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 Srchloride and Sm-ethylenediamine-tetra-methylene phosphonate (Sm-EDTMP), while the more recently approved a emitter Ra-chloride plays an increasing role in this scenario. Based on clinical experience acquired for over two decades, 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 Sr-chloride and 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 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 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 Lu especially attractive is the very high thermal neutron capture cross-section of the target Lu, through the reaction Lu(n,c)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 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 Lu and hence the increasing global demand for this radionuclide in the coming years can be met comfortably. In this regard, enriched 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 Lu should decrease significantly, as more producers will entry into the market. Moreover, Lu can also be produced through thermal neutron irradiation of natural Lu. Preliminary screening of Lu-polyphosphonate complexes suggested that EDTMP has favorable properties to be considered for further investigations. Indeed, biodistribution studies in animals have revealed selective accumulation of Lu-EDTMP in the skeleton (up to *60 % of injected activity) with major renal clearance, while a feasibility clinical study in 10 patients with skeletal S. Mazzarri F. Guidoccio G. Mariani (&) Regional Center of Nuclear Medicine, University of Pisa, Via Roma 57, 56126 Pisa, Italy e-mail: giuliano.mariani@med.unipi.it