Y-dotatoc in Association with Amino Acid Infusion: a Phase I Study

The aim of this study was to determine the maximum tolerated dose of YDOTATOC per cycle administered in association with amino acid solution as kidney protection in patients with somatostatin receptorpositive tumours. Forty patients in eight groups received two cycles of Y-DOTATOC, with activity increased by 0.37 GBq per group, starting at 2.96 and terminating at 5.55 GBq. All patients received lysine ± arginine infusion immediately before and after therapy. Forty-eight percent developed acute grade I–II gastrointestinal toxicity (nausea and vomiting) after amino acid infusion whereas no acute adverse reactions occurred after YDOTATOC injection up to 5.55 GBq/cycle. Grade III haematological toxicity occurred in three of seven (43%) patients receiving 5.18 GBq, which was defined as the maximum tolerable activity per cycle. Objective therapeutic responses occurred. Five GBq per cycle is the recommended dosage of Y-DOTATOC when amino acids are given to protect the kidneys. Although no patients developed acute kidney toxicity, delayed kidney toxicity remains a major concern, limiting the cumulative dose to ~25 Gy. The way forward with this treatment would seem to be to identify more effective renal protective agents, in order to be able to increase the cumulative injectable activity and hence tumour dose. Introduction Somatostatin plays a major role in the physiological regulation of hormones and organs. Its effects are mediated by high-affinity G-coupled membrane receptors (SSRs), five subtypes of which – sst1–5 [1] – have been cloned and partially characterised [2,3]. However, the functional roles of each of these SSRs in target tissues have not been fully defined. SSRs are over-expressed in a variety of cancers of neuroendocrine origin, including gastroenteropancreatic tumours and pituitary adenomas. Lymphoma, lung cancer and breast cancer cells may also express SSRs. The synthesis and clinical application of the somatostatin analogue octreotide in the 1980s opened up a new era in the treatment and management of