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
), 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 111
In-pentetreotide (OctreoScan) gamma-camera and SPECT imaging or, preferably, 68
Ga-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, 18
F-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.
Even if a patient is eligible for PRRT based on the previously provided guidelines, it may not be the best choice relative to
other therapeutic options such as surgery, mTOR inhibitors, chemotherapy, external beam radiation, or a variety of liver-directed therapies (bland embolization, chemoembolization, or radioembolization) for those with liver dominant disease. This area is an active area of discussion and research, and the consideration is not only what will have great therapeutic benefit, but also which will have less toxicity now and in the future (23
). Another possibility is combination therapies, which may have a greater benefit than the sum of their parts, for instance, by using radiosensitizing chemotherapies in conjunction with radioembolization or PRRT (27
The European Neuroendocrine Tumor Society guidelines have long recommended PRRT as a second-line therapy after progression on SSTR therapy, and this is a very reasonable approach to consider, with the caveats provided earlier. Ultimately, the therapy sequencing decision should ideally be done in the context of a multidisciplinary conference with experts from all the disciplines (oncology, surgery, radiation oncology, NM, radiology, and pathology) represented (1
). Since in many places it is difficult to have so many NET experts, progressive NET patients should be referred to a NET Center of Excellence (aka NET Advanced Care Center), at least once in their care.
Performing the therapy
As compared to other radioisotope therapies such as I-131, Ra-223 dichloride (Xofigo), and I-131 ibritumomab tiuxetan (Zevalin), PRRT is significantly more involved. Having said that, once the therapy program has been set up at an institution, it is relatively straightforward and requires only a reasonable amount of input.
As mentioned earlier for imaging, but even more important for therapy, is to stop octreotide/lanreotide therapy for the appropriate amount of time (24 h for short-acting and 1 month for long-acting formulations) before treatment. The Lutathera is shipped from a radiopharmacy (either in Italy or in New Jersey) to the clinical site either the day before or on the day of the therapy and arrives as a clear liquid in a glass vial. The 177Lu-DOTATATE is then administered over 30 minutes, with another 10 to 20 minutes for infusion of saline to minimize the residual. There are two main recommended methods for administration. The first is referred to as the gravity method and requires the use of two needles inserted into the vial. The instillation of saline (either running via gravity or through a pump) through one needle increases the pressure within the vial and pushes the Lutathera out the other needle, which is attached to the patient. The second method is to manually draw out the contents of the vial into the syringe and then using a shielded, automated syringe-pump to administer the therapy to the patient.
The 177Lu-DOTATATE needs to be given in conjunction with an amino acid (AA) formulation, which is given intravenously through either the same or a second IV line. AAs reduce the residence time of 177Lu-DOTATATE in the kidneys thereby reducing radiation toxicity. Recently, there are various AA formulations available with different amounts of AAs, as well as different osmolalities. The only two necessary AAs are lysine and arginine. More pure formulations of just these two AAs, together with a lower osmolality solution, significantly reduce the nausea associated with their infusion. Depending upon which AAs are used (and their emetogenic potential) and the patient’s sensitivity, a variable amount of anti-nausea pre medication needs to be given before starting the AAs. Additional PRN anti-nausea medication may also have to be given during the infusion.
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