Peptide receptor radionuclide therapy

A key advantage of PRRT over other methods of radiotherapy is the ability to target delivery of therapeutic radionuclides directly to the tumour or target site. This works because some tumours have an abundance (overexpression) of peptide receptors, compared to normal tissue. A radioactive substance can be combined with a relevant peptide (or its analogue) so that it preferentially binds to the tumour.[2][3] With a gamma emitter as the radionuclide, the technique can be used for imaging with a gamma camera or PET scanner to locate tumours. When paired with alpha or beta emitters, therapy can be achieved, as in PRRT.[4]

The current generation of PRRT targets somatostatin receptors, with a range of analogue materials such as octreotide and other DOTA compounds. These are combined with indium-111, lutetium-177 or yttrium-90 for treatment.[5] ¹¹¹In is primarily used for imaging alone, however in addition to its gamma emission there are also auger electrons emitted, which can have a therapeutic effect in high doses.[6]

⁹⁰Y is bound with DOTATOC for PRRT treatments. The natural somatostatin receptor ligand, the 14 amino acid peptide somatostatin (A), was abridged to the biologically more stable 8 amino acid peptide Octreotide (OC, B). Introduction of a tyrosine into the 3rd position of the Octreotide sequence resulted in Tyr3-Octreotide (TOC, C), which allows for iodination of the tyrosine residue with the γ-emitter ¹²³I and subsequent somatostatin receptor targeted imaging. For the use in PRRT TOC was coupled with the chelator DOTA, to form the octapeptide DOTA-TOC (D).

PRRT radiopharmaceuticals are constructed with three components; the radionuclide, chelator, and somatostatin analogue (peptide). The radionuclide delivers the actual therapeutic effect (or emission, such as photons, for imaging). The chelator is the essential link between the radionuclide and peptide. For ¹⁷⁷Lu and ⁹⁰Y this is typically DOTA (tetracarboxylic acid, and its variants) and DTPA (pentetic acid) for ¹¹¹In.[7] Other chelators known as NOTA (triazacyclononane triacetic acid) and HYNIC (hydrazinonicotinamide) have also been experimented with, albeit more for imaging applications.[8][9] The somatostatin analogue affects biodistribution of the radionuclide, and therefore how effectively any treatment effect can be targeted. Changes affect which somatostatin receptor is most strongly targeted. For example, DOTA-lanreotide (DOTALAN) has a lower affinity for receptor 2 and a higher affinity for receptor 5 compared to DOTA-octreotide (DOTATOC).[6][10]

The body of research on the effectiveness of current PRRT is promising, but limited. Complete or partial treatment response has been seen in 20-30% of patients in trials treated with ¹⁷⁷Lu-DOTATATE or ⁹⁰Y-DOTATOC, among the most widely used PRRT drugs.[1][11][12][13] When it comes to comparing these two PRRT, Y-labeled and Lu-labeled PRRTs, it appears that Y-labeled is more effective for larger tumors, while Lu-labeled is better for smaller and primary tumors. The lack of ɤ-emission with Y-labeled PPRTs is also an important difference between Lu peptides and Y peptide. In particular, with Y-labeled PRRT it becomes difficult to set up a dose of radiations specific to the patient's needs.[14] In most cases PRRT is used for cancers of the gastroenteropancreatic[15] and bronchial tracts, and in some cases phaeochromocytoma, paraganglioma, neuroblastoma or medullary thyroid carcinoma.[1] Various approaches to approve effectiveness and limit side effects are being investigated, including radiosensitising drugs, fractionation regimes and new radionuclides.[16] Alpha emitters, which have much shorter ranges in tissue (limiting the effect on nearby healthy tissue), such as bismuth-213 or actinium-225 labelled DOTATOC are of particular interest.[17]

A comparative cohort study of 1051 neuroendocrine tumor patients undergoing ⁹⁰Y-DOTATOC (n=910) or ¹⁷⁷Lu-DOTATOC (n=141) reported no significant difference in overall survival between the groups. However, patients with high tumor accumulation and multiple lesions seemed to benefit from ⁹⁰Y-DOTATOC, while patients with low tumor burden, solitary lesions and extra-hepatic disease experienced more favorable outcome on ¹⁷⁷Lu-DOTATOC. There were significantly fewer cases of transitory hematotoxicity in the ¹⁷⁷Lu-DOTATOC group compared with the ⁹⁰Y-DOTATOC group (1.4% versus 10.1%, p=0.001).[18]

The randomized controlled phase III Neuroendocrine Tumors Therapy (NETTER-1) trial evaluated the efficacy and safety of ¹⁷⁷Lu-DOTATATE as compared with high-dose octreotide long-acting repeatable (LAR) in patients with advanced progressive somatostatin-receptor positive midgut neuroendocrine tumors. Patients were randomly assigned to receive either ¹⁷⁷Lu-DOTATATE and octreotide LAR at a dose of 30 mg every four weeks for symptom control (n=116) or to only receive octreotide LAR at a dose of 60 mg every four weeks (n=113, control group). In total, 200 out of the 231 patients entered long-term follow-up. Final overall survival in the intention-to-treat population was median 48.0 months in the ¹⁷⁷Lu-DOTATATE group versus median 36.3 months in the control group (p=0.30). In other words, there was numerical difference of 11.7 months, not reaching statistical significance. ¹⁷⁷Lu-DOTATATE was associated with limited acute toxic effects. In neuroendocrine tumor patients with advanced well-differentiated disease and progression on somatostatin analogs, ¹⁷⁷Lu-DOTATATE is likely to reduce the risk of disease progression and be associated with quality-of-life benefits.[19][20]

Therapeutic PRRT treatments typically involve several gigabecquerels (GBq) of activity.[21] Several radiopharmaceuticals allow simultaneous imaging and therapy, enabling precise dosimetric estimates to be made. For example, the bremsstrahlung emission from ⁹⁰Y and gamma emissions from ¹⁷⁷Lu can be detected by a gamma camera. In other cases, imaging can be performed by labelling a suitable radionuclide to the same peptide as used for therapy.[22] Radionuclides that can be used for imaging include gallium-68, technetium-99m and fluorine-18.[21]

Currently used peptides can result in high kidney doses, as the radiopharmaceutical is retained for relatively long periods. Renal protection is therefore used in some cases, taking the form of alternative substances that reduce the uptake of the kidneys.[5][21][23]

PRRT is not yet widely available, with various radiopharmaceuticals at different stages of clinical trials. The cost of small volume production of the relevant radionuclides is high.[24] The cost of Lutathera, a commercial ¹⁷⁷Lu-DOTATATE product, has been quoted by the manufacturer as £71,500 (€80,000 or $94,000 in July 2018) for 4 administrations of 7.4 GBq.[25]

Like any form of radiotherapy, ionising radiation can harm healthy tissue as well as the intended treatment target. Radiation from lutetium (¹⁷⁷Lu) oxodotreotide can cause damage when the medicine passes through tubules in the kidney.[45] Arginine/lysine can be used to reduce renal radiation exposure during peptide receptor radionuclide therapy with lutetium (¹⁷⁷Lu) oxodotreotide.[45]

• Nuclear medicine
• Targeted alpha-particle therapy