18F-FAPI-42 PET/CT and 18F-FDG PET/CT in patients with malignant digestive system neoplasms: a head-to-head comparative study

doi:10.21203/rs.3.rs-4958582/v1

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Research Article

18F-FAPI-42 PET/CT and 18F-FDG PET/CT in patients with malignant digestive system neoplasms: a head-to-head comparative study

https://doi.org/10.21203/rs.3.rs-4958582/v1

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Purpose

Radionuclide-labeled fibroblast activation protein inhibitor (FAPI) is an emerging tumor tracer. We sought to assess the uptake and diagnostic performance of ¹⁸F-FAPI-42 PET/CT compared with simultaneous 2-deoxy-2[¹⁸F]fluoro-D-glucose (¹⁸F-FDG) PET/CT in primary and metastatic lesions in patients with malignant digestive system neoplasms and determine the potential clinical benefit.

Procedures

Forty-two patients (men = 30, women = 12, mean age = 56.71 ± 13.26 years) who underwent ¹⁸F-FDG PET/CT and ¹⁸F-FAPI-42 PET/CT simultaneously for diagnosis, staging, and restaging were enrolled. Quantitative data, including standardized uptake value (SUV), tumor-to-liver ratio (TLR), and tumor-to-blood pool ratio (TBR), were analyzed. Two independent readers performed a visual assessment of lesion number and location on PET/CT images. Interobserver agreement between two examinations was calculated using Cohen’s kappa (κ).

Results

Primary tumor locations included the liver (n = 20), stomach (n = 9), pancreas (n = 5), and intestine (n = 10). More intense ¹⁸F-FAPI-42 uptake and higher tumor-to-background contrast were detected in most primary and metastatic lesions compared with ¹⁸F-FDG, contributing to improved diagnostic accuracy ranging from 95.24–100%. Moreover, additional lesions showing ¹⁸F-FAPI-42 uptake in primary, locoregional and distant metastatic lesions were visualized, especially in multiple liver and peritoneal metastases. Patient-based interobserver agreement varied from moderate to strong, with suboptimal outcomes observed in primary tumors (κ = 0.441, P = 0.01) and preferable results derived from metastatic liver and bone lesions (κ = 1 and 0.896, both P < 0.01). ¹⁸F-FAPI-42 PET/CT resulted in modified treatment strategies for 40.48% (17/42) of patients, while ¹⁸F-FDG PET/CT led to altered therapeutic regimens in only 4.8% (2/42) of patients.

Conclusions

In selected patients with malignant digestive system neoplasms, our study shows that ¹⁸F-FAPI-42 PET/CT is a promising and alternative tool for assessing primary tumors and metastases and aiding staging, restaging, and decision-making, with higher uptake and better lesion visualization compared with ¹⁸F-FDG. In addition, it may shed light into the treatment selection and response assessment for FAP-targeted therapy or immunotherapy.

18F-FAPI-42

18F-FDG

Digestive System Neoplasm

Fibroblast activation protein

PET/CT

Malignant tumors originating from the digestive system constitute a great concern worldwide due to high malignancy and recurrence rates and extensive metastases. According to the latest statistics[1], digestive system neoplasms ranked the second and first place in terms of estimated new tumor cases and deaths in the United States in 2022, respectively. These neoplasms include liver cancer, colorectal cancer, gastric cancer and pancreatic cancer.

It is now understood that different and individualized treatment strategies should be adopted to improve patient outcomes.[2, 3, 4] Accordingly, precise diagnosis, staging and restaging are pivotal. However, serological markers and conventional imaging approaches (including contrast-enhanced CT or MRI) exhibit limitations in the diagnosis of malignant digestive diseases.[5, 6] Molecular imaging, which comprehensively and early reveals cellular or molecular changes in vivo, is an effective modality to improve this situation. Yet, the most widely used radiopharmaceutical, 2-deoxy-2[¹⁸F]fluoro-D-glucose (¹⁸F-FDG), which reflects cellular glucose metabolism (Supplementary Fig. 1), has some limitations in the application of digestive system neoplasms. It is worth noting that disease characterization can be obscured by gastrointestinal inflammation or physiology uptake, and small lesions with low or without ¹⁸F-FDG affinity are often difficult to visualize.[7] In exceptional cases, hepatocellular carcinoma (HCC) with well-differentiated grade[8], signet-ring cell carcinoma of the stomach[9] and peritoneal metastases[10] may exhibit low sensitivity in ¹⁸F-FDG PET scans (a sensitivity of 24% in detecting peritoneal metastases[11]). The above findings emphasize the importance of the quest for novel biomarkers with better sensitivity, specificity, and accuracy.

Fibroblast activation protein (FAP), a type II transmembrane serine protease with both functions of group peptidase and peptide chain endonuclease, is overexpressed in cancer-associated fibroblasts (CAFs) of nearly 90% epithelial carcinomas but is minimally expressed in normal tissues and organs (Supplementary Fig. 1).[12] Accordingly, several small FAP inhibitors (FAPIs) targeting FAP have been developed and adopted for the imaging of various neoplasms, yielding results superior to ¹⁸F-FDG in the detection of primary tumors and metastatic lesions, including in liver cancer, gastrointestinal tumors, breast cancer, and peritoneal metastases.[13, 14] To our knowledge, previous studies have mainly analyzed a specific tumor type, and few have been conducted on the entire digestive system. Thus, this head-to-head comparative study aimed to explore the differences in tracer uptake and diagnostic performance between ¹⁸F-FAPI-42 PET/CT and ¹⁸F-FDG PET/CT in a selected cohort of challenging patients with malignant neoplasms of the digestive system, including primary and metastatic lesions, and their impact on clinical management.

Patient Selection and Evaluation

Patients with suspected or pathologically confirmed malignant digestive system neoplasms were enrolled in this retrospective study between May 2022 and August 2023. All patients were referred to our department for ¹⁸F-FDG PET/CT for diagnosis, staging, or restaging purposes. Additional ¹⁸F-FAPI-42 PET/CT examinations were scheduled within 1 week by experienced nuclear medicine doctors if necessary. A flow chart summarizing the selection process based on the eligibility/exclusion criteria is shown in Fig. 1. This study was approved by the Ethics Committee of The Second Affiliated Hospital, Guangzhou Medical University (2023-hg-ks-36) and was conducted in compliance with the Declaration of Helsinki. Written informed consent was obtained from all individuals.

¹⁸ F-FDG and ¹⁸F-FAPI-42 PET/ CT Imaging and Processing

Two radiopharmaceuticals were both purchased from Atom High Tech Radiopharmaceutical Co., Ltd. (Guangzhou, China) with a radiochemical purity of more than 95%. Patients were required to fast for at least 6 hours, and the blood glucose concentration was checked to ensure that it was less than 11.0 mmol/L before the ¹⁸F-FDG PET/CT, while no extra pre-injection preparation was mandatory for ¹⁸F-FAPI-42. According to the weight of the patients, injected radiopharmaceutical doses were calculated (both 3.7 MBq/kg (0.1 mCi/kg) for ¹⁸F-FDG and ¹⁸F-FAPI-42) with a median of 202.02 (125.8, 334.11) MBq of ¹⁸F-FDG and 219.78 (82.88, 328.56) MBq of ¹⁸F-FAPI-42. Approximately 60 minutes after intravenous injection of two radiopharmaceuticals, 3D tomographic acquisition from the skull base to upper thigh was performed on the same hybrid PET/CT scanner (Discovery 710, GE Healthcare, Waukesha, WI) with 6–8 bed positions and 2.0–2.5 min/position. Local delayed imaging was performed when necessary. The interval between the two examinations was less than 7 days with a median of 2 (1,6) days. All the obtained data were transferred to the AW VolumeShare 7 Workstation (GE Healthcare) for reconstruction using an ordered subset expectation maximization algorithm.

Imaging Analysis and Interpretation

The processed images were independently reviewed by two certified nuclear medicine physicians who knew the clinical data of the patients but were blinded to each other. In terms of visual analysis, the positive lesion was determined when radiopharmaceutical-avid foci presented with an elevated eccentric uptake in contrast to the surrounding normal tissue and could not be explained by physiological or benign tracer uptake. At the same time, anatomical images were evaluated supplementally. A negative uptake was defined as equal to or lower than the surrounding parenchyma. A consensus was reached through discussion if there were cases of disagreement. Quantitative data, including standardized uptake values (SUV, SUV_max, SUV_mean, and SUV_peak), were extracted by drawing the volume of interest (VOI) from positive lesions. The SUVs of the normal liver background with a circular sphere (2 cm diameter) in the healthy right lobes were obtained[15], and the tumor-to-liver ratios (TLR, TLR_max, TLR_mean, and TLR_peak) were obtained, respectively. Additionally, the SUV_max of the mediastinal blood pool was measured, and the maximum tumor-to-blood pool ratio (TBR_max) was calculated.

Reference Standards

The reference standards for the final diagnoses of primary, recurrence, or metastatic lesions were biopsy or surgical pathology, typical contrast-enhanced CT or MRI findings, or clinical imaging follow-up of at least 3 months.

Statistical Analysis

The mean (standard deviation [SD]) and median (range) were used to describe the continuous variables, while frequency and percentage were used to express categorical variables. A two-paired-sample t test or Wilcoxon test was used to compare the values of two radiopharmaceutical uptake according to the normal distribution and homogeneity of variance analyses. Interobserver agreement was assessed using Cohen’s kappa (κ), and the diagnostic efficacy was evaluated. Statistical analyses were performed using SPSS statistics (version 22.0; IBM), and a two-sided p value < 0.05 was considered statistically significant.

Patient Characteristics

Forty-two patients (men = 30, women = 12) with a mean age of 56.71 ± 13.26 years were finally enrolled, including treatment-naïve patients (n = 20) and patients who had undergone treatment at the time of the PET/CT examination (n = 22). The final diagnoses and clinicopathological details of the patients are shown in Table 1.

Table 1

Patient characteristics
General characteristics	n = 42	%
Age(years)	56.71 ± 13.26
Gender
Men	30	73.43%
Women	12	26.57%
Primary tumor types
Liver	18	42.86%
Liver cancer	17
Spindle cell carcinoma of liver	1
Stomach	9	21.43%
Adenocarcinoma of the stomach	5
Gastric ring cell carcinoma	4
Pancreas	5	11.90%
Pancreatic cancer	4
Mucinous tumors of the pancreas	1
Intestine	10	23.81%
Colorectal cancer	6
Duodenal cancer	1
Duodenal neuroendocrine tumor	1
Jejunal cancer	1
Jejunal stromal tumor	1
Treatment situation
Treatment-naïve	20	47.62%
Posttreatment	22	52.38%
Final diagnosis category
Biopsy or surgical pathology	22	52.38%
Typical imaging findings	2	4.76%
Clinical imaging follow-up	18	42.86%

The Uptake of Primary Tumor

The median SUV_max of the mediastinal blood pool in ¹⁸F-FDG was higher than that in ¹⁸F-FAPI (1.62 (1.13, 2.81) vs. 1.41(0.8, 2.52), Z=-3.226, P = 0.001). In addition, the median SUV_max of the liver pool in ¹⁸F-FDG was higher than that in ¹⁸F-FAPI-42 (2.67 (1.6,3.87) vs. 1.63 (0.63,5.7), Z=-3.601, P = 0.000). Patients were next classified according to their primary tumor sites (liver, pancreas, stomach, and intestine). The uptake of neoplasms could be clearly visualized in ¹⁸F-FAPI-42 compared to ¹⁸F-FDG. Interestingly, there were two patients with diffuse ¹⁸F-FAPI-42 uptake in the liver or pancreas associated with liver fibrosis or chronic pancreatitis (Supplementary Fig. 2). Except for intestinal neoplasms, higher uptake values (SUV, TBR, and TLR) were observed in ¹⁸F-FAPI-42 than in ¹⁸F-FDG, especially for malignant neoplasms of the stomach, pancreas, and liver (Fig. 2).

Detection of Primary Tumor

In terms of a head-to-head and patient-based analysis for qualitative visualization, we observed positive agreement in twenty-five patients (25/42, 59.52%) and negative agreement in seven patients (7/42, 16.67%) between both examinations (Supplementary Fig. 3). Subsequently, one patient with negative agreement was pathologically confirmed to be false-negative. Additionally, one liver cancer patient was demonstrated to be ¹⁸F-FDG positive only (while ¹⁸F-FAPI-42 was negative), and nine patients showed ¹⁸F-FAPI-42 positive results only (including four liver cancers, one gastric cancer, one pancreatic cancer, one mucinous tumor of the pancreas, one ampullary cancer of the duodenum, and one jejunal cancer) (Fig. 3). Therefore, the diagnostic accuracies of ¹⁸F-FAPI-42 PET/CT and ¹⁸F-FDG PET/CT were 95.24% and 76.19%, respectively (Table 2). The Cohen’s kappa coefficient of consistency between the two radioactive agents was moderate (κ = 0.441, P = 0.01).

Table 2

Diagnostic Performance of 18F-FDG and 18F-FAPI-42 PET/CT in malignant neoplasms of the digestive system (patient-based analysis)
Location of lesions	Sensitivity (%)		Specificity (%)		Accuracy (%)
Location of lesions	¹⁸F-FAPI-42	¹⁸F-FDG	¹⁸F-FAPI-42	¹⁸F-FDG	¹⁸F-FAPI-42	¹⁸F-FDG
Primary tumor	94.44 (34/36)	72.22 (26/36)	100 (6/6)	100 (6/6)	95.24(40/42)	76.19 (32/42)
Initial tumor	100 (20/20)	70 (14/20)	NA	NA	100 (20/20)	70 (14/20)
Post-treatment tumor	87.5 (14/16)	75 (12/16)	100 (6/6)	100 (6/6)	95.45 (20/22)	81.82 (18/22)
Metastases
Liver	100 (9/9)	100 (9/9)	100 (33/33)	100 (33/33)	100 (42/42)	100 (42/42)
Lymph node	93.75 (15/16)	68.75 (11/16)	100 (26/26)	96.15 (25/26)	97.62 (41/42)	85.71 (36/42)
Peritoneum	100 (7/7)	57.14 (4/7)	100 (35/35)	100 (35/35)	100 (42/42)	92.86 (39/42)
Bone	100 (5/5)	100 (5/5)	97.3 (36/37)	100 (37/37)	97.62 (41/42)	100 (42/42)
Lung, adnexa, and intestine	100 (8/8)	75 (6/8)	100 (34/34)	100 (34/34)	100 (42/42)	95.24 (40/42)
NA, not applicable

Patients were divided into two subgroups according to their history of treatment before PET/CT examination. In twenty individuals with initial consultation, we found that fourteen (14/20, 70%) patients showed positive consistency, while there were no cases of negative agreement. In six patients (6/20, 30%), we found that only ¹⁸F-FAPI-42 was positive (while ¹⁸F-FDG was negative), which included two with liver cancers, one with pancreatic cancer, one with mucinous tumor of the pancreas, one with ampullary cancer of the duodenum, and one with jejunal cancer. Therefore, the accuracy of ¹⁸F-FAPI-42, at 100%, was significantly higher than that of ¹⁸F-FDG, which was 70% (Table 2). Among the twenty-two patients who had received treatment, eleven (11/22, 50%) patients showed consistent positive results, and six (6/22, 27.27%) patients had consistent negative results. Only one patient (1/22, 4.55%, liver cancer) was found to be ¹⁸F-FDG positive, while ¹⁸F-FAPI-42 was negative. Additionally, three patients (3/22, 13.64%), including two with liver cancer and one with gastric cancer, were ¹⁸F-FAPI-42 positive, while ¹⁸F-FDG was negative. Based on these results, the detection accuracy of ¹⁸F-FAPI-42 (95.45%) was consistently higher than that of ¹⁸F-FDG (81.82%) (Table 2).

The Uptake of Metastases

Based on the common sites of metastasis in this study, we divided metastases into different groups, including liver, lymph node, peritoneum, bone, and other few organs (lung, adnexal and intestinal). The results indicated that ¹⁸F-FAPI-42 uptake was significantly higher or equal to ¹⁸F-FDG uptake in all lesions, especially for peritoneal metastases (Fig. 2). Interestingly, one patient with multiple lung metastases of colon cancer demonstrated considerably intense uptake of ¹⁸F-FDG while low or no uptake of ¹⁸F-FAPI-42 (Fig. 3).

Detection of Metastases

Next, a visual assessment of patient-based metastatic lesions was performed. Positive agreement was observed in 9 out of 42 patients (21.43%), and negative agreement was noted in 33 out of 42 patients (78.57%) with liver metastases. This resulted in both 100% accuracy for the two agents (Table 2) and perfect agreement in the two radiopharmaceuticals (κ = 1, P = 0.00). Subsequently, a lesion-based analysis was performed, and ¹⁸F-FAPI-42 detected more lesions (n = 31) than ¹⁸F-FDG (n = 24). Regarding the detection of lymph node metastases, there was a positive consistency between the two radioactive agents in 28.31% of cases (10/42), and negative consistency was observed in 59.52% of cases (25/42). Two individuals showed lesions with ¹⁸F-FDG-avid only (while ¹⁸F-FAPI-42 was negative), and one of them was confirmed as a false positive. Conversely, there were five individuals with lesions showing ¹⁸F-FAPI-42-avid only (while ¹⁸F-FDG was negative) (Fig. 4), particularly in the case of small lymph nodes. Therefore, the detection accuracy was slightly higher for ¹⁸F-FAPI-42 than for ¹⁸F-FDG (97.62% vs. 85.71%) (Table 2). The consistency assessment between the two radiopharmaceuticals was good (κ = 0.62, P = 0.00). Moreover, the evaluation revealed little difference in the quantity of lesions detected between ¹⁸F-FDG (n = 74) and ¹⁸F-FAPI-42 (n = 76). The positive consistency in peritoneal metastases was 9.5% (4/42), and the negative consistency was 83.33% (35/42). None of the patients with peritoneal metastases exhibited solely ¹⁸F-FDG avidity (negative for ¹⁸F-FAPI-42), whereas three patients exclusively displayed ¹⁸F-FAPI-42-avid lesions (negative for ¹⁸F-FDG) (Fig. 4). Consequently, the accuracy obtained by ¹⁸F-FAPI-42 was higher than that of ¹⁸F-FDG (100% vs. 92.86%) (Table 2). Good agreement was observed between the two radiotracers (κ = 0.776, P = 0.00). However, significantly more peritoneal lesions were detected with ¹⁸F-FAPI-42 (n = 36) than with ¹⁸F-FDG (n = 17). Additionally, both imaging agents demonstrated a positive agreement of 11.9% (5/42) and a negative agreement of 85.71% (36/42) in the case of bone metastases (Fig. 4). One patient showing ¹⁸F-FAPI-42 positive was subsequently confirmed with false-positive. Therefore, the accuracy of ¹⁸F-FAPI-42 was 97.62%, whereas ¹⁸F-FDG maintained a perfect accuracy of 100%, contributing to a strong agreement assessment (κ = 0.896, P = 0.00). Specifically, ¹⁸F-FAPI-42 identified thirty-two metastatic bone lesions, while ¹⁸F-FDG detected twenty-nine lesions under the same conditions.

In cases of metastasis affecting relatively uncommon locations, such as the lung, adnexa, and intestine, the positive agreement rate was 14.29% (6/42), and the negative agreement rate was 80.95% (34/42). The positive lesions were revealed only by ¹⁸F-FAPI-42 (while ¹⁸F-FDG was negative) in two patients. As a result, the accuracy of ¹⁸F-FAPI-42 was 100%, while that of ¹⁸F-FDG was 95.24% (Table 2). The consistency result of the two radiopharmaceuticals was strong (κ = 0.829, P = 0.00). Interestingly, the number of positive lesions detected by ¹⁸F-FDG (n = 73) was considerably higher than that detected by ¹⁸F-FAPI-42 (n = 32), primarily due to a case involving multiple lung metastases from colon cancer (Fig. 3).

Implication of Patient Management

In the patient cohort, 17 out of 42 (40.48%) patients modified their treatment strategies following the ¹⁸F-FAPI-42 scans. Among patients with primary lesions, diagnostic status was corrected in three treatment-naïve patients for whom diagnoses were initially missed or incorrectly assessed on ¹⁸F-FDG PET/CT; diagnostic status was updated following treatment in six patients undergoing restaging. Among patients evaluated for lymph nodes, four treatment-naïve patients experienced an upstaging, while four posttreatment patients underwent restaging, resulting in two downgrades and two upgrades (Supplementary Fig. 4). However, only two patients (2/42, 4.8%) altered their treatment regimens based on ¹⁸F-FDG. Among them, one had an elevated initial lymph node stage, and the other had an increased level of initial distant metastasis.

Malignant neoplasms of the digestive system represent the leading cause of cancer-related death worldwide. Despite the widely recognized applications of molecular imaging, the low sensitivity of ¹⁸F-FDG PET for some specific tumor subtypes has driven research on pan-tumor targets and radiopharmaceuticals.[16] Immunohistochemistry-based pathology has demonstrated significant overexpression of FAP in a variety of digestive tumors.[17] The present study outlines our experience with ¹⁸F-FAPI-42 PET/CT to explore its clinical application value in challenging cases of malignant neoplasms of the digestive system compared with ¹⁸F-FDG. Our results indicated that lower background uptake and increased tumor uptake of ¹⁸F-FAPI-42 in most neoplasms resulted in higher SUV, TBR, and TLR, facilitating clear boundary delineation of tumors and reducing the risk of missed diagnoses. More lesions with obvious activity could be visualized through ¹⁸F-FAPI-42 PET/CT with improved diagnostic accuracy compared with synchronous ¹⁸F-FDG PET/CT both in primary tumors and metastases, especially in multiple liver and peritoneal metastases.

The tumor microenvironment (TME), which plays a vital role in the whole process of tumor development and progression, has surged growing interest in the field of oncology. CAFs presenting in the TME are one of the most prominent factors involved in the processes of tumor growth, proliferation, invasion, and metastasis by secreting cytokines, remodeling extracellular matrix and cell metabolism, and inducing epithelial-mesenchymal transition (EMT) and immune impression.[18, 19] Considering the importance of CAFs and FAP overexpression on the cell surface, significant emphasis has been placed on exploring their potential role in oncology, especially in those tumor types with low or non-avidity uptake of ¹⁸F-FDG. Some studies have assessed head-to-head comparisons between ⁶⁸Ga-FAPI PET/CT and ¹⁸F-FDG PET/CT in lung, nasopharyngeal, esophageal, liver, gastric, pancreatic, breast, and colorectal cancers[7, 20, 21, 22] and found that ⁶⁸Ga-FAPI PET/CT was able to obtain higher tumor uptake and favorable tumor-to-background contrast. With the exception of intestinal tumors, our results were consistent with the above literatures. A possible explanation for the higher ¹⁸F-FDG activities of intestinal tumors might be associated with the intense physiological accumulation of the intestinal tract near lesions on ¹⁸F-FDG PET/CT. Notably, no observed physiological absorption of FAPI PET was observed in the gastrointestinal tract. This absence of nonspecific uptake provides an opportunity to assess the extent of invasion more accurately. Consequently, FAPI PET holds promise for potential applications in intestinal tumors and warrants additional investigation to address the limitations associated with ¹⁸F-FDG.

Accurate characterization of the disease is critical for both initial diagnosis and post-treatment management. Zhang et al. studied ¹⁸F-FAPI PET/CT in the evaluation of focal liver lesions with ¹⁸F-FDG non-avidity in thirty-seven enrolled participants and they found that ¹⁸F-FAPI PET/CT demonstrated high sensitivity in detecting HCC and non-HCC malignancy with ¹⁸F-FDG non-avidity.[23] Similarly, Wang et al. conducted a retrospective study that involved twenty-nine patients with suspected incipient or recurrent HCC who received both examinations. The analysis revealed that ⁶⁸Ga-FAPI-04 PET/CT detected more intrahepatic HCC lesions and had obvious advantages in finding small and well-or moderately differentiated tumors.[20] The same was true for liver metastases.[7] Our patient- and lesion-based analyses also uncovered that ¹⁸F-FAPI-42 PET/CT contributed to the detection of more primary and metastatic liver lesions. The pooled studies targeting the use of ¹⁸F-FDG in detecting HCC reported low sensitivities ranging from 40–68%[24], probably related to the low expression of type 1 glucose transporter protein (Glut 1) and enhanced glucose-6-phosphatase activity causing the dephosphorylation of ¹⁸F-FDG-6-PO4.[25, 26] Although intrahepatic cholangiocarcinoma (ICC) showed increased expression of Glut-1, hexokinase (HK) type II, which is a rate-limiting glycolytic enzyme that mediates glucose uptake, was not expressed.[26] Therefore, less ¹⁸F-FDG is trapped in HCC and ICC. Taken together, available evidence highlights that FAPI PET outperforms conventional ¹⁸F-FDG PET in lighting up primary and metastatic liver lesions.

With respect to detecting gastric cancer, several studies reported significantly better diagnostic sensitivity of FAPI PET than that of ¹⁸F-FDG PET[27], in line with our study findings. Special tumor types, such as signet-ring cell carcinoma of the stomach, exhibit the characteristic of low glucose uptake[9], resulting in an increased false negative of ¹⁸F-FDG PET. Moreover, inflammation of the stomach can enhance glucose affinity, resulting in an increased rate of false positive with ¹⁸F-FDG. Our results substantiated that gastric cancer had a higher uptake level in ¹⁸F-FAPI-42, allowing for more precise visualization of lesions and improved diagnostic confidence compared to ¹⁸F-FDG. Given the overexpression of FAP in tumor-associated stromal cells, imaging strategies targeted to FAP detection hold great potential in this context. It is widely acknowledged that pancreatic cancer is one of the most malignant entities with abundant desmoplastic stroma consisting of CAFs.[28] Our study showed that the primary lesions could be visualized by ¹⁸F-FAPI-42, which was in accordance with other studies.[29, 30] It is worth noting that inflammation-induced fibrosis, such as pancreatitis, could increase false-positive uptake of pancreatic parenchyma. Therefore, a comprehensive consideration that combines FAPI PET with other anatomical or functional image data is pivotal.

In addition to the primary lesion, we also compared the ability of the two radiopharmaceuticals to detect metastases. Our results revealed that ¹⁸F-FAPI-42 was superior to ¹⁸F-FDG in the identification of liver, lymph node, and peritoneal metastases, consistent with previous researches[13, 14], with huge implications for clinical decision-making. A recent study by Alçın et al. showed that FAPI PET could help in the treatment management of breast cancer by improving the nodal staging assessment.[21] Our pathology-based analysis supported the advantages of ¹⁸F-FAPI-42 in guiding staging and restaging, particularly in improving the assessment of lymph node status (Fig. 4). Another finding of this study was that the number of avid bone metastases detected by ¹⁸F-FAPI-42 was almost equal to that of ¹⁸F-FDG. A previous study enrolling thirty patients with bone metastases proposed more abnormal foci detected by FAPI PET.[31] The discrepancy may be related to the relatively small sample size of our study. However, the above study also emphasized that a cautious interpretation of FAPI PET is essential owing to the potential for false-positive bone lesions which was also seen in our study. Thus, further studies are warranted. A patient in this study with multiple lung metastases from colon cancer presented with strong and disseminated uptake of ¹⁸F-FDG, while mild or no uptake was found in ¹⁸F-FAPI-42 (Fig. 3). In this case, the conventional ¹⁸F-FDG is an essential supplement for the insufficiency of ¹⁸F-FAPI-42. To date, few studies have investigated the application of FAPI PET in metastatic lung disease. Further evaluations are necessary to identify whether it has an additional preponderance over ¹⁸F-FDG.

It is now understood that CAFs derived from normal tissue fibroblasts are activated by and interact with tumor cells, leading to the upregulation of FAP expression and tumor progression, invasion, metastasis, immunosuppression, and chemotherapy resistance.[32] Therefore, beyond molecular imaging targeting FAP, the landscape of FAPI-based radionuclide therapy with ¹³¹I[33], ¹⁷⁷Lu[34], ⁶⁴Cu, and ²²⁵Ac[35] and treatment response evaluation including radionuclide therapy[36], immune checkpoint blockade therapy and concurrent treatment[37] in various tumors have received extensive attention in preclinical and clinical research and yielded encouraging outcomes. There have been several studies that have conducted ¹⁷⁷Lu-FAPI targeted radionuclide therapy in metastatic mediastinal sarcoma[38] and metastatic pancreatic adenocarcinoma.[39], which suggests the potential value of FAPI-targeted radionuclide therapy in inoperable tumors with high uptake of FAPI PET. Despite the mentioned prospects, the knowledge we know about FAP in oncology is only the tip of the iceberg. Gaining a more comprehensive understanding of CAFs and FAP biology, as well as exploring the intricacies of pharmacokinetics and radiopharmacy, has the potential to unlock novel diagnostic and therapeutic avenues across a wide spectrum of tumor types in the future.

Over the years, ⁶⁸Ga-labeled radionuclides have been mainly used for FAPI PET imaging. Herein, we used ¹⁸F-labeled FAPI to explore its value compared to ¹⁸F-FDG. The use of an ¹⁸F-labeled FAP ligand is advantageous in terms of productivity, transportability, and storage due to the inherent properties of ¹⁸F. Importantly, it has been reported that ¹⁸F-labeled FAP ligands exhibit superior spatial resolution and enhanced imaging quality (lower positron energy) compared with ⁶⁸Ga-labeled radionuclides.[40]

Limitations also existed in this study. First, our study had a limited number of patients with each tumor subtype, which could potentially introduce bias into the results. Consequently, we opted for a pooled analysis based on the site of onset. Second, due to the constraints of clinical practice, we could not obtain pathological diagnoses for all lesions. Instead, we relied on follow-up examinations using standard anatomical images as one of our diagnostic criteria. Last, we conducted additional ¹⁸F-FAPI-42 PET/CT scans primarily when the results of the initial ¹⁸F-FDG PET/CT were negative or inconclusive. Therefore, it should be borne in mind that our findings may not be broadly applicable to all neoplastic conditions involving the digestive system.

In the context of selected malignant digestive system neoplasms, our study highlights the potential of ¹⁸F-FAPI-42 PET/CT as a promising and alternative tool for assessing primary tumors, detecting metastases, and aiding in staging, restaging, and clinical decision-making, given its superior performance in terms of higher uptake and enhanced lesion visualization when compared to ¹⁸F-FDG PET/CT. Furthermore, our findings encourage further investigation into FAPI PET as an imaging biomarker for digestive system neoplasms. This could have implications for guiding treatment selection and assessing responses to FAP-targeted therapy or immunotherapy.

Consent for Interest

The authors declare that they have no conflict of interest with regard to this study.

Ethics Approval:

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of The Second Affiliated Hospital, Guangzhou Medical University (study Nr.: 2023-hg-ks-36).

Funding:

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions:

HJY, SNJ and MX contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by all authors. The first draft of the manuscript was written by MX. YL and SNJ contributed to revising the manuscript. All authors commented and approved the final manuscript.

Acknowledgments:

The authors gratefully acknowledge all participating patients and thank the nurses and technicians for supporting the imaging procedures at the Department of Nuclear Medicine, the Second Affiliated Hospital, Guangzhou Medical University.

Data Availability:

All research data and computer codes are available from the corresponding author upon request.

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18F-FAPI-42 PET/CT and 18F-FDG PET/CT in patients with malignant digestive system neoplasms: a head-to-head comparative study

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Patient Selection and Evaluation

Imaging Analysis and Interpretation

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Patient Characteristics

The Uptake of Primary Tumor

Detection of Primary Tumor

The Uptake of Metastases

Detection of Metastases

Implication of Patient Management

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