Head-to-head evaluation of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT in recurrent soft tissue sarcoma

Purpose We aimed to evaluate the value of [68 Ga]Ga-DOTA-FAPI-04 PET/CT for the diagnosis of recurrent soft tissue sarcoma (STS), compared with [18F]FDG PET/CT. Methods A total of 45 patients (21 females and 24 males; median age, 46 years; range, 18–71 years) with 13 subtypes of STS underwent [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT examination within 1 week for assessment local relapse or distant metastasis. Positive lesions on PET/CT images were verified by biopsy or 3-month follow-up. Wilcoxon matched-pairs signed-rank test was used to compare the semiquantitative values (SUVmax and TBR) of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 in tumor lesions, and McNemar test was applied to test for differences of both tracers. Results Among the 45 patients, 282 local relapses and distant metastases were identified. Compared to [18F]FDG, [68 Ga]Ga-DOTA-FAPI-04 PET/CT detected more lesions (275 vs. 186) and outperformed in sensitivity, specificity, PPV, NPV, and accuracy for the diagnosis of recurrent lesions (P < 0.001). [68 Ga]Ga-DOTA-FAPI-04 demonstrated significantly higher values of SUVmax and TBR than [18F]FDG PET/CT in liposarcoma (P = 0.011 and P < 0.001, respectively), malignant solitary fibrous tumor (MSFT) (P < 0.001 and P < 0.001, respectively), and interdigitating dendritic cell sarcoma (IDCS) (P < 0.001and P < 0.001, respectively). While mean SUVmax and TBR presented favorable uptake of [18F]FDG over [68 Ga]Ga-DOTA-FAPI-04 in undifferentiated pleomorphic sarcoma (UPS) (P = 0.003 and P < 0.001, respectively) and rhabdomyosarcoma (RMS) (P < 0.001 and P < 0.001, respectively). Conclusion [68 Ga]Ga-DOTA-FAPI-04 PET/CT is a promising new imaging modality for recurrent surveillance of STS, and compares favorably with [18F]FDG for identifying recurrent lesions of liposarcoma, MSFT, and IDCS. Supplementary Information The online version contains supplementary material available at 10.1007/s00259-022-05700-4.


Introduction
Soft tissue sarcomas (STS) are rare and heterogeneous tumors, which contain more than 50 different histologic subtypes according to the World Health Organization (WHO) Bingxin Gu and Xin Liu contributed equally to this work.
This article is part of the Topical Collection on Oncology-Muskoskeletal classification [1]. The prognosis of metastatic STS is dismal, with a median overall survival (OS) of 8-12 months [2]. Thus, optimal imaging of STS is crucial for accurately restaging and detecting local relapse and/or distant metastasis as early and as completely as possible. The most frequent metastatic sites of STS are the lung, followed by bone and lymph nodes [3]. Computed tomography (CT) and magnetic resonance imaging (MRI) serve as the routine means for local relapsed surveillance. But for detecting distant metastasis, [ 18 F]-fluorodeoxyglucose ([ 18 F]FDG) positron emission tomography/computed tomography (PET/CT) shows higher sensitivity and accuracy [4]. Furthermore, [ 18 F]FDG PET/CT is useful for initial staging and restaging, evaluation of treatment response, and predicting treatment efficacy and clinical outcome for STS [5]. However, due to lack of sensitivity among some subtypes of sarcomas, particularly low-grade sarcomas, [ 18 F]FDG PET/CT is not generally recommended for the management of sarcomas [6][7][8].
Recently, new development of PET tracers targeting fibroblast activation protein (FAP), [ 68 Ga]-fibroblast activation protein inhibitor (FAPI), had shown promising results in imaging of sarcomas [9]. FAP is a type II membrane-bound glycoprotein belonging to the dipeptidyl peptidase 4 family, which has both dipeptidyl peptidase and endopeptidase activity. FAP plays a pivotal role in tumor microenvironment, including reduced levels of anti-angiogenic factors, elevated levels of transforming growth factor β, and affected matrix processing enzymes [10]. FAP is overexpressed in cancer-associated fibroblasts (CAFs) in the stroma of more than 90% of epithelial carcinomas [11] and many subtypes of STS (e.g., fibrosarcoma, malignant fibrous histiocytoma, and liposarcoma) [12,13]. In addition to diagnostic imaging, FAP is also considered as a promising target for delivering therapeutic nuclide [14]. This may provide a new approach for recurrent STS to improve survival. Thus, the expression of FAP on different STS needs to be identified.
Inspired by the promising results of [ 68 Ga]Ga-DOTA-FAPI-04 imaging on many epithelial carcinomas [9,15,16], we hypothesized that [ 68 Ga]Ga-DOTA-FAPI-04 would outperform [ 18   patients were kept in a quiet environment for approximately 60 min prior to examination. No adverse or clinically detectable pharmacological effects were observed in any of these patients. All images were obtained on a Biograph mCT Flow scanner (Siemens Medical Solutions). Low-dose CT scanning was performed firstly for location: scanning ranging from the proximal thighs or feet to head, with 120 kV, 100 mAs, CARE Dose4D, slice thickness 3 mm, increment 2 mm, pitch 1.0, rotation time 0.5 s, and soft-tissue reconstruction kernel. Immediately after CT scanning, a PET emission scan that covered the corresponding field of CT was acquired in 3-dimensional mode using FlowMotion with a speed of 2. The emission data were corrected for random scatter and decay. PET image datasets were reconstructed iteratively using an orderedsubset expectation maximization iterative reconstruction by applying CT data for attenuation correction. Fusion images were reviewed and manipulated on a multimodality computer platform (Syngo, Siemens, Knoxville, Tennessee, USA). Two experienced nuclear medicine physicians analyzed and interpreted the images independently, and they reached a consensus in case of inconsistency.

Patient selection
Increased radioactivity of relapsed or metastatic lesions compared with the uptake of surrounding normal tissue was defined as being positive, verified by biopsy or 3-month follow-up. Lesions were considered malignant during follow-up based on (i) typical malignant features (i.e., mass, abnormal density, poor circumscription, and destruction), and (ii) a significant reduction or progression in size after anticancer treatment confirmed by follow-up imaging (i.e., CT and MRI) according to RECIST 1.1 [17]. For quantitative analysis, maximum and mean of standardized uptake value (SUV) normalized to body weight were manually computed for tumor lesions and healthy tissues by drawing a 3-dimensional volume of interest, respectively. Meanwhile, tumorto-background ratio (TBR) for tumor lesions was calculated according to the formula: TBR = tSUVmax/bSUVmean, where tSUVmax is the maximum SUV of tumor lesion, and bSUVmean is the mean SUV of normal tissue.

Statistical analyses
All statistical analyses were performed using SPSS 25.0 (IBM, Armonk, NY, USA). Mean with standard deviation or median with range was used to describe continuous characteristics. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of [ 18

Patients
From May 2020 to May 2021, 45 patients (21 females and 24 males; median age = 46 years, range, 18-71 years) were consecutively enrolled in this study (Fig. 1). All patients were diagnosed with STS and got radical treatment (e.g., surgery, radiotherapy, chemotherapy, or combination therapy) before PET/CT scans. Diagnostic CT or MRI was performed in 30 out of 45 patients prior to PET/CT scans, and positive findings were observed in 29 patients ( Table 1).

Comparison of [ 18 F]FDG and [ 68 Ga]Ga-DOTA-FAPI-04 PET/CT based on different subtypes of recurrent STS
The representative figures of the 13 subtypes of recurrent STS are presented in Fig. 2. Overall, 282 local relapses and distant metastases were identified among the 45 patients. Among these lesions, 13 were verified by biopsy and 269   Table 2 and Table S1). Moreover, [ 18 F]FDG uptake was higher for high-grade STS compared to lowgrade STS. Conversely, low-grade STS showed higher uptake of [ 68 Ga]Ga-DOTA-FAPI-04 than high-grade STS.

Discussion
This prospective study of 45 patients with 13 subtypes of recurrent STS suggests that [ 68 Ga]Ga-DOTA-FAPI-04 PET/ CT is a promising new imaging modality for recurrent surveillance of STS and provides an enhancement to [ 18 F]FDG PET/CT. STS represents a distinct group of rare malignant tumors with high heterogeneity, which remains a major concern in cancer management [18][19][20]. Several previous studies [4,21,22] [24]. Prominent higher uptake of [ 68 Ga]Ga-DOTA-FAPI-04 than [ 18 F]FDG was observed in recurrent lesions of STS in terms of mean SUV max and TBR (P < 0.001), which is in line with previous studies [9,25]. It should be noted that the intensive uptake of [ 68 Ga] Ga-DOTA-FAPI-04 presenting in wound healing, uterus, arthritis, and periodontitis may be misdiagnosed as local relapse or distant metastasis. This is caused by fibrotic activity in these conditions [26]. Thus, more researches focused on non-tumor-specific uptake of FAPI are still needed [27,28]. In a recent study, Koerber el al. [25] reported the imaging of seven subtypes of bone and soft tissue sarcoma by FAPI-PET/CT in fifteen patients, demonstrating the high uptake of FAPI for high-grade sarcomas and low uptake for low-grade sarcomas. However, the patient cohort and tumor subtype are small, and the compounds of FAPI are variance (FAPI-04, FAPI-46, and FAPI-74). These factors may result in data bias. In line with previous studies [4,21], higher [ 18 F]FDG uptake was also observed in high-grade STS compared to low-grade STS in the present study. However, [ 68 Ga]Ga-DOTA-FAPI-04 uptake was lower in high-grade STS than low-grade STS (mean SUV max = 9.45 vs. 13.49) in the present study, which is not consistent with Koerber's research [25]. This may be caused by that the most cases included in the low-grade group were well-differentiated liposarcoma (3/5) and MSFT (1/5), which showed prominent expression of FAP on tumor cell surface [12]. Nevertheless, a significantly higher uptake of [ 68 Ga]Ga-DOTA-FAPI-04 was found for high-grade STS compared to [ 18 [29], hepatic carcinoma [30], and gastrointestinal cancers [31]. The absence of [ 68 Ga] Ga-DOTA-FAPI-04 in normal organs and tissues (e.g., liver, bone, and intestines) will benefit imaging of liver, bone, and abdomen metastases with higher tumor-to-background contrast and better lesion delineation than [ 18 F]FDG PET/CT. However, it should be noted that [ 68 Ga]Ga-DOTA-FAPI-04 was false negative in 7 out of 29 lung metastases (4 from patient #34 and 3 from patient #44, Fig. 6). In a recent animal-based study, Ding et al. [32] found that the expression of FAP was prominent in lung metastatic lesion at the early stage but descended during the progress of tumor metastasis. Thus, the diagnostic performance of [ 68 Ga]Ga-DOTA-FAPI-04 PET in detecting lung metastasis remains uncertain in recurrent STS. Despite advances in chemotherapy, targeted therapy and immunotherapy over the last decades, the prognosis for patients with metastatic STS remains poor [33]. Limited options with clinical efficacy for the metastatic or local advanced STS existed in addition to standard treatment [2]. Recently, Kratochwil et al. [34] reported a case of metastatic sarcoma treated with 90 Y/ 153 Sm-labeled FAPI-46 achieving stable disease for 8 months. Moreover, Ferdinandus et al. [35] demonstrated the potential role of FAP-targeted radioligand therapy in a study of nine patients with solid tumors. Surprisingly, disease control was observed in three patients with sarcomas and one patient with pancreatic ductal adenocarcinoma. These studies indicated that FAP-targeted radioligand therapy may present as a novel promising treatment strategy for incurable recurrent STS. Thus, non-invasive selection of the suitable patients with STS for the coming FAP-targeted radioligand therapy will emerge as a critical issue, and our work serves as a foundation for that.
The major limitation of this study is the relatively low number of patients and limited subtypes of STS. As STS is a large group of malignant tumors, it is hard to enroll all subtypes in a single center. Thus, larger multi-center studies containing more subtypes of STS are still needed to be carried out in the future. Another limitation is that not all [ 68 Ga]Ga-DOTA-FAPI-04 and [ 18 F]FDG positive lesions are pathologically confirmed and examined FAP expression. Nevertheless, these lesions are also verified by continuous follow-up. Furthermore, a positive correlation with [ 68 Ga] Ga-DOTA-FAPI-04 uptake and FAP expression is reported in previous study [30].

Conclusion
The current study demonstrated that

Data availability
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Declarations
Ethics approval All procedures involving human participants were carried out in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any experiments with animals.
Consent to participate Informed consents were obtained from all individual participants included in the study.

Conflict of interest
The authors declare no competing interests.
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