A Practical Guide for the Production and PET/CT Imaging of 68Ga-DOTATATE for Neuroendocrine Tumors in Daily Clinical Practice

Summary

Well-differentiated neuroendocrine tumors overexpress somatostatin receptors which can be utilized for diagnostic imaging with the radiolabeled somatostatin analog ⁶⁸Ga-DOTATATE. This protocol details the radiolabeling of ⁶⁸Ga-DOTATATE, quality control, patient preparation, and subsequent PET/CT imaging. Radiation safety and time constrictions due to the short half-life of ⁶⁸Ga are taken into account.

Abstract

Neuroendocrine tumors are a rare form of cancer that arise from neuroendocrine cells and can be present at almost any location throughout the body. Although heterogeneous in presentation, a common denominator among these tumors is the overexpression of somatostatin receptors. ⁶⁸Ga-DOTATATE is a somatostatin analog labeled with the positron emitter gallium-68 (⁶⁸Ga). For well-differentiated neuroendocrine tumors, ⁶⁸Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) imaging is used for diagnosis, determination of disease burden, and therapy selection.

This protocol details the radiolabeling of ⁶⁸Ga-DOTATATE, quality control, patient preparation, and subsequent PET/CT imaging. Radiolabeling of ⁶⁸Ga-DOTATATE is performed with a fully automated labeling module coupled to a germanium-68 (⁶⁸Ge)/⁶⁸Ga generator. Quality control of the final product evaluates radiochemical purity with instant thin-layer chromatography and solid-phase chromatography, and pH prior to patient injection. Periodic quality control is performed to determine ⁶⁸Ge breakthrough, sterility, and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) content. Patient preparation includes patient instructions, a protocol for ⁶⁸Ga-DOTATATE during treatment with somatostatin analogs, and intravenous administration of the radiopharmaceutical. For PET/CT imaging, the acquisition and reconstruction settings are described. For each step, radiation safety will be highlighted, as well as time constrictions due to the short half-life of ⁶⁸Ga.

Fully automated in-house production and quality control of ⁶⁸Ga-DOTATATE leads to very high success rates (95%) and produces two to four patient dosages per batch, depending on the yield of the generator. In conclusion, ⁶⁸Ga-DOTATATE PET/CT imaging is a noninvasive and fast method of providing information on the tumor burden of neuroendocrine tumors (NETs) while also assisting in diagnosis and therapy selection.

Introduction

NETs are a heterogeneous group of tumors that arises from neuroendocrine cells. They can occur at almost any location in the body but are most common in the gastrointestinal tract, pancreas, and lung¹. Although NETs are a rare disease, their incidence in the United States has risen from 1.09 per 100,000 people in 1973 to 6.98 per 100,000 people in 2012². For an accurate diagnosis and staging of a NET, ⁶⁸Ga-DOTATATE PET/CT is the standard of care. This protocol describes the production and quality control of ⁶⁸Ga-DOTATATE, as well as patient preparation and the acquisition of PET/CT images.

Protocol

1. General radiation and radiopharmaceutical safety

1. Ensure that radioactive materials are only worked with and handled by trained personnel. The dose to hospital staff, patients, and everyone else present should always be kept as low as reasonably achievable (ALARA).
2. Regarding the preparation of radiopharmaceuticals, adhere to national laws, regulations, and guidelines, such as Good Manufacturing Practice (GMP).
   CAUTION: The following protocol is for the ⁶⁸Ga-DOTATATE PET/CT imaging of adults only and is not suitable for children or pregnant women.

2. Preparations required prior to the labeling of ....

Results

Making use of an automated labeling system, 357 batches of ⁶⁸Ga-DOTATATE were produced between December 2014 and October 2018. Of the 357 produced, 17 batches failed and 340 batches were released, leading to an overall success rate of 95.2%. Of the failed batches, 11 were caused by a technical failure, whilst in six cases, the produced ⁶⁸Ga-DOTATATE did not meet specifications. Figure 1 shows a flow chart of produced batches and the numb.......

Discussion

This protocol describes the production and subsequent PET/CT imaging of ⁶⁸Ga-DOTATATE. In order for the efficient use of each produced batch of ⁶⁸Ga-DOTATATE, an optimal workflow with strict timing is required. Since the half-life of ⁶⁸Ga is 68 min, a relatively small time delay of 15 min leads to a 15% loss of radioactivity. This requires active communication between the production facility, the personnel administrating the dose to the patient, and the PET/CT technician. Also, patients s.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Acetonitrile	Biosolve	012007	> 99.9 %
Ammonium acetate	Merck	101116	≥ 98 %
Aqua / Water for injections	Braun
Automated labeling system	Scintomics		GRP 3V
C-18 cartridge	Waters	WAT023501	Sep-Pak C18 Plus Light
Dose calibrator	Veenstra Instruments		VIK-202-5051
EDTA	Merck	324503
Ethanol	Sigma Aldrich	32221-M	≥ 99.8 %
Ga-68 labeling kit	ABX	SC-01
Ge-68/Ga-68 generator	Eckert & Ziegler		1850 MBq
HA-DOTATATE	Scintomics	GRPC/R-000095
HCl 0.1M for elution	ABX	HCl-03
HEPES	Sigma Aldrich	H3375	≥ 99.5 %
Iodine	Sigma Aldrich	207772	≥ 99.8 %, solid
ITLC-SG F254 plates	Merck	105735	TLC Silica gel 60 F254
ITLC-SG paper	Agilent	SGI0001	Glass fiber
Methanol	Sigma Aldrich	32213-M	≥ 99.8 %, Ph. Eur.
Non-vented filter	Merck	SLMPL25SS	Millex-MP filter 0.22 µm
PET/CT	Philips		Gemini TOF
pH indicator strips	Merck	109584	MColorpHast (pH2.0-9.0)
Tryptic soy broth medium	Biotrading	K111F010QK
Vented filter	Merck	SLGV0250S	Cathivex GV 0.22 µm
Well counter	Canberra (now Mirion)		Osprey Digital Tube Base MCA Detector 76 BP76/3M-X