[11C]Methionine and [11C]PBR28 as PET Imaging Tracers to Differentiate Metastatic Tumor Recurrence or Radiation Necrosis

Abstract

Purpose: As stereotactic radiosurgery (SRS) and immunotherapy are increasingly used to treat brain metastases, incidence of radiation necrosis (RN) is consequently rising. Differentiating tumor regrowth (TR) from RN is vital in management but difficult to assess using MRI. We hypothesized that tumor methionine levels would be elevated given increased metabolism and high amino acid uptake, whereas RN would increase inflammation marked by upregulated translocator protein (PBR-TSPO), which can be quantified with specific PET tracers.

Procedures: We performed a feasibility study to prospectively evaluate [11C]methionine and [11C]PBR28 using PET in 5 patients with 7 previously SRS-treated brain metastases demonstrating regrowth to differentiate TR from RN.

Results: Sequential imaging with dual tracers was well-tolerated. [11C]methionine was accurate for detecting pathologically confirmed TR in 7/7 lesions, whereas [11C]PBR28 was only accurate in 3/7 lesions. Tumor PBR-TSPO expression was elevated in both melanoma and lung cancer cells, contributing to lack of specificity of [11C]PBR28-PET.

Conclusion: Sequential use of PET tracers is safe and effective. [11C]Methionine was a reliable TR marker, but [11C]PBR28 was not a reliable marker of RN. Studies are needed to determine the causes of post-radiation inflammation and identify specific markers of RN to improve diagnostic imaging.

Trial registration: ClinicalTrials.gov NCT02433171.

Keywords: PET; [11C]PBR28; [11C]methionine; brain metastasis; radiation necrosis.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Dr. Harriet Kluger reports research grants from Merck, Bristol-Myers Squibb, and Apexigen during the conduct of the study, and personal fees from Merck, Regeneron, Alexion, Prometheus, Corvus, Nektar, Biodesix, Roche-Genetech, Pfizer, Iovance, Immunocore, Array Biopharma, and Celldex, outside of the submitted work. Dr. Chiang reports personal fees from Brainlab, Monteris Medical, and MRI Interventions outside of the submitted work. The other authors declare no conflicts of interest.

Figures

Figure 1.

MRI and PET imaging for [11C]MET and [11C]PBR28. A, Representative images of suspicious lesions for TR or RN as seen on post-gadolinium MRI sequences. Corresponding lesions as seen on PET for [11C]MET and [11C]PBR28. B, Patient 2 had histologically confirmed TR, but had uptake of both [11C]MET and [11C]PBR28 radiotracers. Patient 3 had histologically confirmed RN but had absent uptake of both [11C]MET and [11C]PBR28 radiotracers. Patient 5 had histologically confirmed RN and demonstrated uptake of only [11C]PBR28. Tumor is outlined in a dashed line (top photo, taken at 20X). Characteristic features of RN include vessel hyalinization (arrows), increased immune infiltrate (arrowhead) (bottom photo, taken at 10X), and paucicelluar coagulative necrosis (*) (middle photo, taken at 4X, and bottom photo).

Figure 2.

Quantitation of PBR-TSPO in NSCLC and melanoma. (A-B) PBR, also known as TSPO, protein is present at high levels in human monocytes, but expression is decreased in human NSCLC (P = 0.0038 by t test, mean 0.38 ± 0.045 standard error of the mean [SEM]) and human melanoma (P = 0.0008, 0.40 ± 0.089) cell lines. (C) Human NSCLC (n = 28) and (D) melanoma (n = 13) tissue microarrays were stained with either cytokeratin or S100, respectively, to create a tumor mask. PBR-TSPO immunofluorescence staining intensity was quantitated in tumor cells by AQUA. Representative sections demonstrating tissue with higher and lower PBR-TSPO expression is shown for NSCLC and melanoma cases.