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The Natural Thyroid Diet

The Natural Thyroid Diet

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Figure 1.2. Posttherapeutic 131I-WBS 10 days after a treatment dose of 5550 MBq in the same patient with papillary thyroid carcinoma with persistent elevated serum Tg and a negative diagnostic 131I-WBS 3 months after ablative dose of 1850 MBq. This posttherapeutic 1 31I-WBS was also negative, with only normal biodistribution in the gastrointestinal tract and bladder.

Pacini (25) suggest that diagnostic scanning is of low usefulness when the serum Tg-off T4 is undetectable after initial therapy.

Posttherapeutic (diagnostic) scintigraphy

A consensus for optimal dose of 1311 for ablation has not been reached. Some preferred a dosimetric approach by blood and whole-body and quantitative dosimetry to define the ablative dose. The majority use a standard fixed dose, which can range from 1110 MBq to 7400 MBq (30 mCi-200 mCi), depending on tumor characteristics (18,26), because of its simplicity and safety.

The timing of the acquisition of a post-therapy scan can vary widely. The interval varies from 1 day to 10 days after a therapeutic dose. However, shorter time interval allows less time for soft tissue clearance of radioiodine resulting in a relatively higher soft-tissue background which could make foci less visible and difficult to detect (27,28). More lesions are identified on the post-therapy scans than on the diagnostic scans. Carlisle (22) have found a discrepancy of 10% which alter the treatment management in 5% of the cases. These findings were similar with that of Fatourechi (29). The reasons of detecting more disease on the post-treatment scans compared with the diagnostic scans are probably due to the higher therapeutic doses and the longer time delay (22).

Post-therapy scans are most likely to yield important information when the serum Tg is elevated in a patient who is clinically disease-free with negative diagnostic scans or other conventional radiologic imaging (19,30).

Stunning

The timing and the amount of the diagnostic and therapeutic dose are controversial. There has been controversy concerning whether radiation of the diagnostic dose really has a suppressive effect on the uptake of subsequent therapeutic the so-called stunning-effect (31). For extensive review of stunning see chapter 11.

The issue whether stunning is a real phenomenon and its clinical relevance/ consequence is questionable (32). Our retrospective evaluation of 158 patients, who received a high-dose diagnostic scan with 370 MBq (10 mCi) because of a negative low-dose diagnostic scan with 74 MBq (2 mCi) 1311, demonstrates that diagnostic scan with 74 MBq (2 mCi) is sufficient for correct clinical decision making with regards to further radioiodine treatment, when combined with Tg-off measurements. In 98% of the patients a 370 MBq (10 mCi) dose of 131I for diagnostic WBS had no additional value (33).

rhTSH

The yield of scans seems to be slightly lower with rhTSH than following thyroid hormone withdrawal (17), although another study mentioned a similar diagnostic yield (34). scanning it selfprovides complementary information besides the measurement of Tg after withdrawal (24) or after rhTSH (35). For now it is unclear which specific patient group will have benefit of this follow-up policy with rhTSH (20).

The retrospective review of Robbins (35) showed no significant difference in the rate of complete ablation between a group of patients who were prepared with rhTSH or by thyroid hormone withdrawal. Other reports mention the effectiveness of rhTSH in ablative therapy (26,36). However, in the study ofMenzel (37) there is a significant reduction in the effective half-life of 1311 in patients after rhTSH-stimulated TSH before radioiodine therapy compared with patients after endogenous stimulated TSH. Although the use of rhTSH in the follow up patients with thyroid cancer is proposed (38,39) proper prospective data concerning rhTSH applications are still very poor or even lacking (40).

Lithium

Lithium has an inhibitory effect on the release of iodine from the thyroid but does not change the uptake. The mechanism by which lithium inhibits the secretion of thyroid hormone is not well understood. In vitro, lithium decreases the droplet formation of the colloid of thyroid follicular cells, which is a reflection of a decreased pinocytosis of colloid from the follicular lumen (41). The efficiency of proteolytic digestion of thyroglobulin may also be impaired. For this feature lithium may be useful as an adjuvant for therapy of thyroid cancer.

However, there are very few experiences concerning the application of lithium in thyroid cancer. Only in one study was shown, that lithium prolonged the biological and effective half-lives and increased the accumulation of 1311 by 50% in tumors and 90% in thyroid remnants.

Thus, it is in tumors that are less likely to respond to therapy that lithium may be most useful but further experience is required (42).

Retinoic acid

Retinoic acids are biologically active metabolites of vitamin A. They play an important role in the morphogenesis, differentiation and proliferation of many cells (43,44). Retinoic acid has been used for cancer treatment due to their growth and differentiation effects.

Dedifferentiation changes can occurred in differentiated thyroid cancer. This is accompanied by loss of thyroid-specific function and loss of iodide uptake, which makes the therapy with radioiodine inaccessible. It seems that retinoic acids have the potential for redifferentiating therapy in these advanced stage of thyroid cancer (43,44). Nevertheless, the therapeutic effects of isotretinoin in thyroid cancer is so far very disappointing and further controlled clinical trials are required (45).

Sodium iodide symporter (NIS)

The human NIS gene is localized on chromosome 9p12-13.2. NIS is an integral protein of the basolateral membrane of thyroid gland follicular cells. Uptake of iodide from the interstitium into the cell through the NIS-transporter is an active process.

NIS-expression is inversely related to the degree of differentiation of thyroid cancer cells. NIS is more expressed in differentiated thyroid cancer and often negative in less well-differentiated thyroid cancer. Elucidating of the molecular mechanism of NIS expression in thyroid cancer might have the potential in enhancing the diagnostic and therapeutic management since thyroid cancer tissues with NIS expression take up more and subsequent show a high rate of response to radioiodine therapy than those without NIS expression (46,47) (see also chapter 11).

Blind therapy of 1311

After total thyroidectomy and radioiodine ablation, an elevated serum Tg level as well as positive diagnostic radioiodine scanning, are good indicators of the presence of persistent, recurrent or metastatic thyroid cancer (48,49). However, there is a management dilemma in case of negative diagnostic radioiodine scanning and an elevated serum Tg. Negative diagnostic radioiodine scanning may be caused by factors such as an insufficient rise in serum TSH or iodine contamination (50). Another explanation for negative diagnostic scanning is dedifferentation of the tumor leading to a loss of its iodine trapping ability while Tg production is still preserved. Finally, the presence of microscopic metastases that are too small to be visualized with a diagnostic 1311 dose, which can cause false negative scans. Nowadays in patients with negative diagnostic radioiodine scanning, an empirical therapeutic dose between 100-300 mCi 1311, followed by a posttherapy whole-body scan (WBS) is advocated (24,28,38,51,52). The purpose of this approach is twofold. First, posttherapy radioiodine scanning after highdose 1311 treatment is believed to be the most sensitive tool for localizing residual disease not shown by diagnostic scanning with 2-5 mCi 1311 (28,53,54). Thus detected residual disease can be treated with other forms of therapy, such as surgery or radiotherapy. Second, small metastases not seen on diagnostic scanning may accumulate sufficient1311 after high-dose 1311 treatment, leading to a relevant reduction in tumor load. Several studies have shown a drop in serum Tg after high-dose 1311 treatment in patients with negative diagnostic radio-iodide scanning (54,55). Serum Tg remained the same or Tg increased (28,56). Since patient numbers in these studies are small and follow-up data are scarce, it is still unclear whether such high-dose treatment after negative diagnostic radio-iodide scanning is of benefit for the patient. Recently, several reports were published that show no additional effect of high-dose 131I therapy (52,57,58), except for limited cases as lung metastases (52). High-dose 1311 treatment in patients with negative diagnostic 1311 WBS and detectable serum Tg during hypothyroidism can be used as a diagnostic and prognostic tool (59).

18 FLUORODEOXYGLUCOSE (FDG) General mechanism

The glucose analogue FDG is a tracer of glucose metabolism, and enters cells by the same mechanisms both in benign and malignant tissue. However, the energy metabolism of malignant cells is considerably less efficient than the metabolism in their benign counterparts (60). For example anaerobic glycolysis is strongly increased in malignant cells, which is associated with less energy (ATP) production per molecule of glucose as compared to the energy production resulting from the citric acid cycle. Therefore, the need for glucose molecules and FDG is strongly increased in malignancy, which is the basis for the preferential uptake of FDG in malignancy. FDG is intracel-lularly phosphorylated by a hexokinase into FDG-6-phosphate, which is not further metabolized, in contrast with glucose-6-phosphate. In addition, the FDG-6-phosphate cannot leave the cell again, and the compound is therefore trapped intracellulary. The final accumulation of FDG-6-phosphate is proportional to the glycolytic rate of the involved cell. In some tissues however, the level of phosphatase activity may be variable, and FDG accumulation in liver, kidney, intestine, muscle and some tumor cells may be lower. Apart from the increased glycolysis, it has been demonstrated that levels of transmembrane glucose transporters (e.g. the GLUT-1 transporter) and possibly also of some hexokinase isoenzymes are also increased in malignancy and relate to FDG uptake (61,62,63,64). On the one hand, the uptake mechanism of FDG with selective irreversible trapping of the tracer in malignant tissue is ideal for Positron Emission Tomography (PET) imaging, which has generated the increasing clinical application in oncology. On the other hand, it can be understood that FDG uptake does not exclusively occur in malignant tissues, as also benign tissue requires glucose. Especially activated macrophages, as present in infection and inflammation, are known to accumulate much FDG, sometimes to a degree that interferes with oncological image interpretation (65,66).

Scan method

In PET imaging radioactive tracers are used that emit positrons. After positron emission, the positron annihilates with a ubiquitous electron, which causes emission of two 511 KeV photons, precisely under an 180 degree angle. These photons are simultaneously detected by a ring of detectors, which are the main component of the PET camera.

FDG uptake occurs rapidly after administration, and due to the uptake mechanism, the amount of FDG that is taken up in tumor tissue, increases over time. Due to excretion of FDG, which causes clearance of 'background' uptake, and the decay of the radioactivity (Tl/2 = 110 min) the optimal moment for imaging is generally considered to be 60-90 min after tracer administration.

For precise patient preparation and image protocols we refer to dedicated PET papers or books (67). Briefly, patients are generally injected with FDG in a fasting condition and after oral prehydration. The injected dose varies between 2-8MBq/kg. The scan duration for a whole body scan varies largely, but is in general 30-60 min.

Clinical application

Papillary and follicular thyroid carcinoma

FDG PET is not considered to be a useful method in the primary diagnosis of thyroid cancer. Although this issue has not received much study, the uptake of FDG in thyroid cancer in general appears to be low, and image interpretation may suffer from interfering uptake in benign tumors, such as follicular adenoma. In addition, the diagnosis can nearly always be obtained by other diagnostic methods.

Much more data are available to underscore the value of PET in the follow-up of thyroid cancer patients, such as to detect recurrences or metastases, especially in cases where metastases do not trap radioiodine. Interestingly, there appears to be a complementary uptake of FDG and radioiodine, which has been termed the 'flipflop' phenomen. This means that some metastases within the same patient that do not trap radioiodine may accumulate FDG, and metastases that do not trap FDG, accumulate radioiodine. Some lesions accumulate both tracers. This observation was first described by Joensuu (68). It might be explained by the different degree of tissue differentiation. Well-differentiated thyroid cancer tissue has retained its iodine trapping capabilities, but is metabolically inactive, causing uptake of radioiodine and no or minimal FDG accumulation. Less differentiated thyroid cancer tissue, as may develop during treatment, loses its iodine trapping capability and becomes metabolically more active. This results in FDG positivity and iodine negativity. For this reason, most PET research has focussed on detection of thyroid cancer metastases in radioiodine negative patients with increased thyroglobulin levels, which currently seems to be the best clinical application.

In a recent meta-analysis the value of FDG PET in papillary and follicular thyroid cancer both in patients with negative radioiodine scans and in patients with known neoplastic foci was determined (69). They selected 14 studies that met quality criteria as described by the Cochrane Methods Group on Screening and Diagnostic Tests. Although general evidence levels appeared to be low, precluding quantitative summary, all these studies claimed a positive role for PET, especially in the group of patients with negative radioiodine scans. Sensitivity for finding tumor locations of PET varied between 70 and 95%, and specificity was between 77 and 100%. Considerable heterogeneity existed, however, in the pre-PET data risk profile, such as patient selection criteria concerning variations in TNM stage, Tg levels, radioactive radioiodine dose and levels of TSH. Although troubled by severe methodological problems, the performance of FDG PET appeared to be superior to 99mTc-Sestamibi or Tc99m-furifosmin, and probably Tl-201 scintigraphy. Also the impact on overall clinical outcome of PET was difficult to assess, but, due to the general slow disease progression, that may be true for many diagnostic studies in thyroid cancer.

A frequently observed issue whether PET should be performed during the hypothy-roid state (e.g. after thyroid hormone withdrawal) or in euthyroid state (during thyroxine treatment). In a study van Tol (70) better performance of PET in hypothyroid state was found, but the issue is not clearly settled.

Furthermore, it has been hypothesized that exogenous TSH stimulation with rhTSH increases FDG uptake by differentiated thyroid cancer and seems apparently more accurate than FDG-PET under suppression, in terms of number of detected lesions and tumor/background contrast (71). In a small study this hypothesis has been confirmed (18).

Medullary thyroid cancer

Nearly all imaging modalities (Ultrasonography, CT, MRI, scintigraphy using In-111-octreotide, Tc99m-DMSA-V, MIBG) have limited sensitivities (40-70%) compared to the apparently very high sensitivity of the calcitonin tumor marker (72). Although the clinical course ofmetastatic medullary thyroid cancer can be mild in some patients, others develop clinically relevant metastases (in liver, bone, lungs) that remain undetected until a relatively late stage. Earlier detection of metastases during follow up after primary treatment might therefore have relevant therapeutic implications. Results of FDG PET studies in MTC demonstrate slightly better performance (sensitivity around 75%—specificity 79%) as compared to other imaging modalities, but patient selection probably influences these results (73,74).

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