Highly variable biodistribution of 68Ga labeled somatostatin analogues 68Ga-DOTA-NOC and 68Ga-DOTA-TATE in neuroendocrine tumors: clinical implications for somatostatin receptor directed PET/CT
Original Article

Highly variable biodistribution of 68Ga labeled somatostatin analogues 68Ga-DOTA-NOC and 68Ga-DOTA-TATE in neuroendocrine tumors: clinical implications for somatostatin receptor directed PET/CT

Monica Cheng, Mark Tann

Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA

Contributions: (I) Conception and design: Both authors; (II) Administrative support: M Tann; (III) Provision of study materials or patients: M Tann; (IV) Collection and assembly of data: Both authors; (V) Data analysis and interpretation: Both authors; (VI) Manuscript writing: Both authors; (VII) Final approval of manuscript: Both authors.

Correspondence to: Mark Tann, MD; Monica Cheng, MD. Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 550 N. University Blvd, UH 0655, Indianapolis, IN 46202, USA. Email: matann@iupui.edu; monicacheng520@gmail.com.

Background: Somatostatin receptor (SSTR)-targeted positron emission tomography/computed tomography (PET/CT) imaging has risen to the forefront for neuroendocrine tumor (NET) detection and management, yet the variability of significant uptake variability (SUV) as a semiquantitative measure of disease detection and tumor response to treatment has not been fully explored.

Methods: We assess the reproducibility and interscan variability of SUV metrics of normal tissue and NET in serial 68Ga-DOTA-NOC and 68Ga-DOTA-TATE PET imaging to clinically monitor disease state. Eighty-one patients were enrolled in this retrospective study.

Results: Both primary and metastatic hepatic lesions demonstrated SUV (SUVmean 16.5±8.0). The median SUVmean was 16 for the spleen, 9.7 for the pituitary, 12.6 for the adrenal glands, and 4.8 for the liver. The normal pituitary gland demonstrates focal homogenous uptake with SUVmax range of 4.5–23. The adrenal gland showed uptake with SUVmax range of 4.1–29.4, which is more than two times greater than liver uptake (SUVmean range, 2.3–12.4). Highest physiological uptake seen in the spleen (average SUVmean of 17.3, range of 5.4–34.4).

Conclusions: The highly variable nature of regional SUVmean and SUVmax in both physiologic tissue and lesions suggests the need for incorporation of more reliable quantitative measures for clinical decision making.

Keywords: Neuroendocrine tumors (NETs); liver; pancreas; gastrointestinal tract; 68Ga-DOTA PET imaging; somatostatin receptors (SSTRs); targeted therapy

Submitted Dec 21, 2021. Accepted for publication Mar 14, 2022.

doi: 10.21037/hbsn-21-554

Introduction

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that manifest throughout the body, particularly the gastrointestinal system and lungs (1-4). Despite their differences, these tumors share in common a high expression of somatostatin receptors (SSTRs), a property that has been harnessed by recent molecular imaging methods using SSTR analogs (5). SSTR-targeted probes have become widely utilized across routine clinical contexts for the management of NETs, and open new avenues for precision oncology when paired with a companion receptor-targeted radiotherapeutic agent (6-12). With the rapid adoption of SSTR-targeted positron emission tomography/computed tomography (PET/CT) imaging into the routine clinical management of NETs, it is necessary to evaluate the accuracy and reliability of interpreting the findings of SSTR-PET/CT imaging, particularly if the diagnostic intention extends beyond definition of sites of disease to an attempt to establish a quantitative measure of total tumor burden based on observed uptake values (13-19). SSTRs are found in both normal tissue (e.g., liver, spleen, pituitary, adrenal) and sites of disease; beyond detection of lesions, it is important to understand whether and how the magnitude of uptake observed in SSTR-targeted PET relates to disease state and therapeutic response (5,17,20-22).

The purpose of the present study is to assess the interscan variability and reproducibility of significant uptake variability (SUV) metrics in background tissue and NET deposits on 68Ga-DOTA-NOC and 68Ga-DOTA-TATE PET-CT imaging. We present the following article in accordance with the STROBE reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-554/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The research was approved by the Institutional Review Board at Indiana University in accordance with the Institutional Committee for the Protection of Human Subjects (IRB number: 1411891689). Inform consent for this retrospective study was waived.

Patients

PET/CT image in this study, we analyzed data from 81 patients who underwent routine whole-body 68Ga-DOTA-NOC and/or 68Ga-DOTA-TATE PET/CT (223 scans) to define the location and extent of disease between January 2014 to July 2019 at the Indiana University Health University Hospital, Indianapolis, USA. The 68Ga-DOTA-NOC imaging was performed as a clinical procedure under Expanded Access IND #117255. The 68Ga-DOTA-TATE studies employed the FDA-approved NetSpot™ product. All patients had undergone surgical resection of the primary NET lesion prior to the imaging studies, and had histopathologically proven grade 1–2 NETs. The clinical indications for PET/CT scanning were confirmed or suspected SST-expressing tumors [gastroenteropancreatic NET (48 patients), non-gastroenteropancreatic NET (originating in the lung or mediastinum; 8 patients), and NET of unknown primary (25 patients)]. This study also examined scan-to-scan variability of hepatic metastatic lesions in 21 patients with stable disease (58 PET/CT studies).

Image analysis

PET/CT image analysis was performed on all 81 patients using the MIM software (MIM Software Inc., Cleveland, OH, USA). We defined two groups of patients for the evaluation of target tissues. The first group consisted of all 81 patients (223 PET/CT studies). In this group, we evaluated the physiological 68Ga-DOTA-NOC/TATE uptake by normal target tissues as defined by the normal morphology on the CT part of the 68Ga-DOTA-NOC/TATE PET/CT scan. The normal biodistribution of 68Ga-DOTA-TATE is known to include the spleen, liver, pituitary, and adrenal gland (23). Volume of interests (VOIs) were placed within these organs in areas unaffected by disease. The following parameters were assessed for the normal organs: mean body weight corrected significant uptake variability (SUVmean) for the spleen and liver, and SUVmax for the pituitary and adrenal gland. Attenuation-corrected PET images and PET/CT images were analyzed. PET/CT fusion images were used to place the VOIs for SUVmax and SUVmean measurements. The second group consisted of 21 patients (58 PET/CT studies) who demonstrated stable disease with metastatic hepatic lesions. These studies were subsequently included in the analysis of tumor burden using SUVmean and SUVmax values derived from similarly applied VOI parameters.

Statistical analysis

Data were expressed as mean ± SD, using Microsoft Excel v. 2010. A two-sided t-test was used to determine the significance of differences between normal tissue and metastatic lesions. P values less than 0.05 were considered significant.

Results

Eighty-one patients were enrolled in this retrospective study, and all underwent routine whole-body 68Ga-DOTA-NOC and/or 68Ga-DOTA-TATE PET/CT. The mean age at first imaging was 57 years (range, 23–83 years). The female-to-male ratio was 1.08:1. The clinical indications for PET/CT scanning were confirmed or suspected SST-expressing malignancy (i.e., gastroenteropancreatic NET (48 patients), non-gastroenteropancreatic NET (originating in the lung or mediastinum; 8 patients), and NET of unknown primary (25 patients). Imaging was performed to detect tumor recurrence during post-therapy follow up (223 PET/CT studies). This study also examined interscan variability of hepatic metastatic lesions in 21 patients with stable disease (58 PET/CT studies) (Figures 1-4). The following parameters were assessed for the normal organs: mean body weight corrected SUVmean for the spleen and liver, and SUVmax for the pituitary and adrenal gland.

Figure 1 Interscan variability of SUVs in background tissue and NET. (A-C) Three scans performed over 3 years on a patient with stable disease by CT, showing significant interscan variability of both lesions and background tissues; (D) DOTA-NOC SUV variability. SUV, significant uptake variability; NET, neuroendocrine tumor; CT, computed tomography.
Figure 2 PET/CT demonstrating variable SUVmax values for liver (A-D) and pituitary (E-H) lesions across four time points in the span of 2 years. Patient had stable metastatic midgut neuroendocrine disease over this time period. PET/CT, positron emission tomography/computed tomography; SUV, significant uptake variability.
Figure 3 PET/CT demonstrating variable SUVmax values for a pelvic peritoneal lesion across four time points in the span of 2 years (A-D). This patient had stable metastatic midgut neuroendocrine disease with stable lesion size over this time period, as demonstrated by corresponding CT scans (E-H). PET/CT, positron emission tomography/computed tomography; SUV, significant uptake variability.
Figure 4 PET/CT demonstrating variable SUVmax values for a mesenteric lesion across four time points in the span of 2 years (A-D). This patient had stable metastatic midgut neuroendocrine disease with stable lesion size over this time period, as demonstrated by corresponding CT scans (E-J). PET/CT, positron emission tomography/computed tomography; SUV, significant uptake variability.

The median SUVmean was 16 for the spleen, 9.7 for the pituitary, 12.6 for the adrenal glands, and 4.8 for the liver (Table 1). The normal pituitary gland demonstrates focal homogenous uptake with SUVmax range of 4.5–23. The adrenal gland showed uptake with SUVmax range 4.1–29.4, which is more than two times greater than liver uptake (SUVmean range, 2.3–12.4). Highest normal physiological uptake was seen in the spleen (average SUVmean of 17.3, range of 5.4–34.4) (Figure 1). Metastatic hepatic lesions demonstrated greater variability of SUVmax than SUVmean (24.5±13.1 vs. 16.5±8.0). SUV measures were not significantly different when comparing intra-patient scans of 68Ga-DOTA-NOC and 68Ga-DOTA-TATE, with P values >0.05 for all normal tissue and metastatic hepatic lesions in patients with stable NETs.

Table 1

Descriptive statistics of normal organs and tumor burden of hepatic lesions in the setting of NET disease

Organs Parameter Patients Minimum Median Maximum Mean StDev
Pituitary SUVmax 74 4.5 9.7 23 10.3 4
Spleen SUVmean 59 5.4 16 34.4 17.3 6.7
Liver SUVmean 81 2.3 4.8 12.4 5 2
Adrenal glands SUVmax 73 4.1 12.6 29.4 13 5.6
Tumor burden SUVmean 21 3.7 13 32.7 16.5 8
SUVmax 21 4.2 20.2 55.3 24.5 13.1

NET, neuroendocrine tumor; SUV, significant uptake variability; StDev, standard deviation.

Discussion

SSTR-targeted PET/CT imaging has risen to the forefront for NET detection and management (7-9,16,18), yet the variability of SUV as a semiquantitative measure of disease detection and tumor response to treatment has not been fully explored. The reported studies were performed prior to routine clinical availability of 177Lu-DOTA-TATE for SSTR-targeted radiotherapy, so the data represent the stability of imaging findings in patients undergoing only standard-of-care medical management. For both 68Ga-DOTA-NOC and 68Ga-DOTA-TATE this study demonstrated significant variability in SUV for both normal tissue and metastatic hepatic lesions in patients with stable NETs. In this study, we assess the reproducibility and scan-to-scan variance observed in serial clinical 68Ga-DOTA-NOC and 68Ga-DOTA-TATE PET/CT scans to monitor disease in patients with NETs undergoing only medical management of their disease.

Total injected mass of DOTA-NOC or DOTA-TATE, which can compete with the radiopharmaceutical for SSTR binding, will intrinsically vary with the quantity of 68Ga used in the synthesis (thus, varying with the age of the Ga-68 generator), and with the elapsed time between radiopharmaceutical compounding and administration. For the reported cases, those effects were intrinsically minimized by in-house compounding, and immediate use, of the radiopharmaceuticals. We observed no changes in image appearance that could be correlated with the injected ligand mass. Multiple intra-patient scans demonstrated no significant difference in scan-to-scan variability between 68Ga-DOTA-NOC and 68Ga-DOTA-TATE, with improved reproducibility with DOTA-TATE.

68Ga-SSTR PET/CT offers greater reliability for NET detection than previously utilized radionuclide imaging techniques, including 18F-FDG PET, 18F-DOPA PET, and bone scintigraphy (14,15,20,24-29). Given the significant role 68Ga-SSTR PET/CT plays in the clinical management of NETs, it becomes increasingly important to have a clear understanding of the role that quantified measures of uptake should play in assessing disease activity and prognosis. While quite sensitive for detection of the location of disease, in this study we observe dramatic variability in SSTR-targeted uptake in both normal tissue and tumor lesions, underscoring the limitations of SUV as a semiquantitative measure of NET activity.

SUV variability may be influenced by various factors including image reconstruction techniques and intrinsic scanner properties (20,30,31). Notably, variability of SSTR uptake has been partly attributed to the “tumor sink effect”, a phenomenon in which diminished activity in background organs (e.g., spleen) is correlated with increased tumor burden (32,33). Moreover, because SSTR expression is greatest in well-differentiated tumors, it is possible that undifferentiated tumor clones may become SSTR-negative; thus, 68Ga-SSA uptake values serve as an indirect measure of tumor differentiation in which greater uptake is correlated with improved prognosis (18,34). Indeed, the current study demonstrates that SUVmax of metastatic hepatic lesions in stable disease are greater than averaged normal tissue uptake values. Future studies may further evaluate the prognostic implications in NETs across stable and progressive or changing disease states (35).

The majority of these patients were undergoing treatment with sustained release octreotide to ameliorate NET symptoms. The Sandostatin® LAR Depot package insert indicates that after three doses the serum reaches a steady state concentration of octreotide. So, for patients on maintenance with that therapy, restriction on PET/CT timing should be unnecessary. Nevertheless, for these studies the SSTR-PET was timed to occur in the week leading up to repeat clinical dosing with sustained-release octreotide. It is not known whether individual patients can undergo temporal variations in serum octreotide levels, or the level of anti-octreotide antibodies, that might contribute to the variations seen between scans in the magnitude of 68Ga-DOTA-NOC or 68Ga-DOTA-TATE PET/CT when other clinical evidence (e/g., lesion size on CT) indicates disease stability.

Combined imaging using functional (e.g., 68Ga-DOTA-NOC or 68Ga-DOTA-TATE) and morphological features (e.g., CT/MRI) may also synergistically improve detection of NETs and measurement of therapeutic response (13-19). For example, 18F-FDG PET/CT is a well-established imaging modality that guides management of many oncologic diseases, but has had limited value in evaluating NETs because of their slow growth, reduced metabolic activity, and decreased rates of differentiation. Recent studies, however, have suggested the utility of 18F-FDG in detecting dedifferentiated but morphologically growing lesions with little to no expression of SSTR, which have conflicting 68Ga-DOTATATE findings (15,18,21,36).

In summary, our study demonstrated significant variability in SUV in both normal tissues as well as in primary and metastatic hepatic lesions in patients with stable NETs. The data support the need of incorporation of more reliable quantitative measure in the context of clinical decisions making. Caution is warranted if 68Ga-SSTR PET SUV is used alone as a measure of change in disease status.

Acknowledgments

Presented in part at the Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI), June 11–15, 2021.

Funding: Monica Cheng was the recipient of the Radiological Society of North America (RSNA) Research & Education Foundation Research Medical Student Grant (2020–2021).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-554/rc

Data Sharing Statement: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-554/dss

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-554/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The research was approved by the Institutional Review Board at Indiana University in accordance with the Institutional Committee for the Protection of Human Subjects (IRB number: 1411891689). Inform consent for this retrospective study was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Cheng M, Tann M. Highly variable biodistribution of 68Ga labeled somatostatin analogues 68Ga-DOTA-NOC and 68Ga-DOTA-TATE in neuroendocrine tumors: clinical implications for somatostatin receptor directed PET/CT. Hepatobiliary Surg Nutr 2022;11(5):654-661. doi: 10.21037/hbsn-21-554

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