Peptide receptor radionuclide therapy

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

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

Contents

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. [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]

Y 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 g-emitter I 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). 90Y-DOTATOC Structure.jpg
Y 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 I 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]

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, 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]

Dosimetry

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]

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. [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]

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). [26] [27]

Europe

Marketing authorisation for 177Lu-DOTATATE was granted by the European Medicines Agency on 26 September 2017. [28] 90Y-DOTATOC (international nonproprietary name: yttrium (90Y) edotreotide) and 177Lu-DOTATOC are designated as orphan drugs, but have not yet received marketing authorisation. [29] [30]

United Kingdom

In guidance published in August 2018, lutetium (177Lu) oxodotreotide was recommended by NICE for treating unresectable or metastatic neuroendocrine tumours. [31]

Turkey

The first therapies in Turkey using 177Lu-DOTATATE PRRT were carried out in early 2014, for treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) at the Istanbul University-Cerrahpaşa. [32]

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. [33] 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. [34] [35] 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. [36] [37] [38] [39] [40] [41] [42] [43] [ excessive citations ]

In Australia, most centres synthesise the lutetium-177 peptide on-site from lutetium-177 chloride and the appropriate peptide. [44]

Side effects

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]

See also

Related Research Articles

Radionuclide therapy uses radioactive substances called radiopharmaceuticals to treat medical conditions, particularly cancer. These are introduced into the body by various means and localise to specific locations, organs or tissues depending on their properties and administration routes. This includes anything from a simple compound such as sodium iodide that locates to the thyroid via trapping the iodide ion, to complex biopharmaceuticals such as recombinant antibodies which are attached to radionuclides and seek out specific antigens on cell surfaces.

<span class="mw-page-title-main">Octreotide</span> Octapeptide that mimics natural somatostatin pharmacologically

Octreotide, sold under the brand name Sandostatin among others, is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was first synthesized in 1979 by the chemist Wilfried Bauer, and binds predominantly to the somatostatin receptors SSTR2 and SSTR5.

Natural gallium (31Ga) consists of a mixture of two stable isotopes: gallium-69 and gallium-71. Twenty-nine radioisotopes are known, all synthetic, with atomic masses ranging from 56 to 86; along with three nuclear isomers, 64mGa, 72mGa and 74mGa. Most of the isotopes with atomic mass numbers below 69 decay to isotopes of zinc, while most of the isotopes with masses above 71 decay to isotopes of germanium. Among them, the most commercially important radioisotopes are gallium-67 and gallium-68.

A VIPoma or vipoma is a rare endocrine tumor that overproduces vasoactive intestinal peptide. The incidence is about 1 per 10,000,000 per year. VIPomas usually originate from the non-β islet cells of the pancreas. They are sometimes associated with multiple endocrine neoplasia type 1. Roughly 50–75% of VIPomas are malignant, but even when they are benign, they are problematic because they tend to cause a specific syndrome: the massive amounts of VIP cause a syndrome of profound and chronic watery diarrhea and resultant dehydration, hypokalemia, achlorhydria, acidosis, flushing and hypotension, hypercalcemia, and hyperglycemia. This syndrome is called Verner–Morrison syndrome (VMS), WDHA syndrome, or pancreatic cholera syndrome (PCS). The eponym reflects the physicians who first described the syndrome.

A gallium scan is a type of nuclear medicine test that uses either a gallium-67 (67Ga) or gallium-68 (68Ga) radiopharmaceutical to obtain images of a specific type of tissue, or disease state of tissue. Gallium salts like gallium citrate and gallium nitrate may be used. The form of salt is not important, since it is the freely dissolved gallium ion Ga3+ which is active. Both 67Ga and 68Ga salts have similar uptake mechanisms. Gallium can also be used in other forms, for example 68Ga-PSMA is used for cancer imaging. The gamma emission of gallium-67 is imaged by a gamma camera, while the positron emission of gallium-68 is imaged by positron emission tomography (PET).

<span class="mw-page-title-main">Neuroendocrine tumor</span> Medical condition

Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung, and the rest of the body.

<span class="mw-page-title-main">Octreotide scan</span> Type of medical imaging

An octreotide scan is a type of SPECT scintigraphy used to find carcinoid, pancreatic neuroendocrine tumors, and to localize sarcoidosis. It is also called somatostatin receptor scintigraphy (SRS). Octreotide, a drug similar to somatostatin, is radiolabeled with indium-111, and is injected into a vein and travels through the bloodstream. The radioactive octreotide attaches to tumor cells that have receptors for somatostatin. A gamma camera detects the radioactive octreotide, and makes pictures showing where the tumor cells are in the body, typically by a SPECT technique. A technetium-99m based radiopharmaceutical kit is also available.

<span class="mw-page-title-main">DOTA (chelator)</span> Chemical compound

DOTA (also known as tetraxetan) is an organic compound with the formula (CH2CH2NCH2CO2H)4. The molecule consists of a central 12-membered tetraaza (i.e., containing four nitrogen atoms) ring. DOTA is used as a complexing agent, especially for lanthanide ions. Its complexes have medical applications as contrast agents and cancer treatments.

Indium-111 (111In) is a radioactive isotope of indium (In). It decays by electron capture to stable cadmium-111 with a half-life of 2.8 days. Indium-111 chloride (111InCl) solution is produced by proton irradiation of a cadmium target in a cyclotron, as recommended by International Atomic Energy Agency (IAEA). The former method is more commonly used as it results in a high level of radionuclide purity.

<span class="mw-page-title-main">DOTA-TATE</span> Eight amino-acid long peptide covalently bonded to a DOTA chelator

DOTA-TATE is an eight amino acid long peptide, with a covalently bonded DOTA bifunctional chelator.

<span class="mw-page-title-main">Edotreotide</span> Chemical compound

Edotreotide (USAN, also known as (DOTA0-Phe1-Tyr3) octreotide, DOTA-TOC, DOTATOC) is a substance which, when bound to various radionuclides, is used in the treatment and diagnosis of certain types of cancer. When used therapeutically it is an example of peptide receptor radionuclide therapy.

Advanced Accelerator Applications is a France-based pharmaceutical group, specialized in the field of nuclear medicine. The group operates in all three segments of nuclear medicine to diagnose and treat serious conditions in the fields of oncology, neurology, cardiology, infectious and inflammatory diseases.

The Krenning score is used to grade the uptake intensity of neuroendocrine tumors on somatostatin receptor imaging such as octreotide scan. Typically, peptide receptor radionuclide therapy (PRRT) is considered when the Krenning score is greater than 2.

Sandip Basu is an Indian physician of Nuclear Medicine and the Head, Nuclear Medicine Academic Program at the Radiation Medicine Centre. He is also the Dean-Academic (Health-Sciences), BARC at Homi Bhabha National Institute and is known for his services and research in Nuclear Medicine, particularly on Positron emission tomography diagnostics and Targeted Radionuclide Therapy in Cancer. The Council of Scientific and Industrial Research, the apex agency of the Government of India for scientific research, awarded him the Shanti Swarup Bhatnagar Prize for Science and Technology, one of the highest Indian science awards for his contributions to Nuclear Medicine in 2012.

Matthew Kulke is an American cancer researcher. He is the Chief of Hematology/Oncology, co-director of the BU/BMC Cancer Center and "Zoltan Kohn Professor" at the Boston University School of Medicine. His work has shed light on the molecular characteristics of neuroendocrine tumors and has led to the development of multiple new treatments for this condition. His research studies led to the development and approval of telotristat ethyl, a tryptophan hydroxylase inhibitor, for the treatment of patients with carcinoid syndrome. He has also contributed to early and late stage clinical trials of temozolomide, sunitinib, everolimus, and peptide receptor radiotherapy for neuroendocrine tumors.

Lutetium (<sup>177</sup>Lu) chloride Radioactive compound used for radiopharmaceutical labeling

Lutetium (177Lu) chloride is a radioactive compound used for the radiolabeling of pharmaceutical molecules, aimed either as an anti-cancer therapy or for scintigraphy. It is an isotopomer of lutetium(III) chloride containing the radioactive isotope 177Lu, which undergoes beta decay with a half-life of 6.65 days.

Lutetium (<sup>177</sup>Lu) oxodotreotide Chelate of Lu-177 with DOTA-TATE, a peptide derivative bound to a DOTA molecule

Lutetium (177Lu) oxodotreotide (INN) or 177Lu DOTA-TATE, trade name Lutathera, is a chelated complex of a radioisotope of the element lutetium with DOTA-TATE, used in peptide receptor radionuclide therapy (PRRT). Specifically, it is used in the treatment of cancers which express somatostatin receptors.

Arginine/lysine, sold under the brand name LysaKare, is a fixed-dose combination medication used to protect the kidneys from radiation damage during cancer treatment with a radioactive medicine called lutetium (177Lu) oxodotreotide. It contains L-arginine hydrochloride and L-lysine hydrochloride.

<span class="mw-page-title-main">Somatostatin receptor antagonist</span> Class of chemical compounds

Somatostatin receptor antagonists are a class of chemical compounds that work by imitating the structure of the neuropeptide somatostatin. The somatostatin receptors are G protein-coupled receptors. Somatostatin receptor subtypes in humans are sstr1, 2A, 2 B, 3, 4 and 5. While normally expressed in the gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS), they are expressed in different types of tumours. The predominant subtype in cancer cells is the ssrt2 subtype, which is expressed in neuroblastomas, meningiomas, medulloblastomas, breast carcinomas, lymphomas, renal cell carcinomas, paragangliomas, small cell lung carcinomas and hepatocellular carcinomas.

<span class="mw-page-title-main">Somatostatin inhibitor</span> Class of pharmaceuticals

Somatostatin receptor antagonists are a class of chemical compounds that work by imitating the structure of the neuropeptide somatostatin, which is an endogenous hormone found in the human body. The somatostatin receptors are G protein-coupled receptors. Somatostatin receptor subtypes in humans include sstr1, 2A, 2 B, 3, 4, and 5. While normally expressed in the gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS), they are expressed in different types of tumours. The predominant subtype in cancer cells is the ssrt2 subtype, which is expressed in neuroblastomas, meningiomas, medulloblastomas, breast carcinomas, lymphomas, renal cell carcinomas, paragangliomas, small cell lung carcinomas, and hepatocellular carcinomas.

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  38. ↑ Claringbold, Phillip G.; Price, Richard A.; Turner, J. Harvey (2012-10-18). "Phase I-II Study of Radiopeptide 177Lu-Octreotate in Combination with Capecitabine and Temozolomide in Advanced Low-Grade Neuroendocrine Tumors". Cancer Biotherapy and Radiopharmaceuticals. 27 (9): 561–569. doi:10.1089/cbr.2012.1276. ISSN   1084-9785. PMID   23078020.
  39. ↑ Kesavan, Murali; Claringbold, Phillip G.; Turner, J. Harvey (2014). "Hematological Toxicity of Combined177Lu-Octreotate Radiopeptide Chemotherapy of Gastroenteropancreatic Neuroendocrine Tumors in Long-Term Follow-Up". Neuroendocrinology. 99 (2): 108–117. doi:10.1159/000362558. ISSN   1423-0194. PMID   24714208. S2CID   28778711.
  40. ↑ Claringbold, Phillip G.; Turner, J. Harvey (August 2015). "NeuroEndocrine Tumor Therapy with Lutetium-177-octreotate and Everolimus (NETTLE): A Phase I Study". Cancer Biotherapy and Radiopharmaceuticals. 30 (6): 261–269. doi:10.1089/cbr.2015.1876. ISSN   1084-9785. PMID   26181854.
  41. ↑ Claringbold, Phillip G.; Turner, J. Harvey (2015-06-10). "Pancreatic Neuroendocrine Tumor Control: Durable Objective Response to Combination 177Lu-Octreotate-Capecitabine-Temozolomide Radiopeptide Chemotherapy". Neuroendocrinology. 103 (5): 432–439. doi:10.1159/000434723. ISSN   0028-3835. PMID   26065489. S2CID   207591297.
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  43. ↑ Kesavan, Murali; Turner, J. Harvey; Meyrick, Danielle; Yeo, Sharon; Cardaci, Giuseppe; Lenzo, Nat P. (September 2018). "Salvage Radiopeptide Therapy of Advanced Castrate-Resistant Prostate Cancer with Lutetium-177-Labeled Prostate-Specific Membrane Antigen: Efficacy and Safety in Routine Practice". Cancer Biotherapy and Radiopharmaceuticals. 33 (7): 274–281. doi:10.1089/cbr.2017.2403. ISSN   1084-9785. PMID   29989440. S2CID   51608562.
  44. ↑ De Decker, Mario; Turner, J. Harvey (February 2012). "Automated Module Radiolabeling of Peptides and Antibodies with Gallium-68, Lutetium-177 and Iodine-131". Cancer Biotherapy and Radiopharmaceuticals. 27 (1): 72–76. doi:10.1089/cbr.2011.1073. ISSN   1084-9785. PMID   22149590.
  45. 1 2 "LysaKare EPAR". European Medicines Agency (EMA). Retrieved 22 July 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
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