Comparison of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG Uptake in Esophageal Cancer

Purpose Accurate clinical staging is crucial to managing esophageal cancer. [68Ga]Ga-DOTA-FAPI-04 exhibits good diagnostic performance in various tumors, showing a promising alternative to [18F]FDG. Here, we investigated the diagnostic performance of [68Ga]Ga-DOTA-FAPI-04 PET/CT and [18F]FDG PET/CT in the diagnosis of primary and metastatic lesions of esophageal cancer. Methods Patients with esophageal cancer who underwent concurrent [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT between January 2020 and June 2021 were retrospectively analyzed. [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT uptakes were compared by using the paired samples t test. The McNemar test was used to compare the diagnostic performance between the two techniques. Results Thirty-five patients (ranging from 44-83 years old with a median age of 63.5 years) were evaluated in our study. In treatment-naive patients (n=25), [68Ga]Ga-DOTA-FAPI-04 PET could detect all esophageal cancers, whereas 1 patient with superficial esophageal cancer was negative in FDG but positive in [68Ga]Ga-DOTA-FAPI-04 (T1). [68Ga]Ga-DOTA-FAPI-04 uptake was higher than [18F]FDG in primary lesions (13.8 ± 6.9 vs 10.9 ± 6.8, respectively, P=0.004), involved lymph nodes (9.3 ± 5.2 vs 6.4 ± 5.9, respectively, P=0.002), and bone and visceral metastases (10.4 ± 6.0 vs 6.1 ± 7.5, respectively, P=0.001). In addition, [68Ga]Ga-DOTA-FAPI-04 PET/CT has a higher detection sensitivity than [18F]FDG PET/CT for primary tumors [100% (25/25) vs. 96.0% (24/25), respectively], lymph nodes [95.0% (57/60) vs 75.0% (45/60), P<0.001], and bone and visceral metastases [100% (25/25) vs 72% (18/25), respectively; P= 0.008]. Conclusion [68Ga]Ga-DOTA-FAPI-04 PET/CT has higher tracer uptake value and is superior to [18F]FDG PET/CT in detecting primary and metastatic lesions in patients with esophageal cancer.


INTRODUCTION
With approximately 600,000 new diagnoses and 540,000 deaths in 2020, esophageal cancer is the sixth leading cause of cancerrelated death worldwide (1). Squamous cell carcinoma is the predominant histological type of esophageal cancer in East Asia, East and Southern Africa, and Southern Europe, while adenocarcinoma is most common in Northern and Western Europe, Oceania, and North America. Fibroblast activating protein (FAP) is overexpressed in cancer-associated fibroblasts (CAF) of various epithelial cancers, and at levels in normal tissues (2,3). Therefore, imaging targeting FAP is considered a promising strategy for visualization of the tumor stroma, which is mainly composed of CAFs (4). Gallium-68 ( 68 Ga)-labeled FAP inhibitor ([ 68 Ga]Ga-DOTA-FAPI-04) is a promising PET tracer for imaging a variety of tumors (2,4,5). Studies have shown that [ 68 Ga]Ga-DOTA-FAPI-04 enables fast imaging, showing exceptionally sharp tumor outlines and high tumor-tobackground contrast in a variety of tumors (2,4). In addition, case studies reported the application of [ 68 Ga]Ga-DOTA-FAPI-04 PET/CT in the detection of primary tumors and metastatic lymph nodes in esophageal cancer (5)(6)(7). However, the exact diagnostic utility of [ 68 Ga]Ga-DOTA-FAPI-04 in esophageal cancer has not been systematically analyzed.
Here, we retrospectively compared the potential efficacy of [ 68 Ga]Ga-DOTA-FAPI-04 PET/CT with [ 18 F]FDG PET/CT in the diagnosis of primary and metastatic lesions in patients with esophageal cancer.

Patients
This retrospective study was conducted at the Affiliated Hospital of Southwest Medical University from January 2020 to June 2021. This study was approved by the Ethics Committee of our hospital (AHSWMU-2020-035) and informed consent was obtained from each patient. The inclusion criteria were as follows: (I) patients with newly diagnosed esophageal cancer or esophageal cancer after surgical resection, (II) patients aged 18 (8,9). The radiochemical purity of [ 68 Ga]Ga-DOTA-FAPI-04 and [ 18 F]FDG exceeded 95%. The sterility test was carried out by the radiochemical equipment of our department. The final product was sterile and met all of our institution's required standards prior to use.

PET/CT Imaging
For [ 18 F]FDG PET/CT image acquisition, patients fasted for at least 6 hours and the plasma glucose level was lower than 11 mmol/L (about 200 mg/dL) (10). After an intravenous injection of [ 18 F]FDG 3.7 MBq/kg, the patient rested in a quiet place. The patients were instructed to drink 500 mL of water to stimulate [ 18 F]FDG excretion in the renal calyx and to urinate before scanning. Data were acquired using a PET/CT scanner (uMI780, United Imaging, Shanghai, China) 45 to 60 minutes after intravenous administration. First, a CT scan was performed from the head to the upper thigh (tube current of 120 mA, tube voltage of 120 kV, and slice thickness of 3.00 mm). PET was then performed at the same bed position as the CT scan, 5-6 bed positions, and 3D acquisition mode at 1. ]Ga-DOTA-FAPI-04 was markedly to moderately increased. Diffuse mild or no increase in activity (in the absence of an abnormality on CT and no corresponding abnormality on PET) was considered normal or benign disease. PET/CT results were divided into primary tumor, lymph node metastasis, and distant metastasis. The individual lymph nodes were then divided into four regions including the neck, upper mediastinum, lower mediastinum, and abdomen. Distant involvement, such as lung, liver, bone, pleura, and brain metastases were each classified as a separate site. The largest lesion was measured according to length for individual primary tumor, each lymph node region, and distant involvement site. For [ 18

Patient Characteristics
Between January 2020 and June 2021, 35 patients (32 men, 3 women, median age: 63.5 years old, ranging from 44-83 years) were included in this study. Among these patients, 34 had squamous carcinoma and 1 had adenocarcinoma. Also, 25 patients underwent PET/CT for initial tumor evaluation and 10 patients underwent PET/CT for post-operative recurrence detection. Patient characteristics are summarized in Table 1.

Detection of Primary Cancer
Of the 25 patients initially evaluated, 1 patient was negative in

Detection of Nodal Metastasis
Among the 35 patients, 60 lymph node metastases were examined in 20 patients and 57 of the 60 lymph nodes were correctly identified with [ 68 Ga]Ga-DOTA-FAPI-04 for lymph node involvement (false-positive uptake in 2 lymph nodes and false-negative uptake in 3 lymph nodes). In contrast, 45 of the 60 lymph node metastases were correctly diagnosed by [ 18 F]FDG PET/CT (false-positive uptake in 29 lymph nodes and falsenegative uptake in 15 lymph nodes).
In the nodal region-based analysis, 12 lymph node metastases were not detected by [ 18      The overall 5-year survival rate for patients with esophageal cancer is approximately 40% (15). The presence or absence of lymph node metastases is one of the most important prognostic factors, however, because the location of metastatic lymph nodes is often variable, identification is difficult (16). Regarding the detection of lymph nodes, lymph node staging in patients with esophageal cancer is critical for treatment and prognosis. To our knowledge (17,18), due to the activation of inflammatory cells, non-specific lymph node inflammation will cause increased [ 18 F] FDG uptake. Additionally, the main limitation of [ 18 F]FDG PET/ CT in staging of esophageal cancer is its low to moderate sensitivity for lymph node staging and delineation between viable tumor and regional esophagitis (19). The false-positive rate of [ 18   detecting metastatic lymph nodes in patients with esophageal cancer, which helps to accurately guide clinicians to determine reasonable treatment options. In detecting bone and visceral metastases, [ 68 Ga]Ga-DOTA-FAPI-04 PET/CT detected more abnormal, bone, and pleural lesions than [ 18  Our study also has limitations. First, the patient sample size was relatively small (n=35) and a prospective trial with a larger patient population is required to further investigate the diagnostic performance of [ 68 Ga]Ga-DOTA-FAPI-04 PET/CT. Furthermore, not all lesions were histopathologically confirmed.

CONCLUSION
Our findings demonstrate that [ 68 Ga]Ga-DOTA-FAPI-04 PET/ CT has higher tracer uptake value and is superior to [ 18 F]FDG PET/CT in detecting primary and metastatic lesions in patients with esophageal cancer.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

ETHICS STATEMENT
This retrospective study was obtained approval from the Ethics Committee of the Affiliated Hospital of Southwest Medical University (AHSWMU-2020-035). The patients/participants provided their written informed consent to participate in this study.