What is the comparative diagnostic value of the novel somatostatin analog radiotracers for SSRT PET?

Introduction

Neuroendocrine tumors (NETs) are rare tumors that develop in certain hormone-producing cells of the body’s neuroendocrine system.1 More than half of these tumors originate from the gastrointestinal tract, mainly the small intestine and rectum, and about a quarter are pulmonary in origin. Although the prevalence of NETs is low, the incidence of this malignancy in the United States has been steadily increasing and currently estimated at 8,000 cases annually.2,3

Accurate detection of NETs is crucial for directing patient management.4 However, because NETs are often are small and indolent in nature, they are difficult to identify even with sophisticated imaging modalities.1

SSTR PET

Somatostatin receptors (SSTRs) are typically overexpressed by NETs in a pattern related to tumor type, origin, and grade of differentiation.4,5 As such, SSTR-based radionuclide imaging (largely, SSTR positron emission tomography [PET], which is usually combined with computerized tomography [CT]) has emerged as the preferred imaging technique for identifying NETs.4 The mechanism of this type of imaging involves the binding of a radiolabeled somatostatin analog to SSTRs on tumor cells. Five types of SSTRs have been identified on NETs with type 2 (SSTR2) being the most commonly overexpressed. Historically in this setting, scintigraphy using Indium (In) 111 pentetreotide (more commonly known by its trade name, OctreoScan) was applied.4 OctreoScan is specific for SSTR2 and SSTR5, and provides enhanced precision in identifying tumors when employed with single-photon emission computed tomography (SPECT). However, imaging with OctreoScan is time-intensive as it takes place 4, 24, and up to 48 hours after tracer injection. The use of a mild laxative is also generally required before imaging to enhance visualization of tumors. The sensitivity of OctreoScan largely depends on tumor type and size but is generally around 80% to 100% for carcinoids and 60% to 90% for pancreatic NETs.

Novel radiotracers  

Since the introduction of OctreoScan over a decade ago, several higher-affinity somatostatin analogs labeled with radioisotopes with a more favorable resolution, dosimetry, and safety profile have emerged on to the market.2,4 Gallium (Ga) 68 dotatate (Netspot), 68Ga-dotatoc, and 68Ga-dotanoc (often referred to as the dota radiotracers) are novel somatostatin analog radiotracers that are labeled with a 68Ga tracer via the macrocyclic chelating agent dodecanetetraacetic acid (DOTA).4 Of these, 68Ga-dotatate and 68Ga-dotatoc are available in the United States and are approved for use with PET for detecting SSTR-positive NETs. Table 1 provides a pharmacological comparison of these agents. All dota tracers offer improved convenience compared to OctreoScan by reducing total scanning times from 1 to 2 days to approximately 2 hours; these agents also eliminate the need for laxatives.4-6 The dota tracers have lower radiation dose requirements, and, because they can be employed with PET, offer superior imaging versus OctreoScan SPECT.4,7

Table 1. Comparison of novel radiotracers used for localization of SSTR-positive NETs.11,12

RadiotracerNetspot (68Ga-dotatate)68Ga-dotatoc
FDA approval yearJune 2016August 2019
Receptor specificitySSTR2SSTR5 (predominantly); SSTR2
DosingaAdults and children: 2 MBq/kg (0.054 mCi/kg) IV bolus; maximum dose is 200 MBq (5.4 mCi)Adults: 148 MBq (4 mCi) IV bolus

Children: 1.59 MBq/kg (0.043 mCi/kg); range, 11.1 MBq to 111 MBq (0.3 to 3 mCi) IV bolus
Radiation administeredFor an administered activity of 4 mCi, the typical radiation doses to the bladder wall, spleen and kidneys/adrenals, are about 18 mSv, 16 mSv, and 12 mSv, respectively.

Higher uptake and radiation dose to other organs or pathologic tissues may occur in patients without a spleen.
Imaging initiation40 to 90 minutes after IV administration; data also exists in support of imaging as soon as 30 minutes after administration55 to 90 minutes after IV administration
DistributionSSTR2-expressing organs: pituitary, thyroid, spleen, adrenals, kidney, pancreas, liver, and salivary glands

Lower uptake in the lung and lymph nodes
EliminationUrine: ~12% in the first 4 hours after injectionUrine: ~16% in the first 2 to 4 hours after injection
Adverse drug reactionsPain/burning at the injection site, nausea, and vomitingNausea, pruritus, flushing
Patient preparationPatients should drink a sufficient amount of water to ensure adequate hydration prior to and in the first hours following administration.

Frequent voiding to reduce radiation exposure after administration is recommended.
How suppliedSingle-dose injection kit containing 1 vial of each: radiolabeling preparation (40 mcg dotatate) and buffer solutionIV solution containing 8.5 MBq/mL to 148 MBq/mL (0.5 mCi/mL to 4 mCi/mL) at calibration time; 30 mL multi-dose vial

aRefer to manufacturer’s labeling for calculation, preparation, and calibration details.

Abbreviations: FDA=Food and Drug Administration; Ga=gallium; IV=intravenous; MBq=megabecquerel; mCi=millicuries; mSv=millisievert; SSTR=somatostatin receptors.

The superiority of SSTR PET versus OctreoScan SPECT for the identification of SSTR-positive NETs is well established and supported by the American College of Radiology and the Society of Nuclear Medicine and Molecular Imaging (SNMMI).4,8 However, the comparative diagnostic value of 68Ga-dotatate and 68Ga-dotatoc in PET imaging of NETs remains unclear (see Table 2). The remainder of this review will appraise the comparative diagnostic value of these radiotracers. For improved readability, 68Ga-dotatate will be referred to as Netspot, which is the trade name for the kit that is used to prepare this tracer.

Comparative diagnostic value

In a 2014 meta-analyses by Yang et al (N=416), Netspot and 68Ga-dotatoc both demonstrated high sensitivity (96% and 93%, respectively) and specificity (100% and 85%, respectively) in detecting NETs, though, it is unclear if the differences between the agents were statistically significant.5 While the generalizability of this quantitative review is limited by the inclusion of mostly retrospective, international studies and lack of standardization for CT imaging, improved diagnostic accuracy is suggested with Netspot based on the calculated area under the receiver-operating characteristic curve.

Two international, single-center, cohort studies not included in the aforementioned meta-analysis provide additional intra-patient comparisons of both agents and yield conflicting results with regard to imaging accuracy.9,10 In the first study (n=40), fewer lesions were detected with Netspot vs 68Ga-dotatoc in patients with metastatic NETs.9 In contrast, a smaller study (n=10) demonstrated similar lesion visibility scores at 1, 2, and 3 hours after injection of Netspot and 68Ga-dotatoc in patients with metastatic gastroenteropancreatic (GEP) NETs.10 Intra-lesion variance was present in both studies with occasional lesions being better depicted with 68Ga-dotatoc vs Netspot and vice versa.9,10 Imaging techniques were also not standardized in the Poeppel et al study (contrast-enhanced PET/CT was used with 68Ga-dotatoc while low-dose PET/CT was used with Netspot).

Summary

In 2018, the SNMMI noted a lack of relevant clinical differences between Netspot and 68Ga-dotatoc in their publication on appropriate use criteria for SSTR PET in the setting of NETs.4 Findings from a review of available literature, including 1 meta-analysis and 2 cohort studies, align with this conclusion. While both radiotracers have overlapping sensitivity and specificity for detecting NETs, a 2014 meta-analysis suggests slightly improved imaging accuracy with Netspot.5,9,10 However, intra-lesion variance was present in 2 comparative cohort studies, suggesting that the choice of imaging tracer may include patient/tumor-specific factors. Regardless of which agent is chosen, uptake of these tracers should be confirmed by histopathology or other assessments to avoid image misinterpretation and an incorrect diagnosis.11,12

Table 2. Studies comparing the diagnostic value of Netspot and 68Ga-dotatoc for identification of NETs.5,9,10

CitationDesignOutcomes
Yang et al 20145MA of 10 cohort studies including 416 patients with NETs (age range, 15 to 84 years)

Imaging modalities included Netspot PET/CT and 68Ga-dotatoc PET or PET/CT

For studies that used CT, some used low dose non-enhanced CT while others used contrast-enhanced CT		Sensitivity in NET detection
  • Netspot: 96% (95% CI, 91% to 99%)

  • 68Ga-dotatoc: 93% (95% CI, 89% to 96%)


Specificity in NET detection
  • Netspot: 100% (95% CI, 82% to 100%)

  • 68Ga-dotatoc: 85% (95% CI, 74% to 93%)


Diagnostic accuracy
  • The area under the ROC curve for Netspot and 68Ga-dotatoc was 0.98 and 0.96, respectively, suggesting that Netspot has an advantage over 68Ga-dotatoc in detecting NETs
Velikyan et al 20149Cohort study of 10 patients with metastatic GEP NETs and planned PRRT (age range, 44 to 75 years)

PET/CT with Netspot and 68Ga-dotatoc PET/CT were performed on 2 sequential days
  • The lesion visibility scores for all time points were similar between Netspot and 68Ga-dotatoc (p-values not provided); however, occasional lesions were better depicted with Netspot vs 68Ga-dotatoc and vice versa

  • No statistically significant difference was found in the tumor uptake of Netspot and 68Ga-dotatoc at any time point (p-value not reported)

  • No adverse reactions or side effects were reported by any patient
Poeppel et al 201110Cohort study of 40 patients with metastatic bronchopulmonary or GEP NETs (mean age, 59 years; range, 27 to 81 years)

The average time between application of Netspot low-dose PET/CT and 68Ga-dotatoc contrast-enhanced PET/CT was 14 days
  • Fewer lesions were detected with Netspot vs 68Ga-dotatoc (254 vs. 262; p<0.012)

  • The average number of lesions identified with Netspot vs 68Ga-dotatoc was 8.2 vs 8.5 (p-value not reported)

  • The SUVmax across all lesions was lower with Netspot vs 68Ga-dotatoc (16.0±10.8 vs. 20.4±14.7; p=0.005)

Abbreviations: CI=confidence interval; CT=computed tomography; Ga=gallium; GEP=gastroenteropancreatic; NET=neuroendocrine tumor; MA=meta-analysis; PET=positron emission tomography; PRRT= Peptide Receptor Radionuclide Therapy; ROC= receiver-operating characteristic; SUVmax= maximal standardized uptake value (represents a composite measure of specific receptor binding and internalization, unspecific binding, and effects of tissue perfusion).10

References

  1. Halperin DM YJ. Neuroendocrine tumors. In: Kantarjian HM WR, ed. The MD Anderson Manual of Medical Oncology. 3rd ed: McGraw-Hill Education; 2016. https://accessmedicine.mhmedical.com/content.aspx?bookid=1772&sectionid=121899516&jumpsectionid=121899521. Accessed September 15, 2019.
  2. Desai H, Borges-Neto S, Wong TZ. Molecular imaging and therapy for neuroendocrine tumors. Curr Treat Options Oncol. 2019;20(10):78.
  3. Barrio M, Czernin J, Fanti S, et al. The impact of somatostatin receptor-directed PET/CT on the management of patients with neuroendocrine tumor: a systematic review and meta-analysis. J Nucl Med. 2017;58(5):756-761.
  4. Hope TA, Bergsland EK, Bozkurt MF, et al. Appropriate use criteria for somatostatin receptor PET imaging in neuroendocrine tumors. J Nucl Med. 2018;59(1):66-74.
  5. Yang J, Kan Y, Ge BH, Yuan L, Li C, Zhao W. Diagnostic role of Gallium-68 DOTATOC and Gallium-68 DOTATATE PET in patients with neuroendocrine tumors: a meta-analysis. Acta Radiol. 2014;55(4):389-398.
  6. Lexicomp [database online]. Hudson, OH: Wolters Kluwer Health, Inc; 2019. http://www.lexicomp.com. Accessed September 15, 2019.
  7. Sundin A. Novel functional imaging of neuroendocrine tumors. Endocrinol Metab Clin North Am. 2018;47(3):505-523.
  8. American College of Radiology (ACR). ACR practice parameter for the performance of gallium-68 dotatate PET/CT for neuroendocrine tumors. ACR.org website. https://www.acr.org/-/media/ACR/Files/Practice-Parameters/DOTATATE_PET_CT.pdf. Published 2018. Accessed September 15, 2019.
  9. Velikyan I, Sundin A, Sorensen J, et al. Quantitative and qualitative intrapatient comparison of 68Ga-DOTATOC and 68Ga-DOTATATE: net uptake rate for accurate quantification. J Nucl Med. 2014;55(2):204-210.
  10. Poeppel TD, Binse I, Petersenn S, et al. 68Ga-DOTATOC versus 68Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors. J Nucl Med. 2011;52(12):1864-1870.
  11. Netspot [package insert]. Millburn, NJ: Advanced Accelerator Applications USA, Inc; 2019.
  12. Ga 68 DOTATOC Injection [package insert]. Iowa City, IA: UIHC PET Imaging Center; 2019.

Prepared by:
Katherine Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

October 2019

The information presented is current as September 23, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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