Receptor-mediated radiotherapy with 90Y-DOTA-D-Phe1-Tyr3-octreotide

Abstract

A newly developed somatostatin radioligand, DOTA-[D-Phe1-Tyr3]-octreotide (DOTATOC), has been synthesised for therapeutic purposes, because of its stable and easy labelling with yttrium-90. The aim of this study was to determine the dosage, safety profile and therapeutic efficacy of 90Y-DOTATOC in patients with cancers expressing somatostatin receptors. We recruited 30 patients with histologically confirmed cancer. The main inclusion criterion was the presence of somatostatin receptors as documented by 111In-DOTATOC scintigraphy. 90Y-DOTATOC was injected intravenously using a horizontal protocol: patients received equivalent-activity doses in each of three cycles over 6 months. The first six patients received 1.11 GBq per cycle and the four successive groups of six patients received doses increasing in 0.37-GBq steps. Toxicity was evaluated according to WHO criteria. No patient had acute or delayed adverse reactions up to 2.59 GBq 90Y-DOTATOC per cycle (total 7.77 GBq). After a total dose of 3.33 GBq, one patient developed grade II renal toxicity 6 months later. The maximum tolerated dose per cycle has not yet been reached, although transient lymphocytopenia has been observed. Total injectable activity is limited by the fact that the maximum dose tolerated by the kidneys has been estimated at 20-25 Gy. Complete or partial tumour mass reduction occurred in 23% of patients; 64% had stable and 13% progressive disease. It is concluded that high activities of 90Y-DOTATOC can be administered with a low risk of myelotoxicity, although the cumulative radiation dose to the kidneys is a limiting factor and requires careful evaluation. Objective therapeutic responses have been observed.

Peptide receptor radiotherapy: a new option for the management of aggressive fibromatosis on behalf of the Italian Sarcoma Group

“…The excellent tolerability of this experimental treatment is consistent with the results of our phase I -II study (Paganelli et al, 2001;Chinol et al, 2002;Bodei et al, in press). In this study, toxicity due to 90 Y-DOTATOC, which was mainly haematological, occurred in a minority of patients receiving high activities per cycle (grade III toxicity in three out of seven F 43% F of the patients receiving 5.18 GBq, defined as MTD/cycle) and tended to reverse within 4 weeks.…”

“…They gave their written consent. An ongoing phase I -II study using 90 Y-DOTATOC in patients with solid tumours (Paganelli et al, 2001;Chinol et al, 2002;Bodei et al, 2003) was followed for these patients.…”

Successful receptor-mediated radiation therapy of xenografted human midgut carcinoid tumour

“…Using the highenergy beta emitter 90 Y, coupled to [Tyr 3 ]-octreotide via the chelator DOTA (1,4,7,10-tetraazacyclododecane,1,4,7,10-tetraacetic acid), partial tumour remission was achieved in 7 -24% of the patients (Paganelli et al, 2001;Waldherr et al, 2001;Valkema et al, 2002). Development of new somatostatin analogues with higher receptor affinity and higher degree of receptor internalisation will improve the therapeutic efficacy.…”

Toxicity and dosimetry of177Lu-DOTA-Y3-octreotate in a rat model

“…[1][2][3][4][5] Preliminary results of clinical trials with 111 In-DTPA-OC, a diagnostic radiopharmaceutical approved by the United States Food and Drug Administration, have demonstrated evidence of tumor response to treatment. 1,6 Reported responses include stable disease, but no significant tumor regressions or remissions.…”

“…90 Y-DOTA-Tyr 3 -octreotide ( 90 Y-DOTA-Y3-OC or 90 Y-DOTATOC or SMT487) is currently in clinical trials, with favorable results demonstrating significant tumor regressions. [2][3][4] Preliminary data with 177 Lu-DOTA-tyrosine3-octreotate ( 177 Lu-DOTA-Y3-TATE) are presented in a recently published abstract and suggest a range of responses from tumor shrinkage (8/26) to stable disease (14/26) to partial remission (1/26) to tumor progression (3/26). 5 The progress with somatostatin receptor ligands is very exciting; however, some questions remain to be answered.…”