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. Author manuscript; available in PMC: 2021 Dec 1.
Published in final edited form as: Eur J Nucl Med Mol Imaging. 2020 May 6;47(13):3047–3057. doi: 10.1007/s00259-020-04832-9

Comparison of 68Ga-DOTA-JR11 PET/CT with dosimetric 177Lu-satoreotide tetraxetan (177Lu-DOTA-JR11) SPECT/CT in patients with metastatic neuroendocrine tumors undergoing peptide receptor radionuclide therapy

Simone Krebs 1, Joseph A O’Donoghue 2, Evan Biegel 2, Bradley J Beattie 2, Diane Reidy 3, Serge K Lyashchenko 1,4,5, Jason S Lewis 1,4,5, Lisa Bodei 1,5, Wolfgang A Weber 1,5,6, Neeta Pandit-Taskar 1,5
PMCID: PMC7644587  NIHMSID: NIHMS1591945  PMID: 32378020

Abstract

Purpose:

Paired imaging/therapy with radiolabeled somatostatin receptor (SSTR) antagonists is a novel approach in neuroendocrine tumors (NETs). The aim of this study was to compare tumor uptake of 68Ga-DOTA-JR11 and 177Lu-satoreotide tetraxetan (177Lu-DOTA-JR11) in patients with NETs.

Methods:

As part of a prospective clinical trial, 20 patients with metastatic NETs underwent 68Ga-DOTA-JR11 PET/CT and serial imaging with 177Lu-satoreotide tetraxetan. PET/CT and SPECT/CT parameters for lesion uptake and absorbed dose of 177Lu-satoreotide tetraxetan in lesions were compared using linear regression analysis and Pearson correlation.

Results:

A total of 95 lesions were analyzed on 68Ga-DOTAJR11 PET/CT and 177Lu-satoreotide tetraxetan SPECT/CT. SUVs and tumor-to-normal-tissue ratios on PET/CT and SPECT/CT were significantly correlated (p<0.01), but the degree of correlation was modest with Pearson correlation coefficients ranging from 0.3–0.7. Variation in intra-patient lesional correlation was observed. Nevertheless, in all patients, the lesion SUVpeak uptake ratio for 177Lu-satoreotide tetraxetan vs. 68Ga-DOTA-JR11 was high; even in those with low uptake on 68Ga-DOTA-JR11 PET/CT (SUVpeak ≤ 10), a ratio of 8.0 ± 5.2 was noted. Correlation of SUVpeak of 68Ga-DOTA-JR11 with projected 177Lu-satoreotide tetratexan-absorbed dose (n=42) was modest (r=0.5, p<0.01), while excellent correlation of SUVpeak of 177Lu-satoreotide tetraxetan with projected 177Lu-satoreotide tetraxetan-absorbed dose was noted (r=0.9, p<0.0001).

Conclusion:

Our study shows that 68Ga-DOTA-JR11 PET can be used for patient selection and PRRT and that low tumor uptake on PET should not preclude patients from treatment with 177Lu-satoreotide tetraxetan. The ability to use single time-point SPECT/CT for absorbed dose calculations could facilitate dosimetry regimens, save costs, and improve patient convenience.

Keywords: Somatostatin receptor antagonists, 68Ga-DOTA-JR11, 177Lu-satoreotide tetraxetan, dosimetry, neuroendocrine tumors

INTRODUCTION

Somatostatin receptor (SSTR) imaging is widely used for guiding the management of patients with neuroendocrine tumors (NETs) [1, 2]. 68Ga-DOTA-TATE was recently approved by the US Food and Drug Administration, enabling SSTR positron emission tomography/computed tomography (PET/CT) throughout the US. 68Ga-DOTA-TATE has been shown to be clinically clearly superior to 111In-DTPA-Octreotide [35]. So far, clinical studies have primarily investigated SSTR agonists, such as DOTA-TATE, -TOC, and -NOC and the excellent correlation of the in vivo SUV (mostly SUVmax) on 68Ga-SSTR-PET/CT with the somatostatin receptor subtype 2 (SSTR2) scores determined on immunohistochemistry has been demonstrated [6, 7]. 68Ga-SSTR-PET/CT assists in therapy stratification, including patient selection for peptide receptor radiotherapy (PRRT) with 90Y- or 177Lu-labelled somatostatin analogs, such as 90Y-DOTATOC [8, 9] and 177Lu-DOTA-TATE [1012]. In this regard, the use of the same peptide for imaging and therapy offers a unique theranostic advantage.

Recent developments included the introduction of radiolabeled SSTR2 antagonists [1317]. Preclinical studies have indicated that these compounds bind to significantly more receptor sites than the SSTR agonists currently used for PRRT [13]. This finding was confirmed by quantitative autoradiography of patient-derived tumor samples [18], which demonstrated a more than four-fold increase in the ex vivo binding of the SSTR antagonist 177Lu-DOTA-BASS when compared to the SSTR agonist 177Lu-DOTA-TATE. Wild et al. performed a preliminary clinical study comparing the dosimetry of a 177Lu-labeled therapeutic SSTR antagonist 177Lu-satoreotide tetraxetan (also known as 177Lu-DOTA-JR11, 177Lu-IPN01072, 177Lu-OPS201) with 177Lu-DOTA-TATE in four patients. In this study, the antagonist demonstrated on average a three-fold higher tumor-absorbed dose coefficient and a two-fold higher tumor-to-kidney dose ratio [17]. Of note is that receptor affinity, tumor uptake, and retention of the SSTR2-antagonist JR11 can be influenced by the chelator and radiometal [14]. Indeed, while labelling of DOTA-JR11 with lutetium does not affect its known sub-nanomolar affinity for SSTR2, labeling with gallium unexpectedly decreases the affinity [14]. An alternative version of this antagonist, with NODAGA as chelator (68Ga-satoreotide trizoxetan, IPN01070, 68Ga-NODAGA-JR11) is in development as a theranostic pair with 177Lu-satoreotide tetraxetan [19]. Nevertheless, PET and biodistribution studies in mice bearing SSTR2-expressing xenografts demonstrated slightly higher tumor uptake of 68Ga-DOTA-JR11 than the high-affinity SSTR2 agonist 68Ga-DOTA-TATE [14], supporting its further clinical evaluation.

Previously, we reported favorable biodistribution and dosimetry of 68Ga-DOTA-JR11 for PET imaging of patients with advanced NETs who were candidates for PRRT with 177Lu-satoreotide tetraxetan, which feature the same precursor, DOTA-JR11 [20]. The aim of this study was to compare tumor uptake of 68Ga-DOTA-JR11 with (dosimetric) 177Lu-satoreotide tetraxetan in the same patients with metastasized NETs to determine if PET imaging with 68Ga-DOTA-JR11 could predict uptake of 177Lu-satoreotide tetraxetan, particularly in the context of potential differences in pharmacokinetics, biodistribution, and dosimetry.

MATERIALS AND METHODS

Clinical study with 68Ga-DOTA-JR11 and dosimetric 177Lu-satoreotide tetraxetan

The study was a phase I investigator-initiated study conducted at Memorial Sloan Kettering Cancer Center (MSK), approved by the Institutional Review Board (trial registration ID NCT02609737) and conducted under the auspices of an Investigational New Drug application acknowledged by the FDA. All study participants provided written informed consent before study enrollment.

Twenty patients with progressive, histologically proven, unresectable NETs were imaged with the SSTR2 antagonist 68Ga-DOTA-JR11 as a prelude to PRRT with 177Lu-satoreotide tetraxetan. The first six had extended imaging to facilitate kinetic analysis and normal tissue radiation dose estimates. In preparation for PRRT, all patients underwent serial imaging studies with 177Lu-satoreotide tetraxetan.

68Ga-DOTA-JR11 and 177Lu-satoreotide tetraxetan preparation

DOTA-JR11 was synthesized as previously described [17] and was the precursor for both radiolabeled species. 68Ga-DOTA-JR11 and 177Lu-satoreotide tetraxetan were manufactured by the MSK Radiochemistry and Molecular Imaging Probe Core Facility in compliance with an FDA-approved IND (#128,082) [20].

PET/CT imaging with 68Ga-DOTA-JR11

68Ga-DOTA-JR11 was administered to subjects at a planned activity of 185 MBq (5 mCi) ±10% by slow bolus injection. All 20 patients underwent whole-body (vertex of skull to midthigh) PET/CT imaging (GE PET/CT 710 scanner with time-of-flight) at 60 min (mean 64 min; SD 6) post-injection to determine eligibility for treatment with 177Lu-satoreotide tetraxetan. 68Ga-DOTA-JR11 PET/CT was performed with a standard technique, as previously reported [20].

For the purpose of radiation-absorbed dose estimation and kinetic analyses, additional images were acquired in the first 6 of 20 patients (3 female and 3 male). These included a 25-min/19-frame dynamic acquisition initiated at the time of administration and centered on the upper abdomen to include, at least partly, cardiac left ventricle, liver, spleen, and kidney. Further details related to the dosimetry have been reported [20].

177Lu-satoreotide tetraxetan dosimetry

An infusion of 2,000 mL Aminosyn II 10% solution was initiated 30 min before and continued for 3.5 h after the 177Lu-satoreotide tetraxetan injection to inhibit tubular reabsorption of the radiopeptide [21]. 177Lu-satoreotide tetraxetan was administered at an activity of 1.94 GBq (median). Full details of the methodology and results of radiation dose estimation will be presented in a separate manuscript. Briefly, radiation dose estimates were calculated based on the analysis of serial blood counts and planar scintigraphic images together with a single quantitative SPECT/CT scan of the upper abdomen, including kidneys and sites of known disease, performed at 18–30 h post-injection. All studies were done with the same SPECT/CT scanner (BrightView XCT, Philips) equipped with medium-energy, parallel-hole collimators. Volumes of interest (VOI) were generated to correspond to kidney, spleen, uninvolved liver, bone, and 1–7 index lesions for each patient. The activity concentrations in VOI and the corresponding areas under the curve were estimated. It was assumed that the activity concentration in red bone marrow was equal to that in blood [22]. These data were used to provide input to the radiation dose estimation software package OLINDA/EXM 1.0 [23]. Radiation dose estimates to selected index lesions were generated, considering only the non-penetrating component (i.e., beta particles) of 177Lu emissions.

Image interpretation, lesion detection, and data analysis of 68Ga-DOTA-JR11 and 177Lu-satoreotide tetraxetan

Whole-body PET/CT scans were first interpreted visually and then by semiquantitative analysis without information on the results of other imaging modalities. Any lesions with focal radiotracer uptake not explained by physiologic SSTR2 expression were interpreted as metastatic disease. Only patients that had 68Ga-DOTA-JR11 uptake greater than that in the liver in at least one metastasis of more than 2 cm diameter were considered for therapy. The 177Lu-satoreotide tetraxetan dosimetry SPECT/CT scan performed at 18–30 h was used for comparison. The same lesions were identified and measured for both 68Ga-DOTA-JR11 and 177Lu-satoreotide tetraxetan uptake.

VOI were generated over lesions using a Hermes imaging workstation (Hermes Medical Solutions, Chicago, IL, USA). Typically, a value of 40–50% of maximum tracer uptake was used as a threshold but this was guided by interpretation of the CT scan. A total of 95 lesions were analyzed with a maximum of seven lesions per patient.

For normal tissues (liver, kidney, and spleen), regions of interest (ROI) were drawn within organs over at least five consecutive transaxial PET or SPECT slices and combined to generate VOI using a Hermes imaging workstation. For normal liver, ROI were drawn to exclude disease foci.

Tracer uptake was quantified by standardized uptake value (SUV) normalized to patients’ body weight. For lesion VOI, SUVmax and SUVpeak were recorded in addition to SUVmean. SUVmax referred to the maximum voxel in the VOI, whereas SUVpeak was defined as the mean SUV of the hottest 1 cubic centimeter in the VOI. For normal tissues, only SUVmean within the VOI was used.

Comparative lesion uptake was quantified using tumor-to-normal (TNR) SUV ratios defined as SUVmax (lesion)/SUV (tissue) for spleen, kidney, and liver. As 4 of the 20 patients had prior splenectomy, TNR (spleen) was calculated for only 16 patients.

Statistical analysis

Statistical analysis of PET and SPECT parameters and absorbed dose estimates for 177Lu-satoreotide tetraxetan was performed using linear regression analysis and Pearson correlation (P < 0.05; GraphPad Prism Software).

RESULTS

All 20 enrolled patients (10 women and 10 men aged 22–73 years; mean 54 ± 14 years) with progressive, histologically proven, unresectable NETs, underwent whole-body 68Ga-DOTA-JR11 PET/CT and 177Lu-satoreotide tetraxetan dosimetry scans within 16 ± 9 days between the studies. Patient characteristics and corresponding lesion analysis for all 20 patients are summarized in Table 1.

Table 1.

Demographic and clinical characteristics of patients and corresponding lesion analyses.

Patient Sex Site of primary Grade Correlated lesions (n) Lesions with calculated dose (n)
1 F SI G2 5 1
2 F Pancreas G2 6 1
3 M Pancreas G1 6 3
4 M Stomach G2 5 2
5 M BP Atypical 6 2
6 F Pancreas G2 6 1
7 M Rectum G1 5 2
8 M Pancreas G2 5 2
9 F SI G2 7 2
10 F SI G2 3 2
11 F Pancreas G2 5 3
12 F Pancreas G2 1 1
13 F SI G2 5 2
14 F SI G1 6 4
15 M Pancreas G1 3 1
16 F Pancreas G2 4 4
17 M Pancreas G2 6 4
18 M SI G2 1 1
19 M Renal G3 4 3
20 M Pancreas G1 6 1

F: female; M: male; SI: small intestine; BP: bronchopulmonary; G1: low-grade (well differentiated); G2: intermediate-grade (moderately differentiated); G3: high-grade (poorly differentiated); N/A: not available; n: number

The mean administered activity of 68Ga-DOTA-JR11 was 169 MBq (4.6 mCi); range: 137–192 MBq (3.7–5.2 mCi) with a mean radiochemical purity of 99.95% (range: 99–100%). The mean administered activity of 177Lu-satoreotide tetraxetan was 1848 MBq (49.9 mCi); range 811–2019 MBq (21.9–54.6 mCi) with a mean radiochemical purity of 99.95% (range: 99–100%). Mean injected peptide mass was 81μg (range: 60–97 μg) and 73 μg (range: 48–100 μg), respectively.

68Ga-DOTA-JR11 PET/CT and 177Lu-satoreotide tetraxetan SPECT/CT imaging

68Ga-DOTA-JR11 PET/CT and 177Lu-satoreotide tetraxetan SPECT/CT revealed positive lesions in all 20 patients. On visual inspection, 68Ga-DOTA-JR11 PET and 177Lu-satoreotide tetraxetan SPECT images demonstrated similar favorable biodistribution with minimal or mild uptake in uninvolved liver (Figs. 13).

Fig. 1.

Fig. 1

Patient with concordant lesion uptake of 68Ga-DOTA-JR11 and 177Lu-satoreotide tetraxetan. (a) 68Ga-DOTA-JR11 PET maximum-intensity projection; and (b) 177Lu-satoreotide tetraxetan SPECT maximum-intensity projection images depicting intense uptake in the nodal mass (blue and orange arrows, respectively). Minimal or mild uptake in the liver is seen on PET and SPECT images; more prominent splenic uptake is noted on SPECT compared to PET images.

Fig. 3.

Fig. 3

Patient with markedly discordant lesion uptake. The majority of the nodal and hepatic lesions are not visualized on (a) and (b) 68Ga-DOTA-JR11 PET but are on (c) and (d) 177Lu-satoreotide tetraxetan SPECT. (a) and (c) Transverse, coronal, and sagittal PET/CT and SPECT/CT images set at the level of the crosshairs shown in (b) and (d) maximum-intensity projection images.

Quantitative analysis of 68Ga-DOTA-JR11 indicated mild uptake above blood pool in spleen and uninvolved liver. 177Lu-satoreotide tetraxetan was generally higher in these tissues, especially spleen. Renal uptake was relatively high for both compounds (Table 2).

Table 2.

SUVmean of normal tissues and organs for 60-min 68Ga-DOTA-JR11 PET/CT scan and for 18–30 h 177Lu-satoreotide tetraxetan SPECT/CT scan.

Organ SUVmean
(68Ga-DOTA-JR11)
SUVmean
(177Lu-satoreotide tetraxetan)
Spleen (n=16) 1.4 ± 0.3 9.3 ± 5.5
Liver (n=19) 1.1 ± 0.3 2.4 ± 1.3
Kidney 4.5 ± 1.5 7.3 ± 2.7

Data are mean ± SD; n=20 unless otherwise specified

Interlesional analysis

A total of 95 lesions were analyzed on 68Ga-DOTA-JR11 PET and 177Lu-satoreotide tetraxetan SPECT (Supplementary Table 1). Those lesions included 66 hepatic, 12 nodal, 10 osseus, 5 peritoneal/mesenteric, 1 pulmonary, and 1 splenic metastases. On visual inspection, similar or higher uptake was seen for the majority of lesions on 177Lu-satoreotide tetraxetan SPECT/CT compared to 68Ga-DOTA-JR11 PET/CT. A general concordance was seen in 15 of 20 patients (75 %) (Fig. 1); however, in the remaining five patients, some lesions displayed discordant uptake—distinct in one modality, largely absent in the other (Figs. 2 and 3). Quantitative analysis showed higher uptake of 177Lu-satoreotide tetraxetan than 68Ga-DOTA-JR11 in 92 of 95 lesions (97%). The highest SUV values on PET/CT and SPECT/CT were observed in liver lesions with median SUVpeak of 16 (range 1–82) and 47 (range 8–257), respectively. Summary statistics for SUV and TNR values according to sites of disease are shown in Supplementary Table 1. For all lesions on 68Ga-DOTA-JR11 PET/CT, median SUVpeak was 10 (1–82), TNR spleen 6 (1–48), TNR liver 11 (1–99), and TNR kidney 3.4 (0.3–26). On 177Lu-satoreotide tetraxetan SPECT/CT, median SUVpeak was 40 (5–257), TNR spleen 4 (0.3–80), TNR liver 23 (2–104), and TNR kidney 6 (0.5–50). SUVs and tumor-to-organ ratios on PET and SPECT were significantly correlated, but the degree of correlation was modest, with Pearson correlation coefficients of 0.5 for SUVpeak (p<0.0001), 0.3 for TNR spleen (p<0.01), 0.5 for TNR liver (p<0.0001), and 0.7 for TNR kidney (p<0.0001) (Fig. 4).

Fig. 2.

Fig. 2

Patient with partly discordant lesion uptake. Some of the nodal and hepatic lesions were better visualized on (a) 68Ga-DOTA-JR11 PET maximum-intensity projection (nodal lesions, blue arrows) and are not evident or only faintly seen on (b) 177Lu-satoreotide tetraxetan SPECT maximum-intensity projection images (orange arrows).

Fig. 4.

Fig. 4

Correlation of lesion uptake (SUVpeak) and tumor-to-normal-tissue ratio (TNR) on 68Ga-DOTA-JR11 and 177Lu-satoreotide tetraxetan. Linear regression with 95% confidence band and R2 values of 0.3, 0.1, 0.3, 0.5, 0.002, and 0.2. Lesion sites are noted as follows: orange: liver (n=66); green: lymph nodes, peritoneum/mesentery, spleen (n=18); blue: bone, lung (n=11). S: spleen; K: kidney; L: normal liver. (SUVpeak: n=95, TNR-S: n=74, TNR-L: n=95, TNR-K: n=95, threshold SUVpeak: n=49 and n=46, respectively).

Subgroup analysis

There was a better correlation of tumor uptake for lesions with SUVpeak on PET of > 10 (r=0.5, p<0.001) than for lesions with a lower SUVpeak (≤ 10) (r=0.1, p=ns) (Fig. 4). Additional subgroup analyses, such as pancreatic primary site, did not yield improved lesion correlations.

Intrapatient lesional analysis

Variation in correlation trends was seen across patients for intrapatient lesional uptake. Out of 18 patients with ≥ 3 lesions, 13 patients showed a positive correlation between PET and SPECT SUVpeak, of which 10 were high (r ≥ 0.8) and 3 were relatively low (r < 0.8); 5 patients showed a negative correlation (Supplementary Table 2).

Lesion SUVpeak ratios

For all lesions, the ratio of peak lesion uptake for 177Lu-satoreotide tetraxetan vs. 68Ga-DOTA-JR11 was 5.4 ± 4.8. For lesions with low uptake on PET/CT (SUVpeak ≤ 10), an SUVpeak ratio of 8.0 ± 5.2 was noted and for lesions with SUVpeak > 10 on PET/CT, the ratio was 2.5 ± 1.4.

Correlation of SUVpeak and 177Lu-satoreotide tetraxetan-absorbed dose

The mean lesion-absorbed dose (± SD) for 177Lu-satoreotide tetraxetan was 6.5 (± 4.0) Gy/GBq (42 lesions); correlation with 68Ga-DOTA-JR11 SUVpeak was modest (r=0.5, p<0.01) (Fig. 5a), whereas correlation with 177Lu-satoreotide tetraxetan SUVpeak was high (r=0.9, p<0.0001) (Fig. 5b).

Fig. 5.

Fig. 5

Correlation of lesion SUVpeak for (a) 68Ga-DOTA-JR11 and (b) 177Lu-satoreotide tetraxetan and subsequently achieved lesion-absorbed dose per injected activity (177Lu-satoreotide tetraxetan) (n=42, each). Linear regression with 95% confidence band and R2 values of 0.2 and 0.9.

DISCUSSION

This is the first study investigating the correlation between the theranostic pair of SSTR antagonists 68Ga-DOTA-JR11 and 177Lu-satoreotide tetraxetan, which feature the same precursor, DOTA-JR11. 68Ga-DOTA-JR11 PET/CT and 177Lu-satoreotide tetraxetan SPECT/CT revealed positive lesions in all 20 patients with metastatic NETs. The significant correlation of SUVs and tumor-to-normal-tissue ratios on PET and SPECT indicate that 68Ga-DOTA-JR11 PET/CT may serve as a tool for patient selection and PRRT with 177Lu-satoreotide tetraxetan. Indeed, high uptake in all known sites of disease (liver, nodes, bone) as seen on 68Ga-DOTA-JR11 PET/CT was noted during PRRT [24]. Furthermore, our results confirm the excellent targeting properties of this pair of SSTR antagonists for SSTR-positive lesions.

On 68Ga-DOTA-JR11 PET/CT and 177Lu-satoreotide tetraxetan SPECT/CT images, similar favorable biodistribution with minimal or mild uptake in uninvolved liver was seen, potentially facilitating lesion detection. Higher uptake in spleen was seen with 177Lu-satoreotide tetraxetan, possibly related to increased affinity of the Lu-labeled compound for its receptor. Renal uptake was variable for both, similar to observations using SSTR2 agonists, such as DOTA-TOC [25].

Qualitatively, similar or higher lesion uptake compared to background was seen in the majority of lesions on 177Lu-satoreotide tetraxetan SPECT/CT compared to 68Ga-DOTA-JR11 PET/CT. Quantitative analysis confirmed higher uptake of 177Lu-satoreotide tetraxetan than 68Ga-DOTA-JR11 in 92 of 95 lesions (97%). While we observed better lesion visualization on SPECT/CT, Sainz-Esteban et al. reported more lesions (9%) on 68Ga-DOTA-TATE PET/CT than on planar 177Lu-DOTA-TATE scans, which was attributed to the location of these lesions in the abdomen, an area with high background, possible superposition of the bowel obscuring lesions, as well as the small size of these lesions, resulting in a lower sensitivity on planar scans [26]. It should be noted that 68Ga-DOTA-TATE has a 10-fold higher affinity to SSTR2 than 177Lu-DOTA-TATE and different peptide masses were used for the diagnostic and therapeutic compounds.

In our study, SUVs and tumor-to-normal-tissue ratios on PET and SPECT with the SSTR2 antagonist JR11 were significantly correlated (p<0.001). Sainz-Esteban et al. reported significant correlation of 68Ga-/177Lu-DOTA-TATE based on visual intensity scores for lesions in the thorax, abdomen/pelvis, and bones (p<0.05), but not for liver lesions [26]; the degree of correlation was not provided. The modest strength of the correlation in our study might be related to the short half-life of 68Ga (68 min), which limits delayed imaging time points. Post-treatment scans with 177Lu-satoreotide tetraxetan showed the highest tumor uptake between 3–24 h post-injection, while the highest tumor uptake of 177Lu-DOTA-TATE was observed at 1 h post-injection [17, 27]. However, in our study investigating the biodistribution of 68Ga-DOTA-JR11, lesion uptake was observed to be rapid, typically reaching the highest levels (SUVmax of up to 50) by 20–30 min post-injection and in most instances remaining close to plateau thereafter [20].

The influence of chelator moiety and radiometal type on the biologic properties of SSTR antagonists has been demonstrated [15]. Indeed, while labeling of DOTA-JR11 with lutetium does not affect its known sub-nanomolar affinity for SSTR2, labeling with gallium decreases the affinity by about 40-fold [14]. Reasons for the strong influence of the radiometal are likely related to differences in the complex geometry of the coordination compound of the radiometal [28].

We observed variation in lesional correlation of the theranostic pair. Potential reasons include lesion heterogeneity and differences in target densities, as well as disrupted or increased regional blood supply by pathologic tumor vessels that may affect uptake and retention of the radiotracer in the tumors. Nevertheless, in all patients, the lesion SUVpeak uptake ratio for 177Lu-satoreotide tetraxetan vs. 68Ga-DOTA-JR11 was high, especially in those with low uptake on PET (SUVpeak ≤ 10). A ratio of 8.0 ± 5.2 was noted, indicating that even patients with low SSTR-expressing tumor lesions may benefit from treatment with 177Lu-satoreotide tetraxetan. The high tumor uptake of 177Lu-satoreotide tetraxetan in some tumor lesions despite low uptake of 68Ga-DOTA-JR11 is in line with the lower affinity of 68Ga-DOTA-JR11 for SSTR2.

In our study, the correlation of SUVpeak of 68Ga-DOTA-JR11 with the projected therapeutic absorbed dose of 177Lu-satoreotide tetraxetan was modest (r=0.5, p<0.01). So far, no comparison of the pretherapeutic tumor SUV on PET with the absorbed dose of the therapeutic agent using an antagonist has been reported. One study comparing the pretherapeutic tumor SUV for 68Ga-DOTATOC PET with the absorbed dose of 177Lu-Octreotate on the subsequent first treatment cycle in 21 patients with NETs showed high correlation (r = 0.72 (SUVmean) and r = 0.71 (SUVmax), both P ≤ 0.001) [29]. However, conflicting reports on the correlation of lesion uptake on PET with response have been published [3033].

It has been reported that the SSTR expression level directly correlates with the tumor-absorbed dose during PRRT [34]. A high tumor-absorbed dose is thought to be predictive of response to PRRT [10, 35]. The excellent correlation of 177Lu-satoreotide tetraxetan uptake on SPECT/CT at about 24 h post-injection with absorbed dose (Gy/GBq) (r = 0.9, p<0.0001) warrants particular attention; it implies that the kinetics are relatively similar for all lesions. This finding could have a significant impact on clinical dosimetry, which is technically demanding and currently performed by the analysis of serial blood samples and scintigraphic images acquired over several days. Future studies investigating the use of single time-point SPECT/CT for absorbed dose calculations are needed.

CONCLUSION

Our findings support the role of 68Ga-DOTA-JR11 PET/CT as a tool for patient selection and PRRT with 177Lu-satoreotide tetraxetan. The ability to use a single time-point SPECT/CT for absorbed dose calculations could facilitate dosimetry regimens, save costs, and improve patient convenience.

Supplementary Material

259_2020_4832_MOESM1_ESM
259_2020_4832_MOESM2_ESM

Acknowledgments:

We gratefully acknowledge Rashid Ghani and members of the Nuclear Medicine Pharmacy; nuclear medicine nurses Ann Longing and Louise Harris for their help in patient management; clinical research coordinators Alicia Lashley, Hanh Pham, and Martha Ziolkowska, and Clinical Research Manager Bolorsukh Gansukh for their excellent support with patient flow and protocol management; the radiation safety officers and nuclear medicine technologists for their excellent technical assistance; and members of the Department of Medicine at MSK for patient referral. We also thank Leah Bassity for her assistance in editing this manuscript.

Funding: This study was supported in part by the Geoffrey Beene Cancer Research Center at MSK and the MSK Radiochemistry and Molecular Imaging Probe Core was funded in part through NIH/NCI Cancer Center Support Grant P30 CA008748. We gratefully acknowledge funding from the Neuroendocrine Tumor Research Foundation (NETRF) (previously known as the Caring for Carcinoid Foundation). SK was supported in part by NIH/NCI Paul Calabresi Career Development Award for Clinical Oncology K12 CA184746 and by the Clinical and Translational Science Center at Weill Cornell Medical Center and MSK (grant number UL1TR00457). J.S. L. acknowledges support from NIH R35 CA232130. The precursor used in this study was provided by Ipsen.

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

Conflicts of interest/Competing interests:

J. A. O’Donoghue is a consultant for Janssen Pharmaceuticals, Inc. D. Reidy is on advisory boards for Novartis, Ipsen and AAA and has received research support from Novartis, Merck, and Ipsen. J. Lewis serves on advisory boards and has received compensation (or stock) from pHLIP, Inc., Clarity Pharmaceuticals, Varian Medical Systems, InVicro, Inc, Evergreen Theragnostics, Inc., Telix Pharmaceuticals Ltd., and Trace-Ability, Inc. He is a consultant for TPG Capital, L.P., and has received research support (financial and/or reagents) from Eli Lilly and Company, Sapience Therapeutics, Inc., Mabvax Therapeutics Holdings Inc., SibTech, Inc., Thermo Fisher Scientific, ImaginAb, Inc. U.S., Merck & Company, Inc., AbbVie Inc., Bristol-Myers Squibb Company, Genentech, Inc., Y-mAbs Therapeutics, Inc., and Regeneron Pharmaceuticals, Inc. L. Bodei is a consultant (unpaid) for AAA, Ipsen, Clovis, and Curium and receives research support from AAA. W. Weber is on advisory boards and receives compensation from Bayer, Blue Earth Diagnostics, Endocyte, Pentixapharm, and ITG. He has received research support from BMS, Imaginab, Ipsen and Piramal. N. Pandit-Taskar is a consultant, receives honoraria or serves on the advisory board for Actinium Pharma, Progenics, Medimmune/Astrazeneca and conducted research supported by Imaginab, Genentech, Janssen. S. Krebs, E. Biegel, B.J. Beattie, and S.K. Lyashchenko declare that they have no conflicts of interest.

Availability of data and materials: Not applicable.

Code availability: Not applicable.

Ethical approval: All procedures involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent: Informed written consent was obtained from all individual participants included in the study.

REFERENCES

  • 1.Bodei L, Ambrosini V, Herrmann K, Modlin I. Current Concepts in (68)Ga-DOTATATE Imaging of Neuroendocrine Neoplasms: Interpretation, Biodistribution, Dosimetry, and Molecular Strategies. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2017;58:1718–26. doi: 10.2967/jnumed.116.186361. [DOI] [PubMed] [Google Scholar]
  • 2.Barrio M, Czernin J, Fanti S, Ambrosini V, Binse I, Du L, et al. The Impact of Somatostatin Receptor-Directed PET/CT on the Management of Patients with Neuroendocrine Tumor: A Systematic Review and Meta-Analysis. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2017;58:756–61. doi: 10.2967/jnumed.116.185587. [DOI] [PubMed] [Google Scholar]
  • 3.Gabriel M, Decristoforo C, Kendler D, Dobrozemsky G, Heute D, Uprimny C, et al. 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2007;48:508–18. [DOI] [PubMed] [Google Scholar]
  • 4.Srirajaskanthan R, Kayani I, Quigley AM, Soh J, Caplin ME, Bomanji J. The role of 68-GaDOTATATE PET in patients with neuroendocrine tumors and negative or equivocal findings on 111In-DTPA-octreotide scintigraphy. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2010;51:875–82. doi: 10.2967/jnumed.109.066134. [DOI] [PubMed] [Google Scholar]
  • 5.Velikyan I, Sundin A, Sorensen J, Lubberink M, Sandstrom M, Garske-Roman U, et al. Quantitative and qualitative intrapatient comparison of 68Ga-DOTATOC and 68Ga-DOTATATE: net uptake rate for accurate quantification. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2014;55:204–10. doi: 10.2967/jnumed.113.126177. [DOI] [PubMed] [Google Scholar]
  • 6.Kaemmerer D, Peter L, Lupp A, Schulz S, Sanger J, Prasad V, et al. Molecular imaging with (6)(8)Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours. European journal of nuclear medicine and molecular imaging. 2011;38:1659–68. doi: 10.1007/s00259-011-1846-5. [DOI] [PubMed] [Google Scholar]
  • 7.Miederer M, Seidl S, Buck A, Scheidhauer K, Wester HJ, Schwaiger M, et al. Correlation of immunohistopathological expression of somatostatin receptor 2 with standardised uptake values in 68Ga-DOTATOC PET/CT. European journal of nuclear medicine and molecular imaging. 2009;36:48–52. doi: 10.1007/s00259-008-0944-5. [DOI] [PubMed] [Google Scholar]
  • 8.Otte A, Herrmann R, Heppeler A, Behe M, Jermann E, Powell P, et al. Yttrium-90 DOTATOC: first clinical results. European journal of nuclear medicine. 1999;26:1439–47. [PubMed] [Google Scholar]
  • 9.Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29:2416–23. doi: 10.1200/jco.2010.33.7873. [DOI] [PubMed] [Google Scholar]
  • 10.Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26:2124–30. doi: 10.1200/jco.2007.15.2553. [DOI] [PubMed] [Google Scholar]
  • 11.Bodei L, Cremonesi M, Grana CM, Fazio N, Iodice S, Baio SM, et al. Peptide receptor radionuclide therapy with (1)(7)(7)Lu-DOTATATE: the IEO phase I-II study. European journal of nuclear medicine and molecular imaging. 2011;38:2125–35. doi: 10.1007/s00259-011-1902-1. [DOI] [PubMed] [Google Scholar]
  • 12.Delpassand ES, Samarghandi A, Zamanian S, Wolin EM, Hamiditabar M, Espenan GD, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE for patients with somatostatin receptor-expressing neuroendocrine tumors: the first US phase 2 experience. Pancreas. 2014;43:518–25. doi: 10.1097/mpa.0000000000000113. [DOI] [PubMed] [Google Scholar]
  • 13.Ginj M, Zhang H, Waser B, Cescato R, Wild D, Wang X, et al. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:16436–41. doi: 10.1073/pnas.0607761103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Fani M, Braun F, Waser B, Beetschen K, Cescato R, Erchegyi J, et al. Unexpected sensitivity of sst2 antagonists to N-terminal radiometal modifications. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2012;53:1481–9. doi: 10.2967/jnumed.112.102764. [DOI] [PubMed] [Google Scholar]
  • 15.Fani M, Del Pozzo L, Abiraj K, Mansi R, Tamma ML, Cescato R, et al. PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the difference. J Nucl Med. 2011;52:1110–8. doi: 10.2967/jnumed.111.087999. [DOI] [PubMed] [Google Scholar]
  • 16.Wild D, Fani M, Behe M, Brink I, Rivier JE, Reubi JC, et al. First clinical evidence that imaging with somatostatin receptor antagonists is feasible. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2011;52:1412–7. doi: 10.2967/jnumed.111.088922. [DOI] [PubMed] [Google Scholar]
  • 17.Wild D, Fani M, Fischer R, Del Pozzo L, Kaul F, Krebs S, et al. Comparison of somatostatin receptor agonist and antagonist for peptide receptor radionuclide therapy: a pilot study. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2014;55:1248–52. doi: 10.2967/jnumed.114.138834. [DOI] [PubMed] [Google Scholar]
  • 18.Cescato R, Waser B, Fani M, Reubi JC. Evaluation of 177Lu-DOTA-sst2 antagonist versus 177Lu-DOTA-sst2 agonist binding in human cancers in vitro. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2011;52:1886–90. doi: 10.2967/jnumed.111.095778. [DOI] [PubMed] [Google Scholar]
  • 19.Mansi R, Fani M. Design and development of the theranostic pair (177) Lu-OPS201/(68) Ga-OPS202 for targeting somatostatin receptor expressing tumors. Journal of labelled compounds & radiopharmaceuticals. 2019;62:635–45. doi: 10.1002/jlcr.3755. [DOI] [PubMed] [Google Scholar]
  • 20.Krebs S, Pandit-Taskar N, Reidy D, Beattie BJ, Lyashchenko SK, Lewis JS, et al. Biodistribution and radiation dose estimates for (68)Ga-DOTA-JR11 in patients with metastatic neuroendocrine tumors. European journal of nuclear medicine and molecular imaging. 2019;46:677–85. doi: 10.1007/s00259-018-4193-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Bodei L, Cremonesi M, Zoboli S, Grana C, Bartolomei M, Rocca P, et al. Receptor-mediated radionuclide therapy with 90Y-DOTATOC in association with amino acid infusion: a phase I study. European journal of nuclear medicine and molecular imaging. 2003;30:207–16. doi: 10.1007/s00259-0021023-y. [DOI] [PubMed] [Google Scholar]
  • 22.Forrer F, Krenning EP, Kooij PP, Bernard BF, Konijnenberg M, Bakker WH, et al. Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA(0),Tyr(3)]octreotate. European journal of nuclear medicine and molecular imaging. 2009;36:1138–46. doi: 10.1007/s00259-009-1072-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2005;46:1023–7. [PubMed] [Google Scholar]
  • 24.Reidy-Lagunes D, Pandit-Taskar N, O’Donoghue JA, Krebs S, Staton KD, Lyashchenko SK, et al. Phase I Trial of Well-Differentiated Neuroendocrine Tumors (NETs) with Radiolabeled Somatostatin Antagonist (177)Lu-Satoreotide Tetraxetan. Clinical cancer research : an official journal of the American Association for Cancer Research. 2019;25:6939–47. doi: 10.1158/1078-0432.Ccr-19-1026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Jamar F, Barone R, Mathieu I, Walrand S, Labar D, Carlier P, et al. 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. European journal of nuclear medicine and molecular imaging. 2003;30:510–8. doi: 10.1007/s002-59-003-1117-1. [DOI] [PubMed] [Google Scholar]
  • 26.Sainz-Esteban A, Prasad V, Schuchardt C, Zachert C, Carril JM, Baum RP. Comparison of sequential planar 177Lu-DOTA-TATE dosimetry scans with 68Ga-DOTA-TATE PET/CT images in patients with metastasized neuroendocrine tumours undergoing peptide receptor radionuclide therapy. European journal of nuclear medicine and molecular imaging. 2012;39:501–11. doi: 10.1007/s00259-011-2003-x. [DOI] [PubMed] [Google Scholar]
  • 27.Nicolas GP, Schreiter N, Kaul F, Uiters J, Bouterfa H, Kaufmann J, et al. Sensitivity Comparison of (68)Ga-OPS202 and (68)Ga-DOTATOC PET/CT in Patients with Gastroenteropancreatic Neuroendocrine Tumors: A Prospective Phase II Imaging Study. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2018;59:915–21. doi: 10.2967/jnumed.117.199760. [DOI] [PubMed] [Google Scholar]
  • 28.Heppeler A, Froidevaux S, Maecke HR, Jermann E, Behe M, Powell P, Hennig M. Radiometal-Labelled Macrocyclic Chelator-Derivatised Somatostatin Analogue with Superb Tumour-Targeting Properties and Potential for Receptor-Mediated Internal Radiotherapy. Chemistry — A European Journal. 1999;5:1974–1981. doi:. [DOI] [Google Scholar]
  • 29.Ezziddin S, Lohmar J, Yong-Hing CJ, Sabet A, Ahmadzadehfar H, Kukuk G, et al. Does the pretherapeutic tumor SUV in 68Ga DOTATOC PET predict the absorbed dose of 177Lu octreotate? Clinical nuclear medicine. 2012;37:e141–7. doi: 10.1097/RLU.0b013e31823926e5. [DOI] [PubMed] [Google Scholar]
  • 30.Kratochwil C, Stefanova M, Mavriopoulou E, Holland-Letz T, Dimitrakopoulou-Strauss A, Afshar-Oromieh A, et al. SUV of [68Ga]DOTATOC-PET/CT Predicts Response Probability of PRRT in Neuroendocrine Tumors. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging. 2015;17:313–8. doi: 10.1007/s11307-014-0795-3. [DOI] [PubMed] [Google Scholar]
  • 31.Campana D, Ambrosini V, Pezzilli R, Fanti S, Labate AM, Santini D, et al. Standardized uptake values of (68)Ga-DOTANOC PET: a promising prognostic tool in neuroendocrine tumors. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2010;51:353–9. doi: 10.2967/jnumed.109.066662. [DOI] [PubMed] [Google Scholar]
  • 32.Ambrosini V, Campana D, Polverari G, Peterle C, Diodato S, Ricci C, et al. Prognostic Value of 68Ga-DOTANOC PET/CT SUVmax in Patients with Neuroendocrine Tumors of the Pancreas. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2015;56:1843–8. doi: 10.2967/jnumed.115.162719. [DOI] [PubMed] [Google Scholar]
  • 33.Toriihara A, Baratto L, Nobashi T, Park S, Hatami N, Davidzon G, et al. Prognostic value of somatostatin receptor expressing tumor volume calculated from (68)Ga-DOTATATE PET/CT in patients with well-differentiated neuroendocrine tumors. European journal of nuclear medicine and molecular imaging. 2019;46:2244–51. doi: 10.1007/s00259-019-04455-9. [DOI] [PubMed] [Google Scholar]
  • 34.Kwekkeboom DJ, Kam BL, van Essen M, Teunissen JJ, van Eijck CH, Valkema R, et al. Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocrine-related cancer. 2010;17:R53–73. doi: 10.1677/erc-09-0078. [DOI] [PubMed] [Google Scholar]
  • 35.Cremonesi M, Botta F, Di Dia A, Ferrari M, Bodei L, De Cicco C, et al. Dosimetry for treatment with radiolabelled somatostatin analogues. A review The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the So. 2010;54:37–51. [PubMed] [Google Scholar]

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