Recent PET/CT studies with FAP inhibitors have been well developed, revealing strong PET signals across dozens of major cancers, especially digestive system cancers [6, 7, 16, 17]. However, limited data about 99mTc-labelled FAPIs in clinical have been reported, with only application in two patients (ovarian and pancreatic cancer) [10]. Here we evaluated the biodistribution of a newly developed 99mTc-HFAPi and demonstrated its value for initial staging and restaging in digestive system cancers.
Based on time-dependent biodistribution of 99mTc-HFAPi in nontarget organs, optimal T/B ratios with limited noise were achieved by image acquisition at 60–90 min after injection. Almost all primary malignancies showed marked uptake of 99mTc-HFAPi, especially in gastric cancers, with median T/B ratios of 7.01. In addition, 99mTc-HFAPi might be superior to anatomic assessment for detecting local relapse, which is particularly useful in the presence of elevated tumour markers but no clinical or morphological evidence, as previously indicated [9].
The liver is the main site of metastasis and a major cause of death in digestive system malignancies [18]. The detection of liver metastasis is typically based on multi-modality imaging, including ceCT, MRI, and 18F-FDG PET/CT, but all have limitations. Although ceCT is commonly used for diagnosing liver metastasis, its accuracy does not always meet clinical requirements [19, 20]. ceMRI is suggested to have advantage over ceCT in detecting small liver metastases (< 10 mm); however, criticism has been directed towards it because the cost does not match the clinical benefit [19, 21, 22]. 18F-FDG PET/CT is not routinely indicated for initial staging of digestive tract tumours [23–25] because of its low sensitivity for liver metastasis, particularly in patients who have received preoperative chemotherapy [20, 26, 27]. The low background of the normal liver leads to the potential application of FAPI tracers in patients with suspected liver metastases [7, 28]. Our findings support the implementation of 99mTc-HFAPi SPECT/CT in the identification of liver metastasis. Basically, 99mTc-HFAPi demonstrated satisfactory sensitivity (88.2%) for detecting liver metastasis. Moreover, due to the low expression of FAP in benign liver lesions [29], an extremely high specificity (100%) of 99mTc-HFAPi was achieved. Four cases of suspected liver metastasis in ceCT were negatively detected by 99mTc-HFAPi with minimal uptake, and the lesions were proven to be benign by biopsy or multi-modality imaging, thus excluding from metastasis and restaging from M1 to M0 and allowing the chance for radical surgery. Overall, 99mTc-HFAPi provided an accurate diagnosis of suspected liver metastases, which may avoid unnecessary misdiagnosis, correct tumour staging and promote clinical oncological decisions.
According to a previous study, FAPI imaging identifies more lesions in skeletal metastases than 18F-FDG PET/CT [9]. A similar result was observed in our study: 2 patients with multiple skeletal uptake of 99mTc-HFAPi were considered to have bone metastasis, which was not detected by ceCT. These results further demonstrate the diagnostic advantage of 99mTc-HFAPi for distant metastasis, thus improving the staging of cancer and treatment modification.
As previously reported, inflammation-induced fibrosis revealed positive uptake of FAPIs [30], and our study showed that tuberculosis can take up 99mTc-HFAPi to some extent. Moreover, uterine fibroids demonstrated elevated 99mTc-HFAPi uptake, which might be attributed to the activated fibroblasts, with similar results in previous studies [31, 32]. However, unlike a previous report in which hepatobiliary elimination of FAPI-19 resulted in a lack of tumour accumulation [8], in our study, significant and stable 99mTc-HFAPi uptake was observed by tumours, and low liver uptake was observed in the 4-h period, indicating no redistribution to the liver during the enterohepatic cycle.
For 2 false-negative cases of primary malignancies, one showed obviously low expression of FAP by IHC staining, while the other had moderate expression, suggesting that the difference between FAP expression and imaging results may indicate changes in protein functional status; in fact, other membrane proteins have different functional states in different conformations [33] thus are inaccessible to inhibitors. Regardless, the reason remains to be explored.
There are several limitations to this study. First, a small patient cohort limited the statistical significance for some kinds of cancers, such as oesophageal, pancreatic, and gallbladder cancer. Second, although being the ideal reference standard, histopathological examination was not available in all lesions because of ethical and technical reasons. Third, due to relatively poor resolution of SPECT/CT, small lesions such as lung nodules and small lymph nodes were not well detected.
Despite these limitations, to the best of our knowledge, this article might be the first application of a new 99mTc-labelled FAPI for digestive system tumours from a clinical perspective, and we confirmed its diagnostic efficacy in tumour staging and restaging, providing an important basis for clinical application and subsequent studies. Further prospective studies with larger populations in head-to-head comparisons of 99mTc-HFAPi SPECT/CT and 68Ga-FAPI PET/CT are warranted to best comment on the superiority of the tracers to clarify the role of SPECT/CT.