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Revolutionizing cancer diagnosis and dose biodistribution: a meta-analysis of [68ga] FAPI- 46 vs. [18f] FDG imaging

Systematic Reviews volume 14, Article number: 109 (2025) Cite this article

Abstract

Background

Advancements in novel peptides significantly affect cancer diagnosis by targeting cancer-specific markers, thereby improving imaging modalities, such as positron emission tomography combined with computed tomography (PET/CT) for more accurate tumor detection. This systematic review and meta-analysis aimed to assess the diagnostic accuracy of [18F] Fluorodeoxyglucose (FDG) and 68Ga-fibroblast activation protein inhibitor (FAPI- 46) PET/CT for early cancer detection.

Methods

A comprehensive search was conducted in Scopus, MEDLINE, Web of Science, and Embase databases up to March 28, 2024, using MeSH keywords. Titles and abstracts were screened to identify studies on hybrid [68Ga] FAPI- 46 and [18F] FDG, followed by a detailed full-text evaluation. Only cohort or cross-sectional studies published in English, focusing on the clinical diagnosis of cancer patients, were included, while reviews, case reports, conference proceedings, and abstracts were excluded. Random-effects meta-analysis was used for the estimation of pooled specificity and sensitivity with 95% confidence intervals (CIs). In addition, the heterogeneity was assessed across studies and subgroup meta-analyses for the detection rate via Stata.

Results

Among the 615 retrieved studies, nine articles were incorporated in the present systematic review, with five (n = 144 patients) eligible for meta-analysis. For [68Ga] FAPI- 46, the pooled sensitivity and specificity compared with immunohistopathology were 0.96 (95% CI 0.84, 0.99) and 0.92 (95% CI 0.53, 0.99), respectively, with a positive likelihood ratio (LR +) of 4.41 (95% CI 1.64, 11.79) and a negative likelihood ratio (LR −) of 3.07 (95% CI 1.01, 9.37). For [18F] FDG, pooled sensitivity and specificity compared with immunohistopathology were 0.73 (95% CI 0.34, 0.93) and 0.83 (95% CI 0.57, 0.95), with an LR + of 12.73 (95% CI 1.43, 113.45) and an LR − of 0.32 (95% CI 0.11, 0.17). The pooled odds ratio for the detection rate on a per-lesion basis was 1.73 (95% CI 0.99, 3.02) for [68Ga] FAPI- 46 compared with [18F] FDG. The pooled weighted mean differences in the standardized uptake value (SUVmax) for primary tumor uptake and the tumor-to-background ratio (TBR) in [68Ga] FAPI- 46 vs. 18F-FDG were 4.40 (95% CI − 0.7, 9.5) and 6.18 (95% CI 1.74, 10.61), respectively. Moderate to high heterogeneity was noted because of the variations in patient selection, interpretation criteria, and scanning procedures.

Conclusions

This study revealed that [68Ga] FAPI- 46 outperforms [18F] FDG in cancer diagnosis, with higher sensitivity (0.96 vs. 0.73) and specificity (0.92 vs. 0.83). [Ga] FAPI- 46 improved tumor detection with higher SUVmax and TBR. While FDG had a higher LR +, its lower LR − highlighted more false negatives. Accordingly, [68Ga] FAPI- 46 exhibited superior accuracy and reliability than FDG in cancer diagnosis.

Systematic review registration

PROSPERO CRD 42023472270.

Graphical Abstract

Peer Review reports

Background

Cancers, as a leading cause of death worldwide, have caused extensive research efforts to develop early and accurate diagnostic techniques. Precise diagnosis and staging are essential keys for effective disease management, which typically utilize computed tomography (CT) [1,2,3], magnetic resonance imaging (MRI) [4, 5], or nuclear medicine imaging, like positron emission tomography (PET) [6,7,8] using different radiopharmaceuticals, such as fluorine- 18 (18F)-labeled fluorodeoxyglucose (FDG) [9,10,11,12]. The development of PET scans has significantly advanced cancer diagnosis due to focusing on cellular metabolism [13,14,15,16]. Cancer cells characterized by increased glucose metabolism, exhibit higher uptake of [18F] FDG compared to non-cancer cells. This enhanced uptake facilitates the detection and visualization of tumors through PET imaging, providing valuable diagnostic insights [17,18,19,20]. Accordingly, [18F] FDG is widely recognized as a key radiotracer in cancer imaging, aiding in the identification and staging of various malignancies [21,22,23,24]. The whole-body [18F] FDG-PET/CT imaging also highlights metabolic differences in lung cancer patients, distinguishing those with and without cancer-associated cachexia and revealing systemic metabolic alterations in cachectic individuals [19, 25]. Moreover, the effectiveness of [18F] FDG PET/CT in detecting unknown primary cancers is influenced by the distribution of metastatic sites [26, 27]. Various FDG-PET/CT parameters have demonstrated its potential as prognostic indicators of treatment outcomes in patients with oropharyngeal squamous cell carcinoma [28, 29]. On the other hand, [18F] FDG PET/CT has some drawbacks, such as false positives, which are caused by inflammation, and limited sensitivity in detecting tumors with low glycolytic activity. Additionally, the presence of high physiological uptake can obscure the visibility of lesions [30,31,32].

The above limitations of [18F] FDG have led to the exploration of more effective pharmaceutical-based imaging agents. Among these, [68Ga] fibroblast activation protein inhibitor- 46 ([68Ga] FAPI- 46) has significantly attracted attention due to its enhanced targeting capabilities as [68Ga] FAPI- 46 has the ability to significantly increase the accuracy of initial cancer staging and the detection of biochemical recurrence [8, 33]. [68Ga] FAPI- 46 binds to fibroblast activation protein (FAP), which is overexpressed in the stromal components of over 90% of epithelial carcinomas. It has emerged as a valuable tracer in oncology in order to improve diagnostic accuracy and treatment outcomes [34,35,36]. FAPs are highly expressed by cancer-associated fibroblasts in different cancer types, while their expression remains relatively low in normal tissues. The application of [68Ga] FAPI- 46 in diagnostic imaging, via PET/CT scans, enhances tumor detection [37,38,39]. Additionally, [68Ga] FAPI PET/CT exhibits greater sensitivity than [18F] FDG PET/CT across different cancers [40,41,42,43,44]. FAPI PET is also able to accurately delineate head and neck squamous cell carcinoma (HNSCC) for radiotherapy planning [45,46,47], leading to high detection rates across numerous solid tumors, including lung, head and neck, urogenital, gastric, colorectal, and pancreatic cancers [45, 48,49,50,51]. Furthermore, [68Ga] FAPI- 46 PET/CT detects more primary lesions, local recurrences, distant metastases, and nodal metastases than [18F] FDG PET/CT [52,53,54].

These findings suggest that FAPI- 46 may enhance cancer diagnosis and facilitate personalized treatment planning. Modern diagnostic techniques are strongly dependent on advanced imaging modalities, such as PET/CT and PET/MRI, due to the availability of detailed anatomical and functional information [55,56,57]. As a result, FAPI is cancer specific, leading to improved diagnostic accuracy and applicability across a wider range of cancers [58,59,60].

Gao C et al. conducted a meta-analysis to compare [68Ga] FAPI with [18F] FDG PET/CT on gastric malignancy and presented that [68Ga] FAPI was significantly more sensitive than [18F] FDG in evaluating primary tumors, distant metastases, and lymph nodes. However, no significant difference was observed in the lymph node metastasis specificity [61]. Liu X et al. conducted a study comparing [68Ga] FAPI with [18F] FDG PET/CT and revealed that FAPI had a significantly higher detection rate for primary tumors compared to FDG [62]. The meta-analysis by Gege Z et al., showed that [68Ga] FAPI had superior sensitivity in detecting peritoneal metastasis (PM) compared to those of [18F] FDG PET/CT [63]. Although some systematic and meta-analytical studies have compared [68Ga] FAPI with [18F] FDG for diagnosing specific cancers, such as colorectal cancer, primary digestive system cancers, lung cancer, and pelvic cancers, a comprehensive analysis across all cancer types has yet remained lacking. Notably, no systematic or meta-analytical study has yet focused on comparing [68Ga] FAPI- 46 with [18F] FDG across all cancer types [62, 64,65,66,67,68].

This study hypothesizes that [68Ga] FAPI- 46 will outperform [18F] FDG in diagnostic sensitivity and specificity for early cancer detection using PET/CT. This hypothesis is based on the premise that [68Ga] FAPI- 46, due to its higher specificity for tumor-associated fibroblasts, will provide superior tumor visualization and more accurate identification of cancerous lesions, particularly in malignancies with limited [18F] FDG uptake. Additionally, we aim to analyze biodistribution metrics, such as SUV and TBR, to determine whether [68Ga] FAPI- 46 offers improved differentiation between malignant and healthy tissues. Lastly, this study seeks to evaluate various diagnostic factors, including patient characteristics, injected doses, and imaging time points, to provide comprehensive insights into the effectiveness of these radiotracers.

Methods

Protocol and registration

This systematic review and meta-analysis was designed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [69] and also registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42023472270) [17]. Further, the ethical approval and informed consent were not applicable and usable for the current article.

Search strategy

A comprehensive search was performed across the Scopus, MEDLINE, Web of Science (WOS), and Embase databases up to March 28, 2024. The search incorporated terms “FAPI- 46” or “FAPI46” or “FDG” or “18F” or “68Ga” or “Ga68” AND “Cancer” or “Neoplasm” AND “PET/CT” developed using Boolean operators and relevant keywords from the MeSH databases. An example of search strategy in the MEDLINE was as follows: (FAPI- 46]) OR FAPI46 [Title/Abstract]) OR FDG [MeSH Terms]) OR 18F [MeSH Terms]) OR 68Ga [MeSH Terms]) OR Ga68 [Title/Abstract]) AND (PET/CT [MeSH Terms]) AND Cancer [Title/Abstract]) OR (Neoplasm [MeSH Terms]), for more information, you can check the supplementary (Supplementary file 1: Table S1). For more information, please see the Supplementary file 1: Table S1. Additionally, references from pertinent studies were manually checked to ensure comprehensive coverage. After removing duplicates, two independent reviewers (SA and MS) screened the titles and abstracts. Inter-rater reliability for screening studies between two reviewers was calculated using Cohen’s kappa to be 0.87, which is interpreted as almost perfect agreement. Discrepancies were also resolved with a third reviewer, who serves as a mediator.

Inclusion criteria were as follows: (1) studies had to be either cohort (retrospective or prospective) or cross-sectional in design, (2) patients diagnosed with cancer using [68Ga] FAPI- 46 and [18F] FDG, based on established guidelines or an oncologist’s diagnosis, (3) studies were published in English, and (4) studies had clinical, diagnostic, or targeting specialized insights. The studies were included if sensitivity or specificity, or both were elaborately reported. Reviews, letters, case reports, systematic reviews, book chapters, conference papers, and studies that did not focus on both [68Ga] FAPI- 46 and [18F] FDG or failed to specify the FAPI type were excluded from the review.

The information from each article was extracted in two parts: general information (the first author’s name, publication year, country, age, gender, and study population) and specific details (patient recruitment guidelines, sample sources, area under the curve [AUC], true positives [TP], true negatives [TN], false positives [FP], false negatives [FN], sensitivity, and specificity). Two reviewers (SA and MS) independently extracted data from each study. Following this, two authors reviewed and discussed the articles to ensure the accuracy of the extracted information. In the final stage, the selected articles were summarized, and the data were compiled. All disagreements between the two reviewers were addressed to reach a consensus.

Quality assessment

The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool can assess the quality, reliability, and validity of diagnostic accuracy studies, helping researchers and clinicians evaluate the trustworthiness of study findings for future research or clinical practice, respectively. In the current study, two independent reviewers (MS and MD) assessed the risk of bias and applicability concerns using QUADAS- 2, in accordance with the Cochrane Collaboration guidelines, to ensure the methodological quality of the included studies [70].

Each study was evaluated for the patient selection, performance of the index test as well as the reference test, and timing and flow with criteria rated as “yes,” “no,” or “unclear,” based on whether the requirement was met, unmet, or not explicitly addressed. Studies were further categorized as having “low,” “high,” or “unclear” for risk of bias and for concerns regarding applicability.

Statistical analysis

Statistical analyses were conducted using RevMan 5.3 (Cochrane, USA) and Stata version 17.0 (Stata Corp., College Station, TX, USA). The pooled sensitivity and specificity of [68Ga] FAPI and [18F] FDG PET/CT were calculated and compared, with 95% confidence intervals (CI) by random-effects meta-analysis and with forest plots for visual inspection. These measures were quantitatively combined for the generation of a summary receiver operating characteristic (SROC) curve with 95% confidence and prediction regions. Also, the positive likelihood ratio (LR +; the probability that a person with the cancer tested positive/probability that a person without cancer tested positive) and negative likelihood ratio (LR −; the probability that a person with cancer tested negative/probability that a person without cancer tested negative) were calculated to assess the diagnostic test. Heterogeneity, which is related to diagnostic performance variability, like LR + and LR − across different studies, was evaluated using the Q test and I2 statistics (I2 = 0% indicates no observed heterogeneity and I2 ≥ 50% indicates substantial heterogeneity) [71, 72]. Meta-regression and subgroup meta-analyses were not performed, and it was not possible to assess the source of observed heterogeneity across studies because small numbers of studies were included in each meta-analysis, which reduces the power of the meta-analyses models of diagnostic performance. Subgroup meta-analysis was performed using pooled odds ratio for detection rate/detection efficacy on a per-legion basis in [68Ga] FAPI- 46 versus [18F] FDG PET/CT. Meta-analyses of weighted mean difference were also carried out for standardized uptake value (SUVmax) and standardized tumor-to-background ratio for primary tumor uptake and metastasis uptake. The assessment of publication bias was not conducted due to the limited number of studies included in the analysis. Sensitivity analyses were carried out to identify any individual study that might significantly influence heterogeneity and to evaluate the robustness of the findings.

Results

Literature search

Figure 1 illustrates the study selection process based on the PRISMA flow diagram. A comprehensive and in-depth search was performed in four major databases, MEDLINE (n = 107), Scopus (n = 117), Web of Science (n = 150), and EMBASE (n = 241), up to March 28, 2024, resulting in 615 studies. After removing duplicates, 240 unique articles remained for title and abstract screening. At this stage, 231 articles were excluded, including irrelevant studies, reviews, book chapters, and conference abstracts. The full texts of the remaining 9 articles [73,74,75,76,77,78,79,80,81] (197 patients) were then evaluated for eligibility and deemed eligible for qualitative analysis (systematic review). However, four of the studies were not included into the meta-analysis due to insufficient data. Ultimately, five studies, encompassing 144 patients diagnosed using both [68Ga] FAPI- 46 PET/CT and [18F] FDG PET/CT, were included in the meta-analysis. The patients’ mean age ranged from 48.1 to 72.5 years. The primary objective of these studies was to compare the diagnostic performance of [68Ga] FAPI- 46 and [18F] FDG via PET/CT scans for early cancer detection.

Fig. 1
figure 1

PRISMA flowchart for selection of studies

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Studies and patients’ characteristics

The main characteristics were extracted through a review of the published included articles (Table 1). Figure 2A shows that the nine studies included in this review were conducted across various countries, with the majority (55.5%) in Germany. The remaining studies were conducted in Thailand (22.2%), Korea (11.1%), and China (11.1%). Figure 2B illustrates that, of the nine studies, 44.4% were published in “The Journal of Nuclear Medicine”, 22.2% in “Molecular Imaging and Biology”, 11.1% in “Research Square Journal”, 11.1% in “Clinical Nuclear Medicine”, 11.1% in “European Journal of Nuclear Medicine and Molecular Imaging”, and 11.1% in “Asia Ocean Journal of Nuclear Medicine and Biology”. Thus, Germany and “The Journal of Nuclear Medicine” were the most prominent contributors to the included studies. The systematic review consisted of three prospective studies, five retrospective studies, and one single-center exploratory comparative imaging study.

Table 1 Main characteristics of the included studies
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Fig. 2
figure 2

The charts of countries and publishers

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Technical aspects

The technical aspects of [18F] FDG-PET/CT and [68Ga] FAPI- 46 PET/CT from the nine studies are also summarized in Table 1. The administered activity of [18F] FDG varied considerably, ranging from approximately 180 to 320 MBq, while the activity of [68Ga] FAPI- 46 ranged from 80 to 190 MBq. Imaging acquisition times for both tracers were between 10 and 90 min. Most scans concentrated on head and neck cancers; however, other types, including breast, liver, cervical, and lung cancers, were also investigated. The sample sizes of the selected studies varied (6 to 43.) In the detailed assessment of these nine articles to compare the two scanning methods, histopathological diagnosis was considered the gold standard.

Methodological quality of the included studies

Table 2 presents the QUADAS- 2 assessment for all 9 included studies. In the patient selection domain, 44% (4/9) of studies revealed a high risk of bias, due to study design limitations, such as the lack of consecutive or random sampling. Also, the flow and timing domain presented a high risk of bias in 44% of studies, due to incomplete information or results. However, 77% (7/9) of the studies were classified because of a low risk of bias, as [68Ga] FAPI- 46 or [18F] FDG interpretations were blinded to the reference standard (immunohistopathology), or pre-established cutoff values were used to categorize results as positive, negative, or indeterminate. Regarding applicability concerns, the majority of studies (88%, 8/9) were rated with low concerns for patient selection, index test performance, and reference test performance, with no significant issues identified. In summary, regarding the overall judgment, 8 studies (88%) were judged as “at risk of bias” and one study was rated “unclear risk of bias”. Also, only two studies were judges as having “concerns regarding applicability” while seven studies (77%) were considered as “low concern regarding applicability” (Fig. 3).

Table 2 Quality assessment of included studies using QUADAS- 2 tool [ 73,74,75,76,77,78,79,80,81,82 ]
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Fig. 3
figure 3

Summary results of the QUADAS- 2 tool. The proportion of studies with low, high, and unclear concerns. The Proportion of studies with low, high, and unclear risk regarding applicability of bias

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Main findings of qualitative synthesis

This systematic review aimed to compare the diagnostic accuracy of [18F] FDG PET/CT and [68Ga] FAPI- 46 PET/CT based on histopathological findings. The [68Ga] FAPI- 46 has recently emerged as a promising alternative to [18F] FDG, particularly for tumors with high fibroblast content or low metabolic activity [64, 82, 83]. However, [18F] FDG remains effective for cancers with high glucose metabolism, its diagnostic utility is limited by nonspecific uptake in normal tissues and inflammatory sites.

According to the findings, only two studies (22.2%) assessed tumor stage and grade. Additionally, cancer characteristics, such as a primary tumor or metastatic status, were reported in 33.33% [74, 77, 79] of the studies reviewed. The conclusions of the included studies are reported in Table 3.

Table 3 The findings of included studies
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Our systematic review provides compelling evidence that [68Ga] FAPI- 46 PET/CT demonstrates superior diagnostic accuracy compared to [18F] FDG PET/CT across several malignancies, including sarcoma, breast cancer, cholangiocarcinoma, HNSCC, and non-small cell lung cancer (NSCLC). The utilization of [68Ga] FAPI- 46 is associated with enhanced sensitivity and specificity in the detection of both primary and metastatic lesions. Notably, the uptake of [68Ga] FAPI- 46 is particularly pronounced in tumors characterized by high expression of FAP within the tumor stroma, such as grade 3 cholangiocarcinoma. In general, the results present that [68Ga] FAPI- 46 PET/CT, as a promising imaging modality, can improve diagnostic precision in different cancers.

Quantitative synthesis (meta-analysis)

The included studies for the quantitative analysis

The five studies included in the meta-analysis [73, 74, 76, 80, 81] evaluated the diagnostic performance of both [68Ga] FAPI- 46 PET/CT and [18F] FDG-PET/CT for cancer detection. These studies provided TP, TN, FP, and FN, which were used to calculate sensitivity and specificity, key metrics for assessing diagnostic accuracy. Additionally, the studies that reported detection rates and dose biodistribution were further analyzed, and a meta-analysis was conducted for these specific parameters (Table 4).

Table 4 The findings of the included studies in meta-analysis
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Meta-analysis of [68Ga] FAPI- 46 for cancer diagnosis

Five studies [73, 74, 76, 80, 81] assessed the diagnostic accuracy of [68Ga] FAPI- 46 and [18F] FDG PET/CT in cancer detection. Figure 4 presents a forest plot displaying the sensitivity and specificity of the [68Ga] FAPI- 46 studies. The pooled sensitivity was 0.97 (95% CI 0.84–0.99), with the lowest sensitivity at 0.75 (95% CI 0.19–0.99) and the highest, observed in two studies, reaching 1.00 (95% CI 0.79–1.00 and 0.82–1.00). The pooled specificity was 0.92 (95% CI 0.53–0.99), with the lowest specificity at 0.50 (95% CI 0.01–0.99) and the highest, reported in three studies, at 1.00 (95% CI 0.29–1.00, 0.77–1.00, and 0.03–1.00). Figure 5 also depicts the summary receiver operating characteristic (SROC) curve for [68Ga] FAPI- 46, with a curve approaching the upper left corner, indicating a larger area under the curve and, consequently, higher diagnostic precision. Based on the results, [68Ga] FAPI- 46 demonstrated low false negative and false positive rates, supporting its high diagnostic accuracy.

Fig. 4
figure 4

Forest plots of the sensitivity and specificity of 68Ga-FAPI- 46 PET/CT as a diagnostic tool

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Fig. 5
figure 5

Summary receiver operating curve (SROC) plot. Open circle (o) represents the false positive rate (x-coordinate) and sensitivity (y-coordinate) of individual studies. Diamond represents the summary estimate, black circle represents individual studies. Green dash represents the 95% confidence interval ([.68Ga] FAPI- 46 PET/CT as diagnostic tool)

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Meta-analysis of [18F] FDG PET/CT for cancer diagnosis

Figure 6 presents a forest plot summarizing the sensitivity and specificity of the included studies. The pooled sensitivity was 0.73 (95% CI 0.34 to 0.93), with individual sensitivities ranging from a low of 0.33 (95% CI 0.01 to 0.91) to a high of 1.00 (95% CI: 0.79 to 1.00). The overall specificity was 0.83 (95% CI 0.57 to 0.95), with values spanning from 0.50 (95% CI 0.01 to 0.99) to a maximum of 0.93 (95% CI 0.66 to 1.00). Figure 7 shows the SROC curve for [18F] FDG PET/CT. The curve, positioned further from the upper left corner, suggests a smaller area under the curve compared to [68Ga] FAPI, reflecting lower diagnostic accuracy for [18F] FDG PET/CT (Fig. 7). Table 5 presents the results of the meta-analysis comparing the two tracers, [68Ga] FAPI- 46 and [18F] FDG.

Fig. 6
figure 6

Forest plots of the sensitivity and specificity of 18F-FDG PET/CT as a diagnostic tool

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Fig. 7
figure 7

Summary receiver operating curve (SROC) plot. Open circle (o) represents the false positive rate (x-coordinate) and sensitivity (y-coordinate) of individual studies. Diamond represents the summary estimate, black circle represents individual studies. Green dash represents the 95% confidence interval ([18F] FDG PET/CT as diagnostic tool

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Table 5 Meta-analysis of diagnostic accuracy
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Additionally, a region-based meta-analysis was conducted to assess the diagnostic performance of [68Ga] FAPI- 46 PET/CT (Fig. 8), with a 95% CI to quantify the reliability of the findings. This analysis caused the tracer's efficacy to be evaluated in specific anatomical regions, such as the head and neck, and the liver, enhancing the detection of malignancies across various sites. The pooled sensitivity was 0.94 (95% CI 0.82, 0.98), and the specificity was 0.89 (95% CI 0.79, 0.95). Furthermore, the SROC curve reinforces the high diagnostic accuracy of [68Ga] FAPI- 46 PET/CT, particularly in identifying primary and metastatic cancer lesions.

Fig. 8
figure 8

Forest plots of the sensitivity and specificity of [68Ga] FAPI- 46 PET/CT as a diagnostic tool. (Region base analysis)

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Detection rate/detection efficacy

In this meta-analysis, the detection rates and efficiencies were assessed in three groups: primary tumors, lymph nodes, and distant metastasis. Primary tumors: the odds ratio (OR) was 1.73 (95% CI: 0.99, 3.02), indicating a potential advantage in detection rates with the heterogeneity analysis: I2 = 84.86%, and P < 0.001, showing significant variability among studies. For lymph nodes: the OR was 1.28 (95% CI 0.86, 1.91), representing a moderate enhancement in detection rates, and the heterogeneity investigation indicated I2 = 57.44%, and P = 0.13, indicating moderate variability (Fig. 9). Finally, in distant metastases: the OR was 1.09 (95% CI 0.96, 1.24), showing a minimal increase in detection efficiency with the heterogeneity measures: I2 = 0.00%, and P = 0.34, resulting in low variability among studies. Sensitivity analysis for detection rate of primary tumors indicated that the meta-analysis findings were robust (summary ORs, 1.24–2.16). The Pooled odds ratio for the detection rate across all lesions was almost consistent and was not varying for different tumor types. This indicates that the detection efficacy of FAPI- 46 PET/CT was greater than that of FDG PET/CT across all types of lesions, although this difference was not statistically significant.

Fig. 9
figure 9

Forest plot; the pooled estimation of odds ratio for detection rate/detection efficacy on a per-legion basis in [68Ga] FAPI- 46 PET/CT vs. [18F] FDG PET/CT

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Dose distribution

The meta-analysis results show that the comparison of primary tumor uptake between [68Ga] FAPI- 46 PET/CT and [18F] FDG PET/CT yielded a weighted mean difference (WMD) of 4.40 (95% CI − 0.70, 9.50), with substantial heterogeneity (T2 = 33.08, I2 = 89.99%). While [68Ga] FAPI- 46 PET/CT tends to have higher standard uptake values (SUVmax) than 18F-FDG PET/CT, the difference is not statistically significant (Fig. 10). In a sensitivity analysis excluding one study at a time, we consistently found a higher standard uptake values for FAPI- 46 PET/CT (range of summary WMDs, 2.42–5.51).

Fig. 10
figure 10

Forest plot; the pooled weighted mean difference of standardized uptake value (SUVmax) for primary tumor uptake in 68Ga-FAPI- 46 PET/CT vs. 18F-FDG PET/CT. [68Ga] FAPI- 46 PET/CT had higher (but not statistically significant) standard uptake values (SUVmax) than 18F-FDG PET/CT

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Tumor-to-background ratio (TBR), which measures radiotracer contrast between primary tumor and surrounding tissues, was assessed for blood pool, liver, and muscle. In the blood pool, the WMD was 5.51 (95% CI 1.13, 9.89) with significant heterogeneity (I2 = 76.95%), indicating that [68Ga] FAPI- 46 PET/CT likely has a higher TBR than [18F] FDG PET/CT. Liver analysis showed a WMD of 12.32 (95% CI: 4.58, 20.07), also with high variability (I2 = 78.29%) (Fig. 11). Robustness of the findings and meta-analysis model was confirmed in sensitivity analysis of TBR for blood pool (range of summary WMDs, 2.96–6.79) and liver (range of summary WMDs, 8.43–17.95).

Fig. 11
figure 11

Forest plot; the pooled weighted mean difference of standardized tumor-to-background ratio (TBR) for primary tumor uptake in [68Ga] FAPI- 46 PET/CT vs. [18F] FDG PET/CT. TBR was significantly higher for [68Ga] FAPI- 46 PET/CT compared to [18F] FDG PET/CT for blood pool and liver

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Since heterogeneity was considerable and significant in most meta-analyses, it was not possible to perform subgroup meta-analysis or meta-regression to assess the potential sources of inconsistency among studies because small numbers of studies had included in each meta-analysis. Nevertheless, variations in patient selection, tumor stage, patients’ gender, interpretation criteria, and scanning procedures might contribute in heterogeneity among studies.

For metastatic lesions, TBR was again higher for [68Ga] FAPI- 46 PET/CT (WMD = 5.13, 95% CI 2.40, 7.86) compared to [18F] FDG, but the heterogeneity was extremely high (I2 = 97.41%). These findings suggest that [68Ga] FAPI- 46 PET/CT demonstrates superior TBR, particularly for metastatic lesions, but study variability is considerable (Fig. 12).

Fig. 12
figure 12

Forest plot; the pooled weighted mean difference of standardized tumor-to-background ratio (TBR) for metastasis uptake in [68Ga] FAPI- 46 PET/CT vs. [18F] FDG PET/CT. In overall, TBR was higher significantly for [68Ga] FAPI- 46 PET/CT (WMD: 5.13, 95% CI: 2.40, 7.86) compared to [18F] FDG for metastatic lesions

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Discussion

The present systematic review and meta-analysis deeply investigate the available evidence about the diagnostic performance of [68Ga] FAPI- 46 PET/CT in comparison to [18F] FDG PET/CT for cancers. The use of [68Ga] FAPI in PET/CT imaging has been increasing in oncology [43][84, 85]. The obtained findings indicate that the sensitivity of [68Ga] FAPI- 46 is 1.33 times greater than that of [18F] FDG, leading to accurately identifying true positive cancer, particularly in early-stage cancers. Additionally, [68Ga] FAPI- 46 shows a specificity that is 1.1 times higher than that of [18F] FDG, highlighting a more accurate identification of true negative cases associated with the minimum false positives. Moreover, the region-based meta-analysis shows that [68Ga] FAPI- 46 PET/CT has better diagnostic performance with pooled sensitivity at 0.94 and specificity at 0.89 through different anatomical regions, indicating its efficacy in malignancy detection, for primary and metastatic lesions. Regarding detection rates, primary tumors present the OR of 1.73, reflecting a significant advantage in detection efficiency, despite the considerable variability. The detection rate for lymph nodes showed a moderate increase (OR of 1.28) and variability. Contrarily, the detection of distant metastases obtained a minimal OR of 1.09, presenting slight improvement in detection efficiency as well as low variability.

For dose distribution, a higher trend in primary tumors for [68Ga] FAPI was observed than [18F] FDG PET/CT, with a 4.40 WMD. In terms of TBR that computes the contrast between primary tumors and surrounding tissues, [68Ga] FAPI- 46 revealed significantly higher values than [18F] FDG. Particularly, the TBR for the blood pool and liver showed WMDs of 5.51 and 12.32, respectively. Therefore, the TBR for [68Ga] FAPI- 46 was significantly superior to that of [18F] FDG, with a WMD of 6.18, emphasizing its improved capability to differentiate tumors from adjacent tissues; however, there is notable heterogeneity. For metastatic lesions, there has still been an advantage in TBR for [68Ga] FAPI- 46 compared to [18F] FDG. As a result, these results show that [68Ga] FAPI- 46 PET/CT has an ability to improve tumor detection and contrast against background tissues, especially for metastatic cases. However, careful interpretation and further validation are needed in larger patient cohorts due to the variability in the study results.

Compared with [18F] FDG, [68Ga] FAPI- 46 demonstrated superior uptake and lesion detection in grade 3 cholangiocarcinoma, which was correlated with high FAP expression in the tumor stroma; these findings are inconsistent with the findings of the current study [86]. Additionally, [68Ga] FAPI- 46 and [18F] FDG PET/CT provided comparable disease staging in breast cancer patients. However, [68Ga] FAPI- 46 had lower liver and blood pool uptake, leading to a TBR ratio, which may enhance lesion detection. Further validation in larger cohorts is needed to explore its potential for advanced breast cancer therapy [84]. [68Ga] FAPI- 46 PET/CT, as a revolutionary diagnostic method for breast cancer management, has superior TBR, and precise lymph node detection indicates its potential for targeted radionuclide therapies, which is in agreement with the results of the current study [87]. The [68Ga] FAPI- 46 PET/CT can enhance the detection of nodal metastasis in patients with cholangiocarcinomas (CCs) [35, 36], which is in agreement with the current results. Finally, the significance of [68Ga] FAPI PET/CT lies in its superior sensitivity, specificity, higher SUVmax, and improved dose distribution compared to [18F] FDG PET/CT. These advantages have prompted further studies, which consistently align with the findings of the present systematic meta-analysis [34, 49, 62, 88,89,90]. Accordingly, the present article analyzed the characteristics of [68Ga] FAPI and revealed its potential to improve diagnostic accuracy in detecting primary and metastatic lesions.

However, some meta-analyses have compared the diagnostic performance of [68Ga] FAPI and [18F] FDG PET/CT for specific cancer types, such as gastric, abdominal, colorectal, and pelvic cancers [61,62,63,64,65,66,67], a comprehensive analysis, which compares the performance of [68Ga] FAPI and [18F] FDG PET/CT for all cancer types remains absent. Further, despite the growing amount of research in this field, no systematic or meta-analytic study has yet directly compared [68Ga] FAPI- 46 with [18F] FDG across a wide range of malignancies. Therefore, there is a critical need to evaluate and compare the diagnostic accuracy and effectiveness of [68Ga] FAPI- 46 and [18F] FDG for various cancer types to enhance clinical decision-making. [68Ga] FAPI- 46 has a great clinical potential, particularly in oncology for radiotherapy [43, 91] since FAPI- 46 PET/CT can identify tumors, which can likely respond to therapies targeting the tumor stroma, due to its ability to image FAP expression in tumors [92]. Additionally, it facilitates the monitoring of treatment efficacy and the detection of early changes in the tumor microenvironment, showing a potential tool for optimizing personalized cancer treatment strategies.

The comparison between [68Ga] FAPI- 46 and [18F] FDG PET/CT holds important implications for clinical guidelines and future imaging protocols. Due to its higher sensitivity and specificity for FAP, [68Ga] FAPI- 46 could improve tumor detection, especially in cancers with low glucose metabolism, because of less expression of [18F] FDG. This approach can lead to more precise staging, improved treatment planning, and earlier identification of metastases and recurrences [93,94,95]. Moreover, the current systematic review and meta-analysis reveals that [68Ga] FAPI- 46 could improve treatment planning by enhancing tumor detection and staging, particularly in cases with ess effective [18F] FDG PET/CT since higher sensitivity may result in more precise therapy selection, optimizing surgical and radiotherapy decisions [96, 97].

The current systematic review and meta-analysis exhibits some limitations and possible future works, which may affect the interpretation of the results, as follows: (1) the analysis was constrained by a relatively small patients cohort, which may limit the generalizability of the findings by excluding some studies due to the omission of non-English publications and conference abstracts, potentially leading to a selection bias, (2) most included studies employed a case–control design, which could introduce inherent biases and confounding variables. Accordingly, this small sample size can compromise the statistical power and robustness of the overall results, and (3) during the quality assessment, half of the studies were rated as high risk of bias, especially for domains of patient selection and flow and timing, which may also affect the reliability of the findings. Nonetheless, despite these limitations, the clinical implications of the findings remain significant, underscoring the diagnostic potential of [68Ga] FAPI PET/CT in oncology. To address the limitations of this study, future research should focus on expanding the patient population and including non-English studies and conference abstracts to minimize selection bias. Additionally, prioritizing prospective cohort studies or randomized controlled trials can help lessen confounding factors and biases in case–control studies. Increasing the quality of studies through patient selection, randomization, and timing, along with adherence to rigorous methodological standards, will further enhance reliability and reduce bias. In the present review, we prioritized studies that compared both [68Ga] FAPI PET/CT and [18F] FDG PET/CT under similar conditions and sample sizes. However, this approach ensured consistency, it also reduced the number of eligible studies. Future investigations could independently evaluate [68Ga] FAPI PET/CT and [18F] FDG PET/CT in larger, standalone studies to provide more comprehensive insights into their diagnostic capabilities.

Conclusions

[68Ga] FAPI- 46 PET/CT has recently been considered a superior diagnostic agent to [18F] FDG PET/CT for different cancers, due to its higher sensitivity and specificity than [18F] FDG PET/CT. It also improves primary and metastatic tumor detection with a higher TBR, leading to accurate distinguishing of tumors from surrounding tissues. Additionally, [68Ga] FAPI- 46 PET/CT exhibits a great capability to identify malignancies associated with lower uptake in normal tissues, such as the liver and muscle. In clinical practice, these advantages lead to a decrease in false-negative and false-positive results and thus a more dependable diagnosis and treatment planning. Further, the acquisition of imaging data shortly after administration without any requirement for patient fasting, which is crucial for [18F] FDG, can streamline the imaging process. Therefore, these advantages suggest that [68Ga] FAPI- 46 could be positioned as a promising next-generation imaging agent in diagnostic strategies. However, future studies are needed to more validation of its effectiveness and potential in clinical applications. Additionally, limitations, such as small sample sizes, limited clinical data for different cancer types, and variability in performance based on cancer type and patient characteristics could impact its ability to distinguish certain tumors from surrounding tissues. Furthermore, the availability, accessibility, and cost-effectiveness of [68Ga] FAPI- 46 warrant further investigation before its wide implementation in clinical practice.

Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

CT:

Computed tomography

PET:

Positron emission tomography

FAP and FAPI:

Fibroblast activation protein (FAP) inhibitor (FAPI)

CAF:

Cancer-associated fibroblasts

MRI:

Magnetic resonance imaging

PRISMA:

Preferred Reporting Items for Systematic reviews and Meta-Analyses

FDG:

Fluorodeoxyglucose (FDG)

SUV:

Standardized uptake values

TBR:

Tumor-to-breast volume ratio

TP, TN:

True positive and negative

FP, FN:

False positive and negative

SROC:

Summary receiver operating characteristic

AUC:

Area under the curve

QUADAS:

The Quality Assessment of Diagnostic Accuracy Studies

CI:

Confidence intervals

LR:

Likelihood ratio

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Authors and Affiliations

  1. Department of Medical Physics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Samaneh Abbasi & Alireza Montazerabadi

  2. Department of Epidemiology, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran

    Mohsen Dehghani, Mahdieh Sahebi & Masoumeh Sadeghi

  3. Department of Radiology Technology, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran

    Sara Khademi

  4. Fintech in Medicine Research Center, Iran University of Medical Science, Tehran, Iran

    Rasoul Irajirad

  5. Nuclear Medicine and Molecular Imaging Department, Imam Reza International University, Razavi Hospital, Mashhad, Iran

    Zahra Pakdin Parizi

  6. Medical Physics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Alireza Montazerabadi

  7. Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Meysam Tavakoli

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  1. Samaneh Abbasi
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Contributions

S. A. and A. M. conducted the systematic review and wrote the manuscript. M. S. (Sadeghi) did the meta-analysis, M. D., S. KH., M. T., and Z. P rechecked the process and revised the text. M. S (Sahebi) helped conduct a part of analysis. A. M as a supervisor finally rechecked the findings and the text. All authors reviewed, discussed, revised manuscript critically for important intellectual content, and approved the manuscript.

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Correspondence to Masoumeh Sadeghi or Alireza Montazerabadi.

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Abbasi, S., Dehghani, M., Khademi, S. et al. Revolutionizing cancer diagnosis and dose biodistribution: a meta-analysis of [68ga] FAPI- 46 vs. [18f] FDG imaging. Syst Rev 14, 109 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13643-025-02835-x

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Keywords

Systematic Reviews

ISSN: 2046-4053