We report several notable findings from this prospective preliminary study of 68Ga-NODAGA-RGD PET imaging in esophageal or esophagogastric junction cancers. First, the molecular imaging visualization of integrin αvβ3 expression using 68Ga-NODAGA-RGD PET/CT has lower potential in the detection of esophageal or esophagogastric junction malignancies compared to the visualization of glucose metabolism with 18F-FDG PET/CT. However, 68Ga-NODAGA-RGD PET/CT showed different uptake patterns in most primary lesions than 18F-FDG PET/CT, and 68Ga-NODAGA-RGD uptake was not systematically lower, suggesting that 68Ga-NODAGA-RGD may provide complementary information.
The study of molecular imaging of integrin expression focused on esophageal or EGJ malignancies has not previously been well-established in the literature. To the best of our knowledge, the only previous study evaluating RGD imaging on the evaluation of esophageal cancer is a prospective study by Zheng et al., investigating the efficacy of [99mTc]3PRGD2 on standard gamma cameras (Zheng et al., 2019).
Our finding of a lower detection rate of 68Ga-NODAGA-RGD than 18F-FDG imaging in detecting malignancies is not unexpected and is consistent with previous other cancer studies in humans. Zheng et al. found a lower sensitivity than 18F-FDG imaging for detecting small esophageal metastatic lesions in lymph nodes. Beer et al. found a lower sensitivity for lesion detection for 18F-galacto-RGD PET as compared to 18F-FDG PET in eighteen cancer patients, mostly with non–small cell lung cancer (Beer et al., 2008). Haubner et al. demonstrated no increased uptake of 68Ga-NODAGA-RGD in hepatocellular carcinoma compared with the background liver tissue (Haubner et al., 2016). In contrast, 18F-FPPRGD2 showed higher sensitivity and specificity than 18F-FDG in a preliminary PET study on breast cancer by Iagaru et al. (Iagaru et al., 2014).
The finding of a significantly higher uptake with 18F-FDG than with 68Ga-NODAGA-RGD in positive lesions is also not surprising, and consistent with previous studies in humans (Beer et al., 2008; Durante et al., 2020). To explain this difference in tracer uptake Beer et al. argued that 18F-galacto-RGD binds predominantly to endothelial cells, with a substantially smaller number than the number of FDG-avid tumor cells (Beer et al., 2008). As both 18F-Galacto-RGD and 68Ga-NODAGA-RGD demonstrated similar preclinical results (Pohle et al., 2012), this same theory could be applied to our study. However, a significantly lower tracer uptake does not necessarily mean a lower lesion-to-background ratio. In the present study when lesion-to-background ratios in positive lesions were compared, no significant difference was found between 18F-FDG and 68Ga-NODAGA-RGD. Same results were shown in a prospective study by Minamimoto et al. (Minamimoto et al., 2015). By comparing 18F-FPPRGD2 and 18F-FDG uptake values in various non-esophageal cancer patients, those authors showed no significant difference in tumor-to-background ratios between both tracers. The low RGD-based tracer uptake in several areas such as the lung, muscles, fat, the brain, or the myocardium could be an advantage for both qualitative and quantitative evaluation of thoracic, breast or brain lesions (Beer et al., 2008; Minamimoto et al., 2015), or for non-oncological applications such as cardiovascular imaging or inflammatory diseases (Dietz et al. 2021; Ebenhan et al. 2021; Dietz et al. 2022; Zhu et al. 2014).
An encouraging finding is the fact that an osteolytic malignant lesion showed a clearly more intense 68Ga-NODAGA-RGD uptake as compared to 18F-FDG. This result is consistent with preclinical data, which supported that RGD-based PET tracer has the potential to effectively image bone metastases, especially in osteolytic metastases, by targeting of the αvβ3 integrin on osteoclasts and the proinflammatory cells involved at the bone metastatic site (Wadas et al., 2009). In a pilot prospective study of 18F-Alfatide II for detection of skeletal metastases in humans, Mi et al. showed high positive predictive value in the detection of bone metastases, with high lesion-to-background contrast (Mi et al., 2015). This observation is in alignment with the hypothesis that RGD-based imaging may provide complementary information in imaging cancer patients.
We strongly believe that the complementary information provided by molecular imaging of αvβ3 expression could be clinically relevant. αvβ3 integrin is involved in epithelial–mesenchymal transition, which may play a pivotal role in the very early stages of tumorigenesis (Kariya et al., 2021; Liu et al., 2017). Despite 18F-FDG PET should be a preferred method for initial tumor staging, the different uptake pattern especially with some slight extensions into perilesional structures could help to delineate the pre-tumoral niche. 68Ga-NODAGA-RGD uptake could represent a soil-derived factor involved in tumorigenesis which may guide surgical resection or radiotherapy. Further investigations would be still required in the future to elucidate the potential role of 68Ga-NODAGA-RGD in esophageal cancer management.
Limitations
There exist some limitations in our study. 68Ga-NODAGA-RGD uptake was not prognostic for any of the investigated endpoints, but our number of participants is not large enough. The limited statistical power may also explain the absence of significant results in subgroup analysis for different pathological tumor status or histological grade. Immunohistochemistry tests were not performed to assess the correlation between integrin αvβ3 expression and 68Ga-NODAGA-RGD uptake, which has been demonstrated in several animal and clinical studies (Chen et al., 2016; Jeong et al., 2008).