Aggressive thyroid cancer patients exhaust radioiodine therapy as a theranostic option. About 8 decades after the introduction of radioiodine, radiopharmaceuticals based on fibroblast activation protein inhibitors have shown a role in theranostics of thyroid cancer.
The present study compared to diagnostic efficacy of [68Ga]Ga-DOTA.SA.FAPi with [18F]F-FDG-PET/CT in patients with RAI-R FCTCs. It aimed to conduct a systematic evaluation of the difference between FAPi expression and Glucose uptake in the detection of RAI-R FCTC. [68Ga]Ga-DOTA.SA.FAPi showed a higher detection efficiency rate for lymph nodes (sensitivity 95.7% vs 88.6%, p < 0.0001), liver metastases (100% vs. 72%; p < 0.0001), and brain metastases (100% vs. 38.8%; p-0.0003). Overall the results suggest that [68Ga]Ga-DOTA.SA.FAPi has higher detection rates in terms of the number of lymph nodes, liver, lung, and brain metastases as compared to [18F]F-FDG PET/CT.
Although the semi-quantitative parameters such as SULpeak and average values for various metastatic sites were similar between the two radiotracers, [68Ga]Ga-DOTA.SA.FAPi showed the values were substantially superior values for brain and muscle metastases. Similarly, irrespective of the type of FAPi molecule several studies have indicated the favorable property of [68Ga]Ga-FAPi PET scans of low uptake in the normal parenchyma which is beneficial for tumor delineation in particular in the head and neck and liver regions in different cancers (21–23).
Loco-regional lymph node (LN) metastasis is typically one of the initial sites of disease progression in thyroid cancer which eventually progresses to the distant organs. Among the various diagnostic modalities, ultrasonography limits the diagnosis of central compartment lymph nodal metastases as certain LNs are deeply seated around the trachea and overlapped by surrounding structures resulting in false negative results. Currently, though [18F]F-FDG PET/CT is the modality of choice in evaluating RR-DTC and other non-iodine concentrating aggressive variants of thyroid cancer such as Hürthle, insular, PDTC, and ATC, but its use is limited in inflammatory lymphadenopathy which has higher false positive rates. Our study demonstrated that [68Ga]Ga-DOTA.SA.FAPi PET/CT was capable of detecting lymph node metastases more reliably than was [18F]FDG PET/CT (Table 2). This achievement is in agreement with data published previously by Wang et al (23). According to their reports, [68Ga]Ga-FAPi PET/CT imaging can detect lymph node metastases at an earlier stage and has the potential to increase occult lymph node metastasis detection, guiding the more accurate staging of thyroid cancer patients consistent with the higher specificity of the former technique.
[18F]F-FDG exhibited relatively low sensitivity for small metastatic lesions and low specificity for infective lung pathology. Similarly, [68Ga]Ga-DOTA.SA.FAPi also demonstrated mixed uptake in lung metastases. False-negative results in lung metastases were observed on both radiotracers, but in higher percentages on [18F]F-FDG compared to [68Ga]Ga-FAPi. One possible explanation could be the rapid [18F]F-FDG efflux from the tumor cells in highly aggressive metastases. Alternatively, minimal to no uptake in the lung metastases on both radiotracers could be due to the size of the lesions and breathing artifacts. From this standpoint, it remains clear that breathold CT scan with careful clinical follow-up is still an invaluable approach to diagnose small lung nodules with indeterminate uptake on both radiotracers. Further, studies should be conducted in detail regarding this uptake pattern in various subtypes of thyroid cancers.
Diagnosis and detection of PDTC have been controversial from the histopathological staging to the imaging point of view (24). These ambiguities have also made management difficult. Unlike [18F]F-FDG in RR-DTC, its role is not clearly outlined as imaging of choice by the American Thyroid Association (ATA). However, the role of FDG in PDTC is not well researched. Though more often PDTC is an FDG-positive tumor, some studies have shown an intermediate GLUT1 expression and FDG uptake with values between DTC and ATC (25). The remarkably high detection rate of FAPi in PDTC and ATC in all the metastatic sites compared to FDG has unveiled a new option for imaging these aggressive variants which has controversial results involving different uptake patterns and intermediate FDG expression. With FAPI positive expression in all the PDTC lesions, it opens new avenues for systemic treatment options in a patient with limited treatment options or scarce treatment options.
An interesting case to discuss is a case of a 66-year-old female (Fig. 3) with known poorly differentiated thyroid carcinoma who underwent [18F]F-FDG PET/CT for follow-up. A, images from the [18F]F-FDG PET/CT scan demonstrate minimal [18F]F-FDG uptake in the bilateral lung metastases and normal findings in the rest of the organs (Fig. 3A). CT scan axial sections reveal bilateral lung nodules and liver metastases (Fig. 3B). [68Ga]Ga-DOTA.SA.FAPi PET/CT was performed for further evaluation and scan findings reveal intense uptake in bilateral lung nodules, and multiple liver lesions (Fig. 3C). [68Ga]Ga-DOTA.SA.FAPi upscaled the detection of metastases in the lung and liver. Highly aggressive tumors compose 90% of tumor stroma rather than the tumor itself. Hence low glycolytic activity and higher expression of FAPi may be the reason for these discordant findings.
Another case (Fig. 4) of the complementary benefit of imaging with both [18F]F-FDG PET/CT and [68Ga]Ga-FAPi PET/CT is described as follows: In a 65-year-old female with RR-DTC, mediastinal LNs showed intense [18F]F-FDG uptake which was negligible on [68Ga]Ga-DOTA.SA.FAPi PET/CT, on the contrary intense [68Ga]Ga-DOTA.SA.FAPi accumulation was noted in the bilateral lung nodules, liver, and pelvic bone metastases. The diagnostic accuracy improved significantly with a complimentary dual scan approach in this patient with a combination of true positive, false positive, true negative, and false negative on both scans.
Few studies have explored the role of different [68Ga]Ga-labelled FAPi molecules in thyroid cancers which are limited to only a few cases per study. Contrary to our findings, few researchers did not observe the utility of [68Ga]Ga-DOTA.SA.FAPi in low RAI expressing thyroid cancer and demonstrated low parenchymal uptake in RR-DTC. Kratochwil et al. (16) observed low uptake of 68Ga-FAPI-04 in a few cancers including differentiated thyroid cancer with uptake rates (SUVmax < 6). Similarly, Giesel et al. (15) observed dedifferentiated thyroid cancer with flip-flop uptake of [18F]F-FDG was not accumulating [68Ga]Ga-FAPi-04. Huang et al. (26) also observed that patients with iodine uptake negative thyroid cancer exhibited low [68Ga]Ga-FAPi tracer uptake compared with [18F]F-FDG PET. At the current stage, [18F]F-FDG PET/CT is still the PET radiopharmaceutical of choice with its wide availability, cost-effectiveness, and standardization of quantification techniques for restaging, and [68Ga]Ga-FAPi now only has a complementary role.
Although imaging of [68Ga]Ga-FAPi molecules has proved promising imaging radiotracers, the same monomeric compounds when labeled to therapeutic counter parts have shown rapid washout of the radiotracers from the tumor. To improve the tracer kinetics for introducing FAPi-based therapeutic avenues, Moon et al. structurally modified and optimized the monomeric FAPi precursor to homodimeric compounds and successfully showed prolonged tumor retention time (19). Eventually, the same group studied the dosimetry and pharmacokinetics of [177Lu]Lu-DOTAGA.(SA.FAPi)2 homodimeric compound in RR-DTC patients which significantly prolonged tumor retention even up to 168 h, post-treatment (20). However, the study included only RR-DTC patients and future research should focus and explore on the expansion of this treatment option in various radioiodine-resistant thyroid cancer (RAI-R TC) with broader histological variants. Long-term outcomes of [177Lu]Lu-FAPi treatment in various TC’s will accurately reflect and will be the answer to the utility of the treatment.