Digestive system cancers are a significant health concern, impacting multiple organs and being widely prevalent (1). Gastrointestinal cancers account for over 26% of the global cancer incidence and are responsible for more than 35% of cancer-related deaths worldwide (2). In 2018, gastrointestinal tumors accounted for 4.8 million new cases and 3.4 million deaths, with Asia bearing 63% of cases and 65% of deaths. China alone contributed 38% of cases and 41% of deaths (2). Within China, four of the top five cancers leading to mortality are gastrointestinal, including liver cancer (12.85%), gastric cancer (12.48%), esophageal cancer (10.09%), and colorectal cancer (9.63%) (3). These statistics highlight the urgent need for early detection and accurate staging of gastrointestinal cancers(4). While histopathology is the gold standard, advancements in imaging technologies offer a promising non-invasive alternative (5).

Traditional imaging techniques include ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) (6). Due to their cost-effectiveness and accessibility in clinical applications, these methods are widely employed for the detection of gastrointestinal malignancies. However, they possess certain limitations. For instance, ultrasound may produce artifacts due to the intestines’ complex anatomy and high gas content, reducing accuracy (7, 8). Furthermore, current endoscopic ultrasound is limited by insufficient penetration depth and difficulty in observing distant lymph nodes, making accurate assessment challenging (9). Enhanced CT and MRI may fail to accurately differentiate small nodules from atypical lesions in patients with hepatocellular carcinoma (HCC) (10). Furthermore, these imaging techniques may not offer adequate functional data for precise lymph node assessment. These methods frequently exhibit limitations in detecting lymph node metastases and small lesions, highlighting the urgent need for the development of enhanced diagnostic tools (11).

Positron emission tomography (PET) has been a critical tool in molecular imaging over the past decade, frequently employed in the detection of gastrointestinal cancers (12, 13). The ¹⁸F-FDG tracer, which targets abnormal glucose metabolism in tumors, is a key tool in PET imaging. It is extensively used for diagnosing malignant tumors and evaluating treatment effectiveness (14). Recent studies have identified limitations of ¹⁸F-FDG tracers in diagnosing gastrointestinal cancers, particularly in distinguishing between inflammation and malignancy (14–16). Nonspecific lymph node uptake may cause false positives and incorrect treatment decisions (17). Recent studies show that high levels of fibroblast activation protein (FAP) in cancer-associated fibroblasts are linked to tumor growth, metastasis, and prognosis. As a result, FAPI has become a novel imaging agent and has been used in clinical practice since 2018 (18). Ga-labeled FAPI tracers (such as [⁶⁸Ga]Ga FAPI-04 and [⁶⁸Ga]Ga FAPI-46) have shown rapid tumor uptake, with [⁶⁸Ga]Ga FAPI-04 being particularly notable (19). Its potential applications have made [⁶⁸Ga]Ga FAPI-04 the focus of growing research interest. [⁶⁸Ga]Ga FAPI-04 is being studied as a potential alternative to the well-established [¹⁸F]FDG in gastrointestinal oncologic PET imaging. Previous studies conducted by Ouyang et al. and Wang et al. indicated that [⁶⁸Ga]Ga FAPI-04 PET exhibit higher sensitivity than [¹⁸F]FDG PET in diagnosing primary gastrointestinal tumors or gastric cancer (20, 21). However, its diagnostic performance for detecting lymph node metastasis in gastrointestinal tumors has not been reported. Lymph node metastasis is a well-established indicator of cancer spread, and accurate N staging of the tumor is essential for developing effective treatment strategies (22).

The relative sensitivity of [⁶⁸Ga]Ga-FAPI-04 PET compared to [¹⁸F]FDG PET in diagnosing lymph node metastasis in digestive system cancers is currently under debate, given the conflicting findings in the literature. The study by Lin et al. indicates that the diagnostic performance of [⁶⁸Ga]Ga FAPI-04 PET is comparable to [¹⁸F]FDG PET for lymph node metastasis in digestive system cancers (23); however, Gündoğan et al. found that [⁶⁸Ga]Ga FAPI-04 PET has higher sensitivity than [¹⁸F]FDG PET (24). Therefore, we conducted a systematic review and meta-analysis, rigorously collecting and analyzing all head-to-head eligible studies to provide a more conclusive assessment.

This meta-analysis strictly followed the PRISMA-DTA guidelines for Diagnostic Test Accuracy (25). Additionally, the study protocol was registered with the PROSPERO network under the identifier CRD42024572412.

[¹⁸F]FDG PET is utilized for both the initial staging and subsequent restaging of lymph node metastasis in digestive system cancers, ensuring precise assessment and supporting the optimization of therapeutic strategies (43). Recent studies show that [⁶⁸Ga]Ga-FAPI-04 outperforms [¹⁸F]FDG PET in diagnosing primary digestive system tumors. However, there is ongoing debate about their relative effectiveness in detecting lymph node metastasis in digestive system cancers. This is the first systematic review and meta-analysis comparing the detection performance of [⁶⁸Ga]Ga-FAPI-04 PET and [18F]FDG PET for identifying lymph node metastasis in digestive system cancers.

A significant difference in sensitivity was found between [⁶⁸Ga]Ga-FAPI-04 PET and [¹⁸F]FDG PET (P < 0.01), although no difference in specificity was observed (P = 0.20), consistent with previous studies (37, 39). The diagnostic performance of [¹⁸F]FDG PET is limited due to the variable physiological uptake of [¹⁸F]FDG in the gastrointestinal tract, which can interfere with the detection of lesions (44). Additionally, [¹⁸F]FDG shows reduced uptake in certain histological subtypes, such as adenocarcinoma and signet-ring cell carcinoma, further affecting its diagnostic sensitivity (45, 46). In contrast, FAP, which is highly expressed by cancer-associated fibroblasts (CAFs) and minimally in normal tissues, leads to a lower uptake of [⁶⁸Ga]Ga-FAPI in healthy tissue (47). This results in a higher tumor-to-background ratio (TBR), thereby enhancing tumor visualization, particularly in regions with high glucose metabolism (48, 49). The comparable high specificity of both imaging agents in detecting lymph node metastasis may be due to the fact that both modalities provide functional information. When evaluating specific tumor subgroups-pancreatic cancer (2 studies), cholangiocarcinoma (1 study), and colorectal cancer (1 study)-no significant differences in sensitivity or specificity were found between [⁶⁸Ga]Ga-FAPI-04 PET and [¹⁸F]FDG PET. However, in a systematic review by Zhuang et al. (included 3 studies), [⁶⁸Ga]Ga-FAPI-04 PET demonstrated a higher positive detection rate for lymph node metastasis in colorectal cancer compared to [¹⁸F]FDG PET, although sensitivity and specificity were not reported (50). The discrepancies between the findings for specific tumor subgroups and the overall results from the systematic review may be due to the small number of studies and patient samples in our analysis. Additionally, not all lymph node metastases were confirmed by pathological biopsy, with some relying on imaging follow-up as the standard. These factors could contribute to the variability and instability of the results.

Ouyang et al. found that [⁶⁸Ga]Ga-FAPI-04 PET was more effective than [¹⁸F]FDG PET in diagnosing primary cancers of the digestive system, particularly gastric, liver, biliary tract, and pancreatic cancers, with pooled sensitivity and specificity of 0.98 and 0.81, respectively (20). Multiple studies further confirmed the superior accuracy of [⁶⁸Ga]Ga-FAPI-04 PET in these contexts. However, it is important to note that Ouyang et al. did not assess its efficacy in diagnosing lymph node metastasis. To address this research gap, we conducted the first analysis of [⁶⁸Ga]Ga-FAPI-04 PET for diagnosing lymph node metastasis in digestive system cancers. Our findings revealed that [⁶⁸Ga]Ga-FAPI-04 PET has a higher sensitivity of 0.82, compared to 0.51 for [¹⁸F]FDG PET. This underscores the superior diagnostic capability of [⁶⁸Ga]Ga-FAPI-04 PET in this specific application.

[¹⁸F]FDG PET offers advantages such as broad availability, established clinical validation, and valuable metabolic information for tumor assessment. However, it has limitations, including physiological uptake in normal tissues, which complicates lesion detection, and susceptibility to variations in tissue glucose metabolism. In contrast, [⁶⁸Ga]Ga-FAPI-04 PET provides high selectivity for tumor detection, potential for early diagnosis, and theragnostic applications. Our investigation of [⁶⁸Ga]Ga-FAPI-04 PET reveals statistically significant improvements in diagnostic sensitivity (P = 0.04) among gastric cancer patients. By precisely targeting fibrotic and tumor microenvironmental markers, this imaging technique demonstrates enhanced staging capabilities. Preliminary findings suggest potential advancements in early diagnostic strategies for specific patient populations. Nonetheless, its limited availability, the need for broader clinical validation, and concerns about radiation exposure are significant drawbacks. The half-life of [⁶⁸Ga]Ga-FAPI-04 is determined by the ⁶⁸Ga radioisotope, with a half-life of 68 min, which poses certain challenges for its preparation and transportation. In contrast, [¹⁸F]FDG has a longer half-life (109.8 min), potentially offering advantages in transportation and application (51). [⁶⁸Ga]Ga-FAPI-04 synthesis is characterized by extreme sensitivity to reaction conditions, requiring precise technical parameters. The synthesis process demands meticulous control, including temperature regulation precisely at 100°C, specialized reagents like 4-(2-hydroxyethyl) piperazine-1-ethanesulfonic acid, and professional radioisotope synthesis equipment such as cassette-based automated synthesizers (52). Multiple parameters necessitate precise optimization, resulting in a complex synthesis protocol (52). These multifaceted technical complexities may significantly constrain its widespread adoption in clinical practice. The safety assessments in the included studies indicated that no adverse reactions were reported during or after the use of either tracer, suggesting that both are safe for diagnostic purposes. Our findings indicate that [⁶⁸Ga]Ga-FAPI-04 PET offers higher sensitivity and similar specificity compared to [¹⁸F]FDG PET in detecting lymph node metastasis in digestive system cancers. This improved sensitivity could enhance cancer staging accuracy and reduce the need for additional tests or treatments. FAPI-based radiotracers may significantly advance the diagnosis and treatment of digestive system cancers, particularly gastric cancer, leading to more personalized patient care and improved survival outcomes. Molecular imaging with [⁶⁸Ga]Ga-FAPI-04 demonstrates heightened diagnostic precision in lesion identification, potentially mitigating false-negative occurrences and reducing unnecessary subsequent radiological assessments (53, 54). Notwithstanding these initial promising indicators, rigorous comparative analyses remain imperative to comprehensively evaluate the tracer’s clinical effectiveness and economic rationalization.

Several limitations should be noted. First, study heterogeneity may have affected the sensitivity and specificity results, with meta-regression suggesting that sample size (>50, <50) could be a contributing factor. Second, our results indicate significant publication bias in the specificity estimates for both [⁶⁸Ga]Ga-FAPI-04 PET and [¹⁸F]FDG PET. This bias may primarily stem from the substantial overrepresentation of Chinese populations in the literature, with the majority of included studies originating from Chinese research centers. Third, due to technical and ethical constraints, not all positive lesions were confirmed by histopathology, necessitating the use of morphological criteria and follow-up imaging as reference standards. Fourth, the limited number of head-to-head studies has hindered our ability to compare the diagnostic performance of tools for specific gastrointestinal tumors, such as liver, duodenal, and appendiceal cancers. To address this gap, future research should prioritize head-to-head studies on these specific tumors. Additionally, to validate the current findings, further research involving diverse populations and well-designed prospective studies is required.

[⁶⁸Ga]Ga-FAPI-04 PET showed higher sensitivity but comparable specificity to [¹⁸F]FDG PET in detecting lymph node metastasis of digestive system cancers, particularly in gastric cancer. Both tracers performed similarly in biliary tract, pancreatic, and colorectal cancers. However, due to the limited sample sizes and notable heterogeneity observed in the current studies, there is a pressing need for larger prospective multicenter studies. Such research should focus on underrepresented populations outside of China and specific cancer subtypes, such as liver and duodenal cancers, to enhance the generalizability of findings and validate the efficacy of [⁶⁸Ga]Ga-FAPI-04 PET in diverse clinical settings.

Question: Is [⁶⁸Ga]Ga-FAPI-04 PET more effective than [¹⁸F]FDG PET in detecting lymph node metastasis in patients with digestive system cancers?

Pertinent findings: In a meta-analysis of 15 studies including 617 patients, [⁶⁸Ga]Ga-FAPI-04 PET showed significantly higher sensitivity (0.82 vs. 0.51) and similar specificity (0.91 vs. 0.81) compared to [¹⁸F]FDG PET for detecting lymph node metastasis in digestive system cancers.

Implications for patient care: [⁶⁸Ga]Ga-FAPI-04 PET may provide more accurate lymph node staging in patients with digestive system cancers, potentially leading to better treatment planning and patient outcomes.