The aim was to assess the relevant distribution of the novel PET tracer ⁶⁸Ga-DOTATATE in neuroendocrine tumors (NETs) with combined positron emission tomography / computed tomography (PET/CT) and compare its performance with that of ¹⁸F-FDG PET/CT.

METHODS.

The imaging findings with ⁶⁸Ga-DOTATATE and ¹⁸F-FDG on 38 consecutive patients with a diagnosis of primary or recurrent NET were compared and correlated with tumor grade on histology based on ki67 and mitotic index.

RESULTS.

The sensitivity of ⁶⁸Ga-DOTATATE PET/CT was 82% (31 of 38) and that of ¹⁸F-FDG PET/CT was 66% (25 of 38). The sensitivity of combined ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET/CT was 92% (35 of 38). There was greater uptake of ⁶⁸Ga-DOTATATE than ¹⁸F-FDG in low-grade NET (median SUV 29 vs 2.9, P < .001). In high-grade NET there was higher uptake of ¹⁸F-FDG over ⁶⁸Ga-DOTATATE (median SUV 11.7 vs 4.4, P = .03). There was a significant correlation with predominant tumor uptake of ⁶⁸Ga-DOTATATE or ¹⁸F-FDG and tumor grade on histology (P < .0001).

CONCLUSIONS.

⁶⁸Ga-DOTATATE PET/CT is a useful novel imaging modality for NETs and is superior to ¹⁸F-FDG for imaging well-differentiated NET. Functional imaging with both ⁶⁸Ga-DOTATATE and ¹⁸F-FDG has potential for a more comprehensive tumor assessment in intermediate- and high-grade tumors. Cancer 2008. ©2008 American Cancer Society.

Neuroendocrine tumors (NETs) have distinct biological and clinical characteristics, in particular a high density of somatostatin receptors at the cell membrane. It is this property that allows the use of radiolabeled somatostatin analogs for imaging of these tumors.1 DOTA-DPhe¹,Tyr³-octreotate (DOTATATE) is a somatostatin-2 receptor (SSR-2) analog, which is radiolabeled with ⁶⁸Ga, a positron emitter.2, 3 ⁶⁸Ga (t_½ 68 minutes, β⁺ 88%) is produced by a ⁶⁸Ge/⁶⁸Ga generator; production is not dependent on a cyclotron. ⁶⁸Ga-DOTATATE has high affinity for SSR-2, is rapidly excreted from nontarget sites, offers good target to nontarget imaging properties, and hence is an ideal potential candidate tracer for imaging NETs.2-5 Recent studies have indicated that ⁶⁸Ga-labeled DOTA peptide DOTATOC has potential to improve imaging for NET over conventional ¹¹¹indium pentetreotide.5-7

NETs, however, typically have a wide range of cellular differentiation. ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) is of limited value in well-differentiated NETs as these tumors often have near-normal glucose turnover.⁸ As both ¹⁸F-FDG and ⁶⁸Ga-DOTATATE exploit distinct tumor characteristics it is possible that they may be complementary for tumor staging. Higher-grade NETs may show higher metabolic turnover and lose expression of SSRs. To date, however, only a few small series have correlated FDG and/or somatostatin receptor scintigraphy (SSRS) with tumor grade.8-11

Aim

The purpose of this study was to compare the performance of ⁶⁸Ga-DOTATATE and ¹⁸F-FDG in confirmed NET and correlate uptake with tumor grade on histology.

MATERIALS AND METHODS

Patients

We retrospectively reviewed the findings in the first 38 patients (25 male, 13 female, aged 14–71 years, median, 53 years) with confirmed primary or recurrent NETs (6 had pulmonary NET, 28 gastroenteropancreatic NET, and 4 metastatic NET with unknown primary) who underwent both ⁶⁸Ga-DOTATATE PET / computed tomography (CT) and ¹⁸F-FDG PET/CT imaging at our institution. All patients gave informed consent and institutional board ethics approval was received for this retrospective study.

All patients with NET were classified into high-, intermediate-, or low-grade tumors according to the tumor histology reports. The histologic grading was based on recent consensus statements of the European Neuroendocrine Tumor Society, using mitotic index and Ki67 index in staging of NET along with immunohistochemistry (IHC).12, 13 On the basis of this system well-differentiated tumors with a Ki67 index of ≤2% and a mitotic index of <2 per HPF (high power field) were classified as low grade. Tumors with a Ki67 index of between 3%–20% and mitotic count of 2–20 per HPF were classified as intermediate grade. Tumors with poor differentiation and Ki67 index of >20% and mitotic count of >20 HPF were classified as high-grade NET. All tumors had IHC for chromogranin and synatophysin and in a majority also for CD56, PGP9.5, and neuron-specific enolase. Mitotic counts were assessed in at least 40 fields (at ×40) magnification and evaluated in areas showing highest mitotic density. The Ki67 index was determined using MIB-1 antibody and expressed as percent of 2000 tumor cells in areas of highest nuclear binding.

Patients were scanned for 1) staging of primary NETs and 2) detection of suspected recurrent NETs. The clinical indications for ⁶⁸Ga-DOTATATE and ¹⁸F-FDG studies were to assess suitability for surgical resection in patients with primary or localized NETs and in patients with metastatic disease to evaluate for targeted radionuclide therapy. In all cases the histology of the primary tumor was available. The diagnosis of recurrent tumor was based on histology of metastatic sites, imaging features of progressive malignancy, and/or elevated and rising tumor marker levels. For the purposes of correlating uptake of tracers with tumor grade, analysis was confined to those patients where both imaging and histopathology was available.

The ⁶⁸Ga-DOTATATE PET/CT and ¹⁸F-FDG PET/CT studies were performed within 3 weeks of each other.

Combined PET/CT

Images were acquired 1 hour postinjection of 370 MBq of ¹⁸F-FDG or 45–60 minutes after the injection of 120–200 MBq of ⁶⁸Ga-DOTATATE. No adverse effects were observed after the injection of ⁶⁸Ga-DOTATATE. Imaging was performed using dedicated combined GE Discovery ST PET/16 detector CT unit (GE Healthcare, Detroit, Mich); whole-body examinations (brain to mid-thigh) were performed with the patient supine.

The CT exposure factors for all examinations were 120 kVp and 80 mA in 0.8 seconds. Maintaining patient position a whole-body PET emission scan was performed and covered an area identical to that covered by CT. PET acquisition was carried out in 3D with 4 minutes per bed position and 5 slice overlap. PET images were reconstructed using CT for attenuation correction. Transaxial PET data were reconstructed using ordered subsets expectation maximization with 3 iterations and 25 subsets (3D). Transaxial PET slice thickness was 3.27 mm with in-slice pixel size of 4.68 mm. The CT data was reconstructed to axial slices of 3.75 mm and 2.5 mm thickness with a soft tissue reconstruction algorithm and 2.5 mm thickness with a lung reconstruction algorithm.

Image Reporting

The images from ⁶⁸Ga-DOTATATE PET/CT and ¹⁸F-FDG PET/CT were reported in consensus by an experienced dedicated nuclear medicine physician and a dual accredited radiologist/nuclear medicine physician. Areas of abnormal increased focal uptake were documented. The image findings of the 2 modalities were compared with each other and with histology. Tumors were classified as showing either predominant ⁶⁸Ga-DOTATATE or ¹⁸F-FDG uptake according to maximum intensity of tracer uptake (standardized uptake value, SUVmax) and number of detected tumor lesions.

The diagnosis of tumor was established on the basis of histology, elevated and rising hormonal and tumor marker levels, or progressive imaging features of malignancy. Where metastatic disease was confirmed by histopathology at 1 tumor site detected by both ⁶⁸Ga-DOTATATE PET/CT and ¹⁸F-FDG PET/CT, it was assumed that other lesions detected by either imaging modality were metastatic lesions from the primary.

Statistical Analysis

A comparison of numbers of tumors showing positive ⁶⁸Ga-DOTATATE or ¹⁸F-FDG uptake was performed using a McNemar paired test. A P value <.05 was taken as significant for all statistical tests. A Fisher exact test was used to correlate the number of patients with predominant uptake of ⁶⁸Ga-DOTATATE and ¹⁸F-FDG with tumor grade. The Mann-Whitney test was used to test for difference in uptake using SUVmax for individual tracers between different tumor grades. A Wilcoxon matched pairs signed rank test was used to compare uptake of ⁶⁸Ga-DOTATATE and ¹⁸F-FDG within the same tumor grades.

RESULTS

⁶⁸Ga-DOTATATE PET/CT revealed tumor lesions in 31 of 38 patients (SUVmax range, 4.6–50; median SUVmax, 18) with confirmed disease, but failed to detect tumor in 7 of 38 patients. Of these 7 patients ¹⁸F-FDG PET/CT detected disease in 5.

¹⁸F-FDG PET/CT revealed disease in 25 of 38 patients (SUVmax, 2.9–22; median SUV, 9.5) with confirmed tumors, but failed to detect tumor in 13 of 37. Of these 13 patients ⁶⁸Ga-DOTATATE PET/CT detected disease in 10 patients.

The sensitivity of ⁶⁸Ga-DOTATATE PET/CT alone was 82% (31 of 38); for ¹⁸F-FDG PET/CT was 66% (25 of 38); and combined ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET/CT was 92% (35 of 38).

In 3 patients no uptake of either tracer (false-negative) was seen in CT-documented lesions. In these patients histology demonstrated low-grade NET (1 patient), intermediate-grade NET (1 patient), and high-grade NET in a third patient with high-grade goblet cell carcinoid.

Correlation of Tracer Uptake With Tumor Grade and Ki67 Index

In 25 of 38 patients histology was available for sites imaged by PET-CT (Table 1). Thirteen had low-grade NET with Ki67 index ranging from <1% to 2%, 6 intermediate-grade NET with Ki67 index ranging from 5 to 15%, and 6 high-grade NET with Ki67 index 20% to 60%. For these sites there was a significant correlation between low and high tumor grades and tracer uptake (for both ⁶⁸Ga-DOTATATE and ¹⁸F-FDG, Table 2). There was higher uptake of ⁶⁸Ga-DOTATATE in low-grade NET compared with ⁶⁸Ga-DOTATATE uptake in high-grade NET (median SUV 29 vs 4.3, P = .0019). Conversely, there was higher uptake of ¹⁸F-FDG in high-grade NET compared with ¹⁸F-FDG uptake in low-grade NET (median SUV 11.7 vs 2.9, P = .0033). There was also higher uptake of FDG in intermediate versus low-grade NET (median SUV 10.5 vs 2.9, P = .029). There was no significant difference in tracer uptake between low and intermediate for ⁶⁸Ga-DOTATATE and intermediate and high-grade NET for both ⁶⁸Ga-DOTATATE and ¹⁸F-FDG.

Table 1. Correlation of Tracer Uptake of ¹⁸F-FDG and ⁶⁸Ga-DOTATATE With Tumor Grades on Histology

	Tumor	Sites of tumor involvement	Prior medical therapy	Grade	Indication	Method of tissue collection	¹⁸F-FDG SUVmax	⁶⁸Ga-DOTATATE SUVmax
1	Foregut	Mesenteric nodes mediastinal nodes	—	Low	Suspected recurrence	Percutaneous biopsy	3.4	16.9
2	PNET	Retroperitoneal lymph nodes	—	Low	Suspected recurrence	Resection	1.5	34.9
3	PNET	Primary tumor local nodal involvement	—	Low	Primary	Resection	5.4	32.5
4	Typical bronchial carcinoid	Primary tumor	—	Low	Primary	Resection	1.5	26
5	Typical bronchial carcinoid	Primary tumor	—	Low	Primary	Percutaneous biopsy	3.2	12
6	Mid-gut	Liver, retroperitoneal nodes and mesenteric nodes	IF	Low	Suspected recurrence	Percutaneous biopsy	1.6	11.3
7	PNET	Mesenteric and retroperitoneal nodes	—	Low	Suspected recurrence	Surgical excision biopsy	1.8	40
8	PNET	Primary tumor mesenteric nodes	—	Low	Primary	Percutaneous biopsy	5.1	45
9	Unknown primary	Liver	—	Low	Metastatic disease	Percutaneous biopsy	2.3	3.3
10	Mid-gut	Mesenteric nodes	—	Low	Metastatic disease	Surgical excision biopsy	2.3	29
11	PNET		—	Low	Suspected recurrence	Surgical excision biopsy	12	31
12	Typical bronchial carcinoid	Primary tumor	—	Low	Primary	Resection	2.9	18
13	Typical bronchial carcinoid	Primary tumor	—	Low	primary	Resection	4	45
14	Mid-gut	Liver mesenteric nodes	—	Intermediate	Suspected recurrence	Percutaneous biopsy	9	50
15	Unknown primary	Mesenteric retroperitoneal mediastinal nodes	—	Intermediate	Metastatic disease	Percutaneous biopsy	12	4.6
16	PNET	Liver mesenteric nodes bone deposits	FCIST chemo	Intermediate	Suspected recurrence	Percutaneous biopsy	12.6	45
17	Mid-gut carcinoid	Liver mesenteric retroperitoneal nodes	—	Intermediate	Suspected recurrence	Percutaneous biopsy	4.2	25.9
18	Unknown primary	Retroperitoneal nodes	—	Intermediate	Metastatic disease	Percutaneous biopsy	13.9	5
19	PNET	Liver retroperitoneal node	—	Intermediate	Suspected recurrence	Surgical excision biopsy	2	1.8
20	Mid-gut	Mesenteric retroperitoneal mediastinal cervical nodes	Y90 lanreotide	High	Suspected recurrence	Surgical excision biopsy	7.4	2.7
21	PNET	Primary tumor liver	—	High	Primary	Percutaneous biopsy	4.1	1.6
22	PNET	Primary tumor mesenteric nodes liver	—	High	Primary	Percutaneous biopsy	14.6	6
23	Unknown primary	Mesenteric retroperitoneal inguinal nodes	—	High	Metastatic disease	Surgical excision biopsy	12.5	7.5
24	Mid-gut	Retroperitoneal nodes lung deposits	—	High	Suspected recurrence	Surgical excision biopsy	10.8	8.9
25	Mid-gut	Mesenteric retroperitoneal nodes liver	Bleomycin, cisplatin, etopiside	High	Suspected recurrence	Surgical excision biopsy	16.4	1.9

PNET indicates pancreatic neuroendocrine tumor; ⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTA-DPhe¹,Tyr³-octreotate; ¹⁸F-FDG, ¹⁸F-Fluorodeoxyglucose; FCIST, 5 Fluorouracil cisplatin and streptozocin; IF, interferon.

Table 2. Numbers of Patients Showing Predominant Uptake of ⁶⁸Ga-DOTATATE or ¹⁸F-FDG According to Tumor Grade

	Predominant uptake of ⁶⁸Ga-DOTATATE	Predominant uptake of ¹⁸F-FDG	Total
High/intermediate-grade NET	3	11	14
Low-grade NET	21	0	21
Total	24	11	35

Two-tailed P < .0001. Fisher exact T-test.
NET indicates neuroendocrine tumors; ⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTA-[SCAP]D[R]Phe¹,Tyr³-octreotate; ¹⁸F-FDG, ¹⁸F-Fluorodeoxyglucose.

There was a significant correlation between numbers of patients showing predominant uptake of ⁶⁸Ga-DOTATATE or ¹⁸F-FDG and tumor grade (Table 3). There was greater uptake of ⁶⁸Ga-DOTATATE over ¹⁸F-FDG in low-grade tumors (Table 3, median SUVmax 29 vs 2.9, P <.001). In high-grade tumors there was higher uptake of ¹⁸F-FDG over ⁶⁸Ga-DOTATATE (Table 3, median SUVmax 11.7 vs 4.3, P = .03). There was no significant difference in uptake of tracers for intermediate-grade NET.

Table 3. SUVmax of ⁶⁸Ga-DOTATATE and ¹⁸F-FDG According to Tumor Grade

	⁶⁸Ga-DOTATATE	¹⁸F-FDG	P
All NET	16.9 (1.6–50)	4.2 (1.4–16.4)	.005
Low-grade NET Ki67 index ≤2%	29 (3.3–45)	2.9 (1.5–12)	<.001
Intermediate NET Ki67 index 3%–20%	15.5 (1.8–50)	10.5 (2.0–13.9)	NS
High-grade NET Ki67 index >20%	4.4 (1.6–8.9)	11.7 (4.1–16.4)	.03

SUVmax is the median SUVmax with range in parentheses.
SUVmax indicates maximum standardized uptake value; NET, neuroendocrine tumor; ⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTA-[SCAP]D[R]Phe¹,Tyr³-octreotate; ¹⁸F-FDG, ¹⁸F-Fluorodeoxyglucose.

Lesion Analysis

⁶⁸Ga-DOTATATE and ¹⁸F-FDG detected a total of 293 lesions, 186 were positive with ⁶⁸Ga-DOTATATE and 176 with ¹⁸F-FDG (Table 4). Lesion size ranged from 6 to 13 cm in diameter. In addition, there were a further 10 lesions (6 liver metastases, 2 mesenteric nodes, 2 peritoneal nodules) that were negative for both ⁶⁸Ga-DOTATATE and ¹⁸F-FDG but with confirmed tumor on histology and/or serial imaging with CT. Five of these lesions were small (7–13 mm). Tumor size otherwise did not significantly affect tracer uptake.

Table 4. Number of Lesions Demonstrating ⁶⁸Ga-DOTATATE and/or ¹⁸F-FDG Uptake in High-, Intermediate-, and Low-Grade NET Tumors

	High-grade NET	Intermediate-grade NET	Low-grade NET	Total
Uptake of ⁶⁸Ga-DOTATATE and ¹⁸F-FDG	5	45	21	71
Uptake of ⁶⁸Ga-DOTATATE but not ¹⁸F-FDG	0	18	97	115
Uptake of ¹⁸F-FDG but not ⁶⁸Ga-DOTATATE	72	33	0	105
No uptake of either ⁶⁸Ga-DOTATATE or ¹⁸F-FDG	2	5	3	10
Total	79	101	121	303

NET indicates neuroendocrine tumors; ⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTA-[SCAP]D[R]Phe¹,Tyr³-octreotate; ¹⁸F-FDG, ¹⁸F-Fluorodeoxyglucose.

There were 6 sites (2 in lung, 1 in hilar lymph node, 1 in mediastinal lymph node, 2 in cervical nodes) of increased tracer uptake at sites of inflammation with ¹⁸F-FDG (Fig. 1). No cases of ⁶⁸Ga-DOTATATE uptake at sites of inflammation were documented.

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

(A) ⁶⁸Ga-DOTATATE and (B) ¹⁸F-FDG PET/CT images from a patient with well-differentiated (‘typical’) bronchial carcinoid tumor. The primary tumor (left hilum, arrow) is positive for (A) ⁶⁸Ga-DOTATATE but negative for (B) ¹⁸F-FDG. Histology showed that the left lung had postcollapse pneumonitis that was negative for (A) ⁶⁸Ga-DOTATATE uptake but positive for (B, broken arrow) ¹⁸F-FDG.

In high-grade NET only 5 of 79 detected lesions were positive with ⁶⁸Ga-DOTATATE and only 2 of 79 negative for ¹⁸F-FDG uptake. Conversely, in patients with low-grade NET 21 of 123 detected lesions were positive with ¹⁸F-FDG while only 3 lesions were negative for ⁶⁸Ga-DOTATATE uptake. No lesion exhibited exclusive uptake of either ⁶⁸Ga-DOTATATE in high-grade or ¹⁸F-FDG in low-grade NET.

In 3 patients (1 low grade and 2 intermediate grade) the tumor exhibited variable affinity for tracers at different sites, so that some lesions were positive only with ⁶⁸Ga-DOTATATE and others only with ¹⁸F-FDG in the same tumor. In 4 patients there was variable uptake of tracers at the same lesion site (Fig. 2).

Impact on Management of ¹⁸F-FDG PET/CT

In 4 patients (3 high-grade NET and 1 intermediate-grade NET) ⁶⁸Ga-DOTATATE showed low and ¹⁸F-FDG more intense and more widespread uptake (Fig. 3). In view of this pattern it was felt that radionuclide therapy would not be appropriate and therefore the patients were assigned to receive systemic chemotherapy.

DISCUSSION

PET-CT has been of limited use in the imaging of NET, as the most widely available tracer has reduced sensitivity for well-differentiated NET. The development of selective Ga-68 DOTA-labeled somatostatin analogs allows the use of PET-CT to selectively image somatostatin receptor subtype 2 and offers the potential of a wider application of PET-CT in NET.2, 3 Recently ⁶⁸Ga-DOTATOC has been shown to be more accurate than conventional imaging with ¹¹¹Indium-pentetreotide.5-7 Our results are the first to report on the use of PET-CT with the related ⁶⁸Ga-DOTA peptide DOTATATE. By using a receptor-targeted approach with ⁶⁸Ga-DOTATATE we have shown an improvement in diagnostic performance of PET-CT imaging of NET tumors relative to ¹⁸F-FDG. Overall, the total number of detected lesions was greater with the combined use of ¹⁸F-FDG and ⁶⁸Ga-DOTATATE than with either tracer alone (Table 4), in keeping with findings of other studies that used a combination of functional imaging modalities.14, 15

In our study tumor grade influenced tracer uptake (Tables 2–4). It is difficult to establish a link between tracer avidity and histopathologic indices of tumor proliferation. In many patients there were a large number of tumor lesions, often with multiple lesions in the same organ (eg, liver metastases). In some patients there was variable uptake of tracer at different lesion sites. Moreover, heterogeneous uptake within tumor lesions indicates percutaneous biopsy may not fully reflect in vivo tumor heterogeneity. Despite these limitations, which to a large extent are inevitable in an imaging study, tumor grade and proliferation appeared to be related to tumor ⁶⁸Ga-DOTATATE and ¹⁸F-FDG uptake. There was higher uptake of ⁶⁸Ga-DOTATATE in low-grade versus high-grade NET. Conversely, there was significantly higher uptake of ¹⁸F-FDG in high-grade versus low-grade NET. In addition, for low- and high-grade NET there was significant difference in relative intensity of tumor uptake of ⁶⁸Ga-DOTATATE versus ¹⁸F-FDG (Table 2).

⁶⁸Ga-DOTATATE PET CT was superior to ¹⁸F-FDG in the detection of NET because of its higher sensitivity in low-grade tumor. Although some studies have shown a correlation between ¹⁸F-FDG uptake and histology of NET as determined by Ki67 index,10, 11 others have failed to demonstrate such a relationship.9 Data from PET somatostatin receptor ligand studies are limited. Dynamic PET studies have shown that while ⁶⁸Ga-DOTATOC uptake is most closely correlated with the pharmacokinetic K₁ parameter, ¹⁸F-FDG uptake is most influenced by the V_B (fractional blood volume) parameter.16, 17 Our observation that ¹⁸F-FDG uptake was high in high-grade tumors may serve as a prognostic indicator.

Although tumor grade was predictive of ⁶⁸Ga-DOTATATE and ¹⁸F-FDG uptake there were 3 patients with low-, intermediate-, and high-grade NETs that showed no uptake of either tracer. The absence of ⁶⁸Ga-DOTATATE in low-grade tumor and ¹⁸FDG in high-grade tumor is difficult to explain. In 1 patient the diagnosis of recurrent NET was based on progressive imaging features of malignancy (peritoneal thickening and ascites) without positive histology. In another patient it is possible that small volume and necrotic nature of tumor resulted in lack of detectable avidity for tracer. Furthermore, in some patients variable tracer uptake was seen at different sites in the same tumor; some tumor lesions showed uptake of ⁶⁸Ga-DOTATATE over ¹⁸F-FDG, while the converse was true of others. Variable tracer uptake was even seen within the same lesion site. These findings suggest the wide spectrum of differentiation of NET, heterogeneity of cellular differentiation within the same tumor mass, and also reflect the potential ability of PET to map these cellular characteristics.

There are data to suggest that patients with well-differentiated NET are suitable candidates for targeted radionuclide therapy with ⁹⁰Y- or ¹⁷⁷Lu-labeled DOTATATE.18-20 In patients with high-grade metastatic NET there is often limited somatostatin receptor expression and systemic chemotherapy may be favored over radionuclide therapy.21 It is speculated that as a prelude to therapy dual imaging with ¹⁸F-FDG and ⁶⁸Ga-DOTATATE in NET may be helpful to map the extent of disease and guide therapy. In our cohort the use of ¹⁸F-FDG led to a change in clinical management from radionuclide to systemic chemotherapy in 25% (4 of 16) of intermediate- and high-grade NET. These NETs had positive ⁶⁸Ga-DOTATATE uptake but with much greater and widespread ¹⁸F-FDG uptake. The ability of PET to reflect tumor heterogeneity within and between tumor sites indicates that with the use of DOTATATE and other functional tracers, such as ¹¹C-5-hydroxytryptophan and ¹⁸F-DOPA, PET-CT may provide a noninvasive metabolic map of in vivo molecular pathology. If the use of PET tracers can be shown with prospective controlled trials to positively impact management then this would help planning and monitoring of therapy to individual tumor biology.22, 23

There are advantages of PET/CT imaging of NETs, as some of the primary lesions are small and difficult to detect with conventional imaging. ⁶⁸Ga-DOTATATE has superior affinity and uptake at the SSR-2, and combined PET and CT imaging of this tracer has superior spatial resolution compared with conventional ¹¹¹In-pentetreotide imaging. This allows more accurate anatomical localization even of small (6 mm) receptor-positive tumor lesions. As ⁶⁸Ga-DOTATATE is generator-produced it can also provide a convenient and cost-effective on-site source of tracer.3 In addition, ⁶⁸Ga-DOTATATE PET allows a more rapid examination relative to ¹¹¹In-pentetreotide.

Study limitations include a rather heterogeneous population of NET types including primary and metastatic lesions. This has to be balanced against a reasonable-sized population especially given that these tumors are relatively rare. Only patients with confirmed clinical diagnosis of primary or metastatic NET were included. Patients free from tumor, which were much harder to identify with retrospective analysis, were not included. Our study cannot therefore comment on the specificity or negative predictive value of ⁶⁸Ga-DOTATATE and ¹⁸F-FDG. Another difficulty is that, although histology was available for all patients this was obviously not possible for all lesions. This is a frequent problem in imaging studies especially given the number of individual metastatic lesions in some of the patients.

Conclusions

This study shows that 1) Well-differentiated NETs show greater avidity for ⁶⁸Ga-DOTATATE and poorly differentiated NETs show greater avidity for ¹⁸F-FDG. 2) ⁶⁸Ga-DOTATATE-PET/CT and ¹⁸F-FDG PET/CT exploit different tumor characteristics of NETs for imaging. The roles of the 2 tracers may be complementary in mapping spread completely in patients with metastatic tumors.

REFERENCES

1 Caplin ME,Buscombe JR,Hilson AJ,Jones AL,Watkinson AF,Burroughs AK. Carcinoid tumor. Lancet. 1998; 352: 799–805.
2 Maecke HR,Hofmann M,Haberkorn U. ⁶⁸Ga-labeled peptides in tumor imaging. J Nucl Med. 2005; 46( suppl 1): 172S–8S.
3 Breeman AP,de Jong M,de Bois E,Bernard BF,Konijnenberg M,Krenning EP. Radiolabeling DOTA-peptides with ⁶⁸Ga. Eur J Nucl Med Mol Imaging. 2005; 32: 478–485.
4 Froidevaux S,Eberle AN,Christe M, et al. Neuroendocrine tumor targeting: study of novel gallium-labeled somatostatin radiopeptides in a rat pancreatic tumor model. Int J Cancer. 2002; 98: 930–937.
5 Hofmann M,Maecke H,Borner R, et al. Biokinetics and imaging with the somatostatin receptor PET radioligand ⁶⁸Ga DOTATOC: preliminary data. Eur J Nucl Med. 2001; 28: 1751–1757.
6 Kowalski J,Henze M,Schuhmacher J,Maecke HR,Hofmann M,Haberkorn U. Evaluation of positron emission tomography imaging using [68Ga]-DOTA-DPhe1-Tyr3-octreotide in comparison to [111In]-DTPAOC SPECT: first results in patients with neuroendocine tumors. Mol Imaging Biol. 2003; 5: 42–48.
7 Gabriel M,Decristoforo C,Kendler D, et al. 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med. 2007; 48: 508–518.
8 Adams S,Baum R,Rink T,Schumm-Drager PM,Usadel KH,Hor G. Limited value of fluorine-18 fluorodeoxyglucose positron emission tomography for the imaging of neuroendocrine tumors. Eur J Nucl Med. 1998; 25: 79–83.
9 Belhocine T,Foidart J,Rigo P, et al. Fluorodeoxyglucose positron emission tomography and somatostatin receptor scintigraphy for diagnosing and staging carcinoid tumors: correlations with the pathological indexes p53 and Ki-67. Nucl Med Commun. 2002; 23: 727–734.
10 Adams S,Baum RP,Hertel A,Schumm-Drager PM,Usadel KH,Hor G. Metabolic (PET) and receptor (SPET) imaging of well-and less well-differentiated tumors: comparison with the expression of the ki-67 antigen. Nucl Med Commun. 1998; 19: 641–647.
11 Pasquali C,Rubello D,Sperti C, et al. NET tumor imaging: can 18F-fluorodeoxyglucose positron emission tomography detect tumors with poor prognosis and aggressive behavior? World J Surg. 1998; 22: 588–592.
12 Rindi G,Kloppel G,Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors:a consensus proposal including a grading system. Virchows Arch. 2006; 449: 395–401.
13 Rindi G,Kloppel G.,Couvelard A., et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2007; 451: 757–762.
14 Le Rest C,Bomanji JB,Costa DC,Townsend CE,Visvikis D,Ell PJ. Functional imaging of malignant paragangliomas and carcinoid tumors. Eur J Nucl Med. 2001; 28: 478–482.
15 Quigley AM,Buscombe JR,Shah T, et al. Intertumoral variability in functional imaging within patients suffering from NET tumors. An observational, cross-sectional study. Neuroendocrinology. 2005; 82: 215–220.
16 Koukouraki S,Strauss LG,Georgoulias V, et al. Evaluation of the pharmacokinetics of 68Ga-DOTATOC in patients with metastatic neuroendocrine tumors scheduled for 90Y-DOTATOC therapy. Eur J Nucl Med Mol Imaging. 2006; 33: 460–466.
17 Koukouraki S,Strauss LG,Georgoulias V,Eisenhut M,Haberkorn U,Dimitrakopolou-Strauss A. Comparison of the pharmacokinetics of ⁶⁸Ga-DOTATOC and ¹⁸[F]FDG in patients with metastatic neuroendocrine tumor scheduled for ⁹⁰Y-DOTATOC therapy. Eur J Nucl Med Mol Imaging. 2006; 33: 1115–1122.
18 Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev. 2003; 24: 389–427.
19 Kaltsas GA,Papadogias D,Makras P,Grossman AB. Treatment of advanced neuroendocrine tumors with radiolabelelled somatostatin analogues. Endocr Relat Cancer. 2005; 12: 683–699.
20 de Jong M,Breeman WA,Valkema R,Bernard BF,Krenning EP. Combination radionuclide therapy using 177Lu- and 90Y-labeled somatostatin analogs. J Nucl Med. 2005; 46( suppl): 13S–7S.
21 Kaltsas GA,Besser GM,Grossmann AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev. 2004; 25: 458–511.
22 Reubi JC,Waser B. Concomitant expression of several peptide receptors in neuroenodocrine tumors: molecular basis for in vivo multireceptor tumor targeting. Eur J Nucl Med Mol Imaging. 2003; 30: 781–793.
23 Krenning EP,Valkema R,Kwekkeboom DJ, et al. Molecular imaging as in vivo molecular pathology for gastroenterohepatic neuroendocrine tumors: implications for follow up after therapy. J Nucl Med. 2005; 46( suppl 1): 76S–82S.

Citing Literature

Volume112, Issue11

1 June 2008

Pages 2447-2455

Functional imaging of neuroendocrine tumors with combined PET/CT using ⁶⁸Ga-DOTATATE (DOTA-DPhe¹,Tyr³-octreotate) and ¹⁸F-FDG