18F-Fluciclovine (18F-FACBC) PET imaging of recurrent brain tumors

Abstract

Purpose: The aim of our study was to investigate the efficacy of 18F-Fluciclovine brain PET imaging in recurrent gliomas, and to compare the utility of these images to that of contrast enhanced magnetic resonance imaging (MRI) and to [11C-methyl]-L-methionine (11C-Methionine) PET imaging. We also sought to gain insight into the factors affecting the uptake of 18F-FACBC in both tumors and normal brain, and specifically to evaluate how the uptake in these tissues varied over an extended period of time post injection.

Methods: Twenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic 18F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had 11C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the 18F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from 11C-Methionine and to contrast-enhanced MRI.

Results: 18F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor 18F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5 ± 2.3), while 11C-Methionine's tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0 ± 2.2). Image contrast was higher with 18F-Fluciclovine compared to 11C-Methionine (p < 0.0001). This was due to 18F-Fluciclovine's lower background in normal brain tissue (0.5 ± 0.2 compared to 1.3 ± 0.4 for 11C-Methionine). 18F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: Vb,k1,k2) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7 ± 2.3 h), and achieving a consistent final distribution volume averaging 1.4 ± 0.2 ml/cc. Tumors equilibrated more rapidly (t1/2ranging from 4 to 148 min, average 57 ± 51 min), with an average distribution volume of 3.2 ± 1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of 11C-Methionine was much faster than that of 18F-Fluciclovine.

Conclusion: Tumor uptake of 18F-Fluciclovine correlated well with the established brain tumor imaging agent 11C-Methionine but provided significantly higher image contrast. 18F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.

Keywords: 11C-methionine; 18F-FACBC; 18F-Fluciclovine; Glioma; PET.

Conflict of interest statement

Blue Earth Diagnostics provided support for the data analysis and paid for a part of Dr. L. Michaud salary.

This research was funded in part by Dr. A.B. Lassman’s grants from Dana Foundation, Brain Tumor Funders’ Collaborative, The Society of Memorial Sloan-Kettering Cancer Center, Brain Tumor Center of Memorial Sloan Kettering Cancer Center, Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center. In the last 12 months, outside the submitted work, Dr. A.B. Lassman received: Personal fees/honoraria from Orbus, Karyopharm, NW Bio, AbbVie, Agios, Bioclinica as an expert blinded independent reviewer of clinical and imaging data for a BMS-sponsored trial, Sapience, Physicians’ Education Resource/Chemotherapy Foundation Symposium; Research support from Genentech/Roche, Amgen, AbbVie, Millenium, Celldex, Novartis, Pfizer, Aeterna Zenaris, Karyopharm, RTOG-Foundation, Kadmon, VBI Vaccines, Beigene, Oncoceutics; and Travel/in-kind support from Orbus, Karyopharm, NW Bio, Oncoceutics, GCAR, Agios, AbbVie, Celgene, Novocure, Tocagen.

Dr. H. Schoder has no actual conflict of interest. He was a consultant for Aileron Pharmaceuticals until June 30, 2018.

Dr. WA. Weber is on advisory boards and receives compensation from Bayer, Blue Earth Diagnostics, Endocyte and Pentixapharm. He has received research support from BMS, Imaginab, Ipsen and Piramal.

B.J. Beattie, Dr. T. Akhurst, P. Zanzonico, Dr. M. Dunphy, Dr. R. Finn, A. Mauguen, and Dr. R. Blasberg declare they have no conflict of interest.

Figures

Fig. 1

Patient survival. a. Patients’ duration of disease (*Patients 24 and 25 last seen date instead of death) expressed as the time between initial surgery and Fluciclovine PET and as time between Fluciclovine PET and death. b. Kaplan Meier survival. The median overall survival is 31.6 months. The 5-year overall survival rate is 33% (95% CI: 16–51%)

Fig. 2

Patient examples. Top row - Patient 11 imaging. Male 61 years old. Primary tumor: GBM grade IV treated by surgery followed by adjuvant RT and chemotherapy (Temozolomide). Four months after the surgery, clinical suspicion of progression. MRI (image a. Axial) evocative of multifocal tumor progression. 18F-Fluciclovine PET (image b. Axial): multifocal tumor uptake SUVmax 4.5, ratio tumor SUVmax/ Contralateral SUVmean 6.9 and ratio tumor SUVmax/ Cerebellum SUVmean 8.1. 11C-Methionine PET (image c. Axial): visual very low tumor uptake SUVmax 5.09, ratio tumor SUVmax/ Contralateral SUVmean 2.5 and ratio tumor SUVmax/ CerebellumSUV mean 2.5. Progression treated by protocol RAD-Iressa. The patient died 7 months after. Autopsy: GBM complicated by bronchopneumonia. Bottom row - Patient 15 imaging. Male 59 years old. Primary tumor: right temporal anaplastic astrocytoma grade III treated by surgery followed by RT and chemotherapy (Temozolomide). Four years after: headaches increased. MRI (image d. Axial) evocative of right temporal tumor recurrence. 18F-FACBC PET (image e. Axial): visual high tumor uptake SUVmax 3.13, ratio tumor SUVmax/ Contralateral SUVmean 13 and ratio tumor SUVmax/ Cerebellum SUV mean 8.5. 11C-Methionine PET (image f. Axial): visual high tumor uptake SUVmax 2.96, ratio tumor SUVmax/ Contralateral SUVmean 5.6 and ratio tumor SUVmax/ Cerebellum SUV mean 3.3. Progression treated by Avastin, surgery and chemotherapy (Temozolomide). The histology report was evocative of a GBM. The patient died 1 year later

Fig. 3

Comparison of various uptake metrics for 18F-Fluciclovine and 11C-Methionine. All measured values are an average over the 25 to 45 min time frame. a. Correlation between maximum tumor SUV’s for the two PET racers. b. Essentially the same comparison as in A but this time the SUVmax values have been normalized by either the normal cerebellum (black circles) or normal contralateral (gray circles) means. c. Shows the correlation between the tumor SUVmax and the same patient’s cerebellar mean for 18F-Fluciclovine (black circles) and 11C-Methionine (gray circles). d. Relationship between the brain uptake for 18F-Fluciclovine and the same patient’s brain uptake of 11C-Methionine in the normal cerebellum (black circles) and in the normal contralateral brain (gray circles)

Fig. 4

Comparison of tumor volumes as assessed on each of three image sets. a. Correlation between volumes determined based on T1 contrast enhanced MRI and 18F-Fluciclovine PET (black circles) and between T1c MRI and 11C-Methionine PET (gray circles). Fitted lines are forced through the origin. b. Comparison between the two PET derived volumes (18F-Fluciclovine vs. 11C-Methionine). Again, fitted line is forced through the origin

Fig. 5

Patient 2 imaging: volumes overlap on MRI reconstruction. Red: MRI tumor volume, orange: 18F-FACBC tumor volume and turquoise: 11C-Methionine tumor volume. Patient 2. Male 62 years old. Primary tumor: astrocytoma grade II treated by surgery. 8 months after first recurrence treated by RT. 9 months after the first recurrence: 2nd recurrence treated by surgery and chemotherapy (Temozolomide). 3 months after the 2nd surgery: blurry vision. MRI: evocative of tumor progression. 18F-FACBC PET: high tumor uptake SUVmax 5.02, ratio tumor SUVmax/ Contralateral SUVmean 7.6 and ratio tumor SUVmax/ Cerebellum SUV mean 8. 11C-Methionine PET: high tumor uptake SUVmax 6.62, ratio tumor SUVmax/ Contralateral SUVmean 3.4 and ratio tumor SUVmax/ Cerebellum SUV mean 3.1. Progression treated by surgery. The histology report was evocative of a GBM. Adjuvant CT (CPT-11) was administrated. 6 months after, clinical deterioration and MRI progression tumor. The patient died 3 months after

Fig. 6

Time vs. activity profiles, along with modelled estimates. Results show 18F-Fluciclovine concentration in various tissues for four selected patients. Blood concentration (triangles), tumor (x’s) and cerebellum (circles). Parameter values associated with the model fits of the tumor and cerebellar time courses are listed in the plot titles. a. Patient #8. b. Patient #12. c. Patient #13. d. Patient #16

Fig. 7

Comparison of the 18F- Fluciclovine and 11C-Methionine uptake time course over the first 45 min. Profiles are shown for two patients: #12 (a.) and #13 (b.). Tumor uptake of 11C-Methionine (x’s). Cerebellum uptake of 11C-Methionine (circles). Tumor uptake of 18F- Fluciclovine (inverted triangle). Cerebellum uptake of 18F-FACBC (triangle). Comparison of time course of tumor to normal cerebellum contrast for four selected patients: 11C-Methionine contrast (c.) and 18F- Fluciclovine contrast with model fitted curves (d.)