¹¹¹In-octreotide, [⁹⁰Y-DOTA]-TOC, and [¹⁷⁷Lu-DOTA]-TATE have all been evaluated for treatment of patients with iodine-refractory DTC with varying success (Table 1). Initial studies have shown that somatostatin-based radiopeptide therapy is feasible in iodine-refractory DTC (Chinol et al. 2002). The reported rates of disease control, defined as responses plus stable disease, vary between 20 and 56 % (Valkema et al. 2002; Virgolini et al. 2002; Stokkel et al. 2004a, b). Studies on the follow-up after treatment revealed a time to progression between 9 and 43 months (Gorges et al. 2001; Waldherr et al. 2001a, b; Teunissen et al. 2005). Comparison of these studies, however, is difficult because of differences in radionuclides, somatostatin analogs, and maximum activities administered. Nevertheless, radiolabeled somatostatin analogs appear to be less effective in treating nonradioiodine avid DTC than other NETs such as GEPs.

The largest study to date investigated response, long-term safety profile, and survival after [⁹⁰Y-DOTA]-TOC treatment in 24 patients with progressive metastasized iodine-refractory thyroid cancer (Iten et al. 2009) and a positive pretherapeutic ¹¹¹In-Octreoscan. Response, defined as decreasing thyroglobulin levels after therapy, was found in 7 (29.2 %) patients. However, the visual grade of tumor uptake in the pretherapeutic ¹¹¹In-Octreoscan and multiple regression analyses did not reveal any significant pretherapeutic predictor of treatment response. The median survival was 33.4 months (range, 3.6–126.8 months) from time of diagnosis and 16.8 months (range, 1.8–99.1 months) from time of the first [⁹⁰Y-DOTA]-TOC treatment. Response to treatment was associated with longer survival from time of diagnosis (hazard ratio [HR], 0.17; 95 % confidence interval [CI], 0.03–0.92; P = .04) and from time of first [⁹⁰Y-DOTA]-TOC therapy (HR, 0.20; 95 % CI, 0.04–0.94; P = 0.04) (Fig. 2). Eight (33.3 %) patients developed hematologic toxicity grade 1–3, and 4 (16.7 %) patients developed renal toxicity grade 1–4.

Ten studies including a total of 86 patients with iodine-refractory thyroid cancer reported the results of treatment with ¹¹¹In-octreotide, [⁹⁰Y-DOTA]-TOC, and [¹⁷⁷Lu-DOTA]-TATE (Table 1). While not overwhelmingly positive in terms of response rate, those patients that do respond have prolonged survival compared to nonresponders from time of diagnosis and first [⁹⁰Y-DOTA]-TOC treatment (Fig. 2).

Although therapy with radiolabeled somatostatin analogs is generally well tolerated, there are currently no reliable predictors of response. SRS can aid in the detection of noniodine avid thyroid malignancies in patients where recurrence is suspected, however, no correlation exists so far between uptake on a pretherapeutic ¹¹¹In-Octreoscan and response to therapy with [⁹⁰Y-DOTA]-TOC. The sstr expression profile in DTC is more heterogeneous than in other types of neuroendocrine neoplasms, such as GEP tumors, and the observed discordance between tumor uptake during SRS and tumor response to radiotherapy with somatostatin analogs may in part be due to the relative expression of somatostatin receptor subtypes (sstr_1-5) and their density on the tumor cell surface. For example, uptake on ¹¹¹In-octreotide scintigraphy is considered to be mainly associated with sstr₂ expression, and less with sstr₁, sstr₃, sstr₄, and sstr₅. (John et al. 1996). Thus, there is a need to understand the pathophysiology underlying response and to develop predictive indices that will identify those patients with DTC likely to respond to radiolabeled somatostatin analog therapy.

The higher prevalence of sstr₂ in HCTC provides a more favorable profile of somatostatin receptor subtype expression compared with PTC and FTC, suggesting that this subgroup of DTC patients may be more responsive to therapy with radiolabeled somatostatin analogs. Preliminary evidence supports this (Table 1), although these results including palliation, prolonged stable disease, minor, or partial remission must be considered anecdotal given the small number of patients (Gorges et al. 2001; Christian et al. 2003; Teunissen et al. 2005). However, when conventional treatment is no longer an option and SRS shows sufficient uptake of ¹¹¹In-octreotide, treatment with [⁹⁰Y-DOTA]-TOC and [¹⁷⁷Lu-DOTA]-TATE should be considered in patients with HCTC.

The ongoing development of somatostatin-based radioligands with a broader receptor subtype profile is of interest given the variability in DTC subtype expression (Reubi et al. 2005). The radiolabeled somatostatin analog DOTA-NOC has high affinity for sstr₂, sstr_3, and sstr₅. Preclinical data and preliminary results with ¹¹¹In and ¹⁷⁷Lu-DOTA-NOC for imaging and therapy are especially encouraging (Wild et al. 2003).