Page 36 - ARNM-2-3

Advances in Radiotherapy
& Nuclear Medicine Molecular imaging of lung cancer

While F-FDG has been highly beneficial, one of its 3.3. Imaging with thymidine cell proliferation
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primary limitations is its significant uptake in normal tissue, biomarker
which can lead to false-positive results. In addition, the Another approach to lung cancer imaging involves
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specificity of F-FDG-PET is reduced in regions affected targeting uncontrolled cell proliferation, which is
by infectious lung diseases. Furthermore, the brain, a often seen in many malignant lesions. 3-Deoxy-3- F-
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common site for lung cancer metastasis, inherently exhibits fluorothymidine ( F-FLT) is a thymidine analog effective
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high F-FDG uptake, resulting in low contrast and making for visualizing and quantifying cell proliferation due to its
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it difficult to distinguish metastatic lesions. Consequently, interaction with the enzyme thymidine kinase 1 (TK1). FLT
there has been significant effort over the past decades to is phosphorylated by TK1 during the S-phase of the cell
develop novel PET tracers with enhanced sensitivity and cycle, which traps it intracellularly. Unlike thymidine, FLT
specificity for lung cancer imaging. 59 is not incorporated into DNA, and its uptake is correlated
3.2. Targeting fibroblast activation protein (FAP) with increased activity of TK1 and cell proliferation. 64,65 In
a 2016 study, Wang et al. compared F-FDG and F-FLT in
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Recently, cancer-associated fibroblasts (CAFs) have lung cancer PET/CT imaging. They observed significantly
emerged as a major target for diagnosis and antitumor higher F-FLT uptake in lung cancer lesions and a higher
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therapy. These fibroblasts express FAP, which is minimally tumor-to-background ratio of 18 F-FDG imaging in
expressed in healthy tissue but is frequently present in many xenografts compared to F-FLT. The study reported a high
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tumors. FAP activity is believed to contribute to tumor specificity (79%) and low sensitivity (71%) for F-FLT as
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development, migration, and metastasis, 21,60 and FAP itself compared to F-FDG, which showed 67% specificity and
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is a potential target for cancer treatment. Radiolabeled 89% sensitivity as reported by Wang et al. These results
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FAP inhibitors (FAPIs) linked to radionuclides have been suggest that while F-FDG is superior for detecting lung
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developed for PET imaging that targets FAP expression in cancer, F-FLT’s higher specificity could make it more
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CAFs. These FAPIs are often labeled with radionuclides effective for distinguishing lung cancer nodules from
like gallium-68, exhibiting a high tumor-to-background other malignancies. 22,66,67 Given F-FLT’s higher specificity
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ratio and rapid renal clearance. 59 and F-FDG’s higher sensitivity, studies have explored
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A few studies have investigated the effectiveness the diagnostic potential of combining both tracers. In a
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of Ga-FAPI-04 as a PET radiotracer in lung cancer multicenter study assessing the diagnostic value of dual
detection. In a 2019 study, Kratochwil et al. examined the tracers in lung cancer, the sensitivity of F-FDG increased
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uptake of Ga-FAPI-04 in various primary, metastatic, and from 87% to 100% when combined with F-FLT, and the
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recurring cancers. Their findings showed a high maximum specificity of F-FLT increased from 77% to about 90%
standardized uptake value (SUV ) (> 12) for lung cancer when combined with F-FDG. 68
max
and low background activity (1.6 SUV for blood and
max
1.4 SUV for muscles). Consequently, the tumor-to- 3.4. Targeting programmed death receptor-1 (PD-1)
max
background ratios for lung cancer and other cancers with Immuno-positron emission tomography (immunoPET)
high uptake exceeded 6. These high tumor-to-background is an imaging modality that has undergone significant
ratios result in excellent image contrast for most of the advancements in recent years. This approach integrates
evaluated patients. 62 the specificity of antibodies with the superior sensitivity
Another study conducted by Giesel et al. in 2021 of PET to visualize antigen expression. Various antibodies
compared the tumor uptake and organ biodistribution and radionuclides have been investigated to develop
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between Ga-FAPI PET/CT and F-FDG PET/CT in immunoPET probes, with zirconium-89 ( Zr) being the
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69,70
71 patients with different cancer types, including nine most commonly used due to its long half-life.
patients with lung cancer. The study found that Ga-FAPI One frequently targeted cancer biomarker in
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and F-FDG had comparable uptakes in primary tumors immunoPET is PD-1. PD-1 is a regulatory protein, and
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and metastasis. In addition, Ga-FAPI exhibited lower its ligands, programmed death ligand 1 (PD-L1) and
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uptake in most normal tissue compared to F-FDG. programmed death ligand 2, are overexpressed in several
These findings indicate that Ga-FAPI PET/CT imaging cancers, including NSCLC, making them predictive
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achieves high image contrast due to significant uptake in biomarkers for these cancers. Monoclonal antibodies that
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diverse types of cancers, comparable to imaging with F- block PD-1, such as pembrolizumab, are routinely used in
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FDG. However, the lower background uptake of Ga-FAPI treating NSCLC and have recently been evaluated as an
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in most normal tissues results in an equal or higher tumor- immunoPET tracer. In a study by Kok et al., Zr-labeled
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to-background ratio for PET imaging with Ga-FAPI. pembrolizumab was used in PET imaging of 11 melanoma
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Volume 2 Issue 3 (2024) 4 doi: 10.36922/arnm.4173