Fibroblast activation protein (FAP), a membrane-anchored peptidase, is highly expressed in cancer-associated fibroblasts in more than 90% of epithelial tumors and contributes to progression and worse prognosis of different cancers. Therefore, FAP is considered a promising target for radionuclide-based approaches for diagnosis and treatment of tumors and for the diagnosis of nonmalignant diseases associated with a remodeling of the extracellular matrix. Accordingly, a variety of quinolone-based FAP inhibitors (FAPIs) coupled to chelators were developed displaying specific binding to human and murine FAP with a rapid and almost complete internalization. Because of a high tumor uptake and a very low accumulation in normal tissues, as well as a rapid clearance from the circulation, a high contrast is obtained for FAPI PET/CT imaging even at 10 min after tracer administration. Moreover, FAPI PET/CT provides advantages over 18F-FDG PET/CT in several tumor entities for initial staging and detection of tumor recurrence and metastases, including peritonitis carcinomatosa.

https://jnm.snmjournals.org/content/jnumed/62/2/160.full.pdf

The Latest Developments in Imaging of Fibroblast Activation Protein

This study aimed to evaluate the potential utility of [68Ga]Ga-FAPI-04 PET/CT for diagnosing primary and metastatic lesions in patients with liver cancer, as well as to compare it with contrast-enhanced CT (CE-CT), liver MRI, and [18F]-FDG PET/CT. We performed a single-center post hoc retrospective analysis of data obtained from a prospective parent study (NCT04416165). This study included 34 patients diagnosed with or suspected hepatic lesions who underwent concomitant [68Ga]Ga-FAPI-04 and [18F]-FDG/CT scans. Moreover, these patients underwent liver MRI (n = 34) and CE-CT (n = 25). Histopathologic (n = 62) or radiographic follow-up (n = 128) served as the reference standard for the final diagnosis. Among the 34 patients, 20, 12, and 2 patients presented with hepatocellular carcinomas, intrahepatic cholangiocarcinomas, and benign hepatic nodules, respectively. The sensitivities of CE-CT, MRI, [68Ga]Ga-FAPI-04, and [18F]-FDG/CT for detecting primary liver tumors were 96%, 100%, 96%, and 65%, respectively. Regarding the diagnosis of all intrahepatic lesions, the per-lesion detection rate of [68Ga]Ga-FAPI-04 PET/CT was slightly lower than that of MRI (85% vs. 100%, P = 0.34) and significantly higher than that of [18F]-FDG PET/CT (85% vs. 52%, P < 0.001). Regarding the diagnosis of all malignant lesions (including extrahepatic disease), the tumor detection rate of [68Ga]Ga-FAPI-04 PET/CT was 87.4%, which was significantly higher than that of [18F]-FDG PET/CT (65.0%, P < 0.001). Our findings indicate that the sensitivity of [68Ga]Ga-FAPI-04 PET/CT to correctly identify primary liver tumors and metastatic lesions is equivalent to that of CE-CT and liver MRI. Moreover, [68Ga]Ga-FAPI-04 PET/CT is better at identifying liver lesions than [18F]-FDG PET/CT, and its use may improve tumor staging, recurrence detection, and implementation of necessary treatment modifications.

Imaging fibroblast activation protein in liver cancer: a single-center post hoc retrospective analysis to compare [68Ga]Ga-FAPI-04 PET/CT versus MRI and [18F]-FDG PET/CT

FAPI ligands (fibroblast activation protein inhibitor), a novel class of radiotracers for PET/CT imaging, demonstrated in previous studies rapid and high tumor uptake. The purpose of this study is the head-to-head intra-individual comparison of 68Ga-FAPI versus standard-of-care 18F-FDG in PET/CT in organ biodistribution and tumor uptake in patients with various cancers. This international retrospective multicenter analysis included PET/CT data from 71 patients from 6 centers who underwent both 68Ga-FAPI and 18F-FDG PET/CT within a median time interval of 10 days (range 1–89 days). Volumes of interest (VOIs) were manually drawn in normal organs and tumor lesions to quantify tracer uptake by SUVmax and SUVmean. Furthermore, tumor-to-background ratios (TBR) were generated (SUVmax tumor/ SUVmax organ). A total of 71 patients were studied of, which 28 were female and 43 male (median age 60). In 41 of 71 patients, the primary tumor was present. Forty-three of 71 patients exhibited 162 metastatic lesions. 68Ga-FAPI uptake in primary tumors and metastases was comparable to 18F-FDG in most cases. The SUVmax was significantly lower for 68Ga-FAPI than 18F-FDG in background tissues such as the brain, oral mucosa, myocardium, blood pool, liver, pancreas, and colon. Thus, 68Ga-FAPI TBRs were significantly higher than 18F-FDG TBRs in some sites, including liver and bone metastases. Quantitative tumor uptake is comparable between 68Ga-FAPI and 18F-FDG, but lower background uptake in most normal organs results in equal or higher TBRs for 68Ga-FAPI. Thus, 68Ga-FAPI PET/CT may yield improved diagnostic information in various cancers and especially in tumor locations with high physiological 18F-FDG uptake.

/pdf/head-to-head-intra-individual-comparison-of-biodistribution-3dxuiupvys.pdf

Head-to-head intra-individual comparison of biodistribution and tumor uptake of 68Ga-FAPI and 18F-FDG PET/CT in cancer patients.

Purpose Fibroblast activation protein (FAP) is a cell membrane-bound serine peptidase, overexpressed in cancer-associated fibroblasts and activated fibroblasts at wound healing/inflammatory sites. Recently, molecular PET/CT imaging with radiolabeled FAP inhibitor (FAPI) has been evaluated in different diseases. We aimed to assess its potential role based on the available literature. Patients and methods We conducted a comprehensive review of the available preclinical and clinical data on FAPI PET/CT in an attempt to summarize its current status and potential future role. Based on that, we have discussed the pathophysiology behind FAP-based imaging, followed by a discussion of FAPI radiopharmaceuticals including their synthesis, biodistribution, and dosimetry. Next, we have discussed studies evaluating FAPI PET/CT in different oncological and nononcological pathologies. The potential of FAPI PET/CT in theranostics has also been addressed. Results Based on the early scientific evidence available, including preclinical and clinical studies, FAPI PET/CT seems to be a promising molecular imaging tool, especially in oncology. It can be used for imaging different types of cancers and outperforms 18F-FDG PET/CT in some of these. Its potential as a theranostic tool warrants special attention. Conclusions Fibroblast activation protein inhibitor PET/CT has the potential to emerge as a powerful molecular imaging tool in the future. However, as of yet, the available evidence is limited, warranting further research and trials in this field.

Fibroblast Activation Protein Inhibitor PET/CT: A Promising Molecular Imaging Tool.

We aimed to compare the roles of 68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT in the evaluation of primary tumor and metastases in primary and recurrent breast cancer. Twenty female patients with histopathologically confirmed primary and recurrent breast cancer were included in the prospective study. All patients underwent FDG and FAPI PET/CT imaging in the same week. The number of primary and metastatic lesions, SUVmax values, and tumor-to-background ratios (TBR) were recorded from both scans. Data obtained were statistically compared. FAPI PET/CT was superior to FDG in detecting breast lesions, as well as hepatic, bone, lymph node, and cerebral metastases in terms of patient- and lesion-based assessments. The sensitivity and specificity of FAPI in detecting primary breast lesions were 100% and 95.6%, respectively, while the sensitivity and specificity of FDG were 78.2% and 100%, respectively. The SUVmax values of primary breast tumors, lymph nodes, lung metastases, and bone metastases were significantly higher on FAPI imaging than FDG imaging (p   0.05). Also, FAPI imaging yielded significantly higher TBR in breast lesions as well as hepatic, bone, brain and lung metastases compared to FDG (p < 0.05). 68 Ga-FAPI-04 PET/CT is superior to 18F-FDG PET/CT in detecting the primary tumor in patients with breast cancer with its high sensitivity, high SUVmax, and high TBR. 68 Ga-FAPI-04 PET/CT is also superior to 18F-FDG PET/CT in detecting lymph node, hepatic, bone, and cerebral metastases because it has lower background activity and higher uptake in subcentimetric lesions.

68 Ga-FAPI-04 PET/CT, a new step in breast cancer imaging: a comparative pilot study with the 18 F-FDG PET/CT

This prospective study aimed to evaluate the potential usefulness of [68Ga]Ga-DOTA-FAPI-04 positron emission tomography/computed tomography (PET/CT) in the oncological evaluation of patients presenting with inconclusive [18F]FDG PET/CT findings [68Ga]Ga-DOTA-FAPI-04 was performed in patients presenting with inconclusive [18F]FDG PET/CT findings Tumour uptake was quantified by the maximum standard uptake value (SUV) Histopathology or follow-up imaging served as the standard for the final diagnosis A total of 68 patients with inconclusive [18F]FDG PET/CT findings underwent additional [68Ga]Ga-DOTA-FAPI-04 PET/CT Of them, 18 (265%) were for discrimination of mass lesions detected on conventional imaging, 6 (88%) for detection of the unknown primary site in biopsy-proven metastatic malignancy, 21 (309%) for the staging of cancer, and the other 23 (338%) for evaluation of suspected disease recurrence Most of the primary and metastatic lesions demonstrated higher uptake of [68Ga]Ga-DOTA-FAPI-04 than did [18F]FDG, which resulted in favourable tumour-to-background contrast in various types of cancer As a result, [68Ga]Ga-DOTA-FAPI-04 PET/CT identified suspicious mass lesions with an accuracy of 12/18 (667%), detected the primary site in 4/6 patients (667%) with unknown malignancy, upgraded tumour staging in 7/21 patients (333%), and detected disease recurrence in 20/23 patients (870%) In patients undergoing oncological evaluation with inconclusive [18F]FDG PET/CT findings, [68Ga]Ga-DOTA-FAPI-04 may have a complementary role in discriminating mass lesions on conventional imaging, locating the primary site of unknown malignancy, modifying tumour staging, and detecting suspected disease recurrence Nevertheless, careful attention should be paid when reading the [68Ga]Ga-DOTA-FAPI-04 PET/CT images in tumours complicated with inflammation

Usefulness of [68Ga]Ga-DOTA-FAPI-04 PET/CT in patients presenting with inconclusive [18F]FDG PET/CT findings

This study aimed to investigate the diagnostic performance of [68Ga]Ga-FAPI PET/CT for primary and metastatic pancreatic carcinoma lesions and compare the results with those of [18F]-fluorodeoxyglucose ([18F]FDG) PET/CT. Patients with suspected or diagnosed pancreatic malignancy, who underwent contemporaneous [18F]FDG and [68Ga]Ga-FAPI PET/CT between June 2020 and January 2021, were retrospectively analyzed. Routine contrast-enhanced CT (CE-CT) is performed in all patients as standardized care. Findings were confirmed by histopathology or radiographic follow-up. We compared radiotracer uptake, diagnostic performance, and TNM (tumor-node-metastasis) classifications. We evaluated 36 participants (25/36 men; median age, 60 years), including 26 patients with pancreatic malignancies and ten patients with pancreatic benign lesions. [68Ga]Ga-FAPI PET/CT showed higher radiotracer uptake and higher sensitivity than [18F]FDG PET/CT in evaluating primary tumors (SUVmax, 21.4 vs. 4.8; sensitivity, 100% vs. 73.1%), involved lymph nodes (SUVmax, 8.6 vs. 2.7; sensitivity, 81.8% vs. 59.1%), and metastases (SUVmax, 7.9 vs. 3.5; sensitivity, 91.5% vs. 44.0%); Compared with [18F]FDG, [68Ga]Ga-FAPI PET/CT upstaged six patients’ TNM staging (6/23, 26.1%) and changed two patients’ clinical management (2/23, 8.7%). Compared with CE-CT, [68Ga]Ga-FAPI PET/CT upgraded TNM staging in five patients (5/23, 21.7%) and changed the therapeutic regimen in only one patient (1/23, 4.3%). Intense [68Ga]Ga-FAPI uptake was observed throughout the pancreas in 12/26 pancreatic malignancies; dual-time point [68Ga]Ga-FAPI PET/CT may differentiate pancreatitis from malignancy. Compared with [18F]FDG PET/CT, [68Ga]Ga-FAPI PET/CT shows higher sensitivity in detecting primary pancreatic tumors, involved lymph nodes, and metastases and is superior in terms of TNM staging. Prospective trials with larger patient population are needed to evaluate whether [68Ga]Ga-FAPI PET/CT could elicit treatment modification in pancreatic cancer when compared with standard of care imaging.

Positron emission tomography and computed tomography with [68Ga]Ga-fibroblast activation protein inhibitors improves tumor detection and staging in patients with pancreatic cancer.

OBJECTIVE We aimed to assess the impact of the treatment modality on the outcome of small cell neuroendocrine cervical carcinoma (SCNEC) using the Surveillance Epidemiology and End Results (SEER) database. METHODS Patients from the SEER program between 1981 and 2014 were identified. Significant factors for cancer-specific survival (CSS) and overall survival (OS) were analyzed using the Kaplan-Meier survival and Cox regression methods. RESULTS A total of 503 SCNEC patients were identified. The 5-year CSS and OS were 36.6% and 30.6%, respectively. The International Federation of Gynecology and Obstetrics (FIGO) stage I to IV distributions was 189 (37.6%), 108 (21.5%), 95 (18.9%), and 111 patients (22.0%), respectively. Within the patients with known treatment strategies, 177 (45.9%) were treated with radical surgery and 209 (54.1%) underwent primary radiotherapy. Local treatment strategies were independent prognostic factor for CSS and OS. The 5-year CSS for radical surgery and primary radiotherapy was 50.0% and 27.9%, respectively (P < .001). The 5-year OS for those who received radical surgery and primary radiotherapy was 57.8%, and 29.6%, respectively (P < .001). In FIGO stage I SCNEC, patients treated with radical surgery had superior CSS (P = .001) and OS (P = .003) than those with primary radiotherapy. However, in FIGO stage II and III SCNEC, there were no differences in CSS and OS with respect to different local treatment strategies. Our results also found that the addition of brachytherapy impacted OS in the FIGO stage III SENCE (P = .002). The 5-year CSS and OS of patients with FIGO IV were only 11.7% and 7.1%, respectively. CONCLUSIONS SCNEC is a rare disease with aggressive clinical behavior. The findings indicate that radical surgery should be suggested for early-stage SCNEC and combining radiation therapy with brachytherapy should be suitable for patients with advanced stage.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.3326

Qin Lin

Papers

Usefulness of [68Ga]Ga-DOTA-FAPI-04 PET/CT in patients presenting with inconclusive [18F]FDG PET/CT findings

Positron emission tomography and computed tomography with [68Ga]Ga-fibroblast activation protein inhibitors improves tumor detection and staging in patients with pancreatic cancer.

Prognostic factors and treatment comparison in small cell neuroendocrine carcinoma of the uterine cervix based on population analyses.

Cardiac angiosarcoma detected using 68Ga-fibroblast activation protein inhibitor positron emission tomography/magnetic resonance

68Ga-fibroblast activation protein inhibitor PET/CT on gross tumour volume delineation for radiotherapy planning of oesophageal cancer.