Abstract
Quinoline-based fibroblast activation protein (FAP) inhibitors (FAPIs) have recently emerged as a focal point in global nuclear medicine, underscored by their promising applications in cancer theranostics and the diagnosis of various nononcological conditions. This review offers an in-depth summary of the existing literature on the evolution and use of FAPI tracers in China, tracing their journey from preclinical to clinical research. Moreover, this review also assesses the diagnostic accuracy of FAPI PET for the most common cancers in China, analyzes its impact on oncologic management paradigms, and investigates the potential of FAP-targeted radionuclide therapy in patients with advanced or metastatic cancer. This review also summarizes studies using FAPI PET for nononcologic disorders in China. Thus, this qualitative overview presents a snapshot of China’s engagement with FAPI tracers, aiming to guide future research endeavors.
The tumor microenvironment, a critical component of tumor tissue, is enriched with cancer-associated fibroblasts, which are prominent entities in various solid tumors. Fibroblast activation protein (FAP), a type II transmembrane serine protease, is a distinct cancer-associated fibroblasts marker with sparse expression in healthy tissues. In contrast, its expression in cancerous tissues correlates with tumor invasiveness, metastatic potential, and prognosis. More than 90% of epithelial tumors exhibit elevated FAP expression, making it a promising target for cancer imaging modalities (1). A seminal contribution from the University of Heidelberg in 2018 introduced a series of FAP inhibitors (FAPIs) formulated explicitly for tumor imaging; this breakthrough garnered rapid international recognition and prompted nuclear medicine institutions globally to explore its implications (2). The ensuing research underscored the diagnostic efficacy of FAPIs in malignancies and illuminated the potential of FAP-targeted radioligands for therapeutic interventions. Moreover, FAPI radiotracers have shown diagnostic utility in various nonmalignant pathologies, advancing the understanding of structural refinement and prompting expanded clinical investigations.
China’s focus on FAPI-centric research has been remarkable. Since an inaugural research article published in 2020 (3), Chinese studies have substantially contributed to the discourse, evidenced by the 421 articles written by Chinese authors and identified via a PubMed search until October 10, 2023 (keywords: ‘FAPI’ OR ‘fibroblast activation protein inhibitor’ AND ‘China’; 1 retraction and 2 corrections were excluded); these articles account for 50% of the global FAPI-centric literature (421/822). Chinese research has mainly focused on tumor types that have a notably high incidence rate in China, such as gastric cancer, liver cancer, and nasopharyngeal cancer. The aim of this review was to cohesively collate and present the preclinical, translational, and clinical evolution of FAPI tracers in the Chinese academic landscape.
PRECLINICAL AND TRANSLATIONAL DEVELOPMENTS IN CHINA
FAPI-04 and FAPI-46 are the most commonly used FAPI tracers in clinical investigations, with molecular weights of approximately 873 and 886, respectively. The small structure of FAPI enables it to rapidly bind to the FAP target. However, it also swiftly detaches, resulting in its rapid elimination from the body. Consequently, various modifications have been explored to enhance tumor uptake and retention of FAPI molecules for radioligand therapies. Multimerization is commonly used to optimize target molecules, particularly for developing radiolabeled arginine-glycine-aspartate (RGD) peptides; a similar approach was used to optimize FAPI molecules.
In 2022, Zhao et al. developed the first FAPI dimer (4). In preclinical models, the FAPI dimer showed 2- to 3-fold-higher tumor uptake and prolonged tumor retention than FAPI-46 when radiolabeled with 68Ga. In addition, the antitumor efficacy of the FAPI dimer labeled with 177Lu was augmented in FAP-positive tumor xenografts (5). Pang et al. were the first to develop a FAPI tetramer that further increased tumor tissue uptake (6). However, the FAPI tetramer also demonstrated increased uptake in some healthy organs, particularly the liver and kidney; this feature may be a double-edged sword for theranostic applications. Moreover, the 177Lu-labeled FAPI tetramer had better tumor uptake and antitumor efficacy than the dimer and monomer in tumors with moderate FAP expression. Thus, radioligand therapy with the FAPI tetramer might be more suitable than that with the FAPI dimer for tumors with moderate to mild FAP expression. However, among the multimeric FAPI variants in China, only 68Ga-DOTA-2P(FAPI)2 has been translated into clinical investigations (4). In healthy volunteers, the 68Ga-DOTA-2P(FAPI)2 effective dose is 1.19E−02 mSv/MBq, comparable to that of 68Ga-FAPI-04 (1.64E−02 mSv/MBq) and slightly higher than that of 68Ga-FAPI-46 (7.80E−03 mSv/MBq) (4). In 3 patients with cancer (21 lesions), tumor uptake was reported to be 2- to 3-fold higher with 68Ga-DOTA-2P(FAPI)2 than with 68Ga-FAPI-46 (SUVmax, 8.1–39.0 vs. 1.7–24.0; P < 0.001).
Heterobivalent probes targeting FAP and other molecular targets have also been developed. For instance,68Ga-FAPI-RGD, a heterobivalent molecule targeting FAP and integrin αvβ3, showed enhanced tumor uptake and image contrast compared with 68Ga-labeled FAPI-02 and cyclic RGDfK monomers in preclinical models (7). In clinical translational studies, 68Ga-FAPI-RGD exhibited promising diagnostic performance equal to or even surpassing that of 18F-FDG in patients with various cancer types, particularly lung, esophageal, and ovarian cancers (7,8). Other heterobivalent probes that target FAP and prostate-specific membrane antigen have shown high tumor accumulation in preclinical models (9,10), although clinical data for FAPI–prostate-specific membrane antigen are still lacking.
Another strategy to enhance tumor uptake and retention of FAPI is to extend its circulation in the blood by conjugating it with other moieties, such as albumin-binding moieties. For instance, Wen et al. reported that a FAPI variant modified with an albumin binder, truncated Evans blue (denoted as EB-FAPI), showed significantly improved tumor uptake and retention compared with FAPI-02 (11). Furthermore, when radiolabeled with 177Lu, EB-FAPI remarkably inhibited tumor growth in U87MG tumor–bearing mice. Other albumin-binding moieties, including the 4-(p-iodophenyl) butyric acid moiety, 4-p-chlorophenyl butyric acid, lauric acid, and palmitic acid, have also been conjugated with FAPI molecules to enhance tumor uptake and retention (12,13). Of the FAPI modifications used to prolong circulation in the blood, only EB-FAPI has been translated for clinical use—for radioligand therapy in patients with refractory cancers. Further details are available in the “Clinical Developments in China” section.
In addition to modifying FAPI to improve tumor uptake and retention, efforts are ongoing in China to facilitate FAPI radiolabeling with various radionuclides. China has more SPECT scanners than PET scanners. Thus, modifying FAPI molecules for labeling with 99mTc and, thus, SPECT imaging might be better suited for China’s current conditions. In this regard, Ruan et al. developed a FAPI-derived ligand that incorporated d-proline (called DP-FAPI) (14). This ligand was radiolabeled with 99mTc to produce 99mTc-DP-FAPI, which exhibited a high tumor-to-background ratio for SPECT imaging. In a subsequent translational study, quantitative SPECT/CT using 99mTc-DP-FAPI demonstrated favorable tumor uptake in 3 patients with gastrointestinal tumors. In addition, Yang et al. developed a FAP-targeting ligand that incorporated an organosilicon-based fluoride acceptor and a DOTAGA chelator, enabling the molecules to be labeled with radionuclides—including 18F, 68Ga, and 177Lu—for theranostic pairing (15). A common limitation of 18F-labeled FAPI tracers is their intense hepatobiliary physiologic uptake; Huang et al. developed a glycopeptide-containing FAPI tracer (called FAPT) to address this issue (16). In both preclinical and translational clinical studies, the physiologic uptake of 18F-FAPT in the gallbladder was lower than that of 18F-FAPI-42 (16). Therefore, 18F-FAPT may perform better than 18F-FAPI-42 in detecting biliary duct system cancers. Figure 1 shows the structure of various individual FAPI molecules developed by Chinese researchers.
Structures of FAP-targeted radiotracers used in clinical practice in China.
Given the development of several modified FAPI tracers, the FAPI variant choice should be anchored to specific diagnostic or therapeutic applications, complemented by a meticulous assessment of the potential benefits and limitations of each option.
CLINICAL DEVELOPMENTS IN CHINA
Tumor Diagnosis
Since Chen et al. introduced the use of the FAPI tracer in patients with various cancers in Xiamen, China, in 2020 and highlighted its diagnostic potential (3), imaging-based FAPI research for cancer in China has surged, with hundreds of studies emerging. For instance, a study by Chen et al. at The First Affiliated Hospital of Xiamen University included 75 patients who had various cancer types and who underwent paired 68Ga-FAPI-04 and 18F-FDG PET/CT; Chen et al. reported that 68Ga-FAPI-04 PET/CT had better diagnostic efficacy than 18F-FDG PET/CT, particularly in detecting liver, peritoneum, and brain metastases (3). Subsequently, several studies further compared 68Ga- or 18F-labeled FAPI and 18F-FDG PET/CT across tumor types (Table 1). To provide a more accurate reflection of the current status of FAPI research in China, we use an arrangement based on anatomic regions, from the top to the bottom of the human body, followed by sections on mesenchymal tissue origin tumors and lymphoma.
Summary of Representative Oncologic Studies with FAPI PET/CT in China
Jiang et al. (17) and Chen et al. (18) preoperatively assessed metastatic lymph node detection in head and neck squamous cell carcinoma and oral squamous cell carcinoma, finding that 68Ga-FAPI-04 had performance superior to that of 18F-FDG in PET/CT. However, both modalities exhibited equivalent effectiveness for assessing primary tumors (17,18). In addition, Gu et al. explored the use of FAPI PET/CT in head and neck cancer of unknown primary origin and with negative 18F-FDG findings, reporting that 68Ga-FAPI-04 PET/CT successfully located the primary tumor in 7 of 18 patients (19). Moreover, in a study involving 39 patients with newly diagnosed nasopharyngeal carcinoma, Zhao et al. reported a significantly higher SUVmax with 68Ga-FAPI-04 PET/CT than with 18F-FDG PET/CT in primary tumors (16.18 vs. 10.11; P < 0.001), regional lymph nodes (11.42 vs. 7.37; P < 0.001), and bone and visceral metastases (6.94 vs. 3.11; P < 0.001), resulting in the detection of more positive lesions (especially for skull base and intracranial involvement) (20). Another study focused on metastatic differentiated thyroid cancer, comparing the diagnostic accuracy of 68Ga-FAPI-04 and 18F-FDG in 35 participants (21). Among the 35 participants, 68Ga-FAPI-04 PET/CT demonstrated higher uptake in metastatic lymph nodes and pulmonary metastases than 18F-FDG. Consequently, 68Ga-FAPI-04 PET/CT exhibited enhanced sensitivity compared with 18F-FDG PET/CT in detecting neck lesions (65/78 vs. 51/78; P = 0.01) and distant metastases (87/110 vs. 65/110; P < 0.001).
To date, only 1 research article investigating FAPI and breast cancer in China has been published; the study included 34 patients with newly diagnosed breast cancer (22). Consistent with the observations for most solid tumors, primary tumor uptake of the radiotracer and the N stage evaluation were better with 68Ga-FAPI-04 than with 18F-FDG. A positive correlation was also observed between the SUVmax of 68Ga-FAPI and the pathologic grade of the primary lesions and the patient’s final stage (P < 0.001).
Regarding lung cancer, Wang et al. (23) and Zhou et al. (24) reported higher tumor uptake and tumor-to-background ratios for 68Ga-FAPI PET/CT than for 18F-FDG PET/CT in detecting primary tumors, positive lymph nodes, and bone lesions, with all comparisons having a significance level of P < 0.01. Intriguingly, in a study involving 68 patients with lung cancer, Wei et al. reported contrasting results: the tumor-to-background ratios derived from 18F-FAPI-04 PET/CT were lower than those derived from 18F-FDG PET/CT in depicting primary tumors, but the tumor-to-background ratios were higher with 18F-FAPI-04 PET/CT than with 18F-FDG PET/CT in depicting metastatic lymph nodes and bone metastases (25). Despite the variations, these studies suggested that 18F-FAPI-04 PET/CT may offer diagnostic accuracy superior to that of 18F-FDG PET/CT.
Numerous studies have shown that 68Ga- or 18F-labeled FAPI PET/CT is better than 18F-FDG PET/CT at detecting primary and metastatic lesions in various digestive tumors, including esophageal, gastric, duodenal, colorectal, liver, biliary tract, and pancreatic cancers (26–33). For instance, a study involving 34 patients with histologically confirmed gastric signet ring cell carcinoma across 4 medical centers demonstrated that 68Ga-FAPI-04 PET had better radiotracer uptake, tumor-to-background ratios, and diagnostic accuracy than 18F-FDG PET in detecting primary or recurrent tumors and metastatic lesions (Fig. 2) (31). Notably, lesion sites in which 18F-FDG was advantageous over 68Ga-FAPI-04 were not present. In addition to PET/CT, multisequence imaging using 68Ga-FAPI-04 PET/MRI has proven effective in identifying lesions in pancreatic cancer, especially in cases of obstructive inflammation and minuscule liver metastases (34). Qin et al. reported that multisequence MRI was advantageous for interpreting metastatic lesions in the liver, uterus, rectum, bones, and ovaries in a cohort of 20 patients with gastric cancer (35). Consequently, multisequence MRI with FAPI PET could enhance the evaluation of soft-tissue lesions.
18F-FDG and 68Ga-FAPI PET imaging of 8 representative patients with gastric signet ring cell carcinoma. 68Ga-FAPI PET outperformed 18F-FDG PET in detecting primary tumors (patients 3, 7, 17, 19, and 33; solid black arrows), local recurrences (patient 12; blue arrows), abdomen lymph node metastases (patients 12, 19, and 27; green arrows), bone metastases (patients 17, 19, and 27), and peritoneal metastases (patients 29 and 33; dotted black arrows). (Adapted with permission of (31).)
On the basis of recent studies conducted by nuclear medicine scientists in China, FAPI PET/CT has considerable potential for imaging sarcomas, a type of cancer with intense FAP expression in tumor cells. In 1 study of 45 patients with recurrent soft-tissue sarcoma and presenting with 282 local relapses and distant metastases, Gu et al. reported that 68Ga-FAPI-04 PET/CT identified more lesions (275/282) than 18F-FDG PET/CT (186/282), with superior sensitivity, specificity, and diagnostic accuracy (P < 0.001) (36). Another study assessed 35 patients with recurrent or metastatic gastrointestinal stromal tumors, finding that 18F-FAPI-42 PET/CT detected more tumor lesions (85/106) than 18F-FDG PET/CT (57/106), with a particularly pronounced difference in the detection of liver metastases (42/48 vs. 16/48; P < 0.001) (37). These findings underscore the potential use of FAPI PET/CT as an emergent and effective imaging modality for monitoring the recurrence of soft-tissue sarcomas and gastrointestinal stromal tumors.
Although the superiority of FAPI PET over 18F-FDG PET has been underscored for various malignancies, the clinical scenario is reversed for lymphoma. In a cohort of 186 participants presenting with 5,980 lymphoma lesions, 18F-FDG PET/CT identified more nodal lesions (4,624 vs. 2,196) and extranodal lesions (1,304 vs. 845) than 68Ga-FAPI PET/CT. Thus, the staging accuracy based on the 18F-FDG PET results was more precise than that based on the 68Ga-FAPI-04 PET results (98.4% vs. 86.0%) (38).
The National Cancer Center in China names lung, colorectal, stomach, liver, breast, esophagus, thyroid, pancreas, prostate, and cervical/uterine cancers as the top 10 cancers on the basis of their incidence rates (39). Although the number of FAPI PET studies has surged in various types of cancer, studies on its clinical application for prostate and cervical/uterine cancers remain nascent, with few case studies being reported—highlighting the urgent need for comprehensive research in this area. In addition, FAPI PET imaging is not without pitfalls. High uptake and similar retention of FAPI tracer are seen in malignant disease and inflammatory processes, leading to potential false-positive findings without careful imaging interpretation. However, this issue could be partly overcome by 18F-FDG PET, in which the delayed scan may help differentiate inflammation from malignancy because inflammatory processes normally show rapid washout and, in general, low avidity. In addition to that in inflammatory disease, increased FAPI uptake in other nononcological conditions (including degenerative disease, fibrotic lesions, and tuberculosis) implies that radiologists should exercise extreme caution and that integrating these and other imaging findings with clinical data is essential for a comprehensive evaluation (40). Therefore, it would be meaningful to generate evidence for FAPI PET to better characterize tumor biology or in cancer types in which 18F-FDG shows shortcomings rather than replicating the entire volume of data available with 18F-FDG.
Impact on Tumor Management
FAPI PET/CT has garnered attention for its favorable tumor-to-background contrast and detection rate in primary and metastatic tumors across most cancer types. Consequently, enhanced detection could improve clinical tumor–node–metastasis (TNM) staging compared with traditional imaging methods, paving the way for optimized therapeutic strategies (20,23,28,41). For instance, imaging with 68Ga-FAPI-04 PET/CT resulted in TNM upstaging in 6 of 23 patients with pancreatic cancer (26.1%) compared with imaging with 18F-FDG (41). Crucially, these staging changes influenced clinical management decisions for 2 of these patients (8.7%). Similarly, in a study in which 68Ga-FAPI-04 PET/CT was compared with contrast-enhanced CT, 68Ga-FAPI-04 PET/CT resulted in TNM upstaging in 5 of 23 patients (21.7%) and prompted changes in the therapeutic approach for 1 patient (4.3%) (41).
The prognostic value of FAPI PET is another pivotal dimension to consider in oncologic management. Clinical oncologists may use this prognostic parameter to identify patients at higher risk of residual disease or relapse, allowing more frequent monitoring and implementation of more aggressive treatment regimens. Zhao et al. first reported that the gross tumor volume (GTV) determined via FAPI PET (GTVFAPI) was an independent prognostic indicator for progression-free survival and overall survival in 34 patients who had esophageal squamous cell carcinoma and were undergoing definitive chemoradiotherapy (Fig. 3A) (42). Intriguingly, Hu et al. found that higher baseline tumor-to-background ratios of blood (i.e., the ratio of the SUVmax of the primary tumor to the SUVmean of the blood) on 18F-FAPI-04 PET/CT scans correlated with a poor response to concurrent chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma (P = 0.046) (43). Additionally, in a study of 37 patients with surgically treated pancreatic ductal adenocarcinoma, Ding et al. reported that the SUVmax derived from 68Ga-FAPI-04 PET/CT was a significant independent prognostic factor for recurrence-free survival (hazard ratio, 2.46; P < 0.05) (44). Moreover, GTVFAPI (also called FAPI-avid tumor volume in their article) correlated with overall survival (hazard ratio, 12.82; P < 0.05) (Fig. 3B) (44). Furthermore, Wu et al. examined the prognostic significance of 68Ga-FAPI PET/CT in patients who had unresectable hepatocellular carcinoma and were undergoing combined PD-1 inhibitor and lenvatinib treatment (45), finding that higher GTVFAPI (also called FAPI-avid tumor volume in their article) was an independent predictor of shorter progression-free survival (hazard ratio, 3.88 [95% CI, 1.26–12.01]; P = 0.020) and overall survival (hazard ratio, 5.92 [95% CI, 1.19–29.42]; P = 0.035). Prognostic insights from FAPI PET can be instrumental in refining the treatment approach and follow-up strategies for oncology patients, potentially improving their clinical outcomes.
Kaplan–Meier plots showing overall survival for 45 patients with unresectable esophageal squamous cell carcinoma (A) and 37 patients with resectable pancreatic ductal adenocarcinoma (B), stratified by GTVFAPI. Definition of GTVFAPI is consistent with that of FAPI-avid tumor volume (FTV). (Adapted with permission of (42) and (44).)
Radiotherapy is the cornerstone treatment for most cancers. Integrating 18F-FDG PET/CT into radiotherapy planning has significantly enhanced the accuracy of outlining target volumes for numerous cancers, notably head, neck, and lung cancers. Similarly, there is a growing interest in the potential of FAPI PET to fine-tune radiotherapy planning. A recent study of PET/CT-guided complementary contouring of contrast-enhanced CT–based GTV in 21 patients with esophageal cancer underscored the adaptability of FAPI PET in this domain (46). When 20% and 30% were used for FAPI SUVmax thresholds, the revised GTV expanded in 4 of 21 participants (19%). Interestingly, a tighter threshold of 40% for FAPI SUVmax expanded the GTV in only 2 participants, highlighting the nuances of FAPI PET for refining radiotherapy strategies depending on the uptake parameters. However, there is a noticeable gap in Chinese research on the utility of FAPI PET in radiotherapy planning for other malignancies.
External-beam radiotherapy is the first-line treatment for nasopharyngeal carcinoma, and 68Ga-FAPI PET/CT seems to better delineate tumors than 18F-FDG PET/CT because of its superior tumor-to-background ratio and enhanced lesion detectability (20). However, 2 studies compared 68Ga-FAPI PET/CT with MRI evaluations, finding that 68Ga-FAPI PET/CT upstaged the T stage in 13 of 47 and 4 of 39 patients and understaged the T stage in 2 of 47 and 2 of 39 patients (20,47). These disparities underscore that although FAPI PET/CT holds promise, it should be viewed as a complementary tool that acts synergistically with other imaging modalities. Nonetheless, this combined approach could reduce uncertainties and inconsistencies in anatomic tumor delineation.
Overall, these findings highlight the potential of 68Ga-FAPI PET/CT as a diagnostic tool and critical component for shaping personalized and effective treatment pathways for patients with cancer. However, there is a dearth of early-response evaluations with FAPI PET. Crucial aspects that need to be addressed are the extent and duration of FAPI uptake in postsurgery areas or tumors treated with radiation (48). Differentiation of viable tumor lesions from fibrotic or inflammatory processes may be challenging in patients who underwent FAPI PET/CT for therapy response evaluation, particularly those who underwent surgical resection and radiation therapy.
Radionuclide Therapy Targeting FAP
In recent years, radionuclide-targeted therapy has emerged as a potential therapeutic alternative for patients with advanced and metastatic cancer, especially those for whom multiple lines of therapy have failed. Notably, targeted radiopharmaceuticals, including 177Lu-DOTATATE and 177Lu-labeled prostate-specific membrane antigen, have shown considerable promise—extending survival in patients with specific tumor types, such as neuroendocrine tumors and prostate cancer (49). However, some therapy-related radionuclides, including 177Lu, 90Y, and 225Ac, are import dependent. For instance, self-produced 177Lu only meets 5% of the domestic demand, and other commonly used medical isotopes rely on imports. In addition, therapy-related radiopharmaceuticals have not been approved by the National Medical Products Administration (although the U.S. Food and Drug Administration has approved ∼60 radiopharmaceuticals for clinical use, whereas China has approved ∼30) (50). To date, only 5 publications by Chinese nuclear medicine physicians, including 4 case reports and only 1 clinical research article, have reported on 177Lu-FAPI radioligand therapy (Table 2; Fig. 4). Two distinct cases, 1 with nasopharyngeal carcinoma and the other with radioiodine-refractory differentiated thyroid cancer, were treated with 177Lu-FAPI-46. The former underwent 1 cycle, and disease progression occurred; the latter received 4 cycles, resulting in stable disease (51,52). Furthermore, reports from the Affiliated Hospital of Southwest Medical University indicated that 177Lu-FAP-2286 was used for 1 patient with lung squamous cell carcinoma and 1 patient with recurrent bladder cancer, and both achieved a partial response after treatment (53,54). Moreover, a dose escalation trial conducted at The First Affiliated Hospital of Xiamen University and involving 12 patients with metastatic radioiodine-refractory thyroid cancer showed promising results with 177Lu-EB-FAPI (denoted as 177Lu-LNC1004) (55). This first-in-humans trial, using a 3 + 3 dose escalation design over a 6-wk treatment cycle, reported a mean whole-body effective dose of 0.17 ± 0.04 (mean ± SD) mSv/MBq. Impressively, the treatment exhibited high 177Lu-EB-FAPI uptake and retention, culminating in a mean absorbed tumor dose of 8.50 ± 12.36 Gy/GBq. The outcomes, based on the RECIST criteria, were as follows: 25% (3/12) partial response, 58% (7/12) stable disease, and 17% (2/12) progressive disease; these data signified overall objective response and disease control rates of 25% and 83%, respectively.
Summary of Representative Studies of FAPI Radioligand Therapy in China
Representative PET maximum-intensity projections showcasing patients with metastatic solid cancer both at baseline and after targeted FAP radionuclide therapy. (Adapted with permission of (51) (A: metastatic nasopharyngeal carcinoma), (52) (B: metastatic thyroid cancer), (53) (C: recurrent bladder cancer), (54) (D: lung squamous cell carcinoma), and (55) (E: metastatic thyroid cancer). F is from our unpublished data (metastatic medullary thyroid cancer).
Despite the promising preliminary findings for 177Lu-EB-FAPI in China, comprehensive prospective randomized controlled trials should be conducted in the coming years. In studies focusing on FAP-targeted radionuclide therapy, striking the right balance between the rate of clearance of the drug and the time it resides in the tumor is imperative. Concurrently, balancing the physical half-life of the radioisotope and the biologic half-life of the ligand is critical for achieving a high therapeutic efficacy with a robust safety profile. Distinctively, FAP-targeted radionuclide therapy zeroes in on tumor-associated fibroblasts, emitting rays that irradiate neighboring malignant tumor cells through the “cross-fire” effect, inducing cell death. This approach differs from other radionuclide therapies that directly target tumor cells. Additionally, understanding the intricacies of the tumor microenvironment is crucial. Bao et al. reported that 177Lu-DOTAGA.(SA.FAPi)2 in combination with poly(ADP-ribose) polymerase inhibitors significantly enhanced therapeutic efficacy in a preclinical triple-negative breast cancer model (56). That study indeed opens a new direction for combining 177Lu-labeled FAPIs with conventional antitumor drugs (56). In future endeavors, enhancing therapeutic outcomes could involve integrating FAP radionuclide therapy with conventional antitumor therapy and immunotherapy.
Nontumor Diagnoses
Activated fibroblasts are also found in conditions involving chronic inflammation, fibrosis, and scar formation, suggesting that FAPI PET/CT may have broad applications for nononcologic conditions, especially systemic autoimmune and rheumatic immune diseases in which activated fibroblasts are essential. To date, FAPI PET/CT has been used to detect lesions and evaluate therapeutic responses in several nononcological diseases in China. For instance, Luo et al. conducted a prospective study comparing 68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT in 26 patients with IgG4-related disease (57). 68Ga-FAPI-04 had significantly higher uptake than 18F-FDG in the involved pancreas, bile duct, liver, and salivary glands (P < 0.01). Additionally, 68Ga-FAPI PET/CT detected the involvement of 13.2% of organs (18/136) in 50.0% of the patients (13/26). Lesion uptake using FAPI PET has also been positively correlated with disease stage or severity in patients with various conditions, such as renal fibrosis (58), interstitial lung diseases (59), Crohn disease intestinal lesions (60), and rheumatoid arthritis (61). When used appropriately, FAP-targeting tracers offer significant advantages and an effective, noninvasive diagnostic strategy for the aforementioned diseases. The potential of FAPI PET in evaluating the therapeutic response has been exclusively assessed in preclinical arthritis studies, suggesting its utility in monitoring treatment responses in rheumatoid arthritis (62).
PERSPECTIVES AND FUTURE DIRECTIONS
FAPI tracers were first reported by a team at the University of Heidelberg in Germany in 2018. Since then, their use in the nuclear medicine field has rapidly gained traction, but FAPI remains in its developmental phase in China. Although advances in preclinical research have improved FAPI uptake and prolonged tumor retention, few studies have translated modified FAPI tracers into clinical applications. Chinese nuclear medicine scientists have reported impressive findings on the diagnostic capabilities of FAPI PET for various tumor types. However, many of these studies were constrained by limited patient populations and lacked corroborative histopathologic results. Despite the promising diagnostic prowess of FAPI, which sometimes rivals or surpasses 18F-FDG, most conclusions have been drawn from single-center studies with relatively small sample sizes. Hence, any assertion that FAPI can replace 18F-FDG is premature, and FAPI should be considered a complementary tool with specific indications. Interestingly, FAP is not exclusive to tumor tissues; it is also present in certain nontumor lesions. This duality broadens the clinical utility of FAPI PET for specific nontumor diseases. However, this necessitates extreme prudence from nuclear medicine specialists and radiologists to accurately differentiate tumors from inflammatory disease. Currently, most FAPI tracers use 68Ga, with scant research on 18F and 99mTc labeling. Given the longer half-life of 18F (109.8 vs. 68.0 min), superior spatial resolution, and more abundant cyclotron production, applying 18F-radiolabeled FAPI variants should be further explored. Additionally, the ubiquity of SPECT/CT machines compared with PET/CT and PET/MRI devices in Chinese hospitals makes 99mTc-labeled FAPI a convenient imaging modality for future clinical applications.
China has only 1 recorded application of FAPI PET for target volume delineation in radiotherapy planning. In contrast, European studies have expanded this to include head and neck cancers, lung cancers, adenoid cystic carcinomas, pancreatic cancers, and gliomas, suggesting future growth areas (13). However, a larger patient pool and consistent threshold standards are essential for future studies. Moreover, early evidence suggests a correlation between parameters derived from FAPI PET and patient prognosis for certain tumors, potentially aiding patient stratification and fostering personalized treatments. In addition to imaging, FAPI radioligand therapy has emerged as a promising avenue in nuclear medicine. Although preliminary results show manageable adverse events and promising efficacy in patients with advanced multiline treatment failures, comprehensive large-sample prospective randomized controlled studies are still lacking.
Most of China’s FAPI research stems from standalone studies at individual centers, often with limited sample sizes. However, because of the wealth of case resources and rapid nuclear medicine progressions in China, there is an urgent call for expansive, multicenter, prospective clinical trials with more extensive participant involvement. In 2021, the China Ministry of Science and Technology and 7 other departments formally released the “Medical Isotope Long-term Development Plan (2021–2035),” which promotes the clinical application of radiopharmaceuticals and calls to advance the research and development of novel radiopharmaceuticals, including the radiolabeled FAPI tracers. Such endeavors will pave the way for formulating and optimizing guidelines and a consensus surrounding FAPI imaging and therapy.
With the dazzling speed of development and tremendous advances of FAPI-related studies in China over the past 4 y, the findings reported by the Chinese clinical and research community should be of high value to the worldwide FAPI community. In addition to the high-quality study performed at some leading institutions in China, the 1.4-billion population of China can also be further explored for various scientific and clinical investigations. With such a large population base, there are many different types of rare disease with significant number of patients (e.g., Ig-G4 related disease, cardiac amyloidosis, cancer of unknown primary origin, gastrointestinal cancer, and biliary–pancreatic cancer), which will definitely provide numerous opportunities for future potential cooperation as well as international multicenter studies. Therefore, with the ever increasing scientific and clinical caliber of research personnel and clinicians in China, we strongly believe the FAPI-related studies from Chinese community will greatly benefit the worldwide FAPI community.
In conclusion, FAPI PET imaging raises exciting opportunities with ease of patient preparation. Rapid uptake and high tumor-to-background ratio allows early imaging. Given the large volume of evidence with 18F-FDG in diagnosis, prognostication, and response assessment, FAPI-based PET imaging may be better approached, at least initially, as a complementary agent to 18F-FDG with specific applications. Chinese nuclear medicine experts are poised to collaborate with international peers, ushering in a groundbreaking phase in the convergence of radionuclide tumor diagnosis and treatment. We expect that through unremitting and collaborative efforts, FAPI-derived radiopharmaceuticals will play a crucial role in improving and enhancing the quality of human life and health care worldwide.
DISCLOSURE
No potential conflict of interest relevant to this article was reported.
- © 2024 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication October 31, 2023.
- Revision received January 29, 2024.
