Receptor-mediated radiotherapy with 90Y-[DOTA0,Tyr3]octreotide: The EIO experience

Aim: Somatostatin receptors subtype 2 (sst2) are over expressed in many tumors, of neuroendocrine origin, central nervous system, breast, lung and lymphatic tissue, thus enabling primary and metastatic masses to be localized by scintigraphy after injecting 111In-octreotide. The use of radiolabeled somatostatin analogues shows potential for therapy as well diagnosis of such cancers. The newer analogue [DOTA0,Tyr3]octreotide (DOTATOC) was synthesized for stable labeling with 90Y, and shows high affinity for sst2. Materials and methods: Our clinical experience with 90Y-DOTATOC in tumors expressing sst2 receptors started with a systematic dosimetric study in 18 patients who were administered with 111In-DOTATOC to estimate the absorbed doses during 90Y-DOTATOC therapy. Furthermore another 70 patients were studied with 90Y-DOTATOC as regards the basic safety profile, with and without the administration of kidney protecting agents (lysine ± arginine). Then, we moved on and treated with 90Y-DOTATOC an overall number of 256 patients, among which 111 received a sufficient cumulative activity to be evaluated as regards the response. Results: 90Y-DOTATOC shows fast blood clearance and elimination from urine, thus implying a low total body irradiation. The kidneys are the expected critical organ in this therapy (3.3 ± 2.2 mGy/MBq), and the high tumor uptake is suitable for localizing high absorbed doses (10.1 -range: 1.4-31.0 mGy/MBq) in the lesions. No major acute reactions were observed after 90Y-DOTATOC injection up to 5.18 GBq, which was defined as the maximum tolerated dose per cycle. Forty-eight percent of patients presented grade 1-2 gastrointestinal toxicity after amino acid infusion. None of the patients developed acute or delayed kidney nephropathy. As comes from our dosimetric studies, maximum cumulative administrable activity with renal protection, should be set in the range of 12-18 GBq. Concerning the response, preliminary data analysis suggests there is no relationship between age, sex, number of cycles and total injected activity, within a range of 7.4 and 21.3 GBq, whereas the type of tumor seems to be more important. The response rate (PR + CR) of 27% appears encouraging, however, considering the state of disease before the enrollment, 80% of patients presented with progressive disease and showed an overall response rate of 75%. Conclusions: Our experience indicate that it is possible to deliver high doses of radioactivity to tumor by administration of 90Y-DOTATOC with objective therapeutic responses in more than 25% of patients. Methods developed to reduce kidney uptake will probably considerably decrease the absorbed dose to this critical organ while increasing the tumor dose