Comparison of [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT for detection of bone metastases of lung cancer

Introduction

Lung cancer is one of the most common malignancies in the world, with an increasing incidence rate year by year, and it is one of the cancers with the highest mortality rates related to tumors (1). The skeleton is one of the main sites of hematogenous metastasis in lung cancer (2), with an incidence rate of approximately 10–15% (3). Bone metastasis in lung cancer often indicates disease progression, poor prognosis, decreased quality of life, and shortened survival time for patients (3). About 50% of lung cancers are diagnosed at an advanced stage, and only 50% of lung cancer patients with bone metastasis exhibit clinical symptoms (4). Therefore, early and accurate detection and diagnosis of bone metastasis in lung cancer are not only significant for the correct staging, treatment, and prognosis of the disease but also play a positive role in preventing and treating bone-related events, improving patients’ quality of life, and extending survival.

Radionuclide imaging techniques, single photon emission computed tomography (SPECT) and positron-emission tomography/computed tomography (PET/CT), are the primary methods for screening bone metastasis. Currently, SPECT remains the preferred screening method for bone metastasis, but its specificity is poor, which can easily lead to misdiagnosis (5). In recent years, increasing studies have demonstrated that PET/CT exhibits superior diagnostic and follow-up performance for bone metastases compared to conventional imaging modalities, including radiography, CT, and magnetic resonance imaging (MRI). Moreover, PET/CT holds significant clinical value in the characterization of bone lesions with indeterminate nature (6,7). Additionally, PET/CT can not only visually represent the involvement of the entire skeleton but also assess the systemic staging of the tumor. Compared to traditional imaging methods, PET/CT often has higher sensitivity and specificity for bone metastasis (8). However, the diagnostic efficacy of PET/CT for different types of bone metastases varies depending on the imaging agent used. Therefore, selecting an appropriate imaging agent is crucial for the diagnosis and differentiation of bone metastasis lesions.

Gallium 68-labeled fibroblast-activation protein inhibitor-04 ([⁶⁸Ga]Ga-FAPI-04) is a promising new PET tracer with good tumor-to-background ratio (TBR), and it has been proven to have significant advantages over fluorine 18-labeled fluorodeoxyglucose ([¹⁸F]FDG) in detecting various types of malignancies and metastases (9-11). Currently, there are numerous studies on the use of [⁶⁸Ga]Ga-FAPI-04 PET/CT for imaging malignancies in different body parts and types. However, a clinical study comparing [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT specifically in detecting bone metastasis in lung cancer has not been reported. Therefore, we intend to compare the diagnostic efficacy of the two imaging modalities for bone metastasis in lung cancer at both the patient and lesion levels. Additionally, we aim to compare the maximum standardized uptake value (SUVmax) based on the two imaging agents in differentiating benign and malignant bone lesions in lung cancer, providing a favorable theoretical basis for selecting an appropriate imaging agent for diagnosing bone metastasis in lung cancer in clinical practice. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-234/rc).

Methods

Patient population

A retrospective analysis was conducted on patients who were diagnosed with lung cancer and underwent both [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT scans between December 2022 and June 2024. The inclusion criteria were as follows: (I) patients with primary lesions confirmed as lung cancer by pathology; (II) lung cancer patients with clinically suspected bone metastases; and (III) all patients underwent [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT imaging within 1 week. The exclusion criteria were (I) patients with a history of malignancies other than lung cancer; and (II) patients who had received anti-tumor (such as radiotherapy and chemotherapy) or anti-inflammatory treatment before the PET/CT examination. All patients signed informed consent forms before each PET/CT examination. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of The Affiliated Hospital of Southwest Medical University (No. 2020035) and individual consent for this retrospective analysis was waived. A total of 25 lung cancer patients were enrolled in the study, including 12 cases of lung adenocarcinoma, nine cases of lung squamous cell carcinoma, three cases of small cell lung cancer, and one case of large cell lung cancer. There were 11 males and 14 females, with a male-to-female ratio of 1:1.27. The age range was 44–78 years, with an average age of 57 years.

PET/CT image acquisition

Imaging equipment and agents

Image acquisition was performed using a PET/CT scanner (uMI780, United Imaging Healthcare, Shanghai, China). The FAPI precursor, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-FAPI-04, was purchased from CSBio (Shanghai, China) Co., Ltd. for research and development purposes. [⁶⁸Ga]Ga-DOTA-FAPI-04 was labeled according to the general protocol described in previous literature (10). [¹⁸F] was produced using a Siemens (Luzhou, China) eclipse HP/RD cyclotron, and [¹⁸F]FDG was prepared using a Beijing Paite Company (Beijing, China) FDG-N automatic synthesis module. Both radiosyntheses were quality-controlled using ultraviolet (UV)-high-performance liquid chromatography (HPLC) and radio-HPLC to ensure a radiochemical purity of over 95%. The final products were sterile and pyrogen-free.

Imaging examination procedure

No special preparations, such as fasting or blood sugar control, were required for patients before the [⁶⁸Ga]Ga-FAPI-04 PET/CT examination. The paired [¹⁸F]FDG PET/CT scan was completed within 1 week, and patients were required to fast for more than 6 hours and control their blood sugar to <11.1 mmol/L before the examination. [⁶⁸Ga]Ga-FAPI-04/[¹⁸F]FDG (1.8–2.2/3.7–5.55 MBq/kg) was injected intravenously through the arm. Patients rested for 60 minutes in a quiet, suitable temperature environment. After emptying the bladder, a CT scan was performed from the top of the skull to the upper middle part of the thigh with scanning parameters of 120 keV tube voltage, 100 mAs tube current, and a 5 mm slice thickness. PET three-dimensional acquisition was then performed, collecting 6–8 bed positions at 3.0–3.5/4.0–4.5 minutes per bed position. CT data was used for attenuation correction, and PET images were iteratively reconstructed to generate transverse, coronal, sagittal tomographic, and three-dimensional projection images.

Interpretation of PET/CT images

[⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT images were independently analyzed by two nuclear medicine physicians with more than 5 years of imaging diagnosis experience. Double-blind reading was adopted between the [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT images, and any disagreements were resolved through departmental discussion. Detected lesions were classified as bone metastasis, possible bone metastasis, lesions of undetermined nature, possible benign lesions, and benign lesions. Radioactive abnormal concentration was considered when the uptake value of [⁶⁸Ga]Ga-FAPI-04 or [¹⁸F]FDG on PET/CT images was higher than the surrounding normal bone background. If CT showed that the corresponding lesion was located at the edge of the vertebral body, osteophytes, around joints, or bone trauma sites, it was considered a possible benign or benign lesion. If CT showed osteolytic, osteoblastic, or mixed changes in the corresponding lesion, it was considered a bone metastasis or possible bone metastasis. If CT showed no obvious bone abnormalities in the corresponding area, the lesion should be suspected as a bone metastasis lesion with normal bone structure, but hyperplasia and infection should be excluded, so it was defined as a lesion of undetermined nature. For the convenience of research, bone metastasis, possible bone metastasis, and lesions of undetermined nature were classified as bone metastasis-positive lesions during statistical analysis. At the same time, the number of lesions was recorded, the region of interest of the lesions was delineated, and the corresponding SUVmax was measured.

Clinical diagnostic criteria for bone metastases

The clinical diagnostic criteria for bone metastases should meet at least one of the following: (I) histopathological confirmation of lung cancer bone metastasis; (II) typical signs of bone metastasis observed on imaging examination such as radiography, CT, MRI, SPECT, PET/CT; and (III) progressive enlargement of lesions or increased number of lesions during clinical and imaging follow-up for over 3 months, with imaging modalities including radiography, CT, MRI, SPECT, and PET/CT. The presence of bone metastases could be confirmed if any one of these imaging modalities observed the progressive enlargement of lesions or increased number of lesions.

Statistical analysis

Data were analyzed using IBM SPSS Statistics version 26.0 and MedCalc version 22.009.

Categorical variables were presented as counts or percentages, while continuous variables were expressed as mean ± standard deviation. Categorical variables were compared using the Chi-squared test; continuous variables were compared using the independent t-test. The diagnostic value of SUVmax from both examinations for benign and malignant bone lesions was analyzed using receiver operating characteristic (ROC) curves, and the optimal diagnostic threshold was determined using the Youden index. Differences in the area under the curve (AUC) were compared by the DeLong test.

Results

Analysis at the case level

Among 25 lung cancer patients, nine cases were confirmed as lung cancer with bone metastasis (36%, including five cases of lung adenocarcinoma, three cases of squamous cell lung cancer, and one case of small cell lung cancer). Of the nine cases, bone metastasis was pathologically confirmed in two cases with lung cancer, typical signs of bone metastasis were observed on imaging examination in four cases, and the remaining three had clinical and imaging follow-up confirmation. There were four males and five females, with a male-female ratio of 1:1.25. The patients’ ages ranged from 47 to 78 years, with an average age of 61 years. Among them, eight cases had multiple bone metastases (multiple bone metastases were defined as two or more lesions, including more than one lesion in the same bone), and one case had a single bone metastasis. [⁶⁸Ga]Ga-FAPI-04 PET/CT accurately detected bone metastases in nine patients, with three false positives (bone inflammation, fractures, fibrous dysplasia of bone, and degenerative bone diseases) and 13 cases without metastasis. [¹⁸F]FDG PET/CT accurately showed bone metastases in seven patients, with one false positive, two false negatives, and 15 cases without metastasis. There were no statistically significant differences in the detection rate, sensitivity, specificity, positive predictive value, negative predictive value, or accuracy between [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT for detecting bone metastases in patients (P>0.05) (Table 1).

Analysis at the lesion level

A total of 161 bone lesions were detected in 25 lung cancer patients. Among these, 133 were lung cancer bone metastases (82.61%). Bone metastasis was pathologically confirmed in three lesions, typical signs of bone metastasis were observed on imaging examination in 59 lesions, and the remaining 71 lesions were confirmed by clinical and imaging follow-up. and the other 28 lesions were benign (including 13 cases of inflammation, seven cases of degeneration and osteophytes, three cases of Schmorl’s nodes, three cases of fibrous dysplasia of bone, one case of discitis, and one case of compression fracture). [⁶⁸Ga]Ga-FAPI-04 PET/CT correctly diagnosed 131 bone metastatic lesions and 15 benign lesions, with 13 false positive lesions (Figures 1,2). [¹⁸F]FDG PET/CT correctly diagnosed 92 bone metastatic lesions and 22 benign lesions. The detection rate, sensitivity, negative predictive value, and accuracy of [⁶⁸Ga]Ga-FAPI-04 PET/CT for detecting lung cancer bone metastases were higher than those of [¹⁸F]FDG PET/CT, with statistically significant differences (P<0.001). There were no statistically significant differences in specificity or positive predictive value between [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT for detecting lung cancer bone metastases (P>0.05), as shown in Table 2. [⁶⁸Ga]Ga-FAPI-04 PET/CT was superior to [18F]FDG PET/CT in detecting osteolytic and normal bone structure metastasis lesion, as well as small bone metastases with a short diameter of less than 1 cm, as shown in Figures 3-5.

Figure 1 A 53-year-old female patient with invasive adenocarcinoma of the left upper lobe (early-stage lung cancer) had suffered a traffic accident injury 10 days prior. The [¹⁸F]FDG PET/CT scan accurately identified the compression fracture of the L4 vertebral body, whereas [⁶⁸Ga]Ga-FAPI-04 PET/CT demonstrated a false positive lesion. [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT images are shown. (A,C) MIP images with a pointed arrow indicating the primary lesion (a subsolid nodule with unremarkable FAPI and FDG uptake), and the dashed arrow indicates the fattening and wedge-shaped deformation of the L4 vertebral body. (B) [⁶⁸Ga]Ga-FAPI-04 PET/CT demonstrates flattening and wedge-shaped deformation of the L4 vertebral body, with increased FAPI expression (dashed arrow, SUVmax =7.33). (D) [¹⁸F]FDG PET/CT shows slightly increased glucose metabolism in the L4 vertebral body (dashed arrow, SUVmax =2.53). The patient recovered well after surgery and showed no abnormalities during follow-up. The final diagnosis was a compression fracture of the L4 vertebral body, rather than bone metastasis. [¹⁸F]FDG, fluorine 18-labeled fluorodeoxyglucose; [⁶⁸Ga]Ga-FAPI-04, gallium 68-labeled fibroblast-activation protein inhibitor-04; CT, computed tomography; FAPI, fibroblast-activation protein inhibitor; FDG, fluorodeoxyglucose; MIP, maximum intensity projection; PET, positron-emission tomography; SUVmax, maximum standardized uptake value.

Figure 2 A 66-year-old male patient with peripheral lung cancer (adenocarcinoma) in the upper lobe of the right lung. The [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT images are shown. (A,C) MIP images with a pointed arrow indicating the primary lesion, and the dashed arrows denote the degenerative osteophytes on the anterior edge of the T9/10 and T11/12 vertebral bodies. (B) [⁶⁸Ga]Ga-FAPI-04 PET/CT demonstrates degenerative osteophytes on the anterior edge of T9/10 and T11/12 vertebral bodies with increased FAPI expression (dashed arrows, SUVmax =3.6). (D) [¹⁸F]FDG PET/CT shows no significant increase in glucose metabolism in the corresponding areas (dashed arrows). The patient recovered well after surgery and showed no abnormalities during follow-up, leading to a final diagnosis of degenerative osteophytes. [¹⁸F]FDG, fluorine 18-labeled fluorodeoxyglucose; [⁶⁸Ga]Ga-FAPI-04, gallium 68-labeled fibroblast-activation protein inhibitor-04; CT, computed tomography; FAPI, fibroblast-activation protein inhibitor; FDG, fluorodeoxyglucose; MIP, maximum intensity projection; PET, positron-emission tomography; SUVmax, maximum standardized uptake value.

Figure 3 A 61-year-old male patient with centrally located lung cancer (squamous cell carcinoma) of the left lung accompanied by cervical lymph node metastasis. The [⁶⁸Ga]Ga-FAPI-04 PET/CT accurately identified bone metastases, whereas [¹⁸F]FDG PET/CT showed false negatives due to significant background interference around the left temporal bone lesion. [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT images are shown. (A,C) MIP images, where the solid arrows indicate the primary lesion, and the dashed arrows indicate inflammation around the left shoulder joint. (B) [⁶⁸Ga]Ga-FAPI-04 PET/CT demonstrates a slightly reduced local bone density and slightly elevated cortical bone in the left temporal bone, with a short diameter of 0.55cm and abnormally elevated FAPI expression (solid arrows, SUVmax =8.12). (D) [¹⁸F]FDG PET/CT shows significant background interference around the left temporal bone lesion, with no obvious abnormally increased glucose metabolism (solid arrows). The lesion was ultimately diagnosed as an osteolytic bone metastasis, which was confirmed by follow-up. [¹⁸F]FDG, fluorine 18-labeled fluorodeoxyglucose; [⁶⁸Ga]Ga-FAPI-04, gallium 68-labeled fibroblast-activation protein inhibitor-04; CT, computed tomography; FAPI, fibroblast-activation protein inhibitor; FDG, fluorodeoxyglucose; MIP, maximum intensity projection; PET, positron-emission tomography; SUVmax, maximum standardized uptake value.

Figure 4 A 46-year-old female patient with peripheral lung cancer (adenocarcinoma) in the upper lobe of the left lung accompanied by multiple bone metastases (involving the skull, multiple vertebral bodies of the spine, multiple ribs on both sides, and pelvic bones). The [⁶⁸Ga]Ga-FAPI-04 PET/CT accurately identified bone metastases, whereas [¹⁸F]FDG PET/CT showed false negatives due to slightly increased local glucose metabolism of the lesions. [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT images are shown. (A,C) MIP images with a pointed arrow indicating the primary lesion and solid arrows indicating newly detected lesions on [⁶⁸Ga]Ga-FAPI-04 PET/CT. (B) [⁶⁸Ga]Ga-FAPI-04 PET/CT demonstrates no significant bone destruction in the left iliac bone and left sacrum, but abnormally elevated FAPI expression (solid arrows, SUVmax =6.57). (D) [¹⁸F]FDG PET/CT shows slightly increased local glucose metabolism in the left iliac bone and left sacrum (solid arrows, SUVmax =4.15). The final diagnosis of this lesion was osteoblastic bone metastasis, which was confirmed through follow-up. [¹⁸F]FDG, fluorine 18-labeled fluorodeoxyglucose; [⁶⁸Ga]Ga-FAPI-04, gallium 68-labeled fibroblast-activation protein inhibitor-04; CT, computed tomography; FAPI, fibroblast-activation protein inhibitor; FDG, fluorodeoxyglucose; MIP, maximum intensity projection; PET, positron-emission tomography; SUVmax, maximum standardized uptake value.

Figure 5 A 57-year-old female patient with peripheral lung cancer (adenocarcinoma) in the middle lobe of the right lung, accompanied by multiple bone metastases (skull, multiple vertebral bodies of the spine, multiple ribs on both sides, pelvic bones, and limb bones), liver metastasis, and lymph node metastasis. The [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT images are presented. (A,E) MIP images with arrowheads indicating the primary lesion. Compared to [¹⁸F]FDG PET/CT, [⁶⁸Ga]Ga-FAPI-04 PET/CT showed significantly higher tracer uptake, better contrast, and detected more lesions. For instance, (B,F) [⁶⁸Ga]Ga-FAPI-04 PET/CT demonstrated no significant bone destruction in the occipital and left frontal bones, but abnormally increased FAPI expression (solid arrows, SUVmax =11.34). In contrast, [¹⁸F]FDG PET/CT showed high background interference around the left occipital and frontal bones without obvious abnormally increased glucose metabolism, leading to a final diagnosis of bone metastasis lesion with normal bone structure. (C,G) [⁶⁸Ga]Ga-FAPI-04 PET/CT revealed mixed bone destruction in the L2 vertebral body (short diameter of 3.41 cm) and no significant abnormality in bone density of the left 11^th rib at the axillary-dorsal segment. FAPI expression was abnormally increased in these lesions (solid arrows, SUVmax =26.63). On [¹⁸F]FDG PET/CT, glucose metabolism was slightly increased in the L2 vertebral lesion (solid arrows, SUVmax =4.31) but not significantly increased in the left 11^th rib at the axillary-dorsal segment. These lesions were diagnosed as mixed and normal bone structure metastasis lesions, respectively. (D,H) [⁶⁸Ga]Ga-FAPI-04 PET/CT showed decreased bone density in bilateral femoral necks and right ischial tuberosity, and increased bone density in the left ischial tuberosity. These lesions ranged from 0.53 to 2.05 cm in short diameter with abnormally increased FAPI expression (solid arrows, SUVmax =25.61). On [¹⁸F]FDG PET/CT, no significant abnormality in glucose metabolism was observed in the left ischial tuberosity, while other lesions showed slightly increased glucose metabolism (solid arrows, SUVmax =5.09). These lesions were diagnosed as osteolytic and osteoblastic bone metastatic tumors, which were confirmed by follow-up. [¹⁸F]FDG, fluorine 18-labeled fluorodeoxyglucose; [⁶⁸Ga]Ga-FAPI-04, gallium 68-labeled fibroblast-activation protein inhibitor-04; CT, computed tomography; FAPI, fibroblast-activation protein inhibitor; FDG, fluorodeoxyglucose; MIP, maximum intensity projection; PET, positron-emission tomography; SUVmax, maximum standardized uptake value.

Comparison of SUVmax in benign and malignant bone lesions between [68Ga]Ga-FAPI-04 and [18F]FDG PET/CT

Among all 28 benign bone lesions, abnormal tracer uptake was observed in 27 and 12 lesions on [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT, respectively. The corresponding SUVmax values were 4.48±2.27 and 2.95±0.83, respectively, with a statistically significant difference (P<0.01).

In all 133 bone metastases, abnormal tracer uptake was detected in 133 and 95 lesions on [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT, respectively. The corresponding SUVmax values were 11.13±7.00 and 5.55±3.70, respectively, showing a statistically significant difference (P<0.01).

In [⁶⁸Ga]Ga-FAPI-04 PET/CT imaging, the SUVmax for benign and malignant bone lesions were 4.48±2.27 and 11.13±7.00, respectively, indicating a statistically significant difference (P<0.05). In [¹⁸F]FDG PET/CT imaging, the SUVmax for benign and malignant bone lesions were 2.95±0.83 and 5.55±3.70, respectively, also showing a statistically significant difference (P<0.05).

In both [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT imaging, the AUCs of SUVmax for diagnosing bone metastases were 0.856 and 0.724, respectively, with optimal diagnostic thresholds of 5.38 and 3.77 (Figure 6). The sensitivity, negative predictive value, and accuracy of [⁶⁸Ga]Ga-FAPI-04 PET/CT in the differential diagnosis of lung cancer bone metastasis were higher than those of [¹⁸F]FDG PET/CT (P<0.05). However, there were no statistically significant differences in specificity or positive predictive value between the two imaging modalities (P>0.05). The diagnostic performance indicators corresponding to the optimal diagnostic thresholds are shown in Table 3. Additionally, there was a statistically significant difference in the AUC of SUVmax between [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT (P<0.05).

Figure 6 Comparison of ROC curves for SUVmax in diagnosing bone metastases from lung cancer between [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT imagings. [¹⁸F]FDG, fluorine 18-labeled fluorodeoxyglucose; [⁶⁸Ga]Ga-FAPI-04, gallium 68-labeled fibroblast-activation protein inhibitor-04; AUC, area under the curve; CT, computed tomography; FAPI, fibroblast-activation protein inhibitor; FDG, fluorodeoxyglucose; PET, positron-emission tomography; ROC, receiver operating characteristic; SUVmax, maximum standardized uptake value.

Discussion

This study explored the role of [⁶⁸Ga]Ga-FAPI-04 PET/CT in the diagnosis of bone metastases from lung cancer, comparing it with [¹⁸F]FDG PET/CT. The diagnostic efficacy of [⁶⁸Ga]Ga-FAPI-04 PET/CT for bone metastases from lung cancer was generally superior to that of [¹⁸F]FDG PET/CT. Specifically, the detection rate, sensitivity, negative predictive value, and accuracy of [⁶⁸Ga]Ga-FAPI-04 PET/CT were significantly improved at the lesion level. We compared the SUVmax of lesions based on [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT to distinguish benign and malignant bone lesions in lung cancer. Compared to [¹⁸F]FDG PET/CT, [⁶⁸Ga]Ga-FAPI-04 PET/CT exhibited superior image contrast and higher SUVmax. Additionally, the optimal diagnostic threshold SUVmax of 5.38 contributed to improved sensitivity, negative predictive value, and accuracy in differential diagnosis of bone metastases from lung cancer.

Currently, comparative studies between [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT have been clinically evaluated in various malignancies and some benign diseases. Most initial studies were conducted in mixed populations with different malignancies (12,13). Chen et al. compared the diagnostic effects of [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT in 75 patients with 12 different types of tumors, including 54 cases of staging and 21 cases of recurrence detection (10). They found that the detection rate of [⁶⁸Ga]Ga-FAPI-04 PET/CT for all 12 malignancies was higher than that of [¹⁸F]FDG PET/CT. Meanwhile, compared to [¹⁸F]FDG PET/CT, [⁶⁸Ga]Ga-FAPI-04 PET/CT also showed higher sensitivity for lymph nodes and skeletal/visceral metastases such as liver metastasis, peritoneal cancer, and brain metastasis. In another study, Chen et al. evaluated the effectiveness of [⁶⁸Ga]Ga-FAPI-04 PET/CT in 68 patients with uncertain [¹⁸F]FDG PET/CT results. The accuracy of [⁶⁸Ga]Ga-FAPI-04 PET/CT for the diagnosis of suspicious masses (n=18), unknown primary lesions (n=6), and tumor recurrence (n=23) was 66.7%, 66.7%, and 87.0%, respectively. Notably, in patients undergoing tumor staging (n=21), [⁶⁸Ga]Ga-FAPI-04 PET/CT showed more lesions (n=18, 85.7%) than [¹⁸F]FDG PET/CT, with 33.3% (n=7) resulting in modified staging. Moreover, in this study, the SUVmax of primary and metastatic lesions was higher for [⁶⁸Ga]Ga-FAPI-04 PET/CT than for [¹⁸F]FDG PET/CT, with better image contrast (11). Koerber et al. demonstrated the positive role of [⁶⁸Ga]Ga-FAPI-04 PET/CT in the diagnosis, staging, and radiotherapy planning of lower gastrointestinal tumors. Compared to CT/MRI anatomical imaging, [⁶⁸Ga]Ga-FAPI-04 PET/CT identified new lesions in 47% of patients with colorectal cancer, mostly new organ metastases. This led to treatment changes in 73.3% of cases. Among untreated patients, 50% had a changed tumor-node-metastasis (TNM) staging (14). Additionally, studies have reported the significant superiority of [⁶⁸Ga]Ga-FAPI-04 PET/CT over [¹⁸F]FDG PET/CT in the diagnosis and staging of various malignancies, such as lung cancer (15), breast cancer (16), gastric cancer (17), esophageal cancer (18), sigmoid colon cancer (19), and cholangiocarcinoma (20). These studies highlight its advantage in detecting metastatic lesions, which may contribute to more accurate diagnosis, staging, and treatment response evaluation.

Our results indicate that, limited by the number of cases, there was no significant difference in diagnostic efficacy between [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT for patients with bone metastases from lung cancer at the case level. However, at the lesion level, the detection rate, sensitivity, negative predictive value, and accuracy of [⁶⁸Ga]Ga-FAPI-04 PET/CT for identifying bone metastases from lung cancer were significantly higher than those of [¹⁸F]FDG PET/CT. These findings are consistent with previous studies by Chen and Koerber (10,11,14), demonstrating the overall superiority of [⁶⁸Ga]Ga-FAPI-04 PET/CT over [¹⁸F]FDG PET/CT in diagnosing bone metastases from lung cancer at the lesion level.

In addition to its expression in malignancies, increasing studies show the uptake of [⁶⁸Ga]Ga-FAPI-04 in non-malignant diseases. Recent literature reports increased uptake of [⁶⁸Ga]Ga-FAPI-04 in immunoglobulin G4 (IgG4)-related diseases (21), Erdheim-Chester disease (22), tuberculosis (23), liver cirrhosis (24), myocardial infarction (25), inflammatory diseases (such as thyroiditis, pancreatitis, and radiation-related inflammation), and some benign tumors (such as angiomyolipoma and elastofibroma) (26,27). Fibroblast-activation protein is also expressed in activated fibroblasts during any tissue remodeling process, including inflammation, wound healing, and fibrosis, such as in the liver or lung, arthritis, and atherosclerosis (28). Therefore, the uptake of [⁶⁸Ga]Ga-FAPI-04 may reflect the content of activated fibroblasts in the above diseases, potentially leading to false positives.

In our cases, false positives on [⁶⁸Ga]Ga-FAPI-04 PET/CT were mainly due to bone inflammation, fractures, fibrous dysplasia of bone, and degenerative bone diseases (such as osteophytes and Schmorl’s nodes). The uptake of [⁶⁸Ga]Ga-FAPI-04 in these benign bone lesions may be related to the presence of fibroblasts. Combining corresponding CT images can make it easier to distinguish between degenerative bone diseases and bone metastases, improving the specificity of PET/CT. However, due to the high sensitivity of [⁶⁸Ga]Ga-FAPI-04 to bone lesions, it may be difficult to accurately characterize lesions in cases of bone inflammation, fractures, and fibrous dysplasia. In such cases, detailed clinical manifestations, past medical history, and history of trauma become particularly important. Our study reinforces that although [⁶⁸Ga]Ga-FAPI-04 PET/CT has higher uptake rates and better image contrast, it may not be more tumor-specific than [¹⁸F]FDG PET/CT in characterizing some bone lesions. This should be especially noted.

In early clinical studies, Giseel et al. performed [⁶⁸Ga]Ga-FAPI-04 PET/CT on 50 patients with lung cancer, pancreatic cancer, esophageal cancer, head and neck tumors, and colorectal cancer. They found that compared to [¹⁸F]FDG PET/CT, [⁶⁸Ga]Ga-FAPI-04 PET/CT had a better TBR, especially in the brain, liver, and oral/pharyngeal mucosa, where the background activity was significantly lower than that of [¹⁸F]FDG PET/CT (29). This resulted in high contrast in these areas. These findings highlight the potential advantages of [⁶⁸Ga]Ga-FAPI-04 PET/CT in detecting regions where [¹⁸F]FDG PET/CT has limitations due to high physiological activity, such as the brain, liver, and oropharyngeal areas. Chen et al.’s study also found that [⁶⁸Ga]Ga-FAPI-04 PET/CT had a better TBR compared to [¹⁸F]FDG PET/CT, and most tumors had higher SUVmax for primary and metastatic lesions (10). In another study, Kratochwil et al. evaluated [⁶⁸Ga]Ga-FAPI-04 PET/CT in 80 patients with 28 different cancers. They found that although SUVmax varied among different tumors, there was no significant difference in SUVmax between primary and metastatic lesions. High SUVmax were seen in lung cancer, sarcoma, esophageal cancer, breast cancer, and cholangiocarcinoma; moderate SUVmax were observed in hepatocellular carcinoma, colorectal cancer, head and neck tumors, ovarian cancer, pancreatic cancer, and prostate cancer; and low SUVmax were noted in pheochromocytoma, differentiated thyroid carcinoma, adenoid cystic carcinoma, and gastric cancer (9). Based on these studies, we hypothesize that in primary lesions with relatively high SUVmax, such as lung cancer, the bone metastases may also have relatively high uptake. Additionally, even in situations where the background of [¹⁸F]FDG PET/CT is relatively high in head and neck bones, the high TBR of [⁶⁸Ga]Ga-FAPI-04 PET/CT allows for good visibility of bone metastases, despite its potentially lower SUVmax. This provides an explanation for the higher detection rate and sensitivity of [⁶⁸Ga]Ga-FAPI-04 PET/CT for lung cancer bone metastases.

SUVmax, as the most commonly used semi-quantitative indicator in PET/CT imaging to measure the degree of tumor uptake of radiotracers, is often clinically applied to distinguish malignant tumors from benign lesions and to indicate the malignancy of tumors (30). Based on our research findings, the SUVmax of bone malignancies on both [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT was significantly higher than that of benign bone lesions; furthermore, the SUVmax of both benign and malignant bone lesions on [⁶⁸Ga]Ga-FAPI-04 PET/CT was notably higher than on [¹⁸F]FDG PET/CT. In the imaging of [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT, the AUCs of SUVmax for diagnosing bone metastases were 0.856 and 0.724, respectively, with optimal diagnostic thresholds of 5.38 and 3.77. Correspondingly, the sensitivity, negative predictive value, and accuracy of [⁶⁸Ga]Ga-FAPI-04 PET/CT in differentiating lung cancer bone metastases were higher than those of [¹⁸F]FDG PET/CT. Our research indicates that, in terms of tracer uptake in benign and malignant bone lesions, [⁶⁸Ga]Ga-FAPI-04 PET/CT exhibits superior image contrast and higher tracer uptake values compared to [¹⁸F]FDG PET/CT. There was a significant difference in the AUC of SUVmax for diagnosing bone metastases between the two examinations, and the sensitivity, negative predictive value, and accuracy of [⁶⁸Ga]Ga-FAPI-04 PET/CT in differentiating lung cancer bone metastases were higher than those of [¹⁸F]FDG PET/CT when using the optimal diagnostic threshold of SUVmax. Interestingly, these results are consistent with findings at the lesion level.

There are limitations in this study: (I) due to its retrospective nature, selection bias may occur in patient selection. (II) Consistent with most existing studies, only the SUVmax was employed as a semi-quantitative parameter for PET/CT in our analysis. Subsequent research could incorporate comprehensive evaluation of multiple metabolic parameters derived from PET/CT, including peak standard uptake value, mean standard uptake value, metabolic tumor volume, total lesion glycolysis, and TBR. (III) For ethical and practical reasons, it is not possible to perform histopathological confirmation on every bone lesion. (IV) The number of lung cancer patients is relatively small, so this study did not reflect the differences between [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT at the case level. Further expanding the sample size is necessary for future research.

Conclusions

Overall, compared to [¹⁸F]FDG PET/CT, [⁶⁸Ga]Ga-FAPI-04 PET/CT significantly improves the detection rate of lung cancer bone metastases at the lesion level. Additionally, [⁶⁸Ga]Ga-FAPI-04 PET/CT offers superior image contrast and higher SUVmax, which also helps to improve the accuracy of lung cancer bone metastasis diagnosis. This suggests the potential role of [⁶⁸Ga]Ga-FAPI-04 PET/CT in the treatment, monitoring, and follow-up of bone metastases, allowing for more accurate staging of patients. It may also be used to identify high-risk populations who could benefit most from adjuvant therapy, enabling precision individualized treatment and improving patient outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-234/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-234/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-234/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of The Affiliated Hospital of Southwest Medical University (No. 2020035) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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