Oncology—Beyond Fluorodeoxyglucose

Gastroenteropancreatic and Lung Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are a diverse group of epithelial neoplasms that may occur in almost any organ but most commonly arise in the gastroenteropancreatic region (70%) and lung (20%). Well-differentiated neuroendocrine tumors in these regions were previously called carcinoids ( Fig. 13.1 ). Although they often produce specific clinical syndromes due to their unique secretory products (“carcinoid syndrome”), the majority of the tumors are nonfunctioning. Many NET tumors are well differentiated, and these patients have prolonged survival; however, some grow more aggressively and become metastatic. The initial clinical diagnosis can be difficult because of their nonspecific clinical manifestations, depending on the specific amines/peptides secreted, and their small size ( Table 13.1 ). Gastroenteropancreatic NETs are classified on the basis of the Ki-67 proliferation index or the mitotic count ( Table 13.2 ).

Resection of NETs can potentially cure the patient of the malignancy and amine/peptide production; however, this is often not possible due to the extent of disease. Management guidelines emphasize that resection should be the first-line treatment for patients with advanced tumors if 90% of the disease burden is resectable. However, only 5% to 20% of patients meet this criterion. Liver-directed therapies (embolization, radiofrequency ablation, chemoembolization, and radioembolization) are used in appropriate cases. Chemotherapy has not been very effective, but somatostatin (Sandostatin), mTOR inhibitors (everolimus), and tyrosine kinase inhibitors (sunitinib) can extend survival. With metastatic disease, 5-year survival rates are less than 50%.

Computed tomography (CT), ultrasonography, and magnetic resonance imaging (MRI) are used for initial evaluation, but detection rates are not high due to the small size of the tumors and variable location. Because well-differentiated NETs express high levels of somatostatin receptors (SSTRs), SSTR-targeted radionuclide imaging (e.g., In-111 pentetreotide or Ga-68 dotatate) can detect and functionally characterize these tumors. The primary tumor and regional or distant metastases can also often be detected. Expression of SSTRs is associated with a good prognosis, whereas lack of expression of SSTRs and overexpression of GLUT (FDG uptake) is predictive of poor prognosis and survival.

The normal human hormone somatostatin is a 14-amino-acid peptide produced in the hypothalamus, pituitary gland, brainstem, gastrointestinal tract, and pancreas. Somatostatin receptors are found on many normal cells as well as tumors of neuroendocrine origin. In the central nervous system, somatostatin acts as a neurotransmitter. Outside of the brain, it inhibits the release of growth hormone, insulin, glucagon, gastrin, serotonin, and calcitonin. It also inhibits angiogenesis, is involved in the immune function of leukocytes, and has an antiproliferative effect on tumors.

Five different subtypes of human SSTRs have been identified, expressed to varying degrees on different tumors. Therapeutic drugs have been developed that readily bind to these receptors. Octreotide (Sandostatin) and lanreotide (Somatuline) are somatostatin analogs used clinically to inhibit growth in acromegaly and to control symptoms of carcinoid syndrome. Radiopharmaceuticals have also been developed that bind to SSTRs.

Diagnostic SSTR Radiopharmaceuticals

Indium-111 Pentetreotide (OctreoScan)

OctreoScan was approved by the U.S. Food and Drug Administration (FDA) in 1994 for imaging of NETs. This radiolabeled SSTR binding agent has high affinity for subtypes 2 and 5 ( Fig. 13.2 ). It has high-energy emissions (171, 245 keV), relatively slow pharmacokinetics, and thus unfavorable dosimetry (see Appendix 1 ), which limits the administered dose to 6 mCi (222 MBq) and adversely affects image quality.

Normal Distribution

Splenic and renal uptake is quite high. Lesser uptake is seen in the liver. Low-level hepatobiliary excretion increases intestinal clearance over time ( Fig. 13.3 ). The kidneys rapidly excrete the radiopharmaceutical, with 85% of the dose cleared from the body by 24 hours after injection. Uptake may be seen in the pancreas in the region of the uncinate process; this must not be confused with tumor. Radiotracer uptake is also be seen with benign inflammatory conditions (e.g., thyroiditis, granulomatous disease, inflammatory bowel disease, postradiation therapy, and at sites of recent surgery) due to the SSTRs present on human immune cells (e.g., mononuclear leukocytes, peripheral blood lymphocytes, and macrophages).

Methodology

An imaging protocol is described in Box 13.2 . Early planar imaging at 4 hours after injection permits visualization of tumor uptake before bowel excretion; however, 24-hour imaging has a higher tumor-to-background ratio and is more sensitive for tumor detection ( Fig. 13.4 ). Delayed imaging at 48 hours can further confirm tumor uptake versus bowel activity. With single-photon emission computed tomography with computed tomography (SPECT/CT), imaging only at 24 hours is routine, and it improves tumor identification and localization ( Fig. 13.5 ).

Box 13.2

Indium-111 Pentetreotide (OctreoScan): Protocol Summary

Patient Preparation

• None

Radiopharmaceutical

• Children: 0.14 mCi/kg (5 MBq/kg)

• Adults: 6 mCi (222 MBq) In-111 octreotide, intravenously

Instrumentation

• Gamma camera: Large field of view

• Collimator: Medium energy

• Windows: 20% centered at 173 keV and 247 keV

Acquisition

• Imaging: Planar whole body and SPECT or SPECT/CT of abdomen and or other indicated site at 24 hours

  • If only planar imaging: 4 and 24 hours; 48-hour images may occasionally be useful

Whole-Body Images

• Dual-head camera 6 cm/min (approximately 40 minutes head to below hips)

• 1024 × 512 word matrix

SPECT

• 128 × 128 matrix, 3-degree angular sampling, 360-degree rotation, 35 sec/stop

• Fusion to CT or SPECT/CT preferable

CT, Computed tomography; SPECT, single-photon emission computed tomography; SPECT/CT, single-photon emission computed tomography with computed tomography.

Accuracy

The sensitivity of In-111 pentetreotide for tumor detection is reported to be high for carcinoid tumors (85%–95%; Box 13.3 ). However, a lower sensitivity of approximately 75% occurs with pancreatic NETs (e.g., gastrinomas, glucagonomas, vasoactive intestinal polypeptide-secreting tumors [VIPomas], and nonfunctioning islet cell tumors). Because of high normal liver uptake, liver metastases are not always detected. Detection may be reduced in patients on octreotide therapy; thus, the study should be performed immediately before the patient’s monthly therapeutic injection.

Box 13.3

Sensitivity of Indium-111 Pentetreotide (OctreoScan) for Various Applications

High

• Carcinoid (86–95%)

• Islet cell tumors (75–100%)

  • Gastrinoma, glucagonoma, VIPoma

• Adrenal medullary tumors (>85%)

  • Pheochromocytoma, neuroblastoma, paragangliomas

• Small-cell lung cancer (80–100%)

Moderate

• Medullary thyroid (50–75%)

• Insulinoma (25–70%)

• Medulloblastoma (61–93%)

• Meningioma (50% and 100% reported)

Low

• Pituitary adenoma

• Astrocytoma grade IV (higher in grades I and II)

• Breast cancer

• Melanoma

• Renal cell carcinoma

VIPoma, Vasoactive intestinal polypeptide-secreting tumor.

Gallium-68 (Ga-68) Dotatate (DOTA-0-Tyr3-Octreotate )

Several Ga-68-labeled somatostatin receptor positron emission tomography (PET) imaging agents have been investigated, including Ga-68 dotatoc, dotanoc, and dotatate (see Fig. 13.2 ). These short amino acid–chelator conjugates demonstrate superior affinity for somatostatin receptors compared with In-111 pentetreotide. The three dota agents are similar in imaging accuracy. Ga-68 dotatate (NetSpot) was approved by the FDA in 2016 for imaging of neuroendocrine tumors. The radionuclide, Ga-68, is produced in a Germanium 68/Ga-68 generator, similar to a Molybdenum-99/Tc-99m generator. The parent Ge-68 has a half-life of 271 days; thus, the generator can be used for at least a year. The Ga-68 daughter has a half-life of 68 minutes. In a high-volume clinic, a generator can make sense. Alternatively, some commercial radiopharmacies maintain a generator and distribute individual radiopharmaceutical doses on a regional basis. The recommended dose is 0.054 mCi/kg (2 MBq/kg) up to 5.4 mCi (200 MBq).

Normal Distribution

Ga-68 dotatate binds with high affinity to SSTR-2 receptors. Uptake is seen in the pituitary, thyroid, and salivary glands; spleen; adrenals; kidney; prostate; and liver ( Fig. 13.6 ). Normal uptake may also be seen in the uncinate process, similar to that seen with In-111 pentetreotide. There is no brain uptake, but focal activity in the nonenlarged pituitary is normal. Cardiac uptake is absent, and lung uptake is low. Twelve percent of the administered dose is excreted in the urine by 4 hours postinjection.

Methodology

A Ga-68 dotatate PET/CT study requires considerably less patient time than SPECT/CT In-111 pentetreotide. PET/CT imaging begins approximately 1 hour after injection of the radiopharmaceutical. The total time from injection to the completion of imaging is about 2 hours, similar to routine F-18 FDG oncologic imaging. The radiation dose to the patient is less with Ga-68 dotatate compared with In-111 pentetreotide (see the Appendix).

Accuracy

In a large retrospective study of 728 patients with NETs, Ga-68 dotatate had a sensitivity of 94% and a specificity of 92%. The highest accuracy was for primary midgut tumors. In a comparison study of 131 patients with NETs and unknown primaries, Ga-68 dotatate PET/CT had a higher detection rate (95%) compared with In-111 pentetreotide SPECT/CT (31%) or CT or MRI (46%) ( Fig. 13.7 ). Additional clinical information is found in 70% to 80% of Ga-68 dotatate cases compared with pentetreotide (OctreoScan), and a change in clinical management is reported to occur in greater than 40% of patients ( Figs. 13.8 and 13.9 ). Patients with poorly differentiated tumors may not have uptake and may benefit from F-18 FDG PET, although these patients have a poorer prognosis. The use of intravenous contrast with SSTR PET/CT increases the detection rate for liver metastases and small bowel primaries. SSTR PET/MRI is also reported to provide improved detection of liver metastases.

Other Neuroendocrine Tumors

Because neuroendocrine cells are spread throughout the body, NETs can develop in many different places, including in endocrine glands. Other NETs include medullary carcinoma that starts in the C cells of the thyroid, parathyroid carcinoma or parathyroid adenoma, thymic neuroendocrine cancer, pheochromocytoma that starts in the chromaffin cells of the adrenal glands, paraganglioma, neuroblastoma, pituitary gland tumors, neuroendocrine tumors of the ovaries and testicles, Merkel cell carcinoma, a type of nonmelanoma skin cancer, and small-cell lung cancer.

Therapeutic Radionuclides Bound to SSTRs

High doses of In-111 pentetreotide have been investigated for peptide receptor radionuclide therapy (PRRT) of NETs, taking advantage of the radionuclide’s Auger and conversion electron emissions. Although showing effectiveness, more promising results were found using a pure beta emitter, Yttrium-90 (Y-90), bound to other SSTRs, dotatoc and dotatate. In spite of increased survival, bone marrow and renal toxicity were a significant problem.

Lutecium-177 (Lu-177) Dotatate (Lutathera) Therapy for Neuroendocrine Tumors

As an alternative to Y-90, Lu-177 labeled to dotatate, a beta and gamma emitter, was investigated. Retrospective studies had shown similar effectiveness without the side effects of Y-90. In 2017 a phase 3 multicenter randomized prospective controlled trial of Lu-177 dotatate ( Fig. 13.10 ) was published that studied therapeutic effectiveness in patients with advanced midgut (jejunum, ileum, proximal colon) NETs who had disease progression while on standard first-line octreotide therapy. The investigation reported that compared with octreotide therapy, Lu-177 dotatate resulted in longer progression-free survival (65% vs.11% at 20 months), a significantly higher response rate (18% vs. 3%), and a lower risk of progression, 79% lower than high-dose octreotide therapy. Clinically significant myelosuppression occurred in <10% of patients. Risk of death was 60% lower. Renal toxicity was not a problem with amino acid infusion. Lutathera was approved for clinical use by the FDA in early 2018.

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