Research ArticleClinical Investigations

Comparison of 68Ga-DOTANOC and 68Ga-DOTATATE PET/CT Within Patients with Gastroenteropancreatic Neuroendocrine Tumors

Damian Wild, Jamshed B. Bomanji, Pascal Benkert, Helmut Maecke, Peter J. Ell, Jean Claude Reubi and Martyn E. Caplin
Journal of Nuclear Medicine March 2013, 54 (3) 364-372; DOI: https://doi.org/10.2967/jnumed.112.111724

Abstract

Somatostatin receptor PET tracers such as [68Ga-DOTA,1-Nal3]-octreotide (68Ga-DOTANOC) and [68Ga-DOTA,Tyr3]-octreotate (68Ga-DOTATATE) have shown promising results in patients with neuroendocrine tumors, with a higher lesion detection rate than is achieved with 18F-fluorodihydroxyphenyl-l-alanine PET, somatostatin receptor SPECT, CT, or MR imaging. 68Ga-DOTANOC has high affinity for somatostatin receptor subtypes 2, 3, and 5 (sst2,3,5). It has a wider receptor binding profile than 68Ga-DOTATATE, which is sst2-selective. The wider receptor binding profile might be advantageous for imaging because neuroendocrine tumors express different subtypes of somatostatin receptors. The goal of this study was to prospectively compare 68Ga-DOTANOC and 68Ga-DOTATATE PET/CT in the same patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and to evaluate the clinical impact of 68Ga-DOTANOC PET/CT. Methods: Eighteen patients with biopsy-proven GEP-NETs were evaluated with 68Ga-DOTANOC and 68Ga-DOTATATE using a randomized crossover design. Labeling of DOTANOC and DOTATATE with 68Ga was standardized using a fully automated synthesis device. PET/CT findings were compared with 3-phase CT scans and in some patients with MR imaging, 18F-FDG PET/CT, and histology. Uptake in organs and tumor lesions was quantified and compared by calculation of maximum standardized uptake values (SUVmax) using volume computer-assisted reading. Results: Histology revealed low-grade GEP-NETs (G1) in 4 patients, intermediate grade (G2) in 7, and high grade (G3) in 7. 68Ga-DOTANOC and 68Ga-DOTATATE were false-negative in only 1 of 18 patients. In total, 248 lesions were confirmed by cross-sectional and PET imaging. The lesion-based sensitivity of 68Ga-DOTANOC PET was 93.5%, compared with 85.5% for 68Ga-DOTATATE PET (P = 0.005). The better performance of 68Ga-DOTANOC PET is attributed mainly to the significantly higher detection rate of liver metastases rather than tumor differentiation grade. Multivariate analysis revealed significantly higher SUVmax in G1 tumors than in G3 tumors (P = 0.009). This finding was less pronounced with 68Ga-DOTANOC (P > 0.001). Altogether, 68Ga-DOTANOC changed treatment in 3 of 18 patients (17%). Conclusion: The sst2,3,5-specific radiotracer 68Ga-DOTANOC detected significantly more lesions than the sst2-specific radiotracer 68Ga-DOTATATE in our patients with GEP-NETs. The clinical relevance of this finding has to be proven in larger studies.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of tumors that originate from the diffuse neuroendocrine system of the gastrointestinal tract or bronchopulmonary system. They are characterized by the overexpression of somatostatin receptors. To date, 5 somatostatin receptor subtypes (sst1–sst5) have been identified, all of which are expressed with differing frequencies in GEP-NETs. For example, sst2 and sst5 are expressed at a high density in 70%–100% of GEP-NETs (1). These receptors have been used as a target for diagnostic and therapeutic radiotracers. [111In-diethylenetriaminepentaacetic acid (DTPA)]-octreotide, an sst2-specific tracer, was the first radiolabeled somatostatin analog to become an integral part of the routine diagnostic work-up of patients with GEP-NETs (2). 90Y- and 177Lu-labeled DOTA-conjugated sst2 tracers such as 90Y-DOTATOC ([90Y-DOTA,Tyr3]-octreotide) and 177Lu-DOTATATE ([177Lu-DOTA,Tyr3]-octreotate) are being successfully introduced in peptide receptor radionuclide therapy (3,4).

Most clinically used radiolabeled somatostatin analogs are agonists, which bind with high affinity only to sst2. Although most NETs express sst2, the distribution and density of sst2 is often variable and sometimes too low for effective somatostatin receptor targeting (1). This is likely the reason for the wide sensitivity range (60%–100%) of 111In-DTPA-octreotide scintigraphy and SPECT in the detection of NETs (5). One possible approach to overcoming this problem is the use of radiolabeled tracers with affinity to more than one somatostatin receptor subtype. Gastrinomas, ileal carcinoids, and VIPomas express sst2 or sst5 with an incidence of almost 100% (1). [DOTA,1-Nal3]-octreotide (DOTANOC) is a peptide that promises to target a broader range of somatostatin subtype receptors, including sst2, sst3, and sst5 (6,7). Preliminary results in single patients suggest that this new radiopeptide locates more metastases than do sst2-specific tracers (7,8). This finding is supported by Asnacios et al., who found sst3 and sst5 expression in 111In-DTPA-octreotide–negative tumors (9).

Furthermore, 68Ga-based radiopharmaceuticals such as 68Ga-DOTANOC showed higher binding affinities to sst2 and sst5 than do the respective lutetium and indium derivatives. The higher binding affinity resulted in significantly higher tumor uptake in a tumor-bearing rat model (8). This finding is relevant because metallic 68Ga is a positron emitter with a half-life of 68 min that is ideal for molecular PET imaging. Recently, somatostatin receptor PET using 68Ga-DOTATOC or 68Ga-DOTATATE showed promising results in patients, with a higher lesion detection rate than was achieved with 111In-DTPA-octreotide scintigraphy and SPECT (10–12). But more important, somatostatin receptor PET changed the clinical management in most patients with negative or inconclusive findings on 111In-DTPA-octreotide scintigraphy (12). Currently, 68Ga-DOTATOC, 68Ga-DOTATATE, and 68Ga-DOTANOC are the most established somatostatin receptor PET tracers (13). Comparison of 68Ga-DOTATOC and 68Ga-DOTATATE (both sst2-specific tracers) in the same patient revealed comparable diagnostic accuracy for the detection of NET lesions (14). Another study compared the tumor detection rates between 68Ga-DOTATATE PET (sst2-specific PET) and 68Ga-DOTANOC PET (sst2,3,5-specific PET) in the same patient (15).

Our study had 3 aims: first, to perform a prospective patient- and lesion-based comparison of 68Ga-DOTATATE and 68Ga-DOTANOC PET in the same patient; second, to establish whether there is any correlation between tumor grade and lesion identification using 68Ga-DOTATATE and 68Ga-DOTANOC PET; and finally, to evaluate whether 68Ga-DOTANOC PET/CT alters clinical management in patients with negative 68Ga-DOTATATE PET/CT findings.

MATERIALS AND METHODS

Patients and Study Design

This prospective single-center study compared 68Ga-DOTATATE and 68Ga-DOTANOC PET/CT in the same patient using a crossover design in random order. All recruited patients were under prospective follow-up at the Neuroendocrine Tumor Unit, Royal Free Hospital, London. Inclusion criteria were age 25–85 y, biopsy-proven metastatic GEP-NET (G1–G3), and an indication for staging or restaging imaging including CT scanning or MR imaging as part of the patients’ general surveillance. Exclusion criteria were known disseminated disease, pregnancy, kidney insufficiency (creatinine level > 1.5 mg/dL), treatment with short-acting somatostatin analogs less than 3 d before somatostatin receptor PET, and octreotide depot injection less than 4 wk before somatostatin receptor PET. All patients underwent sst2 and sst2,3,5 PET/CT (68Ga-DOTATATE and 68Ga-DOTANOC PET/CT) at the University College London Hospital.

The study was approved by the local institutional review board, and written informed consent was obtained in accordance with provisions of the Declaration of Helsinki.

Synthesis and Radiolabeling of DOTATATE and DOTANOC

The peptide–chelator conjugates [DOTA,Tyr3]-octreotate (DOTATATE) and [DOTA,1-Nal3]-octreotide (DOTANOC) were synthesized by standard Fmoc solid-phase synthesis on 2-chlorotritylchloride resin on a peptide synthesizer (Switch 24; Rink CombiChem Technologies), according to a general procedure described previously (6). 68Ga-DOTATATE and 68Ga-DOTANOC were labeled under sterile conditions in an isolator using a modification of the method described by Zhernosekov et al. (16) and Shastry et al. (17). Briefly, a TiO2-based commercially available 68Ge–68Ga generator (Eckert and Ziegler) was eluted with 0.1N hydrochloric acid. Chemical purification and volume concentration of 68Ga was performed in an 80% acetone/0.15N HCl solution using a cation exchange resin (400-mesh AG 50W-X8 resins; Bio-Rad). Afterward, about 60 μg of DOTATATE or DOTANOC were incubated with 600–1,200 MBq of 68Ga at 90°C for 10 min (pH, ∼3.5). For further purification, the reaction solution was passed over a C18 cartridge (Sep-Pak; Waters), washed with 3 mL of saline, and eluted with 1 mL of 50% ethanol. The final product was diluted with 7 mL of saline and then subjected to sterile filtration using a Millex 0.22-μm filter (Millipore). The labeling yield was analyzed by silica gel instant thin-layer chromatography (Pall Inc.) and by high-performance liquid chromatography using a Luna 5-μm, C18 (2) 50 × 3.0-mm column (Phenomenex) and an acetonitrile–water gradient. The labeling yield and radiochemical purity of 68Ga-DOTATATE and 68Ga-DOTANOC were greater than 98% at a specific activity of 14.5–34 GBq/μmol.

Imaging

68Ga-DOTATATE and 68Ga-DOTANOC PET/CT scans were obtained within 6–48 h of each other in all patients except patient 2, who had 27 d between scans. Images were acquired 54–73 min after injection of 155 ± 17 MBq (mean ± SD) (range, 135–170 MBq) of 68Ga-DOTATATE and 60–74 min after injection of 155 ± 12 MBq (130–170 MBq) of 68Ga-DOTANOC. The administered mass of 68Ga-DOTATATE and 68Ga-DOTANOC was 28 ± 7 μg (17–43 μg) and 33 ± 7 μg (21–45 μg) (P > 0.08), respectively. All patients were scanned with the same dedicated PET/CT unit (Discovery ST 16; GE Healthcare) from the vertex to the mid thigh.

The CT exposure factors for all examinations were 140 kVp and 80–120 mAs. PET acquisition was performed in 3 dimensions with 4 min per bed position and a 5-slice overlap. PET images were reconstructed using an ordered-subsets expectation maximization (OSEM) algorithm with 3 iterations and 25 subsets and with CT-based attenuation correction.

The presence of lesions was confirmed by 3-phase, thin-section multidetector CT or gadolinium-enhanced MR imaging. In all patients with poorly differentiated neuroendocrine carcinoma (G3), additional 18F-FDG PET/CT scans were obtained using a dedicated PET/CT unit (Discovery ST 16; GE Healthcare) and a standard protocol (18). All scans were performed within 6 wk of one another.

Diagnostic (3-phase) CT scans were obtained on a Brilliance 64-slice scanner (Phillips Medical System) or a Lightspeed scanner (GE Healthcare). All scans were acquired at 120 kVp and variable amperage, depending on body habitus. The scans were reconstructed at 3-mm (Brilliance) or 5-mm (Lightspeed) intervals. Intravenous contrast material (Omnipaque 300; GE Healthcare) was administered via a pump injector (E-Z-EM) at 3.5 mL/s.

The MR scanner was a 1.5-T Achieva (Phillips Medical Systems). All scans were acquired using the Synergy Sense body coil. Contrast material (Dotarem; Guerbet) was administered via a cannula in an antecubital vein using a pump injector (Medrad) at 1.5 mL/s with a 20-mL saline flush.

Image Analysis

Two experienced dedicated nuclear medicine physicians independently assessed the 68Ga-DOTATATE and 68Ga-DOTANOC PET/CT scans. The physicians were unaware of the patients’ identities, type of scan, or results of other imaging modalities. The number of lesions that could be identified clearly as a single focus was determined for each patient. To enable a methodic and consistent approach to the identification of lesions, 4 categories of lesion sites were specified: lymph nodes, liver, bone, and other locations. Afterward, 68Ga-DOTATATE and 68Ga-DOTANOC PET/CT scans were compared in both a patient-by-patient and a lesion-by-lesion analysis. A dual-accredited radiologist/nuclear medicine physician compared areas of abnormal tracer uptake with CT, MR imaging, and 18F-FDG PET/CT to confirm the presence of lesions.

68Ga-DOTATATE and 68Ga-DOTANOC organ and tumor uptake was quantified using maximum standardized uptake values (SUVmax). Organ uptake was measured by drawing regions of interest over 3 consecutive transaxial PET slices, whereas tumor uptake was determined using PET VCAR (volume computer-assisted reading) software (GE Healthcare).

Statistical Analysis

The sensitivity and 95% confidence interval of both imaging modalities were calculated according to the method of Blaker et al. (19). The statistical significance of the difference in sensitivity between the 2 tracers was analyzed by testing for equality of proportions (20).

The organ update was compared using the Wilcoxon matched-pairs signed-rank test.

Linear mixed-effects models were used to describe the association between SUVmax (and tumor-to-background activity ratio [TBR]) and multiple explanatory variables by treating them as fixed effects. To properly reflect the structure of the repeated data, patient number and lesion number nested within patient were treated as random effects. The model was adapted to reflect the crossover design of the study (i.e., paired 68Ga-DOTATATE and 68Ga-DOTANOC measures per lesion). Ki-67 index, type of tracer, and location of the lesion were used as explanatory variables. Only significant interactions were included in the final model. All continuous variables were log-transformed and centered on the mean (response variables were not centered). The residuals of model fits were repeatedly visually inspected for violations of model assumptions, and the Akaike information criterion was used for model selection.

RESULTS

From 21 consecutive enrolled patients, 3 patients were excluded from analysis due to disseminated disease (1 patient) or insufficient comparison with morphologic imaging (2 patients). The remaining 18 patients (8 women and 10 men; mean age ± SD, 58 ± 12 y) were eligible for inclusion in this study. Patient characteristics are summarized in Table 1.

View this table:
TABLE 1

Characteristics of Study Population

Both 68Ga-DOTATATE PET and 68Ga-DOTANOC PET revealed disease in 17 of 18 patients (94.4%; 95% confidence interval, 73.4%–99.7%). In 1 patient neither tracer was able to identify the tumor, and this patient had a histologically confirmed high-grade hindgut neuroendocrine tumor.

None of the patients experienced any subjective symptoms after the injection of either radiotracer.

Lesion Analysis

In total, 248 lesions were confirmed by cross-sectional and PET imaging (Table 2) 68Ga-DOTANOC PET and 68Ga-DOTATATE PET detected 232 and 212 lesions, respectively. CT was performed on all patients, MR imaging on 7 of 18 patients, and 18F-FDG PET on all patients with G3 GEP-NETs. The overall sensitivity of 68Ga-DOTANOC PET was 93.5% (95% confidence interval, 89.4%–96.1%), compared with 85.5% (95% confidence interval, 80.6%–89.9%) for 68Ga-DOTATATE PET (P = 0.005). This difference is attributed mainly to the significantly higher detection rate of liver metastases with 68Ga-DOTANOC PET (Figs. 1–3⇓⇓) (P < 0.001). In patient 2, for example, 68Ga-DOTANOC PET detected all 3 liver metastases whereas 68Ga-DOTATATE PET detected only 1 liver metastasis (Figs. 1 and 2). Slightly more bone lesions were detected with 68Ga-DOTATATE PET (Table 2). Neither 68Ga-DOTANOC PET nor 68Ga-DOTATATE PET showed significant advantages in the detection of lesions in the remaining organs, including lymph nodes. However, 68Ga-DOTANOC PET detected 7 of 8 pancreatic NETs whereas 68Ga-DOTATATE PET detected only 3 of 8 pancreatic NETs. In patients 2 and 7, both tracers detected a pancreatic lesion (uncinate process) that was not confirmed by cross-sectional and follow-up imaging.

FIGURE 1.
FIGURE 1.

68Ga-DOTATATE (A) and 68Ga-DOTANOC (B) whole-body PET scans from patient 2. Both scans were performed within 27 d of each other. There are 3 focal 68Ga-DOTANOC–avid lesions in right liver lobe (B), whereas 68Ga-DOTATATE shows only 1 liver lesion (A). Arrows show lesions that were only 68Ga-DOTANOC–avid.

FIGURE 2.
FIGURE 2.

68Ga-DOTATATE (A and B) and 68Ga-DOTANOC (C and D) PET/CT scans and contrast-enhanced CT scans (E and F) from patient 2 (addendum to Fig. 1). Both PET/CT scans were obtained within 27 d of each other. Large arrow shows focal 68Ga-DOTANOC uptake in hypodense liver lesion (E) that is not 68Ga-DOTATATE–avid (A). There is subtle but definite 68Ga-DOTANOC uptake in liver segment 7 (small arrow) without 68Ga-DOTATATE and CT correlation (B and F, respectively). In this patient, right hemihepatectomy was performed as curative attempt. Histology confirmed 68Ga-DOTANOC PET/CT findings.

FIGURE 3.
FIGURE 3.

68Ga-DOTATATE (A) and 68Ga-DOTANOC (B) whole-body PET scans, 68Ga-DOTATATE (C) and 68Ga-DOTANOC (D) PET/CT scans, and T2-weighted MR scan from patient 8. Both PET/CT scans were obtained within 48 h of each other. Small arrow shows subtle but definite 68Ga-DOTANOC uptake (B and D) in segment 6, without MR imaging or 68Ga-DOTATATE correlation (A, C, and E). Large kidney metastasis (large arrow) shows higher uptake of 68Ga-DOTANOC than of 68Ga-DOTATATE, with SUVmax of 20.9, compared with 12.3. In this patient, left kidney resection and segmentectomy of liver (segments 5 and 6) were performed as curative attempt. Histology confirmed 68Ga-DOTANOC PET/CT findings.

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TABLE 2

Lesion-Based Comparison of 68Ga-DOTATATE PET, 68Ga-DOTANOC PET, and Conventional Imaging (CT, MR Imaging, or 18F-FDG PET/CT)

The tumor grade of all patients was determined histologically using mitotic rates and Ki-67 indices (European Neuroendocrine Tumor Society proposal for grading GEP-NETs) (21): 4 patients had low-grade (G1), 7 intermediate-grade (G2), and 7 high-grade (G3) GEP-NETs. The higher sensitivity of 68Ga-DOTANOC PET in patients with G1 GEP-NETs can be explained by the larger portion of liver lesions in this subgroup (Table 2).

Among the 18 patients, management was altered in 3 patients (patients 8, 10, and 12) after 68Ga-DOTANOC PET/CT. These patients had more extensive surgery than initially planned because 68Ga-DOTANOC PET/CT revealed more extensive disease than 68Ga-DOTATATE PET/CT and morphologic imaging.

Tumor and Organ Uptake

SUVmax was available for 104 lesions. Table 3 shows the median SUVmax for 68Ga-DOTANOC and 68Ga-DOTATATE, together with the interquartile range. Overall, there was higher tumor uptake of 68Ga-DOTATATE than of 68Ga-DOTANOC (Table 3). However, in some patients (patients 2, 9, 10, 11, 12, 14, 15, and 20) median tumor SUVmax was higher for 68Ga-DOTANOC (Figs. 1–3). The tumor uptake of both tracers was highly organ-specific (Table 3). The highest tumor uptake was found in the liver, and the lowest tumor uptake was found in the bone.

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TABLE 3

Median Tumor Uptake (SUVmax) and Interquartile Range of 68Ga-DOTATATE and 68Ga-DOTANOC

Importantly, the tumor uptake of 68Ga-DOTATATE and 68Ga-DOTANOC was dependent on tumor grade. Table 3 shows that the median SUVmax decreased as the tumor grade increased. Multivariate analysis using a mixed-effects model with the categoric variable tumor grade (G1–G3) revealed a significantly higher SUVmax in low-grade (G1) than in-high grade (G3) tumors (P = 0.009). This finding was less pronounced with 68Ga-DOTANOC (P = 0.003). 68Ga-DOTATATE showed significantly higher uptake than did 68Ga-DOTANOC in G1 and G2 tumors but not in G3 tumors.

Quantification of tracer uptake in organs revealed significantly higher uptake of 68Ga-DOTATATE in all relevant organs except the pituitary and bone marrow (Table 4). In the bone marrow, 68Ga-DOTANOC showed significantly higher uptake than did 68Ga-DOTATATE (P < 0.001). In the pituitary, however, no significant difference was found between the tracers. Organ uptake was not dependent on tumor grade.

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TABLE 4

Median Organ Uptake (SUVmax) and Interquartile Range of 68Ga-DOTATATE and 68Ga-DOTANOC

An important characteristic of a successful imaging probe is a high TBR. 68Ga-DOTANOC showed a significantly higher TBR in lesions of the liver, whereas 68Ga-DOTATATE showed a significantly higher TBR in lesions of the bone (Table 5). TBRs for both tracers were significantly lower in the liver than in any other organs (P < 0.001). The grade of differentiation did not have a significant effect on the TBR of the 2 tracers.

View this table:
TABLE 5

Median TBR and Interquartile Range for 68Ga-DOTATATE and 68Ga-DOTANOC

DISCUSSION

Somatostatin receptor PET has shown promising results in NETs, with a higher lesion detection rate than is achieved with 18F-fluorodihydroxyphenyl-l-alanine PET, somatostatin receptor SPECT, CT, or MR imaging (10,11,22,23). Currently, 68Ga-DOTATOC, 68Ga-DOTATATE, and 68Ga-DOTANOC are the most established somatostatin receptor PET tracers (13). Comparison studies by Poeppel et al. (14) (comparison of 68Ga-DOTATATE and 68Ga-DOTATOC) and Kabasakal et al. (15) (comparison of 68Ga-DOTATATE and 68Ga-DOTANOC) showed a similar diagnostic accuracy for these tracers for the detection of NETs. In our study, we prospectively compared 68Ga-DOTATATE PET/CT and 68Ga-DOTANOC PET/CT in the same patient. In contrast to the findings of Kabasakal et al. (15), we detected significantly more lesions with 68Ga-DOTANOC PET (sensitivity, 93.5%) than with 68Ga-DOTATATE PET (sensitivity, 85.5%). The better performance of 68Ga-DOTANOC PET is attributed mainly to the significantly higher detection rate of liver metastases.

There are 2 possible explanations for this finding. First, normal liver uptake of 68Ga-DOTANOC is significantly lower than that of 68Ga-DOTATATE, resulting in a significantly higher TBR and tumor detection rate for 68Ga-DOTANOC than for 68Ga-DOTATATE. This finding is a surprise, as the more lipophilic radiotracer 68Ga-DOTANOC is expected to show higher liver uptake. However, the C-terminal carboxylate group of DOTATATE may be responsible for some of the anion transport mechanism of 68Ga-DOTATATE into human liver cells (24).

The broader somatostatin receptor binding profile of 68Ga-DOTANOC might be another explanation for the better performance of 68Ga-DOTANOC in the detection of liver metastases. This assumption is supported by tumor uptake studies. 68Ga-DOTANOC, which binds specifically to sst2, sst3, and sst5 (7), showed higher tumor uptake in 14 of 39 liver metastases despite having a 10 times lower sst2 affinity than the sst2-specific tracer 68Ga-DOTATATE (8). Thus, sst3,5-mediated accumulation of 68Ga-DOTANOC might be the reason for the higher 68Ga-DOTANOC uptake in about one third of liver metastases.

68Ga-DOTATATE shows significantly higher uptake in all organs with predominant sst2 expression (25–32). However, intense 68Ga-DOTANOC uptake is found in the pituitary, which is the only organ that shows consistently high sst2 and sst5 expression (25,33,34). Again, sst5-mediated accumulation of 68Ga-DOTANOC might be the explanation for this finding.

We have reviewed the somatostatin receptor expression of different normal organs to the best of our knowledge. However, this is a difficult task because sst1–sst5 in vitro detection has been studied with distinctly different methods (polymerase chain reaction [PCR], immunohistochemistry, autoradiography) with often contradictory results (25–34).

The significantly lower uptake of 68Ga-DOTANOC in normal pancreas tissue is likely responsible for the higher tumor detection rate in the pancreas (7 tumors), compared with that for 68Ga-DOTATATE (3 tumors). In 2 patients with multiple endocrine neoplasia type 1, 68Ga-DOTATATE detected only one pancreatic tumor whereas 68Ga-DOTANOC detected multiple pancreatic tumors. This finding was clinically relevant because the treatment was altered in both patients, who underwent more extensive surgery. Altogether, 68Ga-DOTANOC changed treatment in 3 of 18 patients (17%). Both tracers showed false-positive results in the pancreas (uncinate process) of 2 patients. This false-positive finding has been described before (35). There was 1 further false-positive result with 68Ga-DOTATATE in the prostate. The false-positive findings were confirmed by more than 1 y of follow-up, morphologic imaging (MR imaging), and biopsy of the prostate.

In contrast to liver metastases and pancreatic tumors, bone metastases were significantly more frequently detected by 68Ga-DOTATATE PET than by 68Ga-DOTANOC PET. This difference can be explained by the lower background activity (bone marrow activity) of 68Ga-DOTATATE, resulting in a significantly higher TBR. Unfortunately the mechanism of 68Ga-DOTATATE and 68Ga-DOTANOC accumulation in the bone marrow is not known. Therefore, no assumption can be made as to whether somatostatin receptor expression is responsible for the difference in bone marrow uptake between the 2 radiotracers. There was no difference in the tumor detection rate between the 2 tracers in lymph nodes or any other organs.

Comparison of tumor grade and detection rate showed that 68Ga-DOTANOC detected significantly more lesions than did 68Ga-DOTATATE in patients with G1 GEP-NETs. This difference can be explained by the larger proportion of liver lesions in this patient subgroup. There was no significant difference between the 2 tracers in the tumor detection rate of G2 and G3 tumors. Within the literature, there is evidence that somatostatin receptor PET is of limited value in patients with G3 NETs and that 18F-FDG PET may be more suitable in these cases (18). In our study, however, 68Ga-DOTATATE and 68Ga-DOTANOC PET detected significantly more G3 lesions (82% and 90%, respectively) than did 18F-FDG PET (58%). Importantly, tumor uptake of 68Ga-DOTATATE and 68Ga-DOTANOC was dependent on tumor grade. The median tumor SUVmax decreased as the tumor grade increased. This finding can be explained by the loss of somatostatin receptors during the process of tumor dedifferentiation.

To our knowledge, only our group and Kabasakal et al. (15) compared 68Ga-DOTATATE and 68Ga-DOTANOC PET/CT in the same patient. Several factors may explain the difference between our findings and those of Kabasakal. First, the studied patient populations were relatively small, with overlapping confidence intervals for sensitivity. A higher bone-to-liver lesion ratio in the study of Kabasakal et al. might additionally explain the better performance of 68Ga-DOTATATE in their study than in ours. Furthermore, their Figure 3 (patient 5) attracts some attention because the pituitary shows almost no uptake of 68Ga-DOTANOC—in contrast to their Figure 1 (15) and our data. Importantly, we always found high uptake of 68Ga-DOTANOC in the pituitary. The minimal uptake of 68Ga-DOTANOC in the pituitary in their study indicates either a quality problem with the radiotracer (36) or possible saturation of sst receptors, which may influence the performance of the tracer and explain the discordant results compared with our study.

The most relevant limitation of this study was the lack of pathologic confirmation of most lesions (238/248 lesions). For ethical and practical reasons, it was not possible to obtain histologic verification of all lesions. However, in all patients who had surgery, 68Ga-DOTANOC findings were histologically confirmed (4/18 patients). Furthermore, the presence of lesions was confirmed by CT and, where indicated, by MR imaging and 18F-FDG PET/CT. The combination of CT, MR imaging, and 18F-FDG PET/CT detected more lesions than 68Ga-DOTANOC or 68Ga-DOTATATE PET.

CONCLUSION

The sst2,3,5-specific radiotracer 68Ga-DOTANOC detected significantly more lesions than did the sst2-specific radiotracer 68Ga-DOTATATE in our patients with GEP-NETs. Because of the small size of our study population, additional, larger, trials are needed to confirm whether our results are of clinical relevance and would justify the widespread adoption of 68Ga-DOTANOC over 68Ga-DOTATATE.

DISCLOSURE

The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. This work was supported in part by the Swiss National Science Foundation (grant PASMP3-123269), the Novartis Foundation, the Department of Health’s NIHR Biomedical Research Centre’s funding scheme, and the King’s College London and UCL Comprehensive Cancer Imaging Centre CR-U.K. and EPSRC, in association with the MRC and DoH (England). No other potential conflict of interest relevant to this article was reported.

Acknowledgments

We thank Irfan Kayani for assistance in interpreting CT and MR imaging results.

Footnotes

  • Published online Jan. 7, 2013.

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  • Received for publication July 23, 2012.
  • Accepted for publication September 25, 2012.
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