A primary commonality among many NETs (especially lung and GEP-NETs, more variable for other NETs) is their expression of the G protein-coupled SSTRs, of which there are five known subtypes in humans. Several peptides have been developed to bind with SSTRS, with variable affinity. Table 6.1 shows the relative binding affinity of a subset of these, focused on the imaging compounds.

The human somatostatin molecule is a hormone used by neuroendocrine cells for neurotransmission and cell proliferation. It has two active forms, one composed of 28 amino acids and the other 14 amino acids. An abbreviated version of the human somatostatin molecule, composed of 8 amino acids, with a much longer plasma half-life, is octreotide (Sandostatin^®). Octreotide was FDA-approved in 1988 for symptom control in patients with functional NETs (3). However, it is also known to have anti-proliferative effects and is practically used in that way for patients with low- or intermediate-grade, metastatic, inoperable NET (4). A slight variation of this peptide is lanreotide (Somatuline^®), which is also used for the same indications.

To allow imaging and therapy of NETs, several variations of the octreotide peptide have been developed and labeled with gamma-, positron-, or beta-emitting isotopes for these various applications (5). The isotope connects to the peptide with one of two structural linkers, either diethylenetriaminepentaacetic acid (DTPA) or tetraazocyclodecanetetraacetic acid (DOTA). Aside from octreotide, the other peptide used is octreotate. These different radiopharmaceuticals (peptide-linker-isotope combinations) have different binding affinities to the various subtypes of SSTRs as well as dosimetry in normal organs (Table 1) (6,7,8,9). Ultimately, the images as well as lesional dosimetry are similar but not the same (4,7,10).

Historically, the first approach to both nuclear imaging and therapy of NETs was with Indium-111 DTPA-octreotide (or In111-pentetreotide; Octreoscan^TM) (5). In-111 allows for gamma-imaging and this has been the mainstay of nuclear imaging of NETs since the 1980s. The imaging protocol is somewhat cumbersome as the radiopharmaceutical injection is followed 24 and (often) 48 h afterward with whole-body planar imaging with or without SPECT/CT. Even further delayed imaging is sometimes necessary and the patient is requested to have regular bowel movements during this time (with the use of over-the-counter laxatives if needed) to increase the specificity of the scan. The next generation of imaging agents used the positron-emitting isotope Gallium-68 (⁶⁸Ga) bound to either octreotide or octreotate using the DOTA-linker (6). Three peptides based on this concept include DOTA-TATE, DOTA-TOC, and DOTA-NOC. In June 2016, ⁶⁸Ga-DOTATATE (NetSpot, Advanced Accelerator Applications [AAA]) was FDA approved, thereby providing a PET-imaging alternative to the long-used ¹¹¹In-pentetreotide (Figs. 6.1,6.2,6.3). Aside from the improved resolution of positron emission tomography (PET) over planar as well as SPECT gamma camera imaging, the imaging protocol is also much more favorable as the whole-body scan is done at 60 min post injection. In fact, in all key aspects (resolution, imaging time, radiation dose, sensitivity, and resultant change in clinical management), ⁶⁸Ga-DOTATATE is superior to ¹¹¹In-pentetreotide and should, therefore, be used whenever possible. There are still some areas that are struggling with the availability of Ga68-DOTATATE locally, or insurance denials, but these issues will become less in the future.

There is some controversy about the proper preparation for these scans, with regard to stopping octreotide or lanreotide therapy. Since those medications will compete with the same SSTRs for imaging, they can theoretically cause a reduction in uptake and, therefore, decrease the sensitivity of the scan. Results are somewhat mixed, but the general guidance is to stop short-acting medications for 24 h before imaging, and long-acting medications for 1 month before imaging, if possible.

Therapy is also possible with In-111 from the auger electrons that are produced by the photons, which results in DNA damage, and this was the first therapeutic approach tried. However, efficacy was low. As such, the next generation of therapeutic radionuclides used were the beta-emitting isotopes Yttrium-90 (Y-90) and Lutetium-177 (Lu-177) bound to the same linker and peptide combinations described earlier for imaging. Both of these therapeutic isotopes are still in use today (more so in Europe than in the United States) although Lu-177 is the only one that has both FDA and European medicines agency (EMA) approval and is commercially available.

While both Y-90 and Lu-177 are primarily beta-emitting radioisotopes, there are some differences between them. Y-90 has a half-life of 2.7 days, energy of 935 keV, a path length of 12 mm in soft tissue, and no primary gamma emission. Lu-177 has a half-life of 6.7 days, energy of 133 keV, path length of 2 mm in soft tissue, and additional 113 keV (6.6%) and 208 keV (11%) gamma emission. Primarily, it is theorized that the higher energy (and the resulting longer path length) of Y-90 will provide greater efficacy for larger tumors (11). This has been investigated in several clinical trials (12). Unfortunately, the longer path length can also result in greater toxicity to surrounding normal tissue such as bone marrow or the kidneys, although this is still limited (11). As such, Lu-177 was chosen for commercialization given similar efficacy but lower toxicity, as compared to Y-90.

The use of a radionuclide attached to a peptide for the purpose of therapy is generally termed peptide receptor radionuclide therapy (PRRT). It is not specific to NETs, but NET therapy using a somatostatin analog attached to Lu-177 is currently the most advanced and only FDA-approved example of PRRT. Furthermore, this combination of imaging and therapeutic isotopes utilizing the same target is a good example of theranostics, which is a portmanteau of the words therapy and diagnostics, and is a powerful concept in the field of NM.

Because of regulatory and funding differences between the United States and Europe, much of the initial work on PRRT for NETs has been done in Europe, primarily in the Netherlands and Germany, as well as a few other places in the world. The first patient treated with ¹⁷⁷Lu-DOTATATE was in 1997, and since then, various sites in Europe have gained considerable experience with this therapy. While valuable, the majority of the studies have been smaller Phase I and II trials.

Even very early prospective studies on ¹⁷⁷Lu-DOTATATE with only 35-50 patients showed partial response rates of 10% to 25%, as well as improvements in QoL measures in those with metastatic NET who were refractory to traditional therapies (13,14). Follow-up studies in much larger (500-600 patients, but single institution) cohorts continued to show favorable outcomes with 30% objective response rates, 40-month progression-free survival
(PFS), and low G3 and G4 toxicities (15). Recent publications from these groups focus on long-term tolerability and outcomes (again in larger groups of 400-800 patients), showing favorable toxicity profiles regarding the kidneys and bone marrow (with greater renal toxicity in those treated with Y-90 vs. Lu-177) and low levels of significant toxicity otherwise, with the suggestion for individual predilections toward radiation (16). The worst outcomes were very small percentages of patients developing acute leukemia (<1%) or myelodysplastic syndrome (<2%), in the context of PFS of 29 months and overall survival (OS) of 63 months (17,18).

The FDA approval of Lutathera is for the treatment of SSTR-positive GEP-NETs, including foregut, midgut, and hindgut NETs in adults (20). It should be noted again that this therapy can also be used for other NETs such as those arising from the lung, as well as pheochromocytomas, paragangliomas, medullary thyroid cancer, and Merkel cell carcinomas, but the data are much more limited, and so is not the focus of this chapter. However, these applications are indicated in the joint International Atomic Energy Agency (IAEA), European Association of Nuclear Medicine (EANM); Society of Nuclear Medicine and Molecular Imaging (SNMMI) guidelines for this therapy (21). The primary considerations for patient selection for this therapy are the tumor grade, SSTR density based on nuclear imaging, operability, distribution of disease, progression, and laboratory values.

Tumor grade and SSTR density based on imaging are linked concepts. The therapy is most effective in patients who have high expression of SSTRs on their tumor cells (22). This is typically true for well-differentiated tumors (23,24), which is why the NETTER-1 trial required patients to have either low- or intermediate-grade tumors (Ki-67 <20%). Poorly differentiated or high-grade carcinomas (Ki-67 >20%) are more variable in their SSTR expression. Those in the Ki-67 range of 20% to 50% may have high-enough SSTR expression to warrant PRRT, while those above 50% generally do not. The assessment of SSTR expression is based on ¹¹¹In-pentetreotide (OctreoScan) gamma-camera and SPECT imaging or, preferably, ⁶⁸Ga-DOTATATE PET imaging. The majority of the patient’s lesions should have uptake greater than the liver background to be eligible for the therapy. There are ongoing studies on specific standardized uptake value (SUV) values or cutoffs to use for therapy and how it relates to outcomes (25). It is also worthwhile to note that because of those issues, ¹⁸F-FDG PET may also have a role in the determination of proper patient selection and response assessment for these patients (26), especially those with high-grade tumors.

Since partial or complete surgical removal of tumors is always preferred when possible, PRRT is reserved for patients with locally aggressive and inoperable diseases. Furthermore, the disease is typically metastatic to multiple sites making other approaches such as liver-directed therapy, or external beam radiation, less appealing. Disseminated metastases within the liver are another example where PRRT should likely be favored over liver-directed therapies alone. Lastly, the disease needs to be progressing on standard-dose SSTR therapy with either Octreotide or Lanreotide. In the clinical trials, progression was typically confirmed radiographically (with either CT or MR) using response evaluation criteria in solid tumors (RECIST) criteria. Another area of consideration here is the role of OctreoScan or 68Ga-DOTATATE PET to show progression (e.g., when the disease is radiographically stable or only slightly enlarging, but the SUVs on PET imaging have increased significantly). This is presently an area of ongoing research.

Patients should meet certain laboratory values to ensure that potential transient collateral damage to the bone marrow and the kidneys will not be an issue. The laboratory cutoffs from the NETTER-1 and early access program (EAP) trials were as follows, and it would be reasonable to continue to check these same values for clinical patients at screening, and during the therapy. Patients should have a serum creatinine <1.7 mg/dL (or a creatinine clearance >50 mL/min calculated by the Cockroft-Gault method), hemoglobin >8 g/dL, white blood cell count >2000/mm³, platelets >75,000/mm³, total bilirubin less than three times the upper limits of normal, and a serum albumin >3 g/dL, unless the prothrombin time is within the normal range.