Ga-FAPI-04 PET for Detecting Occult Peritoneal Metastasis in Locally Advanced Gastric Cancer: Diagnostic Performance and Cost Analyses in a Single-Center, Prospective Cohort Study.

MATERIALS AND METHODS

Study Design
This prospective, observational, single-center cohort study was conducted at West China Hospital in accordance with the ethical principles of the Helsinki II Declaration. The study was approved by the Ethics Committee of West China Hospital, and written informed consent was provided by all patients before 68Ga-FAPI-04 PET/CT. This study was registered in the Chinese Clinical Trial Registry (ChiCTR2300067591), and the study protocol was published elsewhere (18). Additional study methods are described in the supplemental materials, available at http://jnm.snmjournals.org) (19–22).

Participants
We enrolled patients age 18 y or older with an Eastern Cooperative Oncology Group performance status of 0 to 1. Eligible patients had histologically confirmed gastric or gastroesophageal junction (Siewert type III) adenocarcinoma and were diagnosed with advanced gastric cancer (cT4a-b, N0–3, M0) using contrast-enhanced CT, according to the 8th edition of the American Joint Committee on Cancer staging system. All patients were scheduled to undergo curative-intent surgery in accordance with national guidelines. Exclusion criteria included suspected distant metastatic gastric cancer on CT staging, allergic constitution, and a history of abdominal inflammatory diseases (e.g., peritonitis, pancreatitis, cholecystitis, inflammatory bowel disease). Patients with contraindications to laparoscopic staging were also excluded.

Procedures
All potentially eligible patients were discussed during the gastric cancer multidisciplinary team meeting. Consenting patients underwent 68Ga-FAPI-04 PET/CT within 14 d before laparoscopic staging. 68Ga-FAPI-04 PET/CT images were reviewed before laparoscopic staging by 2 board-certified nuclear medicine physicians, and any dissenting opinions were resolved through discussion. Surgeons were masked to the preoperative 68Ga-FAPI-04 PET/CT imaging results. Laparoscopic staging was performed using the “Huaxi 4-step” procedure, which has been used at our center for many years (23). During surgery, approximately 500 mL of peritoneal lavage fluid was routinely collected after laparoscopic exploration and immediately submitted for cytologic examination. Laparoscopic staging combined with peritoneal washing cytology served as the reference standard for the final diagnosis, and histopathologic examination of peritoneal implants was performed when indicated.
Data were collected using study-specific data collection forms, starting at recruitment. All data were stored electronically in a secure database, and strict confidentiality was maintained.

Outcomes
The primary outcome was the proportion of eligible patients in whom 68Ga-FAPI-04 PET/CT altered the treatment strategy from curative to palliative intent treatment. The secondary outcomes included the following: evaluation of the diagnostic accuracy of 68Ga-FAPI-04 PET/CT for OPM, such as sensitivity, specificity, accuracy, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio in patients with locally advanced gastric cancers; assessment of peritoneal carcinomatosis lesion detectability using SUVmax and target-to-background ratio (TBR), where TBR1 is tumor SUVmax–to–background SUVmax and TBR2 is tumor SUVmax–to–background SUVmean; comparison of peritoneal metastasis locations between 68Ga-FAPI-04 PET/CT and laparoscopic staging (24); and analysis of net cost impact, calculated by comparing cost savings from avoiding unnecessary gastrectomies with 68Ga-FAPI-04 PET/CT versus laparoscopic staging.

Cost Analysis
To assess the cost impact of 68Ga-FAPI-04 PET/CT and laparoscopic staging, 4 staging strategies were modeled in a theoretic decision tree to calculate the total costs of each strategy: no 68Ga-FAPI-04 PET/CT or laparoscopic staging (strategy 1), laparoscopic staging alone (strategy 2), 68Ga-FAPI-04 PET/CT alone (strategy 3), and the use of both 68Ga-FAPI-04 PET/CT and laparoscopic staging (strategy 4). The probability of positive or negative outcomes after 68Ga-FAPI-04 PET/CT and laparoscopic staging were calculated based on the observed frequencies. For each staging strategy, a decision-tree model depicted 2 alternative scenarios: gastrectomy and no gastrectomy. Patients without OPM or other metastases (negative outcome) were allocated to the gastrectomy branch, whereas those with OPM or other metastases (positive outcome) did not undergo gastrectomy. Direct costs of laparoscopic staging included surgery, anesthesia fees, pathology tests, postoperative-associated costs for 3 days, whereas the direct cost of gastrectomy included surgery, anesthesia fees, pathology tests, and postoperative-associated costs for 7 days. Average unit costs of 68Ga-FAPI-04 PET/CT, laparoscopic staging, gastrectomy, anesthesia fees, pathology tests, and hospitalization expenses (before insurance reimbursement) were obtained from the settlement list from West China Hospital in China. Cost analyses were performed using TreeAge Pro 2021 (TreeAge Software LLC).

Statistical Analysis
Statistical analyses were performed using R version 4.2.3. The primary analysis was performed by the study biostatistician, and the report was reviewed by a second author for accuracy. The area under the curve was calculated based on sensitivity and specificity. Quantitative data were presented as mean ± SD if normally distributed or as median and interquartile range. Categoric variables are presented as numbers and percentages. Student t test and χ2 test were used to compare means and categoric variables, respectively. Fisher exact test was applied if the theoretic frequency was fewer than 5 in any group. The diagnostic performance of 68Ga-FAPI-04 PET/CT was assessed using sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios. Accuracy was calculated as the proportion of true positives and true negatives among all tested cases. Lesion detectability parameters, including SUVmax and TBR, were also calculated. A 2-tailed P value of less than 0.05 was defined as statistically significant.

RESULTS

Participant Characteristics
In total, 121 patients were screened between November 2022 and August 2024, and 109 patients were enrolled (Fig. 1). Six patients were unwilling to participate in the study and therefore excluded. Another 6 patients did not undergo laparoscopic staging because of hypothyroidism (n = 2), coronary heart disease (n = 3), or refusal to undergo surgery (n = 1). Baseline characteristics of the study population are summarized in Table 1. Most tumors (n = 85; 78.0%) were located in the stomach, with the remaining 24 (22.0%) appearing in the esophagogastric junction (Siewert type III). Most primary tumors were staged as T4a (n = 100; 91.7%), with 9 (8.3%) staged as T4b. All patients (n = 109) underwent 68Ga-FAPI-04 PET/CT before laparoscopic staging and tolerated the examinations without complications.

68Ga-FAPI-04 Uptake in Primary Tumors and Peritoneal Metastases
All patients exhibited a 68Ga-FAPI-04-avid primary tumor. As shown in Table 2, the mean SUVmax of 68Ga-FAPI-04 uptake in the primary tumor was 14.87 ± 6.12 across all enrolled patients. No significant difference in 68Ga-FAPI-04 uptake in the primary tumor was found between signet ring cell carcinoma and non–signet ring cell carcinoma (mean SUVmax, 13.55 vs. 15.44, respectively; P = 0.145). The mean TBR1 and TBR2 of the primary tumor were 11.22 ± 4.89 and 15.69 ± 6.65, respectively. Patients with OPM exhibited significantly higher mean SUVmax and TBR2 values in the primary tumors compared with those without OPM (P = 0.010 and P = 0.009, respectively).

Diagnostic Performance of 68Ga-FAPI-04 PET/CT in OPM
Seventeen of 109 patients were diagnosed with OPM after 68Ga-FAPI-04 PET/CT. Laparoscopic staging with pathology confirmed 16 cases of peritoneal metastases: 7 with macroscopic (P1) and cytology-positive (CY1) disease; 6 with P1CY0, and 3 with P0CY1. Of all patients, 12 were diagnosed with OPM, whereas 88 were not found to have OPM by both 68Ga-FAPI-04 PET/CT and laparoscopic staging. As shown in Table 3, the sensitivity of 68Ga-FAPI-04 PET/CT for detecting OPM was 75.0%, and the specificity was 94.6%. The overall diagnostic accuracy of 68Ga-FAPI-04 PET/CT was 91.7%. For 68Ga-FAPI-04 PET/CT, the positive and negative predictive values were 70.6% and 95.7%, respectively. The positive and negative likelihood ratios of 68Ga-FAPI-04 PET/CT for the detection of OPM were 14.2 and 0.3, respectively. Receiver-operating-characteristic curve analysis yielded an area under the curve of 0.83 (95% CI, 0.72–0.94). There was a high concordance in OPM localization between 68Ga-FAPI-04 PET/CT and laparoscopic exploration, with 9 of 12 patients showing consistent localization (Supplemental Table 1).

Two Typical Cases of Peritoneal Metastasis
Figures 2 and 3 display 2 typical images of peritoneal metastasis: 1 in the right upper quadrant of the abdomen and the other in the right paracolic gutter. No abnormalities were detected on the corresponding enhanced CT scan at the initial diagnosis. However, a notable increase in 68Ga-FAPI-04 uptake was observed on 68Ga-FAPI-04 PET/CT examination. Subsequent laparoscopic staging verified that the presence of tiny implants at the corresponding site was peritoneal metastasis.

Changes in Tumor Staging After 68Ga-FAPI-04 PET/CT
Seventeen patients (15.6%) were theoretically upstaged to stage IV for OPM on 68Ga-FAPI-04 PET/CT examination; no other distant metastases were detected in any patient (Fig. 4). In fact, treatment intent changed from curative to palliative in 12 of these 17 patients. For the remaining 5 patients, OPM was not confirmed by laparoscopic staging or peritoneal cytology, so they were still treated with curative intent. As shown in Figure 4, 2 patients initially staged as IIB and 3 patients initially staged as III experienced an upstaging after 68Ga-FAPI-04 PET/CT diagnosis, but their staging remained unchanged after laparoscopic exploration. Conversely, 4 patients initially staged as III were upstaged to IV after laparoscopic exploration, whereas their staging remained unchanged after 68Ga-FAPI-04 PET/CT examination.

Cost Analysis
Figure 5 presents a decision tree analyzing the cost impact of laparoscopic staging and 68Ga-FAPI-04 PET/CT across 4 modeled staging strategies. In a theoretic model where laparoscopic staging alone was performed preoperatively for patients with locally advanced gastric cancer, 16 futile gastrectomies would have been performed (strategy 2). Conversely, if only 68Ga-FAPI-04 PET/CT was performed preoperatively, 17 futile gastrectomies would have been performed (strategy 3). Based on diagnostic performance of 68Ga-FAPI-04 PET/CT, we proposed performing laparoscopic staging only for 68Ga-FAPI-04–positive patients and avoiding it for 68Ga-FAPI-04–negative patients (strategy 4). When no peritoneal abnormalities were detected on 68Ga-FAPI-04 PET/CT, 84.0% (n = 92) of patients could potentially avoid laparoscopic staging. Conversely, in cases where high 68Ga-FAPI-04 uptake was observed, laparoscopic staging would be performed in 17 patients (16%) as a supplemental method to detect peritoneal metastasis. Using this strategy, the number of futile gastrectomies would be reduced to 12. If all patients underwent gastrectomy without 68Ga-FAPI-04 PET/CT and laparoscopic staging (strategy 1), the total cost would be $9,550.50 per patient. Staging with 68Ga-FAPI-04 PET/CT (strategy 3) reduced costs by $727.60 per patient, whereas laparoscopic staging (strategy 2) increased costs by $251.70 per patient. Compared with laparoscopic staging (strategy 2), 68Ga-FAPI-04 PET/CT (strategy 3) achieved a net cost savings of $979.30 per patient. To enhance the clinical applicability of the theoretic strategies, we developed a new approach (strategy 4) based on the higher negative predictive value of 68Ga-FAPI-04 PET/CT. If no peritoneal abnormalities were detected by 68Ga-FAPI-04 PET/CT, laparoscopic staging could be omitted; however, if significant uptake was observed in the peritoneum, laparoscopic staging was required to confirm peritoneal metastases. This strategy resulted in a minimal net cost savings of $232.30 per patient compared with laparoscopic staging (strategy 2), while significantly reducing the need for laparoscopic staging by 84% and preventing 11% of futile gastrectomies.

DISCUSSION
In our study, 68Ga-FAPI-04 PET/CT demonstrated a sensitivity of 75.0% and a specificity of 94.6% in detecting OPM, with an overall diagnostic accuracy of 91.7%. Notably, the negative predictive value reached 95.7%, allowing clinicians to confidently exclude OPM in clinical practice. These findings highlight the significant advantages of 68Ga-FAPI-04 PET/CT and emphasize its role as a standard method for detecting OPM in patients with locally advanced gastric cancer.
By targeting the tumor stroma, which constitutes most of the tumor volume, 68Ga-FAPI-04 PET/CT is considered more sensitive for detecting small tumor lesions (25). Compared with 18F-FDG PET/CT, 68Ga-FAPI-04 PET/CT demonstrated superior sensitivity in detecting peritoneal metastases, particularly in gastrointestinal and ovarian cancers, because of its minimal physiologic intestinal uptake, thereby providing more accurate guidance for treatment decisions (14,26–29). However, existing studies evaluating 68Ga-FAPI-04 PET/CT for detecting peritoneal metastases have notable limitations. Most were retrospective in design, included heterogeneous cohorts of gastrointestinal malignancies with small sample sizes (27,30), and often lacked laparoscopic staging as the reference standards. These methodologic constraints limit the robustness and generalizability of their findings (17,31,32). Even the limited prospective studies in gastric cancer assessed all peritoneal metastases rather than specifically addressing OPM, and subgroup analyses further inflated detection rates (16,33). To our knowledge, this prospective cohort study is the first to adopt laparoscopic staging as the reference standard for evaluating the diagnostic value of 68Ga-FAPI-04 PET/CT in detecting OPM in gastric cancer.
The false-positive rate of 68Ga-FAPI-04 PET/CT cannot be overlooked, as 5 false-positive lesions were identified in our study. One possible explanation is the false-negative findings from laparoscopic staging, which has a reported false-negative rate of 2.8%–17.2% (8,34–38), were potentially influenced by whether patients underwent open bursa omentalis surgery. Although peritoneal metastasis in the transverse mesocolon and omentum majus is a concern, the necessity of visualizing the bursa omentalis during laparoscopic exploration remains controversial (34,39). In our study, we used a 4-step procedure that does not include routine visualization of the bursa omentalis during laparoscopic staging. One false-positive 68Ga-FAPI-04 PET/CT case showed abnormal activity on the pancreas surface, a blind spot in laparoscopic staging (Supplemental Fig. 1). This finding highlights the need for further investigation into the procedure and scope of laparoscopic staging. Additionally, we speculate that chronic inflammation combined with fibrosis may contribute to false-positive results.
The false-negative rate of 68Ga-FAPI-04 PET/CT is a critical consideration for its clinical application. In our study, 4 false-negative lesions were observed on 68Ga-FAPI-04 PET/CT, with 3 patients diagnosed as having positive peritoneal cytology (CY1) only. Retrospective studies have reported that 12.5% of patients had positive peritoneal cytology in the absence of macroscopic metastases (40). Similarly, a prospective study found that 0.6% of patients with no or low-level clinically suspicious lesions and 5.8% of patients with suspicious peritoneal lesions were diagnosed with peritoneal metastasis based on positive peritoneal cytology (P0 and CY1) (22). In our study, 2.8% of patients without macroscopic metastases were found to have positive peritoneal cytology, highlighting the limited ability of 68Ga-FAPI-04 PET/CT in detecting CY1. Furthermore, small-volume tumors may be underestimated because of partial-volume effects, low metabolic activity, and the limited resolution of PET imaging, all of which could contribute to the false-negative rate of 68Ga-FAPI-04 PET/CT (41,42).
The detection rate of OPM using PET/CT is critical for economic evaluations. Routine 18F-FDG PET/CT is not recommended because of its high costs and limited effectiveness, reducing the rate of unnecessary gastrectomies by only 3% (43). When the detection rate of occult metastatic disease was 10%, the addition of 18F-FDG PET/CT resulted in an estimated cost savings per patient with locally advanced gastric cancer but failed to identify any peritoneal metastases in the study (44). In contrast, our study found that 68Ga-FAPI-04 PET/CT, when compared with laparoscopic staging, prevented futile gastrectomies in nearly 16% of patients, resulting in a potential savings of $565.30 per patient. Given the high negative predictive value (95.7%) of 68Ga-FAPI-04 PET/CT for diagnosing OPM in our study, we proposed an optimized diagnostic workflow (strategy 4) for patients with locally advanced gastric cancer in which patients first undergo 68Ga-FAPI-04 PET/CT. If no peritoneal abnormalities are observed, laparoscopic staging can be omitted. If high 68Ga-FAPI-04 uptake is detected in the peritoneum, laparoscopic staging will be performed to confirm peritoneal metastases. This strategy is economically comparable to laparoscopic staging but aims to reduce unnecessary laparoscopic staging and gastrectomies by relying on 68Ga-FAPI-04 PET/CT findings.
This study had several limitations. First, this was a single-center prospective study with a relatively small number of enrolled patients. Future studies involving larger cohorts and multicenter prospective designs would provide a more robust evaluation of the diagnostic efficacy of 68Ga-FAPI-04 PET/CT. Second, we did not compare 68Ga-FAPI-04 PET/CT with 18F-FDG PET/CT in randomized controlled trials, primarily because of the well-recognized limitations of 18F-FDG PET/CT in diagnosing gastric cancer, particularly in detecting OPM. Third, this study focused exclusively on patients with advanced gastric cancer (cT4a–b, N0–3, M0) based on initial staging evaluations using contrast-enhanced CT. However, CT-based diagnoses can be subjective and operator-dependent, potentially introducing variability. Lastly, we did not perform immunohistochemical analyses in this study because of the limited availability of tissue, despite the fact that it is the most direct and rigorous method to determine whether fibroblast activation protein expression originates from tumor cells or cancer-associated fibroblasts within the stroma.

CONCLUSION
The results of this study highlight the added value and minimal risks of using 68Ga-FAPI-04 PET/CT for detecting OPM. As a promising, precise, and rapid staging tool for locally advanced gastric cancer, 68Ga-FAPI-04 PET/CT is particularly valuable for excluding OPM as a diagnoses. Nonetheless, further high-quality, large-scale clinical trials are needed to validate these findings before implementing changes in clinical practice or guidelines.

DISCLOSURE
This work was supported by the Key R&D Program of Sichuan Provincial Department of Science and Technology (No. 2024YFFK0341), 1.3.5 project for disciplines of excellence, and the Resident/Specialist Research Fund of the West China Hospital, Sichuan University. No other potential conflict of interest relevant to this article was reported.