Response to Neoadjuvant Treatment in Locally Advanced Thyroid Cancer

Radiographic response of tumors and lymph nodes to neoadjuvant treatment will be assessed using contrast-enhanced computed tomography (CT) and defined by RECIST v1.1. Complete Response (CR) is defined as disappearance of all target lesions. Partial response (PR) is defined as ≥30% decrease in the sum of the longest diameter of target lesion; progressive disease (PD) as ≥20% increase in the sum of the longest diameter of target lesions. Stable disease (SD) is defined as <20% increase and <30% decrease in the sum of the longest diameter of target lesions. The objective response rate (ORR) will be calculated as the proportion of patients achieving CR or PR.

Pathologic response in resected tumors and lymph nodes will be assessed on hematoxylin and eosin (H&E)-stained slides of the entire tumor bed and all sampled lymph nodes. All slides will be digitally scanned and independently reviewed by two pathologists. Pathological complete response (pCR) is defined as the absence of viable tumor cells in all examined slides. For this study, pathological partial response (pPR) is defined as <50% viable residual tumor, and pathological non-response (pNR) as ≥50% viable residual tumor in the resected specimen.

Time from surgery to the earliest date of disease progression or all-cause death.

Serum thyroglobulin (Tg) levels in patients with DTC and serum calcitonin and carcinoembryonic antigen (CEA) levels in patients with MTC will be measured after definitive surgery. Levels will be:

• compared across subgroups defined by radiographic response (per RECIST v1.1) and pathologic response (e.g., pCR, pPR, pNR) within the neoadjuvant therapy cohort; and
• compared between the neoadjuvant therapy plus surgery group and the upfront surgery group at matched postoperative timepoints.

Percentage of resected participants with no residual tumor (R0) or microscopic residual tumor (R1) on final pathology.

The MGH/MEE-MSK-MD Anderson Surgical Morbidity Complexity Score (SMCS) will be used to assess surgical complexity. The SCMS is a validated 5-level scale [mild (level 0), moderate (level 1), severe (level 2), very severe (level 3), and unresectable (level 4)] that quantifies surgical complexity based on preoperative radiographic assessment of tumor involvement with critical neck structures.、 The SMCS will be collected at enrollment (baseline imaging) and prior to surgery using restaging imaging. The change in SCMS will be reported as the median SCMS value.

Surgery related adverse events (SRAEs) are defined as complications occurring during surgery or within 30 days postoperatively. Postoperative complications will be documented and classified according to the Clavien-Dindo grading system, including but not limited to hemorrhage, hypoparathyroidism, vocal cord palsy, chyle leakage, and wound infection.

Number and percentage of participants experiencing Grade 3 or higher adverse events, assessed according to CTCAE v5.0.

Time from surgery to all-cause death, with survivors censored at the date of last follow-up.

Changes in tumor immune cell composition following neoadjuvant therapy, assessed by single-cell RNA sequencing of tumor tissue obtained at baseline (pre-neoadjuvant biopsy) and at surgery. The outcome measure will be the change in the proportion of major immune cell subsets within the tumor microenvironment.