Research ArticleClinical Investigation

Value of 68Ga-FAPI-04 and 18F-FDG PET/CT in Early Prediction of Pathologic Response to Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer

Ying Miao, Runhua Feng, Teng Yu, Rui Guo, Min Zhang, Yue Wang, Wangxi Hai, Chengfang Shangguan, Zhenggang Zhu and Biao Li
Journal of Nuclear Medicine February 2024, 65 (2) 213-220; DOI: https://doi.org/10.2967/jnumed.123.266403

Abstract

This prospective study investigated whether PET parameters from 18F-FDG and 68Ga-fibroblast activation protein inhibitor (FAPI)-04 PET/CT can predict a pathologic response to neoadjuvant chemotherapy (NAC) early in patients with locally advanced gastric cancer (LAGC). Methods: The study included 28 patients with LAGC who underwent 18F-FDG PET/CT and 68Ga-FAPI-04 PET/CT at baseline and after 1 cycle of NAC. PET parameters including SUV and tumor-to-background ratio (TBR), as well as the change rate of SUV and TBR, were recorded. Patients were classified as major or minor pathologic responders according to postoperative pathology findings. We compared the PET parameters between the 2 pathologic response groups and different treatment regimens and analyzed their predictive performance for tumor pathologic response. Results: Major pathologic responders had significantly lower 68Ga-FAPI change rates (percentage SUVmax [%SUVmax], percentage SUVpeak [%SUVpeak], and percentage TBR [%TBR]) than minor pathologic responders. Among the PET parameters, 68Ga-FAPI %SUVmax (area under the curve, 0.856; P = 0.009), %SUVpeak (area under the curve, 0.811; P = 0.022), and %TBR (area under the curve, 0.864; P = 0.007) were significant parameters for early prediction of pathologic response to NAC in LAGC; they had the same predictive accuracy of 89.29%, with the thresholds of decrease to at least 52.43%, 60.46%, and 52.96%, respectively. In addition, 68Ga-FAPI %SUVmax and %TBR showed significant differences between the different treatment regimens. Conclusion: In this preliminary study, 68Ga-FAPI-04 PET change rate parameters were preferable to 18F-FDG in predicting pathologic response to NAC at an early stage in LAGC. 68Ga-FAPI %SUVmax and %TBR may be better predictors of therapeutic response between different treatment regimens. These findings may help optimize the treatment for patients with LAGC.

In patients with locally advanced gastric cancer (LAGC) before radical surgery, neoadjuvant chemotherapy (NAC) is increasingly being applied because it may help control focal lesions, downstage tumors, increase R0 resection rates, and improve the disease-free and overall survival of patients (1–4). However, the role of preoperative NAC in LAGC remains controversial (5,6). For patients with poor sensitivity to chemotherapy, NAC may not only increase treatment-related adverse effects but also delay the optimal timing of surgery. Tumor regression grade (TRG) is an indicator of pathologic response to NAC and an important prognostic factor after NAC in gastric cancer (7–9). However, TRG can be determined only by postoperative pathology after completion of NAC treatment. Therefore, early prediction of patients with a suboptimal pathologic response and timely adjustment of their treatment plan are clinically important.

18F-FDG PET aids in assessing treatment response in various malignancies (10–13). However, the interference of physiologic or inflammatory accumulation of 18F-FDG in the gastric wall, as well as the low 18F-FDG uptake in signet ring cell carcinoma (SRCC), mucinous adenocarcinoma, and some poorly differentiated carcinomas with a high mucinous component, limits its use for assessing treatment response in patients with gastric cancer (14).

68Ga-labeled fibroblast activation protein inhibitor (FAPI), an emerging PET tracer, targets fibroblast activation protein overexpressed on cancer-associated fibroblasts, which are predominant in the tumor microenvironment (15). The use of FAPI-based tracers has shown promise in the assessment of digestive system tumors, particularly gastric cancer (16,17). Our recent study has substantiated that 68Ga-FAPI-04 PET/CT is better than 18F-FDG in detecting primary gastric cancer lesions and peritoneal metastases, particularly in poorly cohesive carcinoma (PCC) (including SRCC) (18). However, the value of 68Ga-FAPI PET/CT in the assessment of treatment response is still unclear.

Hence, this prospective study aimed to investigate whether PET parameters from 18F-FDG and 68Ga-FAPI-04 PET/CT can be used to predict pathologic response to NAC early. The results would help personalize the treatment for patients with LAGC.

MATERIALS AND METHODS

Patients

This prospective clinical study was approved by the Ruijin Hospital Ethics Committee of Shanghai Jiao Tong University School of Medicine and registered at ClinicalTrials.gov (NCT05140746). Patients were enrolled consecutively from September 2020 to October 2022, and all provided written informed consent. The inclusion criteria were as follows: age of 18–75 y; gastric adenocarcinoma histologically confirmed through gastroscopy; resectable gastric cancer; Eastern Cooperative Oncology Group performance status of 0–1; white blood count greater than 4 × 109/L; absolute neutrophil count greater than 2 × 109/L; hemoglobin greater than 90 g/L; platelets greater than 100 × 109/L; ejection fraction greater than 50%; serum bilirubin less than 1.5 times the upper level of normal; alanine-transaminase and aspartate-transaminase less than 1.5 times the upper level of normal; serum creatinine no more than 1.5 times the upper level of normal or glomerular filtration rate more than 60 mL/min; a signed informed consent form; willingness and ability to comply with the protocol throughout the study period; and no child-bearing plan within 6 mo. Conversely, the exclusion criteria included the following: a second primary malignant disease in the past 5 y, except for basal cell and squamous cell carcinoma of the skin that have been cured; a known hypersensitivity reaction to chemotherapy drugs or with contraindications; severe disease or other unsuitable conditions determined by investigators and inadequate organ function; uncontrollable diabetes or a fasting blood glucose level of at least 11 mmol/L on the test day; severe mental symptoms, unconsciousness, or inability to complete the examination; pregnancy or possible pregnancy; breastfeeding; and noncompliance.

Treatment Schemes

The NAC treatment was based on the SOX regimen (tegafur gimeracil oteracil potassium capsule for 2 wk with oxaliplatin on day 1, every 3 wk for 3 courses). According to randomization, 16 received the SOX regimen alone, 4 received the SOX regimen combined with apatinib, and 8 received the SOX regimen combined with apatinib and camrelizumab. Surgery was performed at a median of 30.5 d (range, 3–6 wk) after NAC completion.

PET/CT Imaging

68Ga-FAPI-04 was prepared according to a previous procedure (18). Briefly, radioactive gallium (68Ga) was extracted from a 68Ge/68Ga generator and added to a reactor vial with 20 μg of DOTA-FAPI-04 (CSBio) and then mixed with NaOAc (1 mol/L, 1 mL) to achieve a pH of 4. An automated synthesis module (Trasis) was used to react the mixture further at 100°C for 10 min. 18F-FDG was routinely synthesized. Patients underwent 18F-FDG PET/CT and 68Ga-FAPI-04 PET/CT imaging covering the whole body (from the top of the head to the upper thigh) at baseline and the upper abdomen after 1 NAC cycle. The interval between 18F-FDG and 68Ga-FAPI-04 PET/CT scans was within 7 d, and the interval between the first cycle of NAC treatment and the postcycle 1 PET/CT scan was 15–20 d. After being injected with 18F-FDG (3.7–4.44 MBq/kg) or 68Ga-FAPI-04 (1.85–2.96 MBq/kg), patients rested for 60–90 or 30–60 min, respectively. Patients with excluded contraindications were then administered 20 mg of hyoscine-N-butylbromide intravenously and then drank approximately 500 mL of water to distend the stomach before scanning. PET/CT scans were performed using a dedicated PET/CT scanner (Biograph Vision 450; Siemens Healthineers). CT images were captured using CARE Dose4D (Siemens) technique (120 kV, automatic mA-modulation), whereas PET images were captured in 3-dimensional mode and reconstructed in a 440 × 440 matrix (iterations, 4, subsets, 5) using the TrueX + TOF (ultraHD-PET; Siemens) method.

Image Analysis

All PET/CT images were independently evaluated by 2 experienced nuclear medicine physicians. Both baseline and postcycle 1 18F-FDG PET/CT and 68Ga-FAPI-04 PET/CT images were analyzed using the syngo.via software (Siemens Molecular Imaging). A spheric region of interest was drawn around tumor lesions, and it was automatically adjusted to a 3-dimensional volume of interest at 60% isocontour (19). PET parameters including the SUVmax and the SUVpeak were recorded. To measure the SUVmean of the mediastinal blood pool background, we set a 10-mm-diameter volume of interest on the descending aorta. Furthermore, we calculated the tumor-to-background ratio (TBR) as tumor lesion SUVmax/mediastinal blood pool background SUVmean; the change rate of SUV (%SUV) as [postcycle 1 SUV – baseline SUV]/baseline SUV × 100%; and the change rate of TBR (%TBR) as [postcycle 1 TBR – baseline TBR]/baseline TBR × 100%.

Pathologic Assessment

The postoperative specimens were examined histopathologically, and the TRG was based on the following: grade 0, complete regression with no viable cancer cells; grade 1, moderate regression with single cancer cells or a small cluster of cancer cells; grade 2, minimal regression with residual cancer but less than fibrosis; grade 3, poor regression with extensive residual cancer, or minimal or no cancer cell death (20). Grades 0 and 1 indicate a major pathologic response, whereas grades 2 and 3 indicate a minor pathologic response.

Statistical Analysis

Statistical analysis was performed using the IBM SPSS Statistics 26.0 software. Continuous variables for SUV, TBR, %SUV, and %TBR are presented as medians and interquartile ranges, whereas categoric variables are expressed as numbers and percentages. The Wilcoxon signed-rank test was used to compare 18F-FDG and 68Ga-FAPI-04 PET parameters, as well as PET parameters at baseline and after 1 NAC cycle. The Mann–Whitney U test was used to compare PET parameters between the major and minor pathologic responders. The Kruskal–Wallis test was used to compare PET parameters between the different regimens. The correlation between variables was assessed using the Spearman rank correlation coefficient. The area under the curve (AUC) was obtained using the receiver operating characteristic curve, and the optimal predictive threshold was further calculated using the Jorden index (i.e., sensitivity + specificity − 1). The predictive performance for tumor pathologic response, including sensitivity, specificity, positive predictive value, negative predictive value, and accuracy, was also analyzed. All statistical data were analyzed using the 2-tailed test, and a P value of less than 0.05 was considered statistically significant.

RESULTS

Patients

Of the 33 potentially eligible patients, 28 were ultimately enrolled and succeeded in completing the study. Figure 1 presents the study’s flowchart. Within the cohort, 6 patients were major pathologic responders, whereas 22 were minor pathologic responders. Table 1 summarizes the clinical and pathologic characteristics of the 28 patients.

FIGURE 1.
FIGURE 1.

Flowchart of study.

View this table:
TABLE 1.

Clinical and Pathologic Characteristics of Patients

Comparison of PET Parameters at Baseline and 1 Cycle After NAC in Patients with LAGC

At baseline, all 28 patients were 68Ga-FAPI-04–avid, whereas 23 of 28 were 18F-FDG–avid. Five patients with non–18F-FDG–avid tumors were confirmed as having PCC (with partial SRCC). Moreover, baseline 68Ga-FAPI-04 SUVmax was significantly higher than 18F-FDG SUVmax (22.15 [18.44–26.59] vs. 12.05 [8.25–19.32], P = 0.007), as well as SUVpeak (14.43 [10.73–15.90] vs. 7 [5.05–13.00], P = 0.003) and TBR (23.01 [15.93–29.24] vs. 7.17 [4.51–11.54], P < 0.001). After 1 NAC cycle, 18F-FDG PET parameters (SUVmax, SUVpeak, and TBR) significantly decreased (P < 0.001, P < 0.001, and P < 0.001, respectively), as did 68Ga-FAPI-04 PET parameters (P = 0.001, P < 0.001, and P = 0.001, respectively). Figure 2 shows the changes in 18F-FDG and 68Ga-FAPI-04 PET parameters at baseline and after 1 NAC cycle in patients with LAGC.

FIGURE 2.
FIGURE 2.

Changes in PET parameters at baseline and after 1 NAC cycle: SUVmax (A), SUVpeak (B), and TBR (C) from 18F-FDG and 68Ga-FAPI-04 PET. **P < 0.01. ***P < 0.001.

Correlations Between PET Parameters and Pathologic Features

Figure 3 presents the correlations between 18F-FDG and 68Ga-FAPI-04 PET parameters and the pathologic features. First, the 18F-FDG baseline and change rate parameters correlated with histologic type, Lauren classification, and differentiation degree, whereas most of the 68Ga-FAPI-04 PET parameters did not correlate with the abovementioned pathologic characteristics. Second, TRG correlated with 68Ga-FAPI-04 change rate parameters including %SUVmax, %SUVpeak, and %TBR but not with the baseline or change rate parameters of 18F-FDG PET. Additionally, the 18F-FDG PET parameters partially correlated with 68Ga-FAPI-04 parameters, but there was no correlation between 18F-FDG and 68Ga-FAPI-04 PET change rate parameters.

FIGURE 3.
FIGURE 3.

Correlations between PET parameters and pathologic features. Red circle denotes positive correlation between 2 factors, whereas blue circle denotes negative correlation. Darker color indicates stronger correlation. P values show statistical difference in correlation between 2 factors. *P < 0.05. **P < 0.01. ***P < 0.001.

Comparison of PET Parameters Between NAC Major and Minor Pathologic Responder Groups

Table 2 compares the 18F-FDG and 68Ga-FAPI PET parameters between the NAC major and minor pathologic responders in the whole cohort. The results showed that major pathologic responders had significantly lower 68Ga-FAPI change rate parameters including %SUVmax, %SUVpeak, and %TBR (P = 0.009, P = 0.022, and P = 0.007, respectively) than minor pathologic responders, whereas both 18F-FDG and 68Ga-FAPI baseline PET parameters and 18F-FDG change rate parameters showed no significant difference between the 2 groups. Supplemental Table 1 further compares the 18F-FDG PET parameters between the 2 responder groups in 23 patients with 18F-FDG–avid tumors (supplemental materials are available at http://jnm.snmjournals.org). The results were consistent with those of the overall cohort. Figure 4 displays representative cases of a major and a minor pathologic responder.

View this table:
TABLE 2.

Comparison of PET Parameters Between NAC Major and Minor Pathologic Responder Groups

FIGURE 4.
FIGURE 4.

18F-FDG and 68Ga-FAPI-04 PET/CT images at baseline and after 1 NAC cycle: major pathologic responder with TRG grade 0 (arrows, A) and minor pathologic responder with TRG grade 3 (arrows, B).

Performance of PET Parameters in Early Prediction of Pathologic Response to NAC

Supplemental Table 2 and Figure 5 present the receiver operating characteristic curves assessing the predictive accuracy of PET parameters in identifying major and minor pathologic responders to NAC. The AUCs for 68Ga-FAPI %SUVmax, %SUVpeak, and %TBR were significant (0.856, 0.811, and 0.864, respectively) among the various PET parameters. Table 3 displays the predictive performance of significant PET parameters in early prediction of pathologic response to NAC. 68Ga-FAPI %SUVmax, %SUVpeak, and %TBR had the same accuracy of 89.29%, with the thresholds of decrease to at least 52.43%, 60.46%, and 52.96%, respectively; the sensitivity, specificity, positive predictive value, and negative predictive value were 83.33%, 90.91%, 71.43%, and 95.24%, respectively.

FIGURE 5.
FIGURE 5.

Receiver operating characteristic curves for ability of PET parameters to predict pathologic response to NAC early.

View this table:
TABLE 3.

Performance of PET Parameters in Early Prediction of Pathologic Response to NAC

Comparison of PET Parameters Between Different NAC Regimens

Figure 6 further compares the 18F-FDG and 68Ga-FAPI change rate parameters among the 3 different regimens. The results showed that 68Ga-FAPI %SUVmax and %TBR were significantly lower in the SOX-plus-apatinib-plus-camrelizumab group than in the SOX group (P = 0.028 and 0.028, respectively). However, there were no significant differences between the other groups and for other PET parameters. According to the postoperative pathology, in the SOX, SOX-plus-apatinib, and SOX-plus-apatinib-plus-camrelizumab groups, there were 1 of 16, 0 of 4, and 5 of 8 patients, respectively, who achieved a major pathologic response.

FIGURE 6.
FIGURE 6.

Comparison of change rate parameters between different NAC regimens: %SUVmax (A), %SUVpeak (B), and %TBR (C) from 18F-FDG and 68Ga-FAPI-04 PET. *P < 0.05. ns = not statistically significant.

DISCUSSION

In this study, TRG correlated with 68Ga-FAPI change rate parameters including %SUVmax, %SUVpeak, and %TBR. Major pathologic responders had significantly lower 68Ga-FAPI change rate parameters than minor pathologic responders. 68Ga-FAPI %SUVmax, %SUVpeak, and %TBR could provide an early indication of pathologic response to NAC in LAGC and outperformed 18F-FDG PET parameters. 68Ga-FAPI %SUVmax and %TBR may be better predictors of therapeutic response between different treatment regimens.

Considering the heterogeneity of gastric cancer, the therapeutic response to NAC is highly variable and is strongly associated with patient prognosis. A 2-center study found that the 3- and 5-y survival rates of patients with gastric cancer with TRG 0–1 after NAC plus surgery were 85.2% and 74.5%, respectively, compared with 28.2%–56.1% and 23%–44.1%, respectively, in patients with TRG 2–3 (7). An earlier metaanalysis of 17 studies on gastroesophageal cancer demonstrated that compared with no or minimal pathologic response after NAC, a major pathologic response is significantly associated with higher overall survival and disease-free survival (8). Therefore, we sought to obtain indirect prognostic information using PET/CT imaging techniques to predict pathologic response to NAC early.

Several studies have explored the value of 18F-FDG PET for therapeutic monitoring in gastric cancer but obtained controversial findings (21). In our study, 18F-FDG PET parameters did not correlate with TRG and were not significantly different between major and minor pathologic responders. This was further verified in 18F-FDG–avid LAGC, as the assessment of metabolic response in non–18F-FDG–avid gastric tumors was considered limited. For PCC (including SRCC), the incidence is on the rise, with a higher proportion of younger women and advanced-stage patients than for non-PCC subtypes, which tend to present as non–18F-FDG–avid tumors, in part due to high mucus content, low tumor cell density, and low glucose transporter 1 expression (22–24). Given their poorer prognosis, effective assessment tools are needed.

Numerous studies revealed that 68Ga-FAPI PET is preferable to 18F-FDG in gastric cancer staging and restaging (22,25–29). Our previous study also confirmed the superiority of 68Ga-FAPI PET over 18F-FDG in detecting gastric cancer primary lesions and peritoneal metastases, especially in PCC including SRCC (18). As observed in our present study, most of the 68Ga-FAPI-04 PET parameters had no significant correlation with the histologic type, Lauren classification, and degree of differentiation of the tumors, consistent with our previous finding (18). This may be because FAPI reflects the characteristics of the tumor stroma rather than the tumor cells. In addition, the value of 68Ga-FAPI PET/CT in the early prediction of NAC treatment response in LAGC remains unclear.

Although previous case reports and series showed the initial value of FAPI PET in monitoring treatment response of breast myeloid sarcoma, peritoneal carcinomatosis, and gastric cancer, our prospective study further indicated that 68Ga-FAPI PET change rate parameters (%SUVmax, %SUVpeak, and %TBR) could predict the pathologic response to NAC in LAGC early (27,29–31). Of these, 68Ga-FAPI %SUVmax and %TBR further discriminated the treatment response between different treatment regimens, suggesting that 68Ga-FAPI PET may have potential applicability for monitoring the efficacy of different treatment regimens. However, baseline 68Ga-FAPI PET parameters did not correlate with therapeutic response in our study—a finding that is inconsistent with the findings of Hu et al. (32). This may be attributed to different criteria used to evaluate the therapeutic response. Additionally, 5 patients with non–18F-FDG–avid tumors (confirmed as PCC with partial SRCC) were all avid on 68Ga-FAPI-04 PET, suggesting the potential of 68Ga-FAPI PET parameters to predict NAC pathologic response early, especially in non–18F-FDG–avid gastric cancer such as PCC (including SRCC). A typical case is shown in Figure 7. However, the fact that no significant changes in 68Ga-FAPI PET parameters were observed in one of our major pathologic responders—possibly because of superimposition of inflammation or fibrosis after chemotherapy—may be a potential pitfall in predicting NAC efficacy that requires further investigation (33).

FIGURE 7.
FIGURE 7.

18F-FDG and 68Ga-FAPI-04 PET/CT images at baseline and after 1 NAC cycle in major pathologic responder with TRG grade 1. Patient had non–18F-FDG–avid LAGC (arrows), confirmed as PCC.

This study had several limitations. First, the sample size was relatively small. Especially, the number of patients showing a major response to NAC was limited, preventing further stratification analysis according to clinicopathologic characteristics. Second, an upper abdominal local PET/CT scan was used as an early evaluation scheme in our study; its use may contribute to underestimation because of the heterogeneity of tumor sensitivity to chemotherapy. For example, one of our patients had a new metastatic lesion in the pelvic peritoneum detected by laparoscopy after NAC completion, despite a significant reduction of 68Ga-FAPI uptake in the primary lesion after 1 NAC cycle. In addition, our study was conducted at a single center; further large, multicenter clinical trials are needed to confirm our conclusion.

CONCLUSION

This preliminary study suggests that 68Ga-FAPI-04 PET change rate parameters appear to be more predictive of the pathologic response at an early stage than 18F-FDG PET parameters. 68Ga-FAPI %SUVmax and %TBR may be better predictors of therapeutic response between different treatment regimens, but this possibility needs to be verified in a larger cohort. This insight may help us understand the sensitivity of chemotherapy and thus optimize treatment regimens.

DISCLOSURE

This work was supported by the Shanghai Municipal Key Clinical Specialty (shslczdzk03403); a joint research development project between Shenkang and United Imaging on clinical research and translation (SKLY2022CRT403); and the Shanghai Jiao Tong University “Star of Jiao Tong University” Program Medical–Industrial Intersection Research Foundation (YG2021QN15). No other potential conflict of interest relevant to this article was reported.

KEY POINTS

QUESTION: Can PET parameters from 18F-FDG and 68Ga-FAPI-04 PET/CT predict a pathologic response to NAC early in patients with LAGC?

PERTINENT FINDINGS: 68Ga-FAPI PET parameters (including %SUVmax, %SUVpeak, and %TBR) could provide an early indication of pathologic response to NAC in LAGC and outperformed 18F-FDG PET parameters. 68Ga-FAPI %SUVmax and %TBR may be better predictors of therapeutic response between different treatment regimens.

IMPLICATIONS FOR PATIENT CARE: Our preliminary findings may help optimize treatment for patients with LAGC.

Footnotes

  • ↵* Contributed equally to this work.

  • ↵† Contributed equally to this work.

  • Published online Dec. 21, 2023.

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  • Revision received November 7, 2023.
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