Is Response Assessment of Breast Cancer Bone Metastases Better with Measurement of 18F-Fluoride Metabolic Flux Than with Measurement of 18F-Fluoride PET/CT SUV?

Our purpose was to establish whether noninvasive measurement of changes in 18F-fluoride metabolic flux to bone mineral (Ki) by PET/CT can provide incremental value in response assessment of bone metastases in breast cancer compared with SUVmax and SUVmean. Methods: Twelve breast cancer patients starting endocrine treatment for de novo or progressive bone metastases were included. Static 18F-fluoride PET/CT scans were acquired 60 min after injection, before and 8 wk after commencing treatment. Venous blood samples were taken at 55 and 85 min after injection to measure plasma 18F-fluoride activity concentrations, and Ki in individual bone metastases was calculated using a previously validated method. Percentage changes in Ki, SUVmax, and SUVmean were calculated from the same index lesions (≤5 lesions) from each patient. Clinical response up to 24 wk, assessed in consensus by 2 experienced oncologists masked to PET imaging findings, was used as a reference standard. Results: Of the 4 patients with clinically progressive disease (PD), mean Ki significantly increased (>25%) in all, SUVmax in 3, and SUVmean in 2. Of the 8 non-PD patients, Ki decreased or remained stable in 7, SUVmax in 5, and SUVmean in 6. A significant mean percentage increase from baseline for Ki, compared with SUVmax and SUVmean, occurred in the 4 patients with PD (89.7% vs. 41.8% and 43.5%, respectively; P < 0.001). Conclusion: After 8 wk of endocrine treatment for bone-predominant metastatic breast cancer, Ki more reliably differentiated PD from non-PD than did SUVmax and SUVmean, probably because measurement of SUV underestimates fluoride clearance by not considering changes in input function.


Detailed methodology for Ki calculation
The measurement of 18 F-fluoride metabolic flux (Ki, also referred to as 18 F skeletal plasma clearance) provides a more reliable assessment of bone metabolism than standardized uptake values (SUV) in circumstances where bone metabolism averaged across the whole skeleton is sufficiently different from normal that the 18 F plasma time-activity curve (TAC) is altered. Examples may include patients with extensive metastatic bone disease ("super scans"), patients with an extensive area of active Paget's disease, and patients with osteoporosis treated with a potent anabolic bone agent such as teriparatide (10,31,32). In such cases the increased avidity of 18 F uptake into bone leaves less tracer available for the circulation or for uptake in soft tissue and the 18 F concentration in plasma is correspondingly reduced.
The 18 F-fluoride semi-population input function (SPIF) was developed so that when combined with a single static PET scan acquired 45 to 90 minutes after injection of tracer it provides a quick and simple method of estimating Ki with little loss of accuracy or precision compared with the conventional 60-minute dynamic PET scan analyzed with an input function generated by continuous arterial sampling (18,24,27). An important advantage of this approach is that it enables measurements of Ki to be made at multiple sites in the skeleton at different bed positions with only a single injection of 18 F-fluoride tracer.
In the SPIF method the "terminal exponential" is defined as the single-exponential curve fitted to between two and four measurements of 18 F venous plasma concentration between 30 and 90 minutes after injection (4). At times greater than 30 minutes 18 F concentrations in venous and arterial blood are in equilibrium and equal. In the example from the present study shown in Figure   S1A, two blood samples were taken at 55 and 85 minutes after injection with plasma concentration measurements of 7.21 and 5.06 kBq/mL after decay correction to the time of injection. The injected activity in this subject was 237 MBq. To generate an estimate of the full plasma TAC between 0 and 90 minutes after injection the terminal exponential calculated from the 55 and 85 minute blood samples is added to a "residual" curve ( Figure S1B) representing the bolus peak and early fast exponentials. The residual curve shown in Figure S1B was produced by averaging data from 10 postmenopausal women who had full arterial blood sampling between 0 and 60 minutes after injection with subtraction of the terminal exponential (4). The residual curve in each of the 10 women was normalised to an injected activity of 100 MBq, and the curves averaged after adjusting the time of peak counts to 30 seconds after initiation of the injection protocol. The full SPIF TAC ( Figure S1C) was created by multiplying the residual curve by 2.37 (allowing for the injected activity of 237 MBq in this instance) and adding the terminal exponential shown in Figure S1A. To ensure that the contribution from the terminal exponential does not exceed the residual curve in the first 30 seconds after injection the terminal exponential in Figure S1A was rolled off to zero using a ramp function at times before 30 seconds (24).
In the example shown in Figure S1C, the terminal exponential accounts for over 80% of the area under the curve between 0 and 90 minutes. The contribution from the terminal exponential exceeds the contribution from the residual curve at times greater than 3 minutes after injection. An important part of the rationale for the SPIF method is that changes in the whole skeleton metabolic flux may alter the terminal exponential, but will have less effect on the residual curve, which is mainly determined by the mixing of the bolus injection throughout the circulation and the rapid early diffusion of 18 F-fluoride ions into soft tissue.
In the analysis of conventional 60-minute 18 F-fluoride dynamic PET scans, the metabolic flux Ki is often calculated from the bone TAC and the arterial input function using the Hawkins compartmental model ( Figure S2) (11). However, provided that the rate constant k4 describing the efflux of tracer out of the bound bone pool is negligibly small, the alternative Patlak analysis method provides a simpler method of calculating Ki from the dynamic scan data. In Patlak analysis the concentration of 18 F in the bone region of interest, Cb(T), at time T after injection is expressed by the following equation: where Cp is the concentration of tracer in plasma and the intercept of the straight line, V, is the volume of distribution in the unbound bone pool ( Figure S2). To allow for equilibration between tracer in plasma and the unbound bone pool in the first 10 minutes after injection, the values of Ki and V are determined by fitting a straight line to the 10-60 minute data (27).
In practice, the assumption that k4 is negligibly small is not strictly valid. where: In this modified analysis the rate constant kloss is varied until the plot of normalized activity against normalized time from 10-60 minutes after injection gives the best fit to a straight line  SUVmean (g/ml), SUVmax (g/ml) and Ki (mL min -1 mL -1 ) at baseline, 8 weeks, percentage change and mean percentage change at 8 weeks in patients with progressive disease (PD) and non-progressive disease (non-PD) PS pain score, BS bone scan, CT computed tomography, ALP alkaline phosphatase, TM tumor marker