Structural Incomplete Response (SIR) in Differentiated Thyroid Cancer (DTC)

Structural incomplete response (SIR) in differentiated thyroid cancer (DTC):
- Is defined as persistent or newly identified locoregional or distant metastases on imaging:
  - Usually in conjunction with elevated thyroglobulin (Tg) and / or anti-thyroglobulin antibody (TgAb) levels
- It is one of four response-to-therapy categories in the ATA dynamic risk stratification system:
  - Alongside excellent, indeterminate, and biochemical incomplete responses
Criteria by Treatment Context:
- The definition of SIR is consistent regardless of surgical extent:
  - Structural evidence of disease confirmed by suspicious imaging or biopsy-proven local or distant metastatic disease
- The TSH goal for patients with SIR:
  - Is maintained below the normal reference range
Prevalence and Outcomes:
- SIR occurs in approximately 2.8% to 10% of DTC patients after initial therapy
- In a cohort of 501 patients treated with total thyroidectomy and RAI:
  - 2.8% had SIR at initial assessment:
    - By last follow-up, 10.2% had structurally incomplete responses
  - Key outcome data include:
    - Patients with an initial SIR:
      - Had an 83.9% rate of continued structural disease over long-term follow-up (mean 10.3 years)
    - All patients categorized as SIR after total thyroidectomy without RAI:
      - Experienced continued presence of disease
    - SIR requires multidisciplinary management tailored to disease status (regional vs. distant metastases, iodine-avid vs. non-iodine-avid disease)
Management:
- Management of SIR depends on:
  - Disease location, RAI avidity, resectability, and rate of progression
- Locoregional disease:
  - Surgery is preferred for resectable locoregional recurrence:
    - With formal compartmental dissection for previously undissected basins
  - RAI therapy:
    - If radioiodine imaging is positive
  - Active surveillance:
    - Is appropriate for non-progressive disease that is stable and distant from critical structures:
      - Small-volume lymph node recurrences often show little progression over years
  - Local therapies (ethanol ablation, RFA, cryoablation):
    - May be considered for limited-burden nodal disease
  - RAI-refractory or progressive disease:
    - Somatic molecular testing for actionable mutations (BRAF, RET, NTRK, ALK fusions; dMMR/MSI/TMB) is recommended for advanced, progressive, or threatening disease
  - Systemic therapy for progressive and/or symptomatic disease:
    - Lenvatinib (preferred; PFS 18.3 vs. 3.6 months, ORR 65%)
    - Sorafenib (PFS 10.8 vs. 5.8 months)
    - Cabozantinib after prior VEGFR TKI (PFS 11.0 vs. 1.9 months)
    - Targeted therapies:
      - Dabrafenib / trametinib (BRAF V600E)
      - Selpercatinib / pralsetinib (RET fusion)
      - Larotrectinib / entrectinib (NTRK fusion)
      - Pembrolizumab (MSI-H/dMMR or TMB-H)
- Disease monitoring is often appropriate for asymptomatic patients with indolent, non-progressive disease and no brain metastases:
  - TKI therapy may not be appropriate for stable or slowly progressive disease
- TSH suppression should be maintained with TSH
References:
- 2025 American Thyroid Association Management Guidelines for Adult Patients With Differentiated Thyroid Cancer. Ringel MD, Sosa JA, Baloch Z, et al. Thyroid : Official Journal of the American Thyroid Association. 2025;35(8):841-985. doi:10.1177/10507256251363120.
- SNMMI Procedure Standard/Eanm Practice Guideline for Nuclear Medicine Evaluation and Therapy of Differentiated Thyroid Cancer: Abbreviated Version. Avram AM, Giovanella L, Greenspan B, et al. Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2022;63(6):15N-35N.
- Thyroid Carcinoma. National Comprehensive Cancer Network. Updated 2025-03-27.
  Thyroid Cancer. Chen DW, Lang BHH, McLeod DSA, Newbold K, Haymart MR. Lancet (London, England). 2023;401(10387):1531-1544. doi:10.1016/S0140-6736(23)00020-X.