CTR-FAPI-guided Precision Surgery for Newly Diagnosed MTC

This is a multicenter, randomized, open-label, non-inferiority Phase III clinical trial, aims to compare 68Ga-CTR-FAPI PET-CT-guided surgery to investigator-chosen surgical approaches to evaluate its efficacy in treating newly diagnosed medullary thyroid carcinoma. This study plans to enroll 150 newly diagnosed MTC patients, who will be randomly assigned in a 2:1 ratio to the experimental group (surgery based on 68Ga-CTR-FAPI PET-CT findings) and the control group (surgery based on the investigator's choice). The primary endpoint is the biochemical cure rate, with secondary endpoints including the biochemical cure rate in the R0 resection subgroup, the unnecessary dissection rate in the biochemical-cured subgroup, 3-year recurrence-free survival, the rate of change in surgical extent, and diagnostic accuracy.

Medullary thyroid carcinoma (MTC) is a relatively difficult-to-treat malignant thyroid tumor with a wide range of metastases. Surgery is the only curative treatment, and accurate assessment of the extent of metastatic disease is crucial for planning the surgical extent. Conventional imaging modalities have limited utility in fully evaluating the extent of MTC involvement. The tumor microenvironment of MTC is rich in cancer-associated fibroblasts (CAFs), which highly express fibroblast activation protein (FAP), whereas normal tissue fibroblasts express little to no FAP. Given the co-localization relationship between MTC cells and CAFs, fibroblast activation protein inhibitors (FAPIs) targeting FAP can be used to localize MTC lesions. The molecular probe CTR-FAPI, developed through covalent modification, improved the detection rate and diagnostic accuracy for MTC, providing a theoretical basis for performing precise surgery for MTC based on the extent of disease revealed by 68Ga-CTR-FAPI PET-CT. This is a multicenter, randomized, open-label, two-arm, non-inferiority Phase III clinical trial. This study plans to enroll 150 newly diagnosed MTC patients, who will be randomly assigned in a 2:1 ratio to the experimental group (surgery based on 68Ga-CTR-FAPI PET-CT findings) and the control group (surgery based on the investigator's choice). The study hypothesizes that CTR-FAPI-guided surgery can identify and resect more positive lesions while avoiding prophylactic dissection of disease-free areas, thereby benefiting patients. Proving the benefit of the former requires complete resection of all positive lesions. However, due to the frequent local invasion and adhesions associated with MTC lesions, achieving R0 resection is difficult in some patients. Therefore, the primary objective is to demonstrate that CTR-FAPI-guided surgery is non-inferior to the investigator's choice in IIT population. The primary endpoint was biochemical cure rate at 1-month post-surgery, defined by normalization of serum calcitonin levels. This parameter represents the strictest curative level for MTC and correlates with survival outcomes. In a nationwide retrospective analysis involving 863 patients, the 10-year overall survival (OS) of biochemical-cured MTC was 97.7%; in comparison, the 10-year OS of non-cured MTC was 70.3%. The secondary objectives are to demonstrate its superiority in the subgroup achieving R0 resection, and to show that it avoids unnecessary lateral neck/upper mediastinum dissection in the subgroup achieving biochemical-cure. Key secondary endpoints include: the biochemical cure rate at 1 month post-surgery in the R0 resection subgroup, and the unnecessary dissection rate in the biochemical-cured subgroup, which address the two important secondary objectives and the study hypothesis. Other secondary endpoints include: 3-year recurrence-free survival, the rate of surgical plan modification in the experimental group, and the diagnostic accuracy of different imaging modalities for MTC lesions.