Prospective comparison of 68Ga-FAPI-04 and 18F-FDG PET/CT for tumor staging in nasopharyngeal carcinoma

Purpose: To explore the difference in the effectiveness of gallium-68 fibroblast activation protein inhibitor (⁶⁸Ga-FAPI-04) PET/CT and fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) PET/CT for the initial staging of patients with nasopharyngeal carcinoma (NPC).

Methods: The Affiliated Hospital of Southwest Medical University hosted this single-center prospective investigation (Clinical Trials registration No.ChiCTR2100044131) between March 2020 and September 2021. Within a week, all subjects underwent MR scans, ⁶⁸Ga-FAPI-04 PET/CT, and ¹⁸F-FDG PET/CT in order. The effectiveness of medical staging employing ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG PET/CT was compared.

Results: Twenty-eight patients with primary NPC were evaluated (mean age53 ± 11 years). ⁶⁸Ga-FAPI-04 PET/CT indicated an elevated recognition rate for diagnosing primary tumors (28/28 [100%] vs. 27/28 [96%]) and lymph node metastases (263/285 [92%] vs. 228/285 [80%]), but a lower detection rate for distant metastases (5/7 [71%] vs. 7/7 [100%]) compared with ¹⁸F-FDG PET/CT. A significant association between the maximum standard uptake value (SUVmax) of ¹⁸F-FDG PET and ⁶⁸Ga-FAPI-04 PET was found in the primary cancers (r = 0.691, p < 0.001). In comparison to ¹⁸F-FDG PET/CT, ⁶⁸Ga-FAPI-04 PET/CT upstaged the T stage in five patients while downstaging the N stage in seven patients. ⁶⁸Ga-FAPI-04 PET/CT corrected the overall staging of five patients on¹⁸F-FDG PET/CT.

Conclusion: ⁶⁸Ga-FAPI-04 PET/CT is preferable to ¹⁸F-FDG PET/CT for NPC staging in terms of the detection efficiency for primary tumors and lymph node metastasis. This is especially true when evaluating the primary cancer and any spread to contiguous tissues. It is possible to improve the staging assessment of NPC by using ⁶⁸Ga-FAPI-04 PET/CT in conjunction with ¹⁸F-FDG PET/CT.

Introduction

Nasopharyngeal carcinoma (NPC) is a prevalent epithelial malignancy; its incidence is related to ethnicity and regional distribution. People in East and Southeast Asia, especially in Fujian and Guangdong areas of China, have a high incidence of NPC (1). In 2020, a survey of 185 countries determined that NPC was newly diagnosed in 133,354 patients and resulted in almost 80,000 fatalities (2). NPC tends to infiltrate locally early and typically involves regional nodes (3). Patients with terminal disease often develop distant metastases (4); thus, early and correct staging of NPC is critical for enhancing the individuals’ quality of life and treatment outcomes (5).

As the first-choice imaging method for NPC, MR is excellent for showing adjacent soft tissue infiltration, skull base bone and intracranial invasion, and retropharyngeal lymph node involvement (6). The National Comprehensive Cancer Network currently recommends fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) PET/CT as a well-proven imaging strategy for NPC management (7), with elevated accuracy and sensitivity for identifying lymph nodes and distant metastases (8, 9). ¹⁸F-FDG reveals the glucose metabolism of abnormalities. Owing to the high physiological glucose utilization in healthy brain tissues and the lesser soft tissue resolution of PET/CT compared to that of MR, the precision of ¹⁸F-FDG PET/CT for the T staging of NPC is insufficient, mainly for the description of the skull base and intracranial invasion (10, 11).

Gallium-68-labeled fibroblast activation protein inhibitor (⁶⁸Ga-FAPI) is a recently developed cancer tracer. It indicates the degree of fibroblast activation protein (FAP) expression (12–14). Cancer-associated fibroblasts overexpress FAP in most epithelial cancers, including NPC, whereas its expression is modest in most healthy tissues and organs. PET/CT using ⁶⁸Ga-FAPI-04 reveals tumors and metastases in various malignant tumors, such as head and neck cancers, with strong tracer uptake in lesions (13–15). ⁶⁸Ga-FAPI has a greater target to background ratio than ¹⁸F-FDG (16). Furthermore, prior research have demonstrated that ⁶⁸Ga-FAPI-04 PET/CT is an effective investigative approach for NPC, especially for the assessment of the primary cancer and any spread to contiguous tissues (17, 18).

Therefore, we carried out a prospective investigation to explore the difference in the effectiveness of ¹⁸F-FDG PET/CT and ⁶⁸Ga-FAPI-04 PET/CT in discovering primary tumor, nodal, and distant metastases in patients with NPC.

Materials and methods

Participants

Between March 2020 and September 2021, the affiliated hospital of Southwest Medical University provided access to this prospective medical trial. The research protocol was approved by both the China Clinical Trials Registry and the Clinical Research Ethics Committee at the previously mentioned hospital (Clinical Trials registration No.ChiCTR2100044131; Ethics Committee approval No.2020035). All individuals gave their written permission after being fully informed. Within seven days, all individuals completed MR scans, ⁶⁸Ga-FAPI-04 PET/CT, and ¹⁸F-FDG PET/CT in order. The acquisition interval between ⁶⁸Ga-FAPI-04 PET/CT and ¹⁸F-FDG PET/CT was at least one day. The criteria for inclusion were: (a) individuals with de novo histopathologically given a diagnosis NPC; (b) subjects participated who had not received antitumor therapy before the evaluation; (c) individuals with cancer who chose to undergo paired ¹⁸F-FDG along with ⁶⁸Ga-FAPI-04 PET/CT tests to stage their disease; and (d) subjects who agreed to follow the protocol procedures, gave their written informed consent, and gave their signatures. The following is a list of the conditions for exclusion: (a) individuals with contraindications for the exams, (b) people with additional primary cancers at the time of the testing, and (c) individuals who began therapy prior to the completion of the three tests.

¹⁸F-FDG and ⁶⁸Ga-FAPI-04 preparation

¹⁸F-FDG was formed utilizing normal procedures and a coincident ¹⁸F-FDG synthesizing form (FDG-N, PET Science & Technology). DOTA-FAPI-04 was acquired from MedChemExpress LLC. As previously mentioned (19), radiolabeling and purifying of ⁶⁸Ga-FAPI-04 were conducted. The radiochemical purity of ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG exceeded 95%, and the finished radiopharmaceuticals were sterile and devoid of pyrogens.

Imaging acquisition

Before undergoing the ¹⁸F-FDG PET/CT evaluation, the subjects abstained from food and drink for at least six hours to ensure that their blood glucose levels were within the accepted values (3.9–6.1 mmol/L). However, there was no need to make any preparations in order to take the ⁶⁸Ga-FAPI-04 PET/CT test. The doses of ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG that were administered via intravenous injection were 3.7 and 1.85 MBq/kg, respectively (19, 20). Following a tracer injection, participants got a PET/CT scan (uMI780, United Imaging Healthcare) 40–60 mins later. All scans were conducted in accordance with a previously outlined technique (21, 22), and the resulting data were provided to a post-processing workstation (Version R002, uWS-MI, United Imaging Healthcare). The PET data were recreated with the help of an algorithm called sorted subset anticipation maximization (two iterations and 20 subsets). Evaluations of the nasopharynx and the cervical area employing contrast-enhanced (CE) MR were carried out using head and neck coils on 1.5-T MR scanners (Achieva 1.5T, Philips, Amsterdam, the Netherlands). We acquired the MR images, containing axial T1-weighted fast spin-echo images immediately before injection of contrast. (repetition time [TR] = 450 ms; echo time [TE] = 15 ms, flip angle = 90°, field of view [FOV] =232 mm × 232 mm, slice thickness = 5 mm, spacing between slices = 1 mm), axial T2-weighted fast spin-echo images (TR = 3,575 ms, TE = 80 ms, flip angle = 90°, FOV =232 mm × 232 mm, slice thickness = 5 mm, spacing between slices = 1 mm), and axial and coronal T2-weighted fat-suppressed spin-echo images (TR = 1,927 ms, TE = 55 ms, flip angle = 90°, FOV =250 mm × 250 mm, slice thickness = 5 mm, spacing between slices = 1 mm). At a rate of 1.5 mL/s, intravenous doses of 0.1 mmol/kg gadopentetate dimeglumine were delivered. Using the exact parameters as the axial T1-weighted fast spin-echo images, the axial T1-weighted fast spin-echo sequence was obtained.

Imaging analysis

Two board-certified nuclear medicine specialists investigated all PET/CT sets of data. To avoid bias, cohort 1 (L.C. and Y.C.) assessed all ¹⁸F-FDG PET/CT pictures, while cohort 2 (Y.Z. and L.Q.) reviewed all ⁶⁸Ga-FAPI-04 PET/CT images. Two board-certified radiologists (D.C. and J.S.) who were blinded to the PET/CT outcomes analyzed the MRI. Investigating any non-physiological uptake employing ¹⁸F-FDG or ⁶⁸Ga-FAPI-04 PET that was higher than the activities of the background blood pool or the activities of the background of the neighboring healthy tissue was the primary focus of the study. On transverse PET scans, regions of interest were outlined for semi-quantitative analysis. The SUVmax was automatically computed to estimate the uptake of ¹⁸F-FDG or ⁶⁸Ga-FAPI-04 in primary cancers, associated lymph nodes, and distant metastases. Clinical staging is based on three different types of images in accordance with the American Joint Committee on Cancer staging system version 8th (23).

Primary lesion evaluation

On PET images, the SUVmax of every primary lesion was recorded. By comparing the radioactivity of the lesion border to that of the nearby healthy tissue, the boundaries were visually evaluated. The border and extent of the invasion were identified if the radioactivity at the border of the injury was significantly greater than that of the nearby healthy tissue. Corresponding CT image was employed to help recognize morphology and localization of the lesions. The extent and border of every lesion were evaluated, and any variation between the three imaging techniques were noted.

Lymph node evaluation

Patients’ lymph nodes were categorized into four sections: the retropharyngeal region, the right and left sides of the neck located above the cricoid cartilage inferior edge, and the region below the cricoid cartilage inferior boundary. Employing ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 PET/CT, the quantity of lesions and SUVmax with the greatest pathological tracer buildup were measured for every lymph node area, and the techniques were compared. According radiographic criteria, the MR identification of metastatic lymph nodes located in the cervical region must meet at least one of the following (9): (a) there was extracapsular expansion or necrosis, (b) in the retropharyngeal region, the lowest axial diameter was 5 mm, and in other locations, it was ≥ 10 mm, and (c) there were ≥ 3 lymph nodes of borderline size.

Distant metastasis evaluation

Except for the primary tumor and nodal metastases, any non-physiological uptake above the activities of the background blood pool or the activities of the background of the neighboring healthy tissue on PET/CT, with or without morphological abnormalities, was classified as a possible distant metastasis. Distant metastases were also considered as positive if the signal is different from that of adjacent background tissues on MRI. Lesions with aberrant tracer uptake and MR signals were counted and localized. The SUVmax of each metastatic lesion was also recorded.

Reference standard

Histopathological analysis of the biopsied or resected samples served as the basis for the definitive diagnosis. In accordance with the criteria of the National Comprehensive Cancer Network (7), CE-MR is the gold standard for assessing the cancer and its invasion of neighboring tissues. Due to technological and ethical constraints, histological verification of all lymph nodes and distant metastases was not achievable. Therefore, the tumor was classified as malignancy based on the confirmation of typical malignant characteristics by multimodal imaging. The duration of the follow-up was over three months. During follow-up following anti-cancer therapies, including chemotherapy, radiation, and/or targeted therapy, a considerable decrease in lesion size was determined to be malignant.

Statistical analyses

All statistical analyses were done by employing SPSS (version 22.0; SPSS Inc.). Categorical data are represented numerically and as a percentage. The expression for continuous variables is the mean standard deviation. Using Spearman’s correlation analysis, the relationship between the kind of pathology and the degree of tracer uptake was found. Employing the paired samples t-test, the SUVmax values of the primary and metastatic lesions were compared between ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 PET/CT. The ¹⁸F-FDG SUVmax was compared between metastatic and non-metastatic lymph nodes using a t-test for independent samples. Two-tailed p-values of < 0.05 were regarded as statistically significant.

Results

Participant characteristics

This investigation comprised twenty-eight individuals (5 women and 23 men) aged 33–75 years (mean = 53 ± 10 years). ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG PET/CT were well tolerated by all subjects, and no ⁶⁸Ga-FAPI-04-related side effects were identified. All individuals were newly diagnosed with nasopharyngeal carcinoma, in which two instances were keratinizing squamous cell carcinoma (WHO Type I), eleven patients were non-keratinizing differentiated carcinoma (WHO Type II), and fifteen patients were non-keratinizing undifferentiated carcinoma (WHO Type III). The clinical data is displayed in Table 1.

TABLE 1

Table 1 Summary of patient basic characteristics.

Diagnostic effectiveness of ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG PET/CT for primary tumors

The PET/CT scan utilizing ⁶⁸Ga-FAPI-04 identified all 28 primary cancers with a detection rate of one hundred percent. ¹⁸F-FDG PET/CT revealed 27 of the 28 primary cancers, which is a 96% detection rate. There was no indication of a greater SUVmax value for ⁶⁸Ga-FAPI-04 PET in the primary malignancies comparing with ¹⁸F-FDG PET (12.1 ± 4.9 vs. 11.7 ± 4.6; p = 0.543) (Table 2). Additional comparison of the connection between the uptake of the two tracers revealed a substantial relation between the SUVmax values of ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG (r = 0.69, p < 0.001). Furthermore, there was no relation among the different histopathological kinds and the SUVmax of the two tracers (p > 0.05). A visual assessment of the primary lesion invasion was performed using the two tracers (Table 3).

TABLE 2

Table 2 The SUVmax comparison between ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 PET/CT in primary tumor, nodal, and distant metastasis.

TABLE 3

Table 3 Visual evaluation of tumor invasion using the 3 modalities.

Nasopharyngeal invasion

Both modalities clearly delineated the boundary and extent of tumor invasion, except in one case (Figure 1) of nonkeratinizing differentiated carcinoma that was not detected by ¹⁸F-FDG PET. Visual evaluation of nasopharyngeal invasion was similar for the two tracers in 27 participants, but of which two cases were found to be inferior to MR.

FIGURE 1

Figure 1 A 49-year-old man with nonkeratinizing differentiated carcinoma. ⁶⁸Ga-FAPI-04 PET/CT showed intensive ⁶⁸Ga-FAPI-04 uptake in the posterior nasopharyngeal wall (A, dotted arrow, SUVmax 3.8), ¹⁸F-FDG PET/CT showed no abnormal ¹⁸F-FDG uptake in the primary tumor (B, dotted arrow). Moreover, ⁶⁸Ga-FAPI-04 PET/CT reveals higher tracer uptake than ¹⁸F-FDG PET/CT in the left supraclavicular lymph node (A, thick arrow, SUVmax 9.4 vs. B, thick arrow, SUVmax 3.8), but the tracer uptake of left cervical (level III) lymph nodes was lower than that of ¹⁸F-FDG PET/CT (A, thin arrow, SUVmax, 4.5–11.0 vs. B, thin arrow, SUVmax, 17.7–19.4).

Parapharyngeal space invasion

Eighteen participants had parapharyngeal space invasion. The extent of lesions on ⁶⁸Ga-FAPI-04 PET/CT was larger than that on MR in one of the 18 participants, while there were two cases with a smaller extent and one case with a larger extent on ¹⁸F-FDG PET/CT compared with MR. There were 2 and 16, respectively, patients with ⁶⁸Ga-FAPI-04 who were dominant and equal to ¹⁸F-FDG.

Skull base bone invasion

Typically, 11 participants had invasion of the skull base bone. ⁶⁸Ga-FAPI-04 PET/CT had a 100% (11/11) positive detection rate and showed a tumor extent and border delineation similar to that of MR. The 11 patients discovered by ¹⁸F-FDG PET/CT included one false-positive case, while one person with skull base invasion went undetected. In 4 of the 11 participants, ⁶⁸Ga-FAPI-04 PET/CT showed a greater degree of skull base bone invasion compared to ¹⁸F-FDG PET/CT (Figure 2).

FIGURE 2

Figure 2 A 45-year-old man with nonkeratinizing differentiated carcinoma. Intense ⁶⁸Ga-FAPI-04 uptake was observed in the left temporal lobe (A, dotted arrow), suggesting intracranial invasion, but ¹⁸F-FDG PET/CT (B) showed no abnormal intracranial ¹⁸F-FDG uptake. Moreover, intense ⁶⁸Ga-FAPI-04 uptake was observed in the occipital and right temporal bone (A, solid arrow), while ¹⁸F-FDG PET/CT only showed low tracer uptake in the right temporal bone (B, solid arrow), which was confirmed by MRI (C, solid arrow). ⁶⁸Ga-FAPI-04 PET/CT revealed more extensive lesions on intracranial and skull base invasion than ¹⁸F-FDG PET/CT.

Intracranial invasion

Typically, 4 participants had an intracranial invasion. The positive detection rates for ⁶⁸Ga-FAPI-04 PET/CT along with ¹⁸F-FDG PET/CT were, respectively, 100% (4/4) and 25% (1/4) (Figure 2). Owing to the physiological high uptake of ¹⁸F-FDG in the brain, both ⁶⁸Ga-FAPI-04 PET/CT and MR revealed a more precise border of intracranial invasion than ¹⁸F-FDG PET/CT.

Diagnostic effectiveness of ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG PET/CT for nodal metastasis

Twenty-seven of the 28 participants (285 lymph nodes) were suspected to have lymph node metastases. For 25/285 lymph nodes, histopathological analysis acted as a reference standard, and for the remaining lymph nodes, morphological analysis and/or follow-up imaging were used. Of the 285 suspected lymph nodes, 234 lymph nodes in 24 participants were considered malignant and 51 lymph nodes were lastly verified as inflammatory. From a total of 285 lymph nodes, ⁶⁸Ga-FAPI-04 PET/CT recognized 263 (false-positive uptake in 2 lymph nodes and false-negative uptake in 20 lymph nodes). By comparison, 228 lymph nodes were successfully detected by ¹⁸F-FDG PET/CT (false-positive uptake in 51 lymph nodes and false-negative uptake in six lymph nodes, Figure 3). MR accurately diagnosed 262 lymph nodes, with two false-positive and twenty-one false-negative lymph nodes, respectively. Only one of the 203 lymph nodes with positive ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG uptake was confirmed to be a false positive. The SUVmax of metastatic lymph nodes was somewhat greater in ¹⁸F-FDG than in ⁶⁸Ga-FAPI-04 (13.6 ± 5.5 vs. 11.7 ± 5.0), but the variation was not substantially significant (p = 0.133. Table 2). Significantly greater ¹⁸F-FDG uptake was seen in the metastatic lymph nodes compared to the non-metastatic reactive lymph nodes (13.6 ± 5.5 vs. 3.2 ± 0.7; p < 0.001).

FIGURE 3

Figure 3 A 57-year-old man with nonkeratinizing undifferentiated carcinoma. An increase ¹⁸F-FDG uptake was observed in the bilateral cervical (level II) lymph nodes (B, arrow, SUVmax 3.3–4.2). However, no abnormal ⁶⁸Ga-FAPI-04 uptake was observed in the cervical lymph nodes (A, arrow). Ultrasound-guided biopsy of the right level II lymph node revealed proliferating lymphoid cells with no signs of metastatic disease. Finally, it was confirmed by follow-up that all the suspected metastatic lymph nodes were reactive.

Diagnostic effectiveness of ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG PET/CT for distant metastasis

Among the 28 participants, seven distant metastases were found in four participants (including three pulmonary and four bone metastases). All distant metastases were detected by ¹⁸F-FDG PET/CT, whereas ⁶⁸Ga-FAPI-04 uptake was negative in two pulmonary metastases (Figure 4). One individual had concurrent bone and lung metastases. Across all evaluations of distant metastases, the SUVmax of ⁶⁸Ga-FAPI-04 did not vary significantly from that of ¹⁸F-FDG (6.6 ± 4.0 vs. 8.3± 5.9; p = 0.450. Table 2).

FIGURE 4

Figure 4 A 48-year-old man with nonkeratinizing undifferentiated carcinoma.⁶⁸Ga-FAPI-04 (A) and ¹⁸F-FDG PET/CT (B) revealed an abnormal nodule in the left lower lobe (A, red arrow, SUVmax 4.9 vs. B, red arrow, SUVmax 8.2). However, the nodule in the left upper lobe showed abnormal uptake on ¹⁸F-FDG PET/CT (B, blue arrow), but not on ⁶⁸Ga-FAPI-04 PET/CT (A, blue arrow). In addition, both ⁶⁸Ga-FAPI-04 (A, green arrow) and ¹⁸F-FDG PET/CT (B, green arrow) revealed abnormal activity in the right femur. Follow-up CT after two cycles of induction chemotherapy showed a reduction in the volume of pulmonary metastases (C, red and blue arrow). Meanwhile, the bone metastasis of the right femur revealed a repair response after treatment, showing osteosclerotic nodule on follow-up CT (C, green arrow).

Variations in tumor staging

The outcomes of the ⁶⁸Ga-FAPI-04 PET/CT, ¹⁸F-FDG PET/CT, and MR imaging were compiled in Table 4, which provides a summary of the cancer staging for each of the 28 subjects. ⁶⁸Ga-FAPI-04 PET/CT underestimated the number of participants in the N staging and M staging by 1. In contrast, ¹⁸F-FDG PET/CT undervalued the T staging in five participants and overestimated the N staging in seven participants. For the overall staging, although ⁶⁸Ga-FAPI-04 PET/CT underestimated the medical stage of two participants, it correctly upgraded the medical staging of ¹⁸F-FDG PET/CT in two participants (from III to IVA) and downgraded the medical staging of ¹⁸F-FDG PET/CT in three participants (two from III to I and one from III to II).

TABLE 4

Table 4 Comparison of MR, ¹⁸F-FDG, and ⁶⁸Ga-FAPI-04 PET/CT-based tumor staging (n = 28).

Discussion

Accurate staging is vital for NPC management. In our investigation, ⁶⁸Ga-FAPI-04 PET/CT revealed more recognition efficiency in diagnosing primary cancers (28/28 [100%] vs. 27/28 [96%]) and lymph node metastases (263/285 [92%] vs. 228/285 [80%]) than¹⁸F-FDG PET/CT. However, in comparison to the efficacy of ¹⁸F-FDG PET/CT in identifying distant metastases, the effectiveness of ⁶⁸Ga-FAPI-04 PET/CT in this regard was lower (5/7, or 71%), coming in at (7/7, or 100%). The combination of ¹⁸F-FDG along with ⁶⁸Ga-FAPI-04 PET/CT led to consistent staging in 21 of the 28 participants, with a concordance rate of 75% for overall staging. Despite the fact that ⁶⁸Ga-FAPI-04 PET/CT underestimated the clinical staging in 2/28 subjects, it corrected the staging of ¹⁸F-FDG PET/CT in 5/28 participants. As a consequence of this, we believe that ⁶⁸Ga-FAPI-04 PET/CT is valuable for NPC diagnosis and staging.

Between the primary tumors’ ¹⁸F-FDG as well as ⁶⁸Ga-FAPI-04 uptake, there was no substantial variations. Interestingly, although the imaging principles of the two tracers were different, our study revealed a significant relation between the primary tumor uptake of ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG, which differed from previous reports (17, 18). Raised ⁶⁸Ga-FAPI-04 uptake in tumors is accompanied by higher glucose metabolism, which is positively correlated with cancer aggressiveness (24, 25). This demonstrates that NPC invasiveness may be predicted employing ⁶⁸Ga-FAPI-04 imaging. Previous studies have shown that ⁶⁸Ga-FAPI-04 PET/CT may increase the recognition rate of primary tumors in FDG-negative head and neck tumor (17, 26). In our investigation, ¹⁸F-FDG could not detect the primary lesion in one patient with squamous cell carcinoma confirmed by biopsy, whereas ⁶⁸Ga-FAPI-04 successfully recognized the primary site in the posterior nasopharyngeal wall. This may be due to the superior tumor-to-background ratio of ⁶⁸Ga-FAPI-04 PET/CT comparing with ¹⁸F-FDG, which may enhance the recognition rate of occult NPC.

A high physiological uptake of ¹⁸F-FDG in normal brain tissue may lead to an underestimation of the presence or extent of tumor invasion on PET/CT (3, 17, 18). Due to the extra benefit of a low brain background, our results confirmed that ⁶⁸Ga-FAPI-04 dominates ¹⁸F-FDG PET/CT in determining malignancy invasion of the parapharyngeal space, skull base bone, and intracranial areas. At present MR is the standard approach for T staging in NPC (7). However, two participants in our study showed a smaller extent of nasopharyngeal invasion on ⁶⁸Ga-FAPI-04 PET/CT than on MR, which may be edema and inflammation rather than tumor invasion, resulting in a positive result on MR (27). Therefore, ⁶⁸Ga-FAPI-04 PET/CT indicated a greater recognition efficiency than ¹⁸F-FDG PET/CT for precise T staging, and it was able to detect the target extent for radiotherapy with a greater degree of precision (17, 18).

Staging of the nodes is essential for the management and prognostication of NPC cases. Because of the high prevalence of inflammatory and reactive hyperplasia in cervical lymph nodes, ¹⁸F-FDG PET/CT has been mentioned to have a greater incidence of producing false-positive outcomes when diagnosing lymph node metastasis (28, 29). In our investigation, the quantity of false-positive lymph nodes on ¹⁸F-FDG PET/CT was substantially more than that on ⁶⁸Ga-FAPI-04 PET/CT and MR (¹⁸F-FDG, 51/279 vs. ⁶⁸Ga-FAPI, 2/216 vs. MR, 2/215), which is consistent with the outcomes of prior investigations (28, 29). Utilising ⁶⁸Ga-FAPI-04 PET/CT, the N staging of the 7 participants was downstaged in comparison to ¹⁸F-FDG PET/CT. However, ⁶⁸Ga-FAPI-04 PET/CT revealed more metastatic lymph nodes without positive tracer uptake than ¹⁸F-FDG PET/CT (20/285 [7%] vs. 6/285 [2%]). Moreover, only one was diagnosed as a false positive out of all 203 lymph nodes with double-positive ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 uptake. Previous research has discovered significant correlations between the uptake of ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 in pairs of double-positive lymph nodes (18). Therefore, in assessing lymph node status in NPC patients prior to treatment, it’s possible that the specificity of ⁶⁸Ga-FAPI-04 PET/CT is greater than that of ¹⁸F-FDG PET/CT. When used in conjunction with one another, ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG PET/CT imaging have the potential to increase diagnostic precision for lymph node metastasis in NPC cases.

NPC is prone to distant metastasis (4). Prior investigations have shown that ⁶⁸Ga-FAPI-04 PET/CT has greater sensitivity than ¹⁸F-FDG in identifying visceral and bone metastases of various malignant tumors, including NPC, and metastatic lesions showed higher tracer uptake on ⁶⁸Ga-FAPI-04 PET/CT (15, 17, 18, 21). However, in our investigation, ⁶⁸Ga-FAPI-04 PET/CT did not have a greater detection efficiency compared to ¹⁸F-FDG for distant metastatic lesions in NPC. There were no substantial variations in the uptake of ⁶⁸Ga-FAPI and ¹⁸F-FDG by metastatic lesions. This is likely due to the small amount of metastatic lesions that were studied (n = 7). In addition to this, the ⁶⁸Ga-FAPI-04 PET missed both of the patient’s pulmonary metastases. Therefore, it is essential to consider false-negative status in pulmonary metastases for M staging when conducting ⁶⁸Ga-FAPI-04 PET/CT.

Our investigation has some limitations. First, the sample size (n = 28) was small, and the number of distant metastatic lesions was particularly low. Consequently, prospective studies with greater cohorts are necessary, especially for the detection of distant metastasis. The morphologic and/or follow-up imaging data also served as the evaluation criterion in our examination because histological verification was not probable for totally nodal and distant metastases owing to ethical and technical considerations. Potential false-negative lesions were not sufficiently assessed, as imaging evaluation was also employed as a reference for cancer staging,

In summary, our preliminary findings suggest that ⁶⁸Ga-FAPI-04 has a positive impact on the clinical stage of NPC. Since ⁶⁸Ga-FAPI-04 PET/CT had better tumor-to-background contrast than ¹⁸F-FDG and less false-positive uptake in inflammatory and reactive proliferative lymph nodes, it improved the capability to recognize primary cancer and lymph node metastases, mainly for the assessment of the skull base and intracranial invasion. Nevertheless, when it comes to the detection of distant metastases, ⁶⁸Ga-FAPI-04 PET/CT does not have an advantage over ¹⁸F-FDG PET/CT. The staging assessment of NPC may be improved utilizing ⁶⁸Ga-FAPI-04 PET/CT in conjunction with ¹⁸F-FDG PET/CT.

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 authors.

Ethics statement

The studies involving human participants were reviewed and approved by The Clinical Research Ethics Committee of the Affiliated Hospital of Southwest Medical University. The patients/participants provided their written informed consent to participate in this study.

Author contributions

HD and JL contributed to the study conception and design. Material preparation and data collection were performed by HD, JL, LQ, TX, LC, QW, LW, YC. HD and YL processed and analysed the data. The first draft of the manuscript was written by HD and JL reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version

Funding

This study was supported in part by the Project of Sichuan Provincial Health Commission, China (Grant 21ZD005).

Acknowledgments

The authors are grateful to the members of Department of Nuclear Medicine, The Affiliated Hospital, Southwest Medical University and Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province for their technical guidance, cooperation and assistance in completing this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Chen YP, Chan A, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet (2019) 394(10192):64–80. doi: 10.1016/S0140-6736(19)30956-0

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin (2021) 71(3):209–49. doi: 10.3322/caac.21660

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Wu HB, Wang QS, Wang MF, Zhen X, Zhou WL, Li HS. Preliminary study of 11C-choline PET/CT for T staging of locally advanced nasopharyngeal carcinoma: comparison with 18F-FDG PET/CT. J Nucl Med (2011) 52(3):341–6. doi: 10.2967/jnumed.110.081190

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Chiesa F, De Paoli F. Distant metastases from nasopharyngeal cancer. ORL J Otorhinolaryngol Relat Spec (2001) 63(4):214–6. doi: 10.1159/000055743

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Lee AW, Ma BB, Ng WT, Chan AT. Management of nasopharyngeal carcinoma: Current practice and future perspective. J Clin Oncol (2015) 33(29):3356–64. doi: 10.1200/JCO.2015.60.9347

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Sun XS, Liu SL, Luo MJ, Li XY, Chen QY, Guo SS, et al. The association between the development of radiation therapy, image technology, and chemotherapy, and the survival of patients with nasopharyngeal carcinoma: A cohort study from 1990 to 2012. Int J Radiat Oncol Biol Phys (2019) 105(3):581–90. doi: 10.1016/j.ijrobp.2019.06.2549

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Caudell JJ, Gillison ML, Maghami E, Spencer S, Pfister DG, Adkins D, et al. NCCN guidelines® insights: Head and neck cancers, version 1.2022. J Natl Compr Canc Netw (2022) 20(3):224–34. doi: 10.6004/jnccn.2022.0016

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Yen RF, Chen TH, Ting LL, Tzen KY, Pan MH, Hong RL. Early restaging whole-body (18)F-FDG PET during induction chemotherapy predicts clinical outcome in patients with locoregionally advanced nasopharyngeal carcinoma. Eur J Nucl Med Mol Imaging (2005) 32(10):1152–9. doi: 10.1007/s00259-005-1837-5

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Ng SH, Chan SC, Yen TC, Chang JT, Liao CT, Ko SF, et al. Staging of untreated nasopharyngeal carcinoma with PET/CT: comparison with conventional imaging work-up. Eur J Nucl Med Mol Imaging (2009) 36(1):12–22. doi: 10.1007/s00259-008-0918-7

PubMed Abstract | CrossRef Full Text | Google Scholar

10. King AD, Ma BB, Yau YY, Zee B, Leung SF, Wong JK, et al. The impact of 18F-FDG PET/CT on assessment of nasopharyngeal carcinoma at diagnosis. Br J Radiol (2008) 81(964):291–8. doi: 10.1259/bjr/73751469

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Zhang Y, Chen Y, Huang Z, Zhang L, Wan Q, Lei L. Comparison of 18F-NaF PET/CT and 18F-FDG PET/CT for detection of skull-base invasion and osseous metastases in nasopharyngeal carcinoma. Contrast Media Mol Imaging (2018) 2018:8271313. doi: 10.1155/2018/8271313

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Kratochwil C, Flechsig P, Lindner T, Abderrahim L, Altmann A, Mier W, et al. 68Ga-FAPI PET/CT: Tracer uptake in 28 different kinds of cancer. J Nucl Med (2019) 60(6):801–5. doi: 10.2967/jnumed.119.227967

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Loktev A, Lindner T, Mier W, Debus J, Altmann A, Jäger D, et al. A tumor-imaging method targeting cancer-associated fibroblasts. J Nucl Med (2018) 59(9):1423–9. doi: 10.2967/jnumed.118.210435

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Giesel FL, Kratochwil C, Lindner T, Marschalek MM, Loktev A, Lehnert W, et al. 68Ga-FAPI PET/CT: Biodistribution and preliminary dosimetry estimate of 2 DOTA-containing FAP-targeting agents in patients with various cancers. J Nucl Med (2019) 60(3):386–92. doi: 10.2967/jnumed.118.215913

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Syed M, Flechsig P, Liermann J, Windisch P, Staudinger F, Akbaba S, et al. Fibroblast activation protein inhibitor (FAPI) PET for diagnostics and advanced targeted radiotherapy in head and neck cancers. Eur J Nucl Med Mol Imaging (2020) 47(12):2836–45. doi: 10.1007/s00259-020-04859-y

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Giesel FL, Kratochwil C, Schlittenhardt J, Dendl K, Eiber M, Staudinger F, et al. Head-to-head intra-individual comparison of biodistribution and tumor uptake of 68Ga-FAPI and 18F-FDG PET/CT in cancer patients. Eur J Nucl Med Mol Imaging (2021) 48(13):4377–85. doi: 10.1007/s00259-021-05307-1

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Zhao L, Pang Y, Zheng H, Han C, Gu J, Sun L, et al. Clinical utility of [68Ga]Ga-labeled fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography for primary staging and recurrence detection in nasopharyngeal carcinoma. Eur J Nucl Med Mol Imaging (2021) 48(11):3606–17. doi: 10.1007/s00259-021-05336-w

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Qin C, Liu F, Huang J, Ruan W, Liu Q, Gai Y, et al. A head-to-head comparison of 68Ga-DOTA-FAPI-04 and 18F-FDG PET/MR in patients with nasopharyngeal carcinoma: a prospective study. Eur J Nucl Med Mol Imaging (2021) 48(10):3228–37. doi: 10.1007/s00259-021-05255-w

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Lan L, Liu H, Wang Y, Deng J, Peng D, Feng Y, et al. The potential utility of [68 Ga]Ga-DOTA-FAPI-04 as a novel broad-spectrum oncological and non-oncological imaging agent-comparison with [18F]FDG. Eur J Nucl Med Mol Imaging (2022) 49(3):963–79. doi: 10.1007/s00259-021-05522-w

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Lan L, Zhang S, Xu T, Liu H, Wang W, Feng Y, et al. Prospective comparison of 68Ga-FAPI versus 18F-FDG PET/CT for tumor staging in biliary tract cancers. Radiology (2022) 304(3):648–57. doi: 10.1148/radiol.213118

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Chen H, Pang Y, Wu J, Zhao L, Hao B, Wu J, et al. Comparison of [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer. Eur J Nucl Med Mol Imaging (2020) 47(8):1820–32. doi: 10.1007/s00259-020-04769-z

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Chen H, Zhao L, Ruan D, Pang Y, Hao B, Dai Y, et al. Usefulness of [68Ga]Ga-DOTA-FAPI-04 PET/CT in patients presenting with inconclusive [18F]FDG PET/CT findings. Eur J Nucl Med Mol Imaging (2021) 48(1):73–86. doi: 10.1007/s00259-020-04940-6

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Huang SH, O'Sullivan B. Overview of the 8th edition TNM classification for head and neck cancer. Curr Treat Options Oncol (2017) 18(7):40. doi: 10.1007/s11864-017-0484-y

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Chen X, Liu X, Wang L, Zhou W, Zhang Y, Tian Y, et al. Expression of fibroblast activation protein in lung cancer and its correlation with tumor glucose metabolism and histopathology. Eur J Nucl Med Mol Imaging (2022) 49(8):2938–48. doi: 10.1007/s00259-022-05754-4

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Moreno-Ruiz P, Corvigno S, Te Grootenhuis NC, La Fleur L, Backman M, Strell C, et al. Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation. Lung Cancer (2021) 155:10–9. doi: 10.1016/j.lungcan.2021.02.028

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Gu B, Xu X, Zhang J, Ou X, Xia Z, Guan Q, et al. The added value of 68Ga-FAPI-04 PET/CT in patients with head and neck cancer of unknown primary with 18F-FDG negative findings. J Nucl Med (2021) 63(6):875–81. doi: 10.2967/jnumed.121.262790

PubMed Abstract | CrossRef Full Text | Google Scholar

27. van den Brekel MW, Runne RW, Smeele LE, Tiwari RM, Snow GB, Castelijns JA. Assessment of tumour invasion into the mandible: The value of different imaging techniques. Eur Radiol (1998) 8(9):1552–7. doi: 10.1007/s003300050585

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Lee SH, Huh SH, Jin SM, Rho YS, Yoon DY, Park CH. Diagnostic value of only 18F-fluorodeocyglucose positron emission tomography/computed tomography-positive lymph nodes in head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg (2012) 147(4):692–8. doi: 10.1177/0194599812443040

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Shang Q, Zhao L, Pang Y, Yu Y, Chen H. 68Ga-FAPI PET/CT distinguishes the reactive lymph nodes from tumor metastatic lymph nodes in a patient with nasopharyngeal carcinoma. Clin Nucl Med (2022) 47(4):367–8. doi: 10.1097/RLU.0000000000003939

PubMed Abstract | CrossRef Full Text | Google Scholar