The emerging potential of 177Lu-EDTMP: an attractive novel option for radiometabolic therapy of skeletal metastases

Abstract

Between 60 and 84 % of patients with solid cancers develop bone metastases, the main complication that severely impairs quality of life and performance status and constitutes one of the major challenges of oncological practice. Among other palliative treatments, therapy with bone-seeking radiopharmaceuticals is part of the armamentarium available in the clinical setting to treat bone pain caused by skeletal metastases. Although several radionuclides have been proposed to this purpose, the most widely used radiopharmaceuticals are the b -emitters 89 Srchloride and 153 Sm-ethylenediamine-tetra-methylene phosphonate ( 153 Sm-EDTMP), while the more recently approved a ?? emitter 223 Ra-chloride plays an increasing role in this scenario.Based on clinical experience acquired for over two decades, 153 Sm-EDTMP has an excellent profile in terms of both efficacy and toxicity, as confirmed by a recent systematic review and meta-analysis of literature on therapy with 89 Sr-chloride and 153 Sm-EDTMP published between 2001 and 2011 [1]. Compared with an overall efficacy for bone palliation of 70 % (either partial or complete) when used as single agents and 74 % when combined with other therapies, the overall toxicity as single agents was 11 %, mostly reversible mild-to-moderate side-effects. Furthermore, interest is growing also on the potential antitumor efficacy of these agents, especially if combined with chemotherapy agents.The market cost of 153 Sm-EDTMP is a drawback limiting a more widespread use of this radiopharmaceutical in low-income countries, thus reviving interest in earlier studies that had explored the potential of 177 Lu as a therapeutic radionuclide to be coupled with EDTMP (US Patent 4898724, 1990. Organic amine phosphonic acid complexes for the treatment of calcific tumors. Wilson DA, Volkert WA, Troutner DE, Goeckeler WF). Lutetium-177 has favorable characteristics such as the low energy b -emission, which should reduce toxicity, and a 6.73 day half-life, which is advantageous for the distribution logistics to distant areas. Moreover, the most important feature which makes the production of 177 Lu especially attractive is the very high thermal neutron capture cross-section of the target 176 Lu, through the reaction 176 Lu(n,c) 177 Lu, the highest (r = 2,060 barns) among all (n,c)-produced radionuclides currently used for therapy. Such large cross-section of the reaction ensures that 177 Lu can be produced with adequately high specific activity for radionuclide therapy applications even when using moderate flux reactors, as those that can be employed for medical use even in several low-income countries. It also ensures that there will be no constraints in the large-scale production of 177 Lu and hence the increasing global demand for this radionuclide in the coming years can be met comfortably. In this regard, enriched 176 Lu (with isotopic abundance above 80 %) is relatively inexpensive (200 euros/mg) and available through multiple sources; furthermore, in the long run the cost of 177 Lu should decrease...

Targeted Palliative Radionuclide Therapy for Metastatic Bone Pain

“…To recapitulate, [ 177 Lu]lutetium may be more available considering the established use in radionuclide therapy for neuroendocrine tumors and prostate cancers. Also, the features of relatively inexpensive [ 177 Lu]lutetium, such as favorable half-life, production in high-specific activity, efficient therapeutic β¯-particles, longer effect with a single administration, lower radiation of bone marrow and sufficient γ-photons for imaging make it an interesting radioisotope in bone-pain palliation therapy [ 32 , 33 , 34 , 109 , 110 ]. The impact of [ 177 Lu]Lu-phosphonate complexes in increasing survival indices is not addressed, fairly.…”

[177Lu]Lu-DOTA-ZOL bone pain palliation in patients with skeletal metastases from various cancers: efficacy and safety results

“…For bone pain palliation it has been labelled with several bisphosphonates such as ethylene diamine tetramethylene phosphonic acid (EDTMP) [ 7 – 9 ], (4-{[(bis(phosphonomethyl)) carbamoyl]methyl}-7,10-bi (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (BPAMD) [ 10 – 15 ] Zoledronate (DOTA-ZOL) [ 16 – 22 ], and DOTMP [ 23 , 24 ]. Zoledronic acid, compared to EDTMP and DOTMP, has significantly higher hydroxyapatite binding and better internalisation by osteoclasts.…”

[177Lu]Lu-DOTA-ZOL Bone Pain Palliation in Patients with Skeletal Metastases From Various Cancers: Efficacy and Safety Results

“…For bone pain palliation it has been labelled with several bisphosphonates such as ethylene diamine tetramethylene phosphonic acid (EDTMP) [7][8][9], (4-{[(bis(phosphonomethyl)) carbamoyl]methyl}-7,10-bi (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (BPAMD) [10][11][12][13][14][15] Zoledronate (DOTA-ZOL) [16][17][18][19][20][21][22], and DOTMP [23,24]. Zoledronic acid, compared to EDTMP and DOTMP, has signi cantly higher hydroxyapatite binding and better internalization by osteoclasts.…”