The role of [99mTc]Tc-HFAPi SPECT/CT in patients with malignancies of digestive system: first clinical experience

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, 19, 20]. With FAPI-specific PET imaging, patients do not require dietary preparation, and high-quality images can be obtained soon after tracer injection (10 min to 1 h, mainly 1 h) [21]. The superior value of [68Ga]Ga-FAPI PET/CT over [18F]FDG in detecting primary and metastatic lesions in digestive system cancers has been confirmed, most lesions showing higher tracer uptake with FAPI imaging, and it exhibits a promising role in the diagnosis, (re)staging, management, and treatment planning of digestive system cancers [22]. 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]Tc-HFAPi and the uptake in different digestive system cancers. Biodistribution studies have shown that [99mTc]Tc-HFAPi has good targeting of malignancies and fast renal clearance, with low uptake in normal organs, leading to a higher tumour-to-background ratio and have a relatively wide imaging time window, indicating it is a suitable clinical imaging agent for digestive system tumours. Comparisons of diagnostic efficiency in digestive system cancers between [99mTc]Tc-HFAPi and ceCT were performed in this study, since CT with contrast is routinely used for preoperational imaging in digestive system cancers based on NCCN guidelines [11,12,13].

Our study demonstrated that [99mTc]Tc-HFAPi and ceCT were comparable in detecting the primary tumours of digestive system. Almost all primary malignancies (n = 33) showed marked uptake of [99mTc]Tc-HFAPi, especially gastric cancers and colon cancers, with median T/B ratios of 7.01 and 6.35, and median SUVmax values of 12.43 and 9.13, respectively. This was in line with the previous PET imaging with 68Ga-labelled FAPI-04 [20], which showed the highest uptake in colon cancers and gastric cancers. Our study also covered small samples of oesophageal squamous carcinoma, pancreatic carcinoma, and anal malignant melanoma, which all showed good detection performance. In the detection of tumour recurrence in patients who received surgery (n = 5), 60% (3/5) of them showed recurrence and all had successful detection by [99mTc]Tc-HFAPi, consistent with the ceCT results. Although the samples were too few, they were particularly useful for their 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, leading to short PFS and extremely poor prognosis [23]. Several imaging methods have been utilized in the detection of liver metastasis, 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 [24, 25]. 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 [24, 26, 27]. [18F]FDG PET/CT is not routinely indicated for initial staging of digestive tract tumours [11,12,13] because of its low sensitivity for liver metastasis, particularly in patients who have received preoperative chemotherapy [25, 28, 29]. The low background of the normal liver leads to the potential application of FAPI tracers in patients with suspected liver metastases [7, 30]. Previous studies with PET FAPI agents have indicated an outstanding role in the diagnosis of liver metastasis [7, 20]. Our findings likewise support the implementation of [99mTc]Tc-HFAPi SPECT/CT in the identification of liver metastasis. In metastatic lesions, the highest uptake of [99mTc]Tc-HFAPi were achieved in liver metastasis, with a median T/B ratio and SUVmax of 4.48 and 7.59, respectively. Basically, [99mTc]Tc-HFAPi demonstrated satisfactory sensitivity (88.2%) for detecting liver metastasis. Moreover, due to the low expression of FAP in benign liver lesions [31], an extremely high specificity (100%) of [99mTc]Tc-HFAPi was achieved. Four cases of suspected liver metastasis in ceCT were negatively detected by [99mTc]Tc-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]Tc-HFAPi provided an accurate diagnosis of suspected liver metastases, which may avoid unnecessary misdiagnosis, correct tumour staging and promote clinical oncological decisions.

In addition to liver metastasis, [68Ga]Ga-FAPI outperformed traditional imaging in detecting bone metastases [9]. In the present study, 2 patients with multiple skeletal metastases showed visible uptake of [99mTc]Tc-HFAPi, which was often missed by ceCT. These results further demonstrate the diagnostic advantage of [99mTc]Tc-HFAPi for various distant metastasis, thus improving the staging of cancer and treatment modification.

The expression of FAP is also widely reported to be avid in tissue modelling, wound healing, and inflammation-induced fibrosis [32]. Our study with 99mTc-labelled FAPI also demonstrated pulmonary tuberculosis with moderate uptake (T/B ratio of 4.36). Moreover, uterine fibroids demonstrated diffuse uptake of [99mTc]Tc-HFAPi, which might be attributed to the activated fibroblasts, as shown in previous PET imaging studies [33, 34].

Altogether 2 primary tumour lesions demonstrated false-negative uptake of [99mTc]Tc-HFAPi. One might be attributed to obviously low expression of FAP, which was revealed by following IHC staining [35], while the other one still had moderate expression on IHC. The mechanisms underlying the discordance between FAP expression and [99mTc]Tc-HFAPi uptake might be due to the liganding of molecules and certain physical influences, which might alter the conformation of some membrane proteins and their functional state (activation or inactivation) [36]. When it is in a nonactivated conformation, it is inaccessible to its targeted inhibitors. However, this still needs to be further confirmed.

We know that sensitivity and specificity are equally important when Youden’s index is used to obtain the best cut-off value. Previous study adopted cut-off value based on the highest Youden’s index [37]. However, a fixed cut-off value often does not meet the needs of clinical decision-making. Different cut-off values are needed according to different disease states and clinical purposes, just as previous study indicated [38]. Here, we listed a series of cut-off values for reference, because larger samples and data from other tumour histotypes and different clinical statuses with [99mTc]Tc-HFAPi are needed to optimize this criterion.

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, further prospective studies with larger populations in head-to-head comparisons of [99mTc]Tc-HFAPi SPECT/CT and [68Ga]Ga-FAPI PET/CT are warranted to best comment on the superiority of the tracers to clarify the role of SPECT/CT.

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. Furthermore, our 99mTc-labelled FAPI might provide some future directions for drug labelling with 188Re, such as integration in FAP targeted diagnosis and targeted radionuclide therapy [10].

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