Staging and treatment of differentiated thyroid carcinoma with radiolabeled somatostatin analogs

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In patients with progressive metastatic (or recurrent) differentiated thyroid carcinoma that either do not take up radioioidine or are unresponsive to continued radioiodine therapy, staging is difficult and treatment options are few. However, in most of these patients uptake of radiolabeled somatostatin analogs is evident on somatostatin-receptor scintigraphy (SRS). Using SRS, patients with sufficient uptake of radiolabeled somatostatin analogs can be selected for high-dose peptide receptor radionuclide therapy (PRRT) as an alternative targeted-treatment option. PRRT with the β-particle-emitting radionuclides 90yttrium (90Y) and 177lutetium (177Lu) gives the best results in terms of objective tumor response. Promising, novel, radiolabeled somatostatin analogs that have a broader receptor affinity profile and, thus, a potentially wider therapeutic range are being tested clinically.

Introduction

Standard therapy in most patients with non-medullary differentiated (papillary, follicular and Hürthle cell) thyroid carcinoma (DTC) involves either total or near-total thyroidectomy followed by ablation of the thyroid remnant with radioiodine. With a reported overall 10-year-survival rate of 75–95%, DTC is regarded as a malignancy with a relatively good prognosis 1, 2, 3. However, tumors recur in ∼20% of patients 2, 3. Long-term follow-up after initial therapy, which is based primarily on measurements of serum thyroglobulin (Tg, see Glossary) in combination with radioiodine whole-body scans (WBSs), is, therefore, obligatory. Additional treatment with radioiodine can be initiated when recurrence and/or metastases are evident and imaged by WBS. However, radioiodine therapy is no longer an option in the 20–30% of patients who have recurrences and/or persistent metastases caused by dedifferentiation with a lack of radioiodine uptake (non-radioiodine-avid) within the tumors (4–6% of patients diagnosed with DTC) 4, 5.

Patients with dedifferentiated DTC have a worse prognosis, largely because they cannot be treated with radioiodine 2, 5, 6. Therefore, alternative, accurate imaging methods for diagnosis, and therapeutic modalities are of interest. Hürthle cell thyroid carcinoma (HCTC), an uncommon form of thyroid cancer that is usually classified as a variant of follicular thyroid carcinoma (FTC), is of special interest because these carcinomas rarely take up radioiodine, even at the time of diagnosis [7]. In this review, we focus on both the staging and the therapeutic potential of radiolabeled somatostatin analogs in patients with non-radioiodine-avid DTC.

Section snippets

Somatostatin receptor scintigraphy

Over ten years ago, we published the first results of patients with DTC who were imaged by somatostatin receptor scintigraphy (SRS) 8, 9. The potential value of SRS in patients with non-radioiodine-avid DTC was clear because, in some patients, either new or more tumor localizations were detected compared with WBS. Furthermore, in some patients with a negative WBS, SRS showed tumor uptake of the radiolabeled somatostatin analog 111indium-diethylene triamine pentaacetic acid (DTPA) octreotide (111

Novel radiolabeled somatostatin analogs in DTC

Alternative radiolabeled somatostatin analogs are under investigation for SRS 27, 28. Gabriel et al. [29] studied the use of a new radiolabeled somatostatin analog 99mTc-EDDA/HYNIC-TOC [99mTc- labeled hydrazinonicotinyl (HYNIC)-Tyr3-octreotide (TOC) coupled with ethylene diamine diacetic acid (EDDA) as a co-ligand] in 54 patients with thyroid cancer and no radioiodine uptake during WBS. The rationale for conducting this study were the favorable characteristics of 99mTc-EDDA/HYNIC-TOC

Therapy with radiolabeled somatostatin analogs

Despite the differences in sensitivity, and variations in the expression of somatostatin receptor subtypes and uptake during 111In-octreotide scintigraphy, SRS has additional diagnostic value in determining either the extent of metastatic disease or recurrences in DTC. Furthermore, the uptake of 111In-octreotide in tumor sites, imaged by SRS, indicates somatostatin receptors on the tumor-cell surface, which might be a potential therapeutic target for somatostatin analogs such as octreotide in

The future of PRRT in DTC

Most of the radiolabeled somatostatin analogs that are used for diagnostic and therapeutic purposes bind with high affinity to sstr2 and with lower affinity for the other receptor subtypes. In DTC, studies indicate that the expression of the different somatostatin receptor subtypes is more variable than in neuroendocrine GEP tumors in which sstr2 is expressed predominantly. The ongoing development of somatostatin-based radioligands with a broader receptor subtype profile is, therefore, of

Concluding remarks

In patients with recurrent and/or metastatic non-radioiodine-avid DTC, SRS can demonstrate tumor sites in a substantial percentage of patients. Therefore, SRS is useful for imaging and to localize tumor sites in patients in whom disease is suspected because of elevated serum Tg level but who are without apparent uptake during post-radioiodine therapy WBS. Localization with SRS might be helpful in the further management of these patients. The sensitivity of SRS is likely to depend on the tumor

Glossary

CT:
spiral computed tomography
DOTA:
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
DTC:
differentiated thyroid carcinoma
DTPA:
diethylene triamine pentaacetic acid
EDDA:
ethylene diamine diacetic acid
18F-FDG:
18F-fluorodeoxyglucose
FTC:
follicular thyroid carcinoma
HCTC:
Hürthle cell thyroid carcinoma
HYNIC:
hydrazinonicotinyl
LAN:
lanreotide
MRI:
magnetic resonance imaging
NOC:
Nal3-octreotide
PDTC:
poorly differentiated thyroid carcinoma
PRRT:
peptide receptor radionuclide therapy
PTC:
papillary thyroid

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