Differentiated Thyroid Cancer: A New Perspective with Radiolabeled Somatostatin Analogues for Imaging and Treatment of Patients

Abstract

Background:

The expression of somatostatin receptors (SSTR) in thyroid cells may offer the possibility to identify metastatic lesions and to select patients for peptide receptor radionuclide therapy (PRRT). We investigated ⁶⁸Ga-DOTATOC positron emission tomography/computed tomography (PET/CT) to select patients with progressive differentiated thyroid cancer (DTC) for PRRT as well as treatment response and toxicity in treated patients.

Methods:

We enrolled 41 patients with progressive radioiodine-negative DTC (24 women and 17 men; mean age=54.3 years, median=59 years, range=19–78 years). In all patients, [¹⁸F]FDG-PET/CT was performed to determine recurrent disease with enhanced glucose metabolism, and ⁶⁸Ga-DOTATOC PET/CT was used to identify SSTR expression. Dosimetric evaluation was performed with ¹¹¹In-DOTATOC scintigraphy. Eleven patients were treated with PRRT receiving a fractionated injection of 1.5–3.7 GBq ⁹⁰Y-DOTATOC/administration. Serial ⁶⁸Ga-DOTATOC PET/CT scans were performed in all treated patients to evaluate treatment response. Parameters provided by ⁶⁸Ga-DOTATOC PET/CT were analyzed as potential therapeutic predictors to differentiate responding from nonresponding. In all treated patients, adverse events and toxicity were recorded.

Results:

⁶⁸Ga-DOTATOC PET/CT were positive in 24/41 of radioiodine-negative DTC patients. Based on the high expression of SSTR detected by ⁶⁸Ga-DOTATOC PET/CT, 13 patients were suitable for PRRT. Two out of 13 patients were not treated due to the lack of fulfillment of other study inclusion criteria. PRRT induced disease control in 7/11 patients (two partial response and five stabilization) with a duration of response of 3.5–11.5 months. Objective response was associated with symptoms relief. Functional volume (FV) over time obtained by PET/CT was the only parameter demonstrating a significant difference between lesions responding and nonresponding to PRRT (p=0.001). Main PRRT adverse events were nausea, asthenia, and transient hematologic toxicity. One patient experienced permanent renal toxicity.

Conclusions:

In our series, SSTR imaging provided positive results in more than half of the cases with radioiodine-negative DTC, and about one third of patients were eligible for PRRT. ⁶⁸Ga-DOTATOC PET/CT seems a reliable tool both for patient selection and evaluation of treatment response. In our experience, FV determination over time seems to represent a reliable parameter to determine tumor response to PRRT, although further investigations are needed to better define its role.

Introduction

The loss of radioiodine (¹³¹I) uptake by thyroid cancer cells poses a major obstacle in both detection and quantification of metastatic disease. In addition, when radioiodine treatment is not effective, disease control becomes more difficult (1,2).

In recent decades, the re-induction of ¹³¹I transport, organification, and retention by thyroid cancer cells have been attempted with controversial results (3 –8). More recently, several biological agents (e.g., inhibitors of RET and MEK) have been evaluated in clinical trials in iodine-refractory patients with progressive disease (9 –12).

Previous studies have described the visualization of metastases from follicular cell-derived thyroid cancer by somatostatin receptor (SSTR) scintigraphy (13), in agreement with the in vitro demonstration of specific SSTR in thyroid cells (14 –16). Based on these premises, peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues, originally introduced for neuroendocrine tumors (NETs) (17), has also been proposed as a therapeutic tool in patients with advanced thyroid cancer (18 –21). A preliminary experience with [⁹⁰Y]-DOTA⁰-Tyr³-octreotide (⁹⁰Y-DOTATOC) PPRT in patients with iodine-refractory thyroid cancer has provided encouraging results (22,23).

We present our experience with ⁹⁰Y-DOTATOC PRRT in a series of patients with progressive radioiodine-negative differentiated thyroid cancer (DTC), selected on the basis of ⁶⁸Ga-DOTATOC positron emission tomography/computed tomography (PET/CT) imaging.

Materials and Methods

Study design

This was a prospective nonrandomized single-arm clinical trial performed at the Nuclear Medicine Unit of Arcispedale Santa Maria Nuova—IRCCS, Reggio Emilia, Italy. The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, the Declaration of Helsinki, and it was approved by Local and National Authorities (EudraCT numbers 2006-000897-65 and 2008-000983-17). All patients gave written informed consent.

Patients

We enrolled 41 consecutive patients (24 women and 17 men; mean age=54.3 years, median age=59 years, range=19–78 years) with progressive radioiodine-negative DTC. Radioiodine-negative progressive DTC was determined according to the American Thyroid Association guidelines (24) as follows: (i) negative ¹³¹I whole-body scan; (ii) thyroglobulin (TG) level either >0.5 ng/mL (n=36) or <0.5 ng/mL in the presence of positive anti-TG antibodies (n=5) during thyrotropin (TSH) stimulation; and (iii) positive cervical ultrasonography (n=12), contrast-enhanced CT (n=28) and 2-deoxy-2-F(18)-fluoro-D-glucose ([¹⁸F]FDG) PET/CT (n=34). Sites of recurrent disease are specified in Tables 1 and 2. Thyroid cancer histology was as follows: papillary thyroid carcinoma (PTC; n=31; tall cells variant n=4); follicular thyroid carcinoma (FTC; n=4); insular thyroid carcinoma (n=4); and Hürthle cell carcinoma (HTC; n=2). All patients had previously received between one and five cycles of ¹³¹I (3.7–41 GBq).

Table 1.

Main Baseline Features of the Patients with Differentiated Thyroid Cancer Treated with Peptide Receptor Radionuclide Therapy

										Disease at enrollment
Pt	Sex	Age	PS (ECOG)	Histology	N,M	Surgery	Total cumulative ¹³¹I (GBq)	Time (months) between 1st and last ¹³¹I	Time (months) to relapse	Site(s)	Imaging modality used to assess PD	Serum TG (ng/mL)
#1	F	59	2	PTC	N1,M0	TT+LND/CND	12.95	11	24	LNs, lung, bone	US, CT, [¹⁸F]FDG-PET/CT	100
#2	M	45	0	PTC	N0,M0	TT+LND	10.36	65	132	Lung	CT, [¹⁸F]FDG-PET/CT	44
#3	F	66	0	FTC	N0,M0	TT+LND	7.4	34	36	Lung	CT, [¹⁸F]FDG-PET/CT	300
#4	M	65	1	Oxyphilic	N1,M1	TT+LND/CND	33.3	29	84	Bone	[¹⁸F]FDG-PET/CT	500
#5	F	69	0	PTC	N0,M0	TT+LND	25.9	80	132	LNs, lung	US, CT, [¹⁸F]FDG-PET/CT	4400
#6	F	60	2	Insular	N1,M0	TT+LND/CND	5.55	N/A	6	Bone	[¹⁸F]FDG-PET/CT	6000
#7	F	55	0	PTC	N1,M1	TT+LND/CND	5.55	N/A	8	LNs, lung, bone	US, CT, [¹⁸F]FDG-PET/CT	670
#8	F	48	1	Insular	N0,M0	TT+LND	10.51	32	36	Bone	[¹⁸F]FDG-PET/CT	7
#9	M	49	0	FTC	N0,M0	TT+LND	16.65	72	12	Bone	CT, [¹⁸F]FDG-PET/CT	84
#10	M	67	1	PTC	N0,M1	TT+LND/CND	14.8	15	24	Bone	[¹⁸F]FDG-PET/CT	30,000
#11	M	43	0	FTC	N0,M0	TT+LND	18.5	36	36	Bone, liver	CT, [¹⁸F]FDG-PET/CT	340

PS, performance status; ECOG, Eastern Cooperative Oncology Group; N,M, Node and Metastases classifications according to AJCC/UICC TNM 7th edition (64); PD, progressive disease; TG, thyroglobulin; PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; TT, total thyroidectomy; LND, lateral neck lymph node dissection; CND, central neck lymph-node dissection; LNs, lymph nodes; US, ultrasonography; CT, computed tomography; [¹⁸F]FDG-PET/CT=2-deoxy-2-F(18)-fluoro-D-glucose positron emission tomography combined with computed tomography.

Table 2.

Main Baseline Features of the Patients with Differentiated Thyroid Cancer Enrolled in the Study but Not Treated with Peptide Receptor Radionuclide Therapy

									Disease at enrollment
Pt	Sex	Age	Histology	N,M	Surgery	Total cumulative ¹³¹I (GBq)	Time (months) between 1st and last ¹³¹I	Time (months) to relapse	Site(s)	Imaging modality used to assess PD	Serum TG (ng/mL)
#12	F	59	PTC	N0,M0	TT+LND	18.87	80	92	LNs, adrenal	US, CT, [¹⁸F]FDG-PET/CT	90
#13	F	54	FTC	N1,M1	TT+LND/CND	14.8	14	N/A	LNs, lung, bone	US, CT, [¹⁸F]FDG-PET/CT	1500
#14	M	65	Oxyphilic	N0,M0	TT+LND	5.55	N/A	120	Lung, bone	CT, [¹⁸F]FDG-PET/CT	0.3^a
#15	F	47	Insular	N1,M1	TT+LND/CND	5.55	N/A	N/A	LNs, lung	CT, [¹⁸F]FDG-PET/CT	10
#16	F	61	Insular	N0,M0	TT+LND/CND	3.7	N/A	10	Thyroid bed, lung	US, CT, [¹⁸F]FDG-PET/CT	0.5^a
#17	M	59	PTC	N1,M1	TT+LND/CND	9.25	14	N/A	Thyroid bed, LNs, lung	US, CT, [¹⁸F]FDG-PET/CT	4.9
#18	M	65	PTC	N1,M0	TT+LND/CND	12.95	41	47	LNs, lung	CT, [¹⁸F]FDG-PET/CT	15
#19	M	19	PTC	N1,M0	TT+LND	7.4	N/A	30	LNs	US, CT, [¹⁸F]FDG-PET/CT	28
#20	F	59	PTC	N0,M0	TT+LND/CND	5.55	N/A	9	LNs, lung, bone	US, CT, [¹⁸F]FDG-PET/CT	57
#21	M	44	PTC	N0,M0	TT+LND	7.4	N/A	168	Lung	CT, [¹⁸F]FDG-PET/CT	32
#22	M	78	PTC	N1,M1	TT+LND/CND	7.4	N/A	N/A	LNs, lung	US, CT, [¹⁸F]FDG-PET/CT	94
#23	F	57	PTC	N1,M1	TT+LND/CND	14.8	50	N/A	LNs, CNS	CT [¹⁸F]FDG-PET/CT	1.3
#24	M	70	PTC	N0,M0	TT+LND	5.55	N/A	52	Lung	CT, [¹⁸F]FDG-PET/CT	0.3^a
#25	F	20	PTC	N0,M0	TT+LND	40.7	5	41	LNs	[¹⁸F]FDG-PET/CT	8
#26	M	29	PTC	N1,M0	TT+LND/CND	33.3	63	45	Unknown	[¹⁸F]FDG-PET/CT	100
#27	F	31	PTC	N1,M1	TT+LND/CND	11.1	81	N/A	LNs	[¹⁸F]FDG-PET/CT	8
#28	F	47	PTC	N0,M0	TT+LND	5.55	N/A	15	Unknown	[¹⁸F]FDG-PET/CT	5
#29	F	36	PTC	N1,M0	TT+LND/CND	20.35	26	30	LNs, bone	CT, [¹⁸F]FDG-PET/CT	11
#30	F	56	PTC	N1,M0	TT+LND/CND	11.1	166	129	LNs	US, CT, [¹⁸F]FDG-PET/CT	50
#31	M	68	PTC	N1,M0	TT+LND/CND	11.1	13	78	Unknown	[¹⁸F]FDG-PET/CT	15.3
#32	F	52	PTC	N0,M0	TT+LND	5.55	72	147	Unknown	[¹⁸F]FDG-PET/CT	139
#33	F	35	PTC	N0,M0	TT+LND	40.7	N/A	4	Unknown	[¹⁸F]FDG-PET/CT	180
#34	F	53	PTC	N1,M0	TT+LND/CND	12.95	62	65	Lung, liver	CT, [¹⁸F]FDG- PET/CT	0.3^a
#35	M	60	PTC	N1,M0	TT+LND/CND	11.1	72	75	LNs	[¹⁸F]FDG-PET/CT	12
#36	M	60	PTC	N0,M0	TT+LND	12.9	23	31	Unknown	[¹⁸F]FDG-PET/CT	7
#37	M	59	PTC	N1,M0	TT+LND/CND	12.95	115	140	Lung, bone	CT, [¹⁸F]FDG-PET/CT	20
#38	F	69	PTC	N1,M0	TT+LND/CND	5.55	N/A	58	Lung	CT, [¹⁸F]FDG PET/CT	29.8
#39	F	63	PTC	N1,M0	TT+LND/CND	14.8	75	81	LNs, lung	CT, [¹⁸F]FDG-PET/CT	3
#40	F	54	PTC	N1,M0	TT+LND/CND	15.91	12	15	Lung	CT, [¹⁸F]FDG-PET/CT	0.3^a
#41	F	70	PTC	N0,M0	TT+LND	22.2	50	51	Lung	CT, [¹⁸F]FDG-PET/CT	27

Positive TGAb.

CNS, central nervous system; TGAb, anti-thyroglobulin antibodies.

Baseline patients' characteristics and previous treatments are detailed in Table 1 for each patient.

⁶⁸Ga-DOTATOC PET/CT was performed in all patients to determine eligibility to PRRT. Patients having high expression of SSTR at ⁶⁸Ga-DOTATOC PET/CT, an adequate hematological profile, and normal creatinine levels were admitted to PRRT. In all patients admitted to PRRT, a dosimetric evaluation with ¹¹¹In-DOTATOC scintigraphy was also performed.

Radiopharmaceutical preparation

⁶⁸Ga-DOTATOC (used for PET/CT), ¹¹¹In-DOTATOC (used for dosimetry), and ⁹⁰Y-DOTATOC (used for PRRT) were synthesized as previously reported (25,26). Radiochemical purity was assessed by chromatographic methods of the preparations resulted always in >95% and 99.8% for ⁶⁸Ga-DOTATOC and ¹¹¹In-/⁹⁰Y-DOTATOC respectively.

PET/CT imaging

PET/CT scans were acquired on a GE Discovery STE™ (GE Healthcare Milwaukee, WI) 45–60 minutes after the injection of ⁶⁸Ga-DOTATOC (2 MBq/kg) or [¹⁸F]FDG (4 MBq/kg). Bed positions (7 –9) with seven-slice overlap were acquired for 4–5 minutes emission time in 3D. The CT exposure factors for all examinations were 120 kVp and 80 mA in 0.8 seconds. PET images were reconstructed using a full 3D ML-OSEM algorithm. Studies were visually and semi-quantitatively assessed.

Standardized uptake value (SUV) calculations were performed on an Advantage Workstation™ (GE Healthcare). Mean and maximum SUV (corrected for patient weight and total injected activity) were recorded in all lesions.

Baseline PET/CT imaging interpretation

⁶⁸Ga-DOTATOC PET/CT results were compared to [¹⁸F]FDG-PET/CT findings. The intensity of uptake in the tumor site was visually and semi-quantitatively assessed using the corresponding surrounding normal tissue as reference standard by a panel of two board-certified, nuclear-medicine physicians blinded to the patients' characteristics. Lesions were scored as 0 when no uptake was observed, 1+ when uptake was fainter than the surrounding normal tissue, 2+ in the presence of uptake similar to the surrounding normal tissue, and 3+ when showing uptake higher than the surrounding normal tissue.

Dosimetry

Dosimetric estimates were determined after the intravenous injection of 185 MBq of ¹¹¹In-DOTATOC with a dual-head gamma camera (Genesys^®, Philips, Amsterdam, The Netherlands, or Symbia-T^®, Siemens, Munich, Germany) using parallel-hole, medium-energy, general-purpose collimators with window photon peaks centered over 247 and 172 keV (window width of 20%), as previously described by Filice et al. (25). Briefly, whole-body scans were performed at 1, 4–6, 20–24, 48, and 72 hours after radiopharmaceutical administration. Blood clearance was determined using blood samples drawn at 30 and 60 minutes, and at 4, 20, and 48 hours after radiopharmaceutical injection. Doses delivered to the tumor lesion and critical organs were obtained using OLINDA/EXM software (27). The dose to the red marrow was calculated from the residence time in blood, assuming no specific uptake, a uniform distribution of activity, and clearance from red marrow equal to that from blood. A correction factor of 1 was used, as described by Cremonesi et al. (28).

Selection of patients eligible for PRRT

Patients fulfilling the following inclusion criteria were admitted to PRRT: (i) adequate laboratory tests (hemoglobin level ≥10 g/dL; leucocytes ≥2.5×10³ per mL; platelets ≥100×10³ per mL; bilirubin levels <2.5 mg/dL; creatinine levels <2 mg/dL); (ii) high expression of SSTR on ⁶⁸Ga-DOTATOC-PET/CT defined as a score 3+ in tumor lesions; (iii) adequate dosimetric estimates to tumor, kidney, liver, red marrow, lung and whole-body; and (iv) exclusion of pregnancy or lactation.

Peptide receptor radionuclide therapy

Repeated administrations of 1.5–3.7 GBq ⁹⁰Y-DOTATOC per cycle were intravenously injected with a time interval between cycles of 6–12 weeks (17). However, in case of toxicity, treatment was delayed until recovery of the normal organ function. For each administration, patients were hospitalized in a shielded environment for 3 days in accordance with local requirements.

As recommended (17), to counteract and reduce the high kidney retention of radiopeptides, an aminoacid infusion was co-administered with PRRT and continued over 2 days following radiopeptide administration. The renal protection was performed as follows: during the first day, mixed commercially available aminoacid infusion was used (1.5 L Proteinsteril Hepa 8% containing 10.72 g l-arginine and 6.88 g l-lysine per liter together with other essential and nonessential aminoacids, were brought to 1.8 L by addition of 300 mL lactate Ringer solution starting 30–60 minutes before the PRRT) during 4 hours. The total l-arginine+l-lysine amount was 26.4 g. The second and third day after PRRT administration, an infusion of 12.5 g lysine in 500 mL of normal saline was administered over 3 hours twice a day (17,29).

None of the patients had been treated with long- or short-acting somatostatin analogs during the previous six and three weeks before receiving PRRT respectively. Repeated administrations were withheld in case of renal toxicity, loss of patient consensus, or denial of further treatment at least three months apart, as well as in case of progressive disease. Thyroxine was administered on a daily basis and continued during PRRT treatment in order to maintain absolute thyrotropin suppression.

Patients' follow-up

Vital signs were monitored before and for 72 hours after each therapeutic radiopharmaceutical infusion. Hematologic parameters and creatinine levels were measured before each cycle and at biweekly intervals until 12 weeks after the last PRRT administration. Then, patients were followed monthly for nine months. All toxicities were recorded. Acute and long-term adverse events were graded according to the Common Terminology Criteria for Adverse Events v3.0 (30).

TG measurements were performed every six months during treatment and were repeated three months after the end of PRRT.

Serial follow-up ⁶⁸Ga-DOTATOC PET/CT studies were repeated after each PRRT administration (one to two weeks before the next administration, and three months after the end of treatment). Areas of radiopharmaceutical uptake in baseline and follow-up studies were compared. The low-dose CT images co-registered with the ⁶⁸Ga-DOTATOC PET imaging were used to evaluate treatment response according to the Response Evaluation Criteria in Solid Tumors (RECIST) (31). In the presence of stable disease (SD) or partial response (PR), a confirmatory scan was performed four weeks after the initial response assessment. Additional standard radiological examinations were performed when needed. Further, the PET-VCAR™ application (GE Healthcare) was used to analyze tumor response considering the functional volume (FV) and functional volume change (ΔFV%) (32). Since RECIST criteria are not appropriate to assess bone lesion responses, we used FV changes over time for such determination.

We also calculated the SUV of each lesion and derived lesion response according to European Organization for Research and Treatment of Cancer (EORTC) criteria; SUV relative to the maximal splenic uptake by dividing the SUV_max of the tumors by the SUV_max of the spleen (SUV_T/S), since this parameter has been proven to be superior to ΔSUV_max in predicting time to progression; and clinical outcome (33). Additionally, we calculated SUV of each lesion relative to the maximal liver uptake (SUV_T/L) and to the muscle (SUV_T/M). Results with both RECIST and PET-derived parameters were compared to clinical benefit and outcome.

Treatment endpoints

Primary endpoints were treatment response and toxicity of PRRT. The overall response rate was defined as the number of participants who showed a response to treatment divided by the total number of participants.

Statistical analysis

Statistical analyses were performed using the SPSS v15 (SPSS Inc., Chicago, IL) software package.

Multiple regression analysis of all the potential predictors of ⁶⁸Ga-DOTATOC PET/CT positivity and clinical response to PRRT was performed using Backward Stepwise method. The following variables were analyzed: age, sex, histopathology, disease stage at diagnosis, disease duration, time to recurrence after primary treatment, serum TG levels, ¹³¹I cycles and cumulative ¹³¹I activity previously received, number and sites of metastasis, and performance status (PS). Additionally, median SUV_max in the most ⁶⁸Ga-DOTATOC avid lesions and provisional absorbed dose in the target lesions were analyzed as potential predictors of ⁶⁸Ga-DOTATOC PET/CT positivity. Pearson coefficients were calculated for the correlations between the SUV values and FV determinations. Kruskal–Wallis and Spearman correlation were used to measure differences in these scores and their correlation with clinical improvement and lesion response to therapy. An uncorrected p-value of <0.05 was assumed to be statistically significant. Sensitivity analyses were performed in the subsets of responders and nonresponders to PRRT for response and toxicity.

Results

Baseline ⁶⁸Ga-DOTATOC PET/CT demonstrated at least one site of radiopharmaceutical uptake in 24/41 (58.5%) patients. In 17/41 patients, ⁶⁸Ga-DOTATOC PET/CT was completely negative, while [¹⁸F]FDG-PET/CT was completely negative in 7/41 cases. Only one patient presented a ⁶⁸Ga-DOTATOC PET/CT positive lesion with a negative [¹⁸F]FDG-PET/CT. [¹⁸F]FDG and ⁶⁸Ga-DOTATOC uptake were similar in 6/23 cases, while a predominant [¹⁸F]FDG or ⁶⁸Ga-DOTATOC uptake was present in 11/23 and 7/23 patients respectively. Figure 1 shows different patterns of uptake on ⁶⁸Ga-DOTATOC PET/CT and [¹⁸F]FDG-PET/CT.

FIG. 1.

Examples of different pattern of uptake of [¹⁸F]FDG (left columns) and ⁶⁸Ga-DOTATOC (right columns) on positron emission tomography combined with computed tomography (PET/CT; PET emission on left panels, and fused PET/CT images on right panels). Subpleural and lymph-node lesions (a) demonstrated similar intensity and extension of both radiopharmaceuticals. Left lung and lymph-node metastatic lesions (b) demonstrated higher ⁶⁸Ga-DOTATOC uptake as compared to [¹⁸F]FDG. (c) and (d) showed intense [¹⁸F]FDG uptake in metastatic lesions of the upper right lung and the lower left lung respectively without significant ⁶⁸Ga-DOTATOC accumulation on corresponding images.

At multivariate analysis, none of the variables considered was associated with ⁶⁸Ga-DOTATOC PET/CT positivity. All patients with negative ⁶⁸Ga-DOTATOC PET/CT imaging had a papillary histology (n=17/31). Metastatic sites of disease (i.e., lymph nodes, lungs, bones) were apparently not related to either a [¹⁸F]FDG or ⁶⁸Ga-DOTATOC preferential uptake. Thirteen patients presented a score of 3+ in tumor lesions on ⁶⁸Ga-DOTATOC PET/CT and hence were suitable for PRRT. However, due to the lack of fulfillment of the other inclusion criteria, only 11 patients were treated with PRRT. Sites of disease for each treated patient are specified in Table 3.

Table 3.

Site of Metastatic Disease Detected by ⁶⁸ Ga-DOTATOC Positron Emission Tomography/Computed Tomography Detailed for Each Treated Patient; ⁹⁰ Y-DOTATOC Administration Data and Treatment Response in Patients Treated with Peptide Receptor Radionuclide Therapy

Pt	Site of disease according to ⁶⁸Ga-DOTATOC	Administrations of ⁹⁰Y-DOTATOC (n)	Days between PRRT administration	Total cumulative activity ⁹⁰Y-DOTATOC (GBq)	Best response (RECIST)	Duration (months)
#1	Lung, bone	2	91	4.329	PD	N/A
#2	Thyroid bed, LNs, lung	4	56; 45; 63	14.911	PR	8
#3	Thyroid bed, LNs, lung	4	91; 84; 70	11.729	SD	7
#4	Thyroid bed, LNs, lung, bone	6	126; 92; 90; 91; 112	12.987	SD	11.5
#5	LNs, lung, bone	3	70; 56	11.050	PR	7.5
#6	Bone	6	126; 92; 90; 91; 140	12.765	PD	N/A
#7	Thyroid bed, LNs, bone	4	63; 63; 56	14.870	SD	3.5
#8	Bone	5	61; 70; 49; 39	14.393	N/A	N/A
#9	LNs, lung, bone	5	63; 63; 77; 56	17.950	SD	8
#10	Bone	3	63; 63	11.170	PD	N/A
#11	Liver, bone	4	56; 42; 70	14.689	PD	N/A

DOTATOC, DOTA⁰-Tyr³-octreotide; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.

Patient specific dosimetry allowed the provision of organ-specific radiation absorbed doses and the estimation of the risk of delayed organ toxicity (Table 4).

Table 4.

Dosimetric Estimates Obtained by ¹¹¹ In-DOTATOC Scintigraphy for All Patients Admitted to Peptide Receptor Radionuclide Therapy

(mGy/MBq)	Tumor	Kidney	Liver	Spleen	Lung	Heart	Bone marrow	Total body
Mean	7.28	6.084	1.25	12.06	1.504	0.24	0.08	0.22
Median	2.20	6.56	1.03	9.25	0.44	0.20	0.07	0.21
Range	0.78–32.80	2.19–9.71	0.50–2.35	4.33–29.20	0.04–8.43	0.08–0.52	0.01–0.18	0.10–0.41
Standard deviation	12.56	2.33	0.59	8.24	3.06	0.15	0.05	0.11

A total of 44 administrations of ⁹⁰Y-DOTATOC (2–6 administrations/patient) at 70±24.6 days apart (range=45–140 days) were injected with a median cumulative activity of 3.5 GBq (range=1.5–3.7 GBq).

A total of 28 ⁶⁸Ga-DOTATOC PET/CT scans were performed in patients undergoing PRRT. Baseline and end-of-study scans were used to evaluate treatment response (Figs. 2 and 3). The overall response assessed by ⁶⁸Ga-DOTATOC PET/CT resulted in PR in 2/11 patients (lasting up to eight months), SD in 5/11 (with a duration up to 11.5 months), while progressive disease (PD) was observed in four cases (Table 3). In all four patients defined as PD, the PD was assessed by ⁶⁸Ga-DOTATOC PET/CT performed three months after the end of treatment. Based on the tumor site, a total of 79 lesions were evaluable for the assessment of PRRT responses. Lesions were localized in the thyroid bed (n=4), lymph nodes (n=19), lungs (n=18), and bones (n=38). Table 5 summarizes overall responses and tumor-site responses in all treated patients. TG values did not show significant differences between baseline and follow-up measurements over time. TG was not significantly correlated with objective responses to PRRT or the calculated ⁶⁸Ga-DOTATOC PET/CT parameters (SUV_max, SUV_T/S, and FV). SUV_max and FV did not demonstrate any significant difference based on tumor site. Among all the ⁶⁸Ga-DOTATOC PET/CT parameters considered, FV was the only one that demonstrated a significant difference between responding (either PR or SD) and nonresponding lesions to PRRT (p=0.001; Fig. 4).

FIG. 2.

⁶⁸Ga-DOTATOC PET/CT in a metastatic Hürthle cell carcinoma at baseline (a) and after administration of 3.4 (b) and 11.7 GBq (c) of ⁹⁰Y-DOTATOC. Pretherapeutic images (upper panel MIP, lower panel transaxial emission, CT and fused PET/CT slices) demonstrated multiple sites of disease in the thyroid bed, lymph nodes, lungs, and bone (a). After treatment (b, c) radiopharmaceutical accumulation persisted with decreased intensity: stable disease up to 11.5 months was achieved.

FIG. 3.

⁶⁸Ga-DOTATOC PET/CT in a metastatic insular TC at baseline (a) and after administration of 7.1 (b) and 12.7 GBq (c) of ⁹⁰Y-DOTATOC. PET/CT images (upper panel MIP, lower panel transaxial emission, CT and fused PET/CT slices) demonstrated multiple bone metastases at baseline (a). After treatment, radiopharmaceutical (b, c) accumulation increased in intensity, extension, and number of lesions, as in the case of progressive disease. However, a symptomatic response was achieved.

FIG. 4.

Reduction of FV between baseline and final ⁶⁸Ga-DOTATOC PET/CT scans in lesions response according to the Response Evaluation Criteria in Solid Tumors (RECIST) (a) and the European Organization for Research and Treatment of Cancer (EORTC) criteria (b). The Kruskall–Wallis test was used to measure differences in FV and its correlation with lesion response to therapy: ΔFV differed significantly in lesions classified as either partial response (PR)/stable disease (SD) and progressive disease (PD) (p=0.001).

Table 5.

Patients and Lesions Response According to RECIST and EORTC Criteria

Response criteria	PR	SD	PD
RECIST criteria:
Patients (n=10^a)	2	4	4
Tumor lesions
Thyroid bed (n=4)	1	2	1
Lymph nodes (n=19)	1	12	6
Lung (n=18)	1	12	5
EORTC criteria:
Patients (n=11)	2	5	4
Bone lesions (n=38)	10	7	21

One patient out of the 11 treated with PRRT was not evaluated by RECIST criteria, since this patient presented only bone metastases.

EORTC, European Organization for Research and Treatment of Cancer.

Main PRRT toxicities were nausea (n=4/11) and asthenia (n=2/11), both grade 1. In 4/11 patients, we observed transient hematologic toxicity (grade 1): 2/11 leukopenia and 2/11 anemia. One patient experienced permanent renal toxicity (grade 2 that arose 16 months after therapy). A transient increase of transaminase levels (grade 1) was recorded in one case. We did not find a significant risk factor in terms of patient characteristics or administered PRRT activities for renal toxicity on multiple regression analysis.

Discussion

The outcome of DTC is excellent in the majority of cases. However, some patients exhibit more aggressive forms, unresponsive to conventional therapies. Partial or complete loss of ¹³¹I concentrating ability is usually associated with tumor dedifferentiation, and only 50% of patients with radioiodine-negative DTC will attain a disease-free status with conventional treatments (34). The loss of ¹³¹I concentration abrogates the utility of diagnostic ¹³¹I-WBS to detect residual/recurrent tumor. Therefore, in patients with negative diagnostic ¹³¹I-WBS and persistently elevated TG, [¹⁸F]FDG-PET and [¹⁸F]FDG-PET/CT has become the standard of care to localize residual/recurrent disease successfully (35). The incapability of dedifferentiated DTC cells to concentrate iodine has stimulated the search for therapeutic approaches alternative to ¹³¹I.

Several data about the role of somatostatin and somatostatin analogues as regulator of growth in normal and neoplastic thyroid tissue have been reported (36 –38). Recently, results have shown a high expression of all types of SSTRs in human nonmedullary thyroid carcinoma tissue (39). Based on these findings, SSTR imaging has been used to evaluate thyroid cancer patients with variable results (sensitivity 25–100%) (23,40) possibly due to major differences in study populations and in the imaging modalities used (32,41 –43).

In our series of patients, ⁶⁸Ga-DOTATOC PET/CT detected SSTR expression in up to 58.5% of iodine-negative DTC. This finding was consistent with data previously reported in radioiodine-negative tumor lesions (36–82%) (44). Interestingly, [¹⁸F]FDG-PET has been reported to be more sensitive compared to ⁶⁸Ga-DOTATOC in the detection of radioiodine-negative lesions (64% vs. 31%), but not in radioiodine-positive lesions (48% vs. 46%), introducing the concept of a concurrent loss of SSTR expression and radioiodine uptake in thyroid cancer cells (44).

Our results confirm the higher diagnostic performance of [¹⁸F]FDG compared to ⁶⁸Ga-DOTATOC to stage radioiodine-negative DTC patients (82.9% vs. 58.5%). The combination of [¹⁸F]FDG-PET/CT and ⁶⁸Ga-DOTATOC PET/CT improved metastasis detection (85.3%) in our series of patients. ⁶⁸Ga-DOTATOC PET/CT cannot be considered as the first-line functional imaging modality in this clinical setting, except for the determination of SSTR status (45). Furthermore, it may disclose the opportunity for PRRT and may be superior to ¹¹¹In-pentetreotide scintigraphy because of the higher affinity of the PET radiotracer for the SSTR type 2, the pharmacokinetic profile, the superior spatial resolution, as well as for the fact that it uses the same radiolabeled moiety employed for PRRT (45 –47).

Among the multiple factors analyzed, we did not find any predictor of [¹⁸F]FDG or ⁶⁸Ga-DOTATOC positivity. In fact, similar uptake patterns in lymph nodes, parenchymal tissues (lungs and liver), and skeletal lesions were found. Additionally, none of the clinical variables included in the multiple regression analysis was associated with ⁶⁸Ga-DOTATOC PET/CT positivity. Interestingly, all cases featuring negative [¹⁸F]FDG-PET/CT and ⁶⁸Ga-DOTATOC PET/CT were PTC. This observation, which may suggest a differential SSTR expression based on the histological type, needs to be addressed in further studies.

SSTR expression at a level considered sufficient to give access to PRRT was found in 13/41 (32%) of our patients. Iten et al. (22) reported a higher rate of recruitment for PRRT in refractory DTC evaluated by Octreoscan scintigraphy. This difference may be explained by the different selection criteria used to admit patients to PRRT. In fact, we selected only patients with high SSTR expression on ⁶⁸Ga-DOTATOC PET/CT, a modality of higher sensitivity as compared with Octeroscan scintigraphy (45), while previous experience excluded PRRT only in patients with completely negative SSTR imaging.

Dosimetric estimates obtained in this series of DTC patients were comparable to dosimetric results to critical organs reported in patients with advanced NETs (25). However, since we used only ¹¹¹In-DOTATOC planar images for dosimetry, dosimetric estimates (especially for tumor lesions) may be affected by some limitations represented by a 2D approach and the relative low-resolution planar scintigraphy as compared to PET/CT (48). However, although we did not perform a comparative analysis between PET/CT and planar images, it is well known that ⁶⁸Ga-DOTATOC PET/CT scanning is superior to ¹¹¹In-DOTATOC planar images in terms of spatial resolution and that it shows more and/or smaller lesions (45). The use of planar scintigraphic images only may also explain why we did not find any relation between tumor dosimetry and outcomes.

⁹⁰Y-DOTATOC PRRT induced disease control in 7/11 patients (2 PR and 5 SD) with a duration of response ranging from 3.5 to 11.5 months. An objective response in this series of patients was associated with a symptomatic response, as previously observed in patients with NET treated with PRRT (25,49). In particular, patients #4 and #7 registered a significant improvement of dyspnea and bone pain respectively.

As expected, PRRT toxicities were mainly hematologic and renal without significant differences from NET treated with this approach (25,49), although our patients had previously received high doses of ¹³¹I.

Treatment response evaluation is a critical aspect in patients with advanced, metastatic radioiodine-negative DTC. Ideally, patient survival may represent a strong indicator of treatment efficacy. Yet, prolonged survival is commonly seen even in patients with diffusely spread, progressive disease. An extended follow-up period on a large series of patients would therefore be required to accomplish this aim. Therefore, both serum markers and imaging findings are commonly adopted to evaluate treatment responses. Although RECIST criteria are the recommended criteria to evaluate treatment response, they are affected by some limitations, particularly in evaluating bone lesion responses. [¹⁸F]FDG uptake may also be extremely heterogeneous in case of metastatic radioiodine-negative DTC. Furthermore, the trend of serum TG levels in case of dedifferentiated tumors may not mirror the course of the disease (50,51).

In our series, the only ⁶⁸Ga-DOTATOC PET/CT derived semi-quantitative parameter significantly associated with either single lesion or individual patient response according to RECIST criteria was the FV variation. This result is consistent with data previously reported for [¹⁸F]FDG-PET/CT in other types of cancer, in which FV changes have been successfully used to predict response to therapy (52). Therefore, as for results with ⁶⁸Ga-DOTATOC in NETs (53), FV assessed by ⁶⁸Ga-DOTATOC PET/CT seems to represent a valuable parameter to predict clinical improvement during patient follow-up. Despite data previously reported in the literature about the predictive role of SUV_T/S (33), our results demonstrate no significant prognostic role of this parameter originally introduced to overcome limitations of SUV determination (54). Moreover, SUV parameters seem not to be adequate in this setting, since a decreased ⁶⁸Ga-DOTATOC uptake in tumors could theoretically reflect loss of SSTR expression, a phenomenon known to occur in NETs undergoing dedifferentiation (55).

The identification of functional imaging parameters to define treatment response is critical for the evaluation of PRRT. In fact, when morphologic criteria are used to identify tumor response to PRRT in NETs, patients with SD or minimal treatment response showed similar survival rates compared to patients presenting PR (56,57). Furthermore, improved quality of life after PRRT does not seem to be clearly associated with a discernible morphologic response to therapy (58). In progressive medullary thyroid cancer, a significant clinical improvement induced by PRRT has been reported, in spite of minor effects in terms of decline in tumor lesions and serum calcitonin levels (43). This could be related to the pattern of cell damage induced by ⁹⁰Y used for PRRT, which is supposed to last over time. Although the necrotic effects will continue to accumulate, the amount of necrotic and fibrotic tissue may result in unchanged lesion size on subsequent examination. This highlights the need for more sensitive imaging methods to monitor the response to PRRT. Thus, the use of functional images may be translated into PRRT response evaluation, as already applied in various tumors, with [¹⁸F]FDG-PET/CT (59 –63).

Our study has some major limitations: first, the small number of patients, and second, their clinical heterogeneity. Additionally, despite the fact that baseline [¹⁸F]FDG-PET/CT and ⁶⁸Ga DOTATOC PET/CT presented discordant results in some patients, suggesting tumor heterogeneity, [¹⁸F]FDG-PET/CT was not repeated at the end of treatment to assess treatment response, making it impossible to compare treatment response with [¹⁸F]FDG-PET/CT and ⁶⁸Ga DOTATOC PET/CT. Despite these unavoidable drawbacks, our preliminary results suggest a possible role for ⁶⁸Ga-DOTATOC PET/CT in the diagnostic work-up of patients with radioiodine-negative metastatic progressive DTC. Moreover, in this clinical setting, PRRT may be a promising treatment option in selected patients, although further studies on larger series of patients are needed.

In conclusion, SSTR expression by ⁶⁸Ga-DOTATOC PET/CT imaging was present in more than half of the patients with progressive radioiodine-negative DTC studied in our series. The combination of [¹⁸F]FDG-PET/CT and ⁶⁸Ga-DOTATOC PET/CT provided an accurate disease restaging. Furthermore ⁶⁸Ga-DOTATOC PET/CT allowed selecting patients suitable for PRRT. ⁹⁰Y-DOTATOC PRRT induced disease control (PR and SD) in 7/11 of treated patients (duration response of 3.5–11.5 months). Main PRRT adverse events included nausea, asthenia, and hematologic and renal toxicities. ⁶⁸Ga-DOTATOC PET/CT seems a reliable tool for both patient selection and evaluation of treatment response. In our experience, FV determination over time seems to represent a reliable parameter to determine tumor response to PRRT, although further investigations are needed to define its role better.

Footnotes

Author Disclosure Statement

All authors declare no competing financial interests exist.

References

Haugen

. 1999. Management of the patient with progressive radioiodine non-responsive disease. Semin Surg Oncol, 16:34–41.

Baudin

, Schlumberger

. 2007. New therapeutic approaches for metastatic thyroid carcinoma. Lancet Oncol, 8:148–156.

Grünwald

, Menzel

, Bender

, Palmedo

, Otte

, Fimmers

, Risse

, Biersack

. 1998. Redifferentiation therapy-induced radioiodine uptake in thyroid cancer. J Nucl Med, 39:1903–1906.

Simon

, Koehrle

, Reiners

, Boerner

, Schmutzler

, Mainz

, Goretzki

, Roeher

. 1998. Redifferentiation therapy with retinoids: therapeutic option for advanced follicular and papillary thyroid carcinoma. World J Surg, 22:569–574.

Kogai

, Taki

, Brent

. 2006. Enhancement of sodium/iodide symporter expression in thyroid and breast cancer. Endocr Relat Cancer, 13:797–826.

Venkataraman

, Yatin

, Marcinek

, Ain

. 1999. Restoration of iodide uptake in dedifferentiated thyroid carcinoma: relationship to human Na+/I- symporter gene methylation status. J Clin Endocrinol Metab, 84:2449–2457.

Short

, Suovuori

, Cook

, Vivian

, Harmer

. 2004. A phase II study using retinoids as redifferentiation agents to increase iodine uptake in metastatic thyroid cancer. Clin Oncol (R Coll Radiol), 16:569–574.

Park

, Zarnegar

, Kanauchi

, Wong

, Hyun

, Ginzinger

, Lobo

, Cotter

, Duh

, Clark

. 2005. Troglitazone, the peroxisome proliferator-activated receptor gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines. Thyroid, 15:222–231.

Antonelli

, Ferri

, Ferrari

, Sebastiani

, Colaci

, Ruffilli

, Fallahi

. 2010. New targeted molecular therapies for dedifferentiated thyroid cancer. J Oncol, 2010:921682.

10.

Ahmed

, Barbachano

, Riddell

, Hickey

, Newbold

, Viros

, Harrington

, Marais

, Nutting

. 2011. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. Eur J Endocrinol, 165:315–322.

11.

Kapiteijn

, Schneider

, Morreau

, Gelderblom

, Nortier

, Smit

. 2012. New treatment modalities in advanced thyroid cancer. Ann Oncol, 23:10–18.

12.

, Grewal

, Leboeuf

, Sherman

, Pfister

, Deandreis

, Pentlow

, Zanzonico

, Haque

, Gavane

, Ghossein

, Ricarte-Filho

, Domínguez

, Shen

, Tuttle

, Larson

, Fagin

. 2013. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med, 368:623–632.

13.

Giammarile

, Houzard

, Bournaud

, Hafdi

, Sassolas

, Borson-Chazot

. 2004. Diagnostic management of suspected metastatic thyroid carcinoma: clinical value of octreotide scintigraphy in patients with negative high-dose radioiodine scans. Eur J Endocrinol, 150:277–283.

14.

Sancak

, Hardt

, Singer

, Klöppel

, Eren

, Güllüoglu

, Sen

, Sever

, Akalin

, Eszlinger

, Paschke

. 2010. Somatostatin receptor 2 expression determined by immunohistochemistry in cold thyroid nodules exceeds that of hot thyroid nodules, papillary thyroid carcinoma, and Graves' disease. Thyroid, 20:505–511.

15.

Krohn

, Stricker

, Emmrich

, Paschke

. 2003. Cold thyroid nodules show a marked increase in proliferation markers. Thyroid, 13:569–575.

16.

Krohn

, Paschke

. 2002. Somatic mutations in thyroid nodular disease. Mol Genet Metab, 75:202–208.

17.

Zaknun

, Bodei

, Mueller-Brand

, Pavel

, Baum

, Hörsch

, O'Dorisio

, O'Dorisiol

, Howe

, Cremonesi

, Kwekkeboom

. 2013. The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging, 40:800–816.

18.

De Jong

, Bernard

, De Bruin

, Van Gameren

, Bakker

, Visser

, Mäcke

, Krenning

. 1998. Internalization of radiolabeled [DTPA0]octreotide and [DOTA0,Tyr3]octreotide: peptides for somatostatin receptor-targeted scintigraphy and radionuclide therapy. Nucl Med Commun, 19:283–288.

19.

Eberle

, Mild

. 2009. Receptor-mediated tumor targeting with radiopeptides. Part 1. General principles and methods. J Recept Signal Transduct Res, 29:1–37.

20.

Waldherr

, Schumacher

, Pless

, Crazzolara

, Maecke

, Nitzsche

, Haldemann

, Mueller-Brand

. 2001. Radiopeptide transmitted internal irradiation of noniodophil thyroid cancer and conventionally untreatable medullary thyroid cancer using. Nucl Med Commun, 22:673–678.

21.

Görges

, Kahaly

, Müller-Brand

, Mäcke

, Roser

, Bockisch

. 2011. Radionuclide-labeled somatostatin analogues for diagnostic and therapeutic purposes in nonmedullary thyroid cancer. Thyroid, 11:647–659.

22.

Iten

, Muller

, Schindler

, Rasch

, Rochlitz

, Oertli

, Maecke

, Muller-Brand

, Walter

. 2009. [(90)Yttrium-DOTA]-TOC response is associated with survival benefit in iodine-refractory thyroid cancer: long-term results of a phase 2 clinical trial. Cancer, 115:2052–2062.

23.

Teunissen

, Kwekkeboom

, Krenning

. 2006. Staging and treatment of differentiated thyroid carcinoma with radiolabeled somatostatin analogs. Trends Endocrinol Metab, 17:19–25.

24.

American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper

, Doherty

, Haugen

, Kloos

, Lee

, Mandel

, Mazzaferri

, McIver

, Pacini

, Schlumberger

, Sherman

, Steward

, Tuttle

. 2009. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 19:1167–1214.

25.

Filice

, Fraternali

, Frasoldati

, Asti

, Grassi

, Massi

, Sollini

, Froio

, Erba

, Versari

. 2012. Radiolabeled somatostatin analogues therapy in advanced neuroendocrine tumors: a single experience. J Oncol, 2012:320198.

26.

Asti

, Atti

, Iori

, Farioli

, Filice

, Versari

. 2012. semiautomated labelling and fractionation of yttrium-90 and lutetiom-177 somatostatin analogues usind disposable syringes and vials. Nucl Med Commun, 33:1144–1152.

27.

Stabin

, Sparks

, Crowe

. 2005. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med, 46:1023–1027.

28.

Cremonesi

, Ferrari

, Zoboli

, Chinol

, Stabin

, Orsi

, Maecke

, Jermann

, Robertson

, Fiorenza

, Tosi

, Paganelli

. 1999. Biokinetics and dosimetry in patients administered with ¹¹¹In-DOTA-Tyr3-octreotide: implications for internal radiotherapy with ⁹⁰Y-DOTATOC. Eur J Nucl Med, 26:877–886.

29.

Jamar

, Barone

, Mathieu

, Walrand

, Labar

, Carlier

, de Camps

, Schran

, Chen

, Smith

, Bouterfa

, Valkema

, Krenning

, Kvols

, Pauwels

. 2003. (⁸⁶Y-DOTA0)-D-Phe1-Tyr3-octreotide (SMT487)—a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion. Eur J Nucl Med Mol Imaging, 30:510–518.

30.

National Cancer Institute 2006 Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf (accessed August 9, 2006 ).

31.

Therasse

, Arbuck

, Eisenhauer

, Wanders

, Kaplan

, Rubinstein

, Verweij

, Van Glabbeke

, van Oosterom

, Christian

, Gwyther

. 2000. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 92:205–216.

32.

Postema

, De Herder

, Reubi

, Oei

, Kwekkeboom

, Bruining

, Bonjer

, van Toor

, Hennemann

, Krenning

. 1996. Somatostatin receptor scintigraphy in non-medullary thyroid cancer. Digestion, 57:36–37.

33.

Haug

, Auernhammer

, Wängler

, Schmidt

, Uebleis

, Göke

, Cumming

, Bartenstein

, Tiling

, Hacker

. 2010. ⁶⁸Ga-DOTATATE PET/CT for the early prediction of response to somatostatin receptor-mediated radionuclide therapy in patients with well-differentiated neuroendocrine tumors. J Nucl Med, 51:1349–1356.

34.

Pacini

, Schlumberger

, Dralle

, Elisei

, Smit

, Wiersinga

. 2006. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol, 154:787–803.

35.

Bannas

, Derlin

, Groth

, Apostolova

, Adam

, Mester

, Klutmann

. 2012. Can (18)F-FDG-PET/CT be generally recommended in patients with differentiated thyroid carcinoma and elevated thyroglobulin levels but negative I-131 whole body scan?. Ann Nucl Med, 26:77–85.

36.

Hoelting

, Duh

, Clark

, Herfarth

. 1996. Somatostatin analog octreotide inhibits the growth of differentiated thyroid cancer cells in vitro, but not in vivo. J Clin Endocrinol Metab, 81:2638–2641.

37.

Siperstein

, Levin

, Gum

, Clark

. 1992. Effect of somatostatin on adenylate cyclase activity in normal and neoplastic thyroid tissue. World J Surg, 16:555–561.

38.

Gabriel

, Andergassen

, Putzer

, Kroiss

, Waitz

, Von Guggenberg

, Kendler

, Virgolini

. 2010. Individualized peptide-related-radionuclide-therapy concept using different radiolabelled somatostatin analogs in advanced cancer patients. Q J Nucl Med Mol Imaging, 54:92–99.

39.

Pazaitou-Panayiotou

, Tiensuu Janson

, Koletsa

, Kotoula

, Stridsberg

, Karkavelas

, Karayannopoulou

. 2011. Somatostatin receptor expression in non-medullary thyroid carcinomas. Hormones (Athens), 11:290–296.

40.

Valsamaki

, Gotzamani-Psarrakou

, Tsiouris

, Molyvda-Athanasopoulou

, Psarrakos

, Papantoniou

, Gerali

, Zerva

. 2006. Tc-99m depreotide imaging of I-131-negative recurrent metastatic papillary thyroid carcinoma. Int J Cancer, 119:968–970.

41.

Garin

, Devillers

, Le Cloirec

, Bernard

, Lescouarc'h

, Herry

, Reubi

, Bourguet

. 1998. Use of indium-111 pentetreotide somatostatin receptor scintigraphy to detect recurrent thyroid carcinoma in patients without detectable iodine uptake. Eur J Nucl Med, 25:687–694.

42.

Ahlman

, Tisell

, Wängberg

, Fjälling

, Forssell-Aronsson

, Kölby

, Nilsson

. 1997. The relevance of somatostatin receptors in thyroid neoplasia. Yale J Biol Med, 70:523–533.

43.

Waldherr

, Pless

, Maecke

, Schumacher

, Crazzolara

, Nitzsche

, Haldemann

, Mueller-Brand

. 2002. Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq (90)Y-DOTATOC. J Nucl Med, 43:610–616.

44.

Middendorp

, Selkinski

, Happel

, Kranert

, Grünwald

. 2010. Comparison of positron emission tomography with [(18)F]FDG and [(68)Ga]DOTATOC in recurrent differentiated thyroid cancer: preliminary data. Q J Nucl Med Mol Imaging, 54:76–83.

45.

Virgolini

, Ambrosini

, Bomanji

, Baum

, Fanti

, Gabriel

, Papathanasiou

, Pepe

, Oyen

, De Cristoforo

, Chiti

. 2010. Procedure guidelines for PET/CT tumour imaging with ⁶⁸Ga-DOTA-conjugated peptides: ⁶⁸Ga-DOTA-TOC, ⁶⁸Ga-DOTA-NOC, ⁶⁸Ga-DOTA-TATE. Eur J Nucl Med Mol Imaging, 37:2004–2010.

46.

Kowalski

, Henze

, Schuhmacher

, Maecke

, Hofmann

, Haberkorn

. 2003. Evaluation of positron emission tomography imaging using [⁶⁸Ga]-DOTA-D-Phe1-Tyr3-octreotide in compar- ison to [¹¹¹In]-DTPAOC SPECT. First results in patients with neuroendocrine tumors. Mol Imaging Biol, 5:42–48.

47.

Buchmann

, Henze

, Engelbrecht

, Eisenhut

, Runz

, Schäfer

, Schilling

, Haufe

, Herrmann

, Haberkorn

. 2007. Comparison of ⁶⁸Ga-DOTATOC PET and ¹¹¹In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging, 34:1617–1626.

48.

Wierts

, de Pont

, Brans

, Mottaghy

, Kemerink

. 2011. Dosimetry in molecular nuclear therapy. Methods, 55:196–202.

49.

Vinjamuri

, Gilbert

, Banks

, McKane

, Maltby

, Poston

, Weissman

, Palmer

, Vora

, Pritchard

, Cuthbertson

. 2013. Peptide receptor radionuclide therapy with ⁹⁰Y-DOTATATE/⁹⁰Y-DOTATOC in patients with progressive metastatic neuroendocrine tumours: assessment of response, survival and toxicity. Br J Cancer, 108:1440–1448.

50.

Zhang

, Jia

, Liu

, Li

, Wang

, Lu

, Zhu

. 2007. A clinical study of all-trans-retinoid-induced differentiation therapy of advanced thyroid cancer. Nucl Med Commun, 28:251–255.

51.

, Kuang

, Xie

, Ma

. 2005. Possible explanations for patients with discordant findings of serum thyroglobulin and ¹³¹I whole-body scanning. J Nucl Med, 46:1473–1480.

52.

Gulec

, Suthar

, Barot

, Pennington

. 2011. The prognostic value of functional tumor volume and total lesion glycolysis in patients with colorectal cancer liver metastases undergoing 90Y selective internal radiation therapy plus chemotherapy. Eur J Nucl Med Mol Imaging, 38:1289–1295.

53.

Gabriel

, Oberauer

, Dobrozemsky

, Decristoforo

, Putzer

, Kendler

, Uprimny

, Kovacs

, Bale

, Virgolini

. 2009. ⁶⁸Ga-DOTA-Tyr3-octreotide PET for assessing response to somatostatin-receptor-mediated radionuclide therapy. J Nucl Med, 50:1427–1434.

54.

Valkema

, Pauwels

, Kvols

, Kwekkeboom

, Jamar

, de Jong

, Barone

, Walrand

, Kooij

, Bakker

, Lasher

, Krenning

. 2005. Long-term follow-up of renal function after peptide receptor radiation therapy with (90)Y-DOTA(0),Tyr(3)-octreotide and (177)Lu-DOTA(0), Tyr(3)-octreotate. J Nucl Med, 46:83S–91S.

55.

Miederer

, Seidl

, Buck

, Scheidhauer

, Wester

, Schwaiger

, Perren

. 2009. Correlation of immunohistopathological expression of somatostatin receptor 2 with standardised uptake values in ⁶⁸Ga-DOTATOC PET/CT. Eur J Nucl Med Mol Imaging, 36:48–52.

56.

Kwekkeboom

, de Herder

, Kam

, van Eijck

, van Essen

, Kooij

, Feelders

, van Aken

, Krenning

. 2008. Treatment with the radiolabeled somatostatin analog [¹⁷⁷Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol, 26:2124–2130.

57.

Bodei

, Cremonesi

, Grana

, Fazio

, Iodice

, Baio

, Bartolomei

, Lombardo

, Ferrari

, Sansovini

, Chinol

, Paganelli

. 2011. Peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging, 38:2125–2135.

58.

Teunissen

, Kwekkeboom

, Krenning

. 2004. Quality of life in patients with gastroenteropancreatic tumors treated with [¹⁷⁷Lu-DOTA0,Tyr3]octreotate. J Clin Oncol, 22:2724–2729.

59.

Terasawa

, Lau

, Bardet

, Couturier

, Hotta

, Hutchings

, Nihashi

, Nagai

. 2006. Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin's lymphoma and diffuse large B-cell lymphoma: a systematic review. J Clin Oncol, 27:1906–1914.

60.

Juweid

, Cheson

. 2006. Positron-emission tomography and assessment of cancer therapy. N Engl J Med, 354:496–507.

61.

Obrzut

, Bykowski

, Badran

, Hayeri

, Hoh

. 2010. Utility of fluorodeoxyglucose-positron emission tomography in the identification of new lesions in lung cancer patients for the assessment of therapy response. Nucl Med Commun, 31:1008–1015.

62.

Herrmann

, Benz

, Krause

, Pomykala

, Buck

, Czernin

. 2011. (18)F-FDG-PET/CT in evaluating response to therapy in solid tumors: where we are and where we can go. Q J Nucl Med Mol Imaging, 55:620–632.

63.

Yanagawa

, Tatsumi

, Miyata

, Morii

, Tomiyama

, Watabe

, Isohashi

, Kato

, Shimosegawa

, Yamasaki

, Mori

, Doki

, Hatazawa

. 2012. Evaluation of response to neoadjuvant chemotherapy for esophageal cancer: PET response criteria in solid tumors versus response evaluation criteria in solid tumors. J Nucl Med, 53:872–880.

64.

Sobin

, Gospodarowicz

, Wittekind

(Eds) 2009. TNM Classification of Malignant Tumours, 7th ed. John Wiley & Sons/UICC, New York.