DOTA-TATE is a compound containing tyrosine3-octreotate, an SSR agonist, and the bifunctional chelator DOTA. SSRs are found with high density in numerous malignancies, including CNS, breast, lung, and lymphatics. The role of SSR agonists in neuroendocrine tumours is well established, and massive SSR overexpression is present in several NETs. -octreotate binds the transmembrane receptors of NETs with highest activity for SSR2 and is actively transported into the cell via endocytosis, allowing trapping of the radioactivity and increasing the probability of the desired double-strand DNA breakage. Trapping improves the probability of this kind of effect due to the relatively short range of the beta particles emitted by 177Lu, which have a maximum range in tissue of <2 mm. Bystander effects include cellular damage by free radical formation.
Clinical applications
Gallium-68 DOTA-TATE
68Ga DOTA-TATE is used to measure tumor SSR density and wholebody bio-distribution via PET imaging. 68Ga DOTA-TATE imagery has a much higher sensitivity and resolution compared to 111In octreotide gamma camera or SPECT scans, due to intrinsic modality differences.
Lutetium-177 DOTA-TATE
DOTA-TATE can be used in the treatment of cancers which express the relevant somatostatin receptors, by combining with the beta emitter lutetium-177. The recommended dosage is four cycles of 7.4 GBq every eight weeks. About four to six hours after infusion, the exposure rate of the patient has fallen to less than 25 μSv/hour at one metre and the patients can be discharged from hospital. Alternatives to 177Lu-DOTATE include yttrium-90 DOTATATE or DOTATOC. The larger range of 90Y may make it more suitable for large tumors with 177Lu reserved for smaller volumes
History
The European Commission approved lutetium oxodotreotide "for the treatment of unresectable or metastatic, progressive, well differentiated, somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours in adults" in September 2017. 177Lu DOTA-TATE was approved in the United States for the treatment of SSTR positive gastroenteropancreatic neuroendocrine tumors, including foregut, midgut and hindgut neuroendocrine tumors in adults, in January 2018. This was the first time a radiopharmaceutical had been approved for the treatment of GEP-NETs in the United States. The U.S. Food and Drug Administration approved lutetium Lu 177 dotatate based primarily on evidence from one clinical trial, NETTER-1 of 229 patients with somatostatin-receptor positive midgut GEP-NETs. Enrolled patients had tumors which could not be surgically removed and were worsening while receiving treatment with octreotide. Patients were randomly assigned to receive either lutetium Lu 177 dotatate with long-acting octreotide or long-acting octreotide, at a higher dose, alone. lutetium Lu 177 dotatate was injected through the vein and long-acting octreotide was injected in the muscle. Both, patients and health care providers knew which treatment was given. The benefit of lutetium Lu 177 dotatate was evaluated by measuring the length of time that tumors did not grow after treatment and compared it to the control group. The FDA considered additional data from a second study based on data from 1,214 patients with somatostatin receptor-positive tumors, including GEP-NETS, who received lutetium Lu 177 dotatate at a single site in the Netherlands, Erasmus MC. All patients received lutetium Lu 177 dotatate with octreotide. Patients and health care providers knew which treatment was given. The benefit of lutetium Lu 177 dotatate was evaluated by measuring if and how much the tumor size changed during treatment. Complete or partial tumor shrinkage was reported in 16 percent of a subset of 360 patients with GEP-NETs who were evaluated for response by the FDA. Patients initially enrolled in the study received lutetium Lu 177 dotatate as part of an expanded access program. The application for lutetium Lu 177 dotatate was granted priority review designation and orphan drug designation. The FDA granted the approval of Lutathera to Advanced Accelerator Applications.
Side effects
The therapeutic effect of 177Lu derives from the ionsing beta radiation it emits, however this can also be harmful to healthy tissue and organs. The kidneys are particularly at risk as they help to remove 177Lu DOTA-TATE from the body. To protect them, an amino acid solution is administered by slow infusion, starting before the radioactive administration and normally continuing for several hours afterwards.
