F-18 FLT PET highlights cancer proliferation

In a review of available PET imaging biomarkers that focus on cellular proliferation as an important key to cancer detection and therapy monitoring, F-18 FLT stood out as a game-changer for its ability to hone in on processes specific to cancer growth. However, in many studies, tracer uptake was underwhelming when compared to standard FDG, according to a scientific paper published May 14 in the Journal of Nuclear Medicine.

Omid S. Tehrani, MD, from the department of oncology at Karmanos Cancer Institute, Wayne State University, Detroit, Mich., and colleagues, discussed several agents that have been developed to target the hallmarks of proliferation in many forms of cancer. These targets include increased metabolic activity and the DNA synthesis pathway.

Currently only F-18 FDG is widely accepted and used in clinical practice for proliferation imaging. Although it finds hotspots of cellular metabolism that inform clinicians about possible cellular proliferation and cell death, FDG does not convey an actual measurement of cancer cell proliferation.

“Another marker of cell growth and proliferation is uptake of the molecules that are needed for synthetic pathways, including labeled amino acids for measuring transport and protein synthesis and nucleosides for DNA synthesis,” wrote Tehrani et al.

One of these used to track cancer cell proliferation is C-11 thymidine, which is taken up into DNA but not by RNA to map proliferation. C-11 methionine is another option, which seeks amino acid transport. The major caveat with C-11 labeled agents is their very short half-life. For this reason, F-18 radiolabeled tracers are more plentiful and used more commonly by more clinicians in this application.

An F-18 radiolabeled biomarker for cell proliferation that has been gaining increasing attention is F-18 39-deoxy-39-fluorothymidine (F-18 FLT). The primary mechanism for its specificity for cell proliferation is in its relationship to thymidine kinase 1, which sequesters FLT for phosphorylation. Thymidine kinase 1 is key, because it is hyper-expressed in multiplying cells. This relationship has been demonstrated in studies involving brain, breast and lung tumors.

F-18 FLT is not ideal, though. Lower standardized uptake than FDG and high kidney, bone marrow and liver background uptake lessen its imaging value. Its use has been primarily in the realm of therapy monitoring.

Still, separate studies have validated F-18 FLT’s use for gauging treatment response in varieties of lymphoma, including non-Hodgkins and diffuse B-cell lymphomas. In one study of 38 patients, PET/CT with F-18 FLT was shown to be both more sensitive and more specific than CT imaging on its own.

Despite the agent’s difficulty with bone marrow, imaging sarcomas is evidently not an issue. Multiple studies, including two involving 36 subjects with bone and soft tissue sarcomas, showed that every lesion was detected using F-18 FLT.

For breast cancer, a somewhat higher background uptake is not a deal-breaker, due to generally lower background activity in normal breast tissue, the researchers wrote. Several studies with F-18 FLT indicated use for imaging cell proliferation.

“F-18 FLT uptake has been shown to correlate with histologic assessment of proliferation by Ki-67 in breast, lung, and brain cancers in a recent analysis of 27 such studies,” wrote the authors. “Changes in F-18 FLT uptake have been detected as early as one week after chemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide. Responding lesions had an average decrease in SUV of 41.3 percent, whereas in nonresponders the SUV increased by 3.1 percent. Several methods are available for analyzing images with F-18 FLT to detect changes after chemotherapy, including SUV, tumor–to–whole blood ratio, and nonlinear regression kinetic models.”

Nervous system cancers are most often imaged with MR, but this modality does not paint a clear picture of proliferation. A study comparing F-18 FDG and FLT and C-11 methionine biomarkers for the detection of grade II and IV gliomas found that while FDG was not effective for differentiation between grades, C-11 methionine and F-18 FLT were both successful and targeted the Ki-67 index. Mean biomarker retention was noted in SUVs for F-18 FLT measured at 2.38 for grade II and 0.36 for grade IV. For C-11 methionine, it was 3.04 for grade II and 5.12, for grade IV. 

F-18 FLT was seen as a challenge in gastrointestinal cancers due to retention in the kidneys, liver, bladder and bone marrow, but studies still showed utility, although not as effectively as FDG. F-18 FLT was similarly dampened in hepatobiliary cancer imaging, with a mixed bag of uptakes making applications less clear for these tumors.

“About two thirds of the lesions showed F-18 FLT uptake higher than in the surrounding liver tissue, with the rest of the lesions being photopenic or a mixture of hot and cold spots,” wrote the authors.

For pancreatic tumors, a study of 41 patients revealed that F-18 FDG had a sensitivity of 91 percent whereas FLT was 70 percent for detecting pancreatic malignancy. Specificity was seen at 50 percent and 75 percent, respectively. Average maximum SUV was 7.9 for FDG and 3.0 for FLT.

Clinical data on the use of these agents for cancers of the urinary tract were sparse. “There are limited clinical data in these cancers, although some case studies have shown promising results such as identifying malignancy in renal cysts,” the researchers wrote.

F-18 FLT uptake after withdrawal of tyrosine kinase inhibitors has been tested in these renal cancers in a study of 16 patients discontinuing treatment with sunitinib. On average, the median F-18 FLT SUV increased 19 percent with the 2-on, 1-off schedule and 15 percent with a 4-on, 2-off schedule.

As with many other varieties of cancers, the authors wrote that F-18 FLT showed lower uptake in head and neck cancers. “Like other areas of the body, F-18 FLT uptake has frequently been reported to be lower than F-18 FDG uptake in these tumors. On the other hand, because of a variety of inflammatory processes that can involve the lymph nodes in the head and neck, discrimination between inflammatory and neoplastic involvement in lymph nodes is not easy.”

Lung cancer was the most prevalent form of cancer studied with F-18 FLT. In a patient population of 25, all with suspected lung cancer, F-18 FLT images were compared before surgery to determine malignancy by expression of Ki-67 and TK1 in histological testing.

Overall static uptake of FLT maximum SUV was p = 0.57, P = 0.006 and maximal immunohistochemical expressions of Ki-67 and TK1, p = 0.69, P <  0.001.  Enzymatic activity was not included here, but was at p = 0.34, P = 0.146.

Lastly, F-18 FLT was seen to positively identify melanoma lesions in a study of 10 patients with stage III tumors.

“We are in an era of targeted therapy and molecular imaging,” concluded the authors. “Using proliferation-specific tracers may help better identify an unknown lesion and help us predict response to the treatment. As F-18 FLT finds more applications in proliferation imaging, its benefits and limitations will be better known. Currently available data have shown application of this agent in solid tumors and bone marrow activity. Major limitations have been in areas with high uptake in the normal background, such as in the genitourinary and hepatobiliary systems. Because of the generally lower uptake of F-18 FLT than of F-18 FDG in most solid tumors, F-18 FLT is not expected to replace F-18 FDG for detection and staging purposes, except for certain lesions.”