Peptide receptor radionuclide therapy

Peptide receptor radionuclide therapy (PRRT) is a type of unsealed source radiotherapy, using a radiopharmaceutical which targets peptide receptors to deliver localised treatment, typically for neuroendocrine tumours (NETs).[1]

Peptide receptor radionuclide therapy
CT scan of non-functioning pancreatic NET before and 6 months after successful treatment with four cycles of 177Lu-DOTATATE.
Specialtyoncology

Side effects

Radiation from lutetium (177Lu) oxodotreotide can cause damage when the medicine passes through tubules in the kidney.[2] Arginine/lysine can be used to reduce renal radiation exposure during peptide receptor radionuclide therapy with lutetium (177Lu) oxodotreotide.[2]

Mechanism

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.[3][4] 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.[5]

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.[6] 111It 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.[7]

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 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.[8] Other chelators known as NOTA (triazacyclononane triacetic acid) and HYNIC (hydrazinonicotinamide) have also been experimented with, albeit more for imaging applications.[9][10] 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).[7][11]

Applications

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, the most widely used PRRT drugs.[1][12][13][14] 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.[15] In most cases PRRT is used for cancers of the gastroenteropancreatic 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 labeled DOTATOC are of particular interest.[17]

Dosimetry

Therapeutic PRRT treatments typically involve several gigabecquerels (GBq) of activity.[18] 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.[19] Radionuclides that can be used for imaging include gallium-68, technetium-99m and fluorine-18.[18]

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.[6][18][20]

Availability

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.[21] 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.[22]

United States

177Lu-DOTATATE (international nonproprietary name: lutetium (177Lu) oxodotreotide) was approved by the FDA in early 2018, for treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs).[23][24]

Europe

Marketing authorisation for 177Lu-DOTATATE was granted by the European Medicines Agency on 26 September 2017.[25] 90Y-DOTATOC (international nonproprietary name: yttrium (90Y) edotreotide) is designated as an orphan drug but has not yet received marketing authorisation.[26]

United Kingdom

In guidance published in August 2018, lutetium (177Lu) oxodotreotide was recommended by NICE for treating unresectable or metastatic neuroendocrine tumours.[27]

Australia

Research in Australia into the use of lutetium-177-labelled antibodies for various cancers began in the Department of Nuclear Medicine at Fremantle Hospital and Health Service (FHHS), Fremantle, Australia in the late 1990s.[28] The first therapies in Australia using 177Lu-DOTATATE PRRT for NET began in February 2005 on a trial basis under the Therapeutic Goods Administration's (TGA) Special Access Scheme (SAS) and compassionate usage of unapproved therapeutic goods.[29][30] Shortly after this, 177Lu-DOTATATE PRRT was provided to Western Australian NET patients on a routine basis under the SAS, as well as under various on-going research trials.[31][32][33][34][35][36][37][38] In February 2015, the FHHS Department of Nuclear Medicine closed and transferred to the new Fiona Stanley Hospital (FSH) in the Perth suburb of Murdoch. During this period, approximately 150 patients received 500 treatment cycles between them at FHHS. From 2015 until mid-2019, approximately another 100 NET patients were provided with 177Lu-DOTATATE therapy at Fiona Stanley Hospital, in addition to approximately 20 prostate cancer patients that received up to six courses of lutetium-177 PSMA PRRT. Patients treated at FHHS and FSH have all been treated as public patients with no cost to the patient apart from some incidental costs. 177Lu-DOTATATE PRRT for NET, and lutetium-177 PSMA and/or actinium-225 PSMA for prostate cancer has also been offered to private (i.e. fee paying) patients by Theranostics Australia at Hollywood Private Hospital in the Perth suburb of Nedlands since 2015, with many of these patients coming from other countries for treatment. Various other hospitals and clinics in Australia, such as the Peter MacCallum Cancer Centre also offer PRRT therapy.

In Australia, most centres synthesise the lutetium-177 peptide on-site from lutetium-177 chloride and the appropriate peptide.[39] The production cost is approximately AU$20,000 (USD14,000) for four administrations of 7.4 to 8 GBq each, at no cost to public patients, as stated above. Private patients typically pay approximately AU$50,000 (USD35,000) for a course of four administrations.

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See also

References
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