical Therapies
For selected metastatic lesions, locoregional treatments can be considered as alternatives to systemic therapy. 1
Site-Specific Approaches:
- Brain metastases (solitary): Stereotactic radiosurgery or neurosurgical resection preferred over conventional radiotherapy 1
- Radioiodine treatment with rhTSH and steroid prophylaxis if RAI-positive 1
- Bone metastases:
- RAI treatment if RAI-positive with dosimetry to maximize dosing and/or external beam radiotherapy 1
- Bisphosphonates or denosumab (bone resorption inhibitors) alone or combined with locoregional treatments 1
- Consider embolization of metastases 1
- Limited evidence for radiofrequency ablation (RFA) or cryotherapy for bone lesions 1
- Lung metastases (oligometastatic): RFA for solitary lesions or those causing specific symptoms due to volume/location 1
- Other sites: Consider surgical resection and/or radiotherapy for selected, enlarging, or symptomatic metastases 1
External Beam Radiotherapy:
Indicated when complete surgical excision is not possible or when there is no significant RAI uptake in the tumor. 1 Image-guided radiotherapy should be used to maximize effectiveness and minimize toxicity. 1
Active Surveillance for Low-Risk Disease
For microcarcinomas (≤1 cm), observation without surgical resection can be considered as a non-surgical management option. 4
Low-risk papillary thyroid cancers have a 99% survival rate at 20 years, and active surveillance represents a promising alternative to immediate surgery for these subclinical lesions. 5
Therapies with Minimal Efficacy
Cytotoxic chemotherapy has shown minimal efficacy in thyroid cancer and is no longer recommended. 1
Traditional chemotherapy is restricted to patients with progressive disease not manageable by other treatment modalities, with results typically disappointing. 1 Chemotherapy should be replaced by enrollment in experimental trials with tyrosine kinase inhibitors. 1
Common Pitfalls and Caveats
- Do not use systemic therapy prematurely: Reserve multikinase inhibitors for truly progressive, symptomatic disease, as they do not cure and have significant toxicity 1
- Verify RAI-refractory status: Ensure lesions are truly non-RAI-avid before abandoning RAI therapy, as FDG-PET-positive/RAI-negative disease indicates more aggressive biology with worse prognosis 1
- Monitor for RAI resistance mechanisms: 60% of aggressive metastatic DTC develops RAI resistance through gene mutations, transport failures, or tumor microenvironment interference 3
- Clinical trial enrollment strongly encouraged: NCCN emphasizes that the best management is within a clinical trial, especially for RAI-refractory disease 1
- Avoid iodinated contrast: When imaging is required, avoid iodinated contrast unless essential, as it interferes with subsequent RAI therapy 1