Sarcomas, a heterogeneous group of malignant tumors originating from mesenchymal cells, present a significant challenge in the field of oncology. These tumors are characterized by their rarity, diversity, and complex biology, which contribute to the difficulties in their diagnosis and treatment. Over the years, the management of sarcomas has been a subject of extensive research, with the aim of improving patient outcomes and survival rates.1, 2, 3 A multidisciplinary approach to patients with sarcomas is one of the cornerstones of their management.4 In this context, the advent of molecular imaging techniques has opened new avenues for the detection, staging, and monitoring of these tumours. One such promising development is the use of Fibroblast Activation Protein Inhibitor (FAPI) in PET imaging.5, 6, 7, 8 PET imaging is currently a multimodality technique done mostly with PET/ CT systems, but also with PET/ MR systems. In this article we will focus on the information supplied by PET and, therefore, we will mostly refer to this multimodality technique as PET imaging.

Fibroblast Activation Protein (FAP) is a type II transmembrane serine protease, known for its overexpression in the stroma of many epithelial cancers, including over 90% of sarcomas.9,10 This protein is predominantly expressed in cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment. Interestingly, FAP expression in most normal tissues is negligible, which makes FAP an attractive target for both diagnostic and therapeutic applications in oncology. The specific overexpression of FAP in tumor stroma, coupled with its limited presence in normal tissues, provides a unique opportunity for targeted imaging and therapy in sarcoma patients.11 In a similar vein, a study by Hamacher et al.12 specifically explored the potential of FAPI PET imaging in the context of sarcomas. The authors conducted a comprehensive investigation into the diagnostic accuracy of FAPI PET imaging in sarcoma patients. They found that FAPI PET imaging could accurately identify sarcomas and monitor their response to treatment. This finding is particularly significant given the inherent challenges associated with the diagnosis and treatment of sarcomas, which include their diverse histological subtypes and variable responses to therapy.

Furthermore, a comprehensive review by Kratochwil et al.13 discussed the role of FAP inhibitors in the broader context of cancer treatment. The authors provided an overview of the current research on FAP inhibitors, discussing their potential use in various types of cancer. They also discussed the potential benefits and drawbacks of using FAP inhibitors in cancer treatment, providing a balanced view of this emerging field. The review highlighted the potential of FAP inhibitors as a novel class of therapeutic agents that could revolutionize the treatment landscape of various cancers. Other studies with 68Ga-labeled or 18F-labeled FAPI compounds have demonstrated favorable characteristics for PET/CT imaging, making them especially interesting for digestive tumors.8

In light of these considerations, the following sections of this paper will provide a comprehensive review of the current knowledge on FAPI PET imaging in sarcomas. We will discuss the principles of FAPI PET imaging, review the existing literature on its use in sarcomas, and explore the potential applications and challenges of this novel imaging technique. Through this review, we aim to provide a balanced view of the potential and limitations of FAPI PET imaging in the management of sarcomas, and to stimulate further research in this promising field.

FAP is a serine protease that is overexpressed in cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment in many cancers, including sarcomas. FAPI, a small molecule inhibitor of FAP, can be radiolabeled and used as a PET tracer, providing high-contrast images due to the specific binding of FAPI to FAP-expressing cells.5,8,14,15

As a result, FAP activity promotes collagen matrix remodeling and fibrosis. The expression of FAP in endothelial cells is interesting as it may help bind and sequester the systemically administered tracer. The relative contribution of endothelial FAP and stromal FAP to tracer binding deserves further analysis, as it may provide insight into the mechanisms of tracer uptake and retention in tumor lesions.14,15

The principles of FAPI PET imaging are based on the specific binding of FAPI radiotracers to FAP, which is highly expressed in the stroma of many cancers, including sarcomas. The radiotracers are labelled with a radioactive isotope, typically Gallium-68, which allows for the visualization of FAP-expressing cells in PET scans.16

Guidelines aiming to assist physicians in recommending, performing, interpreting and reporting the results of FAPI PET/CT for oncological imaging have not been published yet by the main international nuclear medicine societies because the available evidence is still scarce. Compared to the European Association of Nuclear Medicine (EANM) guidelines for 18F-FDG PET/CT for tumor imaging,17 the main differences for FAPI PET/CT, labelled with 68Ga or 18F, are: (1) no specific patient preparation is required (ie, no fasting, no need to control glucose nor insulin, no need to avoid prescan exercise or postinjection movement, and no need for a warm environment postinjection); (2) to optimize PET images prescan hydration and prescan urination may be done to reduce artifacts, as well as 2-hour prescan fasting to limit hepatobiliary physiological uptake; and (3) the most common injection to scan-time (IS) was 60 minutes.7,18 There are still many open issues, ranging from the feasibility of shortening IS times, to the ideal IS time depending on the clinical indication, or the recommended administered activity.7,18 Future research will need to take into account the harmonization of the procedure in order to make results comparable between different centers.17 Also, when evaluating the efficacy of an imaging technique such as FAPI PET, not only aspects such as the diagnostic performance should be evaluated, but also its influence on the survival compared to patients in which this imaging technique is not used.19 Furthermore, this is even more important when analyzing the theranostic value of FAP-targeted radioligand therapy, as has been demonstrated previously for Radium-22319,20 or 177Lu-PSMA in prostate cancer.21,22

The potential applications of FAPI PET imaging are vast. Beyond its use in the diagnosis and staging of cancers, FAPI PET imaging has also been explored in the context of theranostics.23 Theranostics, a term combining therapeutics and diagnostics, refers to the strategy of combining therapeutic and diagnostic capabilities into a single agent. In the case of FAPI, this could potentially allow for the targeted delivery of therapeutic agents to FAP-expressing cells, while simultaneously providing diagnostic imaging information.24,25

The development of FAPI as a theranostic tool would theoretically enable the “search-and-destroy” of these metastasis-initiating cells: 131I-labelled or 90Y-labelled FAPI could not only target the FAP-positive tumor bulk (through its endothelium and stroma), but possibly also disseminated FAP-positive metastasis-initiating tumor cell populations.25 In this regard, although it has been discussed that FAP-targeted radioligand therapy has a great potential for becoming a treatment option for several types of cancer, up to date the available evidence is scarce, consisting in preclinical and case series.25 A recent review by Prive at al.24 found that 35 papers had reported data on more than 100 patients treated with different FAP targeted radionuclide therapies labelled with 177Lu and 90Y. They found that FAP targeted radionuclide therapy resulted in objective responses in difficult to treat end stage cancer patients with manageable adverse events. The authors underlined that although no prospective data was yet available, the available early data encouraged further research.

FAPI PET imaging represents a promising tool in the management of sarcomas. Its ability to target the tumor microenvironment provides a unique advantage over traditional imaging techniques. For instance, it has been reported that FAPI PET imaging could detect primary and metastatic sarcoma lesions with high sensitivity and specificity.26 However, further research is needed to optimize its use and to fully understand its role in the complex landscape of sarcoma theranostics management.

The potential of FAPI PET imaging extends beyond the mere identification of sarcomas. It offers the possibility of a more personalized approach to patient management, allowing for the assessment of tumor heterogeneity, prediction of treatment response, and monitoring of therapy-induced changes in the tumor microenvironment. The ability to visualize and quantify FAP expression in vivo could provide valuable insights into the biology of sarcomas, potentially leading to the discovery of new therapeutic targets.

Moreover, the use of FAPI PET imaging could revolutionize the staging of sarcomas. Traditional imaging techniques, such as CT and MR, provide anatomical information about the tumor and its surroundings. In contrast, FAPI PET imaging offers functional information about the tumor's biological activity, which could lead to a more accurate assessment of the disease stage and prognosis. This could have significant implications for treatment planning and patient stratification, leading to more effective and personalized therapeutic strategies.

However, the implementation of FAPI PET imaging in clinical practice is not without challenges. The heterogeneity of sarcomas, both at the inter- and intra-tumoral level, may affect the uniformity of FAP expression and thus the effectiveness of FAPI PET imaging. Furthermore, the optimal timing and dosage of FAPI for PET imaging in sarcomas need further investigation. The potential radiation exposure associated with PET imaging also warrants careful consideration.

A study by Yao et al. evaluated the performance of 18F-FAPI PET/CT in preprocedural assessment of glioblastoma before radiotherapy.27 The study found that 18F-FAPI PET/CT detected glioblastomas at a lower rate than MRI. However, the positive predictive value (PPV) of the examination was 100%, suggesting its potential usefulness in differentiating controversial lesions detected on MR.27 The study also found that neither the Ki-67 index nor the molecular expression was correlated with the FAPI PET/CT parameters.18 The Ki-67 index is a quantitative measure of cell proliferation in histopathological assessment of glioblastoma and many other tumors. A lower Ki-67 index and IDH-wild-type are linked with poor prognosis.28,29 The lack of correlation between these factors and FAPI PET/CT parameters suggests that FAPI PET imaging may not be able to provide information on these important prognostic factors. The study by Yang et al. also highlighted the limitations of their research, including a small sample size and the lack of FAP labelling on immunohistochemistry for some of the lesions.27 These limitations underscore the need for further research with larger samples to validate the findings and to further investigate the potential of FAPI PET imaging in the management of sarcomas.

The recent emergence of FAPI PET imaging has shown promising results in the diagnosis and monitoring of various cancers. This novel imaging technique utilizes radiolabeled FAPI that binds specifically to FAP-expressing cells, allowing for high-contrast imaging of tumors. Furthermore, FAPI inhibitors serve not only as a valuable diagnostic tool but also as a promising therapeutic target. These inhibitors, by virtue of their ability to selectively bind to fibroblast activation protein (FAP), play a dual role in both identifying and potentially treating various medical conditions. As diagnostic tools, FAPI inhibitors have shown promise in imaging techniques, aiding in the accurate detection and visualization of tumors and other pathological tissues. This diagnostic precision can significantly enhance early detection and diagnosis, thereby facilitating more effective treatment strategies.

Beyond their diagnostic utility, FAPI inhibitors hold immense potential as therapeutic agents. The selective targeting of FAP, often overexpressed in the microenvironment of certain diseases, opens up avenues for targeted therapies. In conditions such as cancer, where FAP is associated with tumor-promoting activities and a supportive microenvironment, inhibiting FAPI presents an opportunity to disrupt these processes and impede disease progression.

The multifaceted nature of FAPI inhibitors underscores their significance in advancing both diagnostic and therapeutic modalities. Continued research in this field holds the promise of further refining these inhibitors, optimizing their efficacy, and expanding their applications across various medical disciplines.

However, while FAPI PET imaging holds promise in the management of sarcomas, like any novel technique, FAPI PET imaging also faces several challenges. One of the main challenges is the potential for false-positive results due to the expression of FAP in non-malignant conditions, such as inflammation and wound healing.30

The lack of correlation between the Ki-67 index or the molecular expression and the FAPI-PET/CT parameters are some of the challenges that need to be addressed in future research. Additionally, the optimal timing and dosing of FAPI radiotracers for different types of cancers are still under investigation.31

Despite these challenges, the potential of FAPI PET imaging in the management of sarcomas and other cancers is undeniable. The development of FAPI as a theranostic tool could revolutionize the management of sarcomas and other FAP-expressing tumors by providing high-quality imaging for diagnosis and staging, while simultaneously delivering targeted therapy to cancer cells.32

Further research in this promising field is needed to optimize this imaging technique and to fully understand its potential and limitations. This could lead to significant advancements in cancer diagnosis and treatment.