Justificación moral del castigo

Abdo Aorta

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Time (secs)

Figure 7.5 Image derived and blood sanq>ling derived activity concentration plotted against time fo r FLT-PET in human subject

7.5

Discussion

Development o f PET as an imaging modality relies on increasing the understanding of currently used tracers in parallel with the development of novel agents. FDG is widely used in oncological imaging and has consistently been shown to be sensitive and specific for a variety of solid tumours [Bomanji JB et al., 2001] including CRC [Huebner et al., 2000]. The information that is obtained from FDG-PET relates to the differential consumption o f glucose between normal and mahgnant tissue. The model for FDG-PET as described in the introduction (chapter 1.3) is widely accepted, but is an oversimplification of the complex metabolism o f glucose. In addition, there are other factors that have an important bearing on FDG uptake and these include tissue oxygenation and glucose utilisation, regional blood flow and the inflammatory reaction surrounding the tumour [Clavo and Wahl, 1996;Lindholm et al., 1993;Yao et al., 1995].

The fact that inflammatory lesions take up FDG may often lead to misinterpretation of FDG-PET scans as has already been described [Kubota et al., 1992;Yamada et al.,

1998;Lindholm et al., 1993]. This is confirmed by the results presented in chapter five o f this thesis, which demonstrates that the signal recorded from FDG may be a

composite area and interfere with the specificity of FDG-PET for malignant tissue [Yao et al., 1995]. In this study, which compared FDG-PET with CT for detecting recurrence there were difficulties in differentiating tumour from active inflammation in the pelvis. This is because the FDG uptake reflects the metabohc activity of a tissue [Strauss et al., 1989] and in areas of active inflammation we know that activated macrophages will be present. These cells avidly consume glucose [Delbeke et al.,

1997;Schlag et al., 1989;Strauss et al., 1989]. All the studies undertaken as part o f this thesis demonstrate extremely high sensitivity for malignant tissue, but specificity is disqjpointing. Although, the specificity for the studies recorded here are lower than most others published [Huebner et al., 2000] it is an aspect o f this technique that needs to be addressed.

Simple measures, such as increasing the experience o f the reporting physician may have improve matters. This is difficult to control for, as all PET centres will go through a learning curve phase. In this chapter I have adopted a different approach by examining a new tracer, FLT.

Shields and colleagues have extensive experience with FLT and have published data on studies o f one human subject with a non-small cell carcinoma of the lung and canine tumour models [Shields et al., 1998]. There is no data that demonstrates any relationship that derived SUVs will have to actual tracer dynamics. This suggests that the SUVs one derives may not relate in any meaningful way to the actual tracer metabolism in the tumour. The use of blood sampling does allow characterisation of the tracer uptake in particular tumours. I have demonstrated the relationship between SUV for FLT and FDG and this appears to be a fair reflection o f tracer uptake.

Sheilds’ paper sets out time activity curves for FLT in bone marrow with acquisitions up to 60 minutes. From the graphical data presented it appears that FLT uptake is still rising at 60 minutes. This suggests that the washout phase has not begun (ie

equilibrium has not been reached). This washout phase will most certainly vary between different normal tissues and tumours. In humans with CRC I have demonstrated that the optimum timing for scanning is 20 minutes p.i. The use of arterial and venous blood sampling was an essential component of this study. It is equally important to demonstrate and characterise possible metabolites in the blood contributing to the radioactivity signal. There appears to be a significant amount of parent compound at both 30 and 90 minutes.

Another important observation in Shields’ paper is the high uptake of FLT in the liver (7.6 at 64 minutes). There may be significant limitations for the use of FLT in treatment monitoring o f CRC. Upto 50% o f CRC patients develop hepatic métastasés. One o f the areas that needed to be clarified is whether delayed imaging may result in high tumour to normal liver contrast. It is possible to use FLT-PET for liver imaging in patients with CRC. This study does demonstrate that the differential uptake of tracer is most marked for FDG. FDG has an approximately 3-fold increase in uptake compared to FLT. This does suggest that FDG may be a more accurate tracer for detecting CLM.

The recent interest in FLT can be gauged by analysing FLT related abstracts in the Proceedings of the 48^ Annual Meeting of the Society of Nuclear Medicine (Toronto, June, 2001). There are several pertinent abstracts, none o f which answer questions

that would allow a non-invasive methodology to be developed. In fact, there appears to be a need for characterisation of FLT dynamics in CRC tissue.

Vesselle and colleagues [Vesselle et al., 2001] describe a methodology for NSCLC using Patlak analysis. This was more accurate than SUV analysis for correlation with cell proliferation rate as assessed immunohistochemically with Ki-67. Dohmen [Dohmen et al., 2001b] describes studies o f FLT in breast cancer with blood sampling to measure clearance and metabolites. There is a suggestion for optimal timing o f imaging, but this may be quite different for CRC. The same group [Shields et al., 2001] also looked at FLT-PET imaging in a variety o f gastrointestinal tumours including the colon. SUV’s varied between 1.5 and 13 in colon cancer patients, which suggests SUV’s will be difficult to interpret without correlation to blood

measurements o f FLT. Also uptake in the liver was significant, raising the question whether late imaging o f the liver may be the optimal means of demonstrating

métastasés. However, there were no timings mentioned. This is o f particular relevance for a subpopulation of patients we intend to study. Dohmen et al [Dohmen et al., 2001a] indicates that there are no FLT metabolites and there is a suggestion that equilibrium is reached at 60 minutes or so. This investigation, however, has not been carried out on CRC.

The published data suggests that invasive monitoring o f arterial and venous blood is necessary. It is however, possible to derive a non-invasive input function using the thoracic aorta or heart. The difficulty with this technique is that simultaneous imaging of a distant site, for example a rectal tumour in the pelvis, and obtaining data from the chest is not possible with current PET technology. In the case of imaging CRC metastasis in close proximity to the heart, the dynamic data collected can be used to validate the use of data collection from the heart to derive an arterial input function.

In conclusion, this preliminary study with FLT in CRC shows that it can be used as a clinical PET tracer but there are limitations when compared to FDG. The tracer has a much lower uptake compared to FDG and proliferating tissues such as bone marrow show confounding uptake. This study does show that non-invasive input function for FLT can be derived and that SUV’s can be related to actual tracer uptake. This study contributes to the knowledge of biological characterisation of FLT dynamics in patients with CRC.

CHAPTER 8