Lutetium-labelled peptides for therapy of neuroendocrine tumours

Treatment with radiolabelled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumours. Symptomatic improvement may occur with 177Lu-labelled somatostatin analogues that have been used for peptide receptor radionuclide therapy (PRRT). The results obtained with 177Lu-[DOTA0,Tyr3]octreotate (DOTATATE) are very encouraging in terms of tumour regression. Dosimetry studies with 177Lu-DOTATATE as well as the limited side effects with additional cycles of 177Lu-DOTATATE suggest that more cycles of 177Lu-DOTATATE can be safely given. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild and less than those from the use of 90Y-[DOTA0,Tyr3]octreotide (DOTATOC). Besides objective tumour responses, the median progression-free survival is more than 40 months. The patients' self-assessed quality of life increases significantly after treatment with 177Lu-DOTATATE. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with 177Lu-DOTATATE. These findings compare favourably with the limited number of alternative therapeutic approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable neuroendocrine tumours

The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours

Peptide receptor radionuclide therapy (PRRNT) is a molecularly targeted radiation therapy involving the systemic administration of a radiolabelled peptide designed to target with high affinity and specificity receptors overexpressed on tumours. PRRNT employing the radiotagged somatostatin receptor agonists (90)Y-DOTATOC ([(90)Y-DOTA(0),Tyr(3)]-octreotide) or (177)Lu-DOTATATE ([(177)Lu-DOTA(0),Tyr(3),Thr(8)]-octreotide or [(177)Lu-DOTA(0),Tyr(3)]-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine tumours expressing the somatostatin receptor subtype 2. Accumulated evidence from clinical experience indicates that these tumours can be subjected to a high absorbed dose which leads to partial or complete objective responses in up to 30 % of treated patients. Survival analyses indicate that patients presenting with high tumour receptor expression at study entry and receiving (177)Lu-DOTATATE or (90)Y-DOTATOC treatment show significantly higher objective responses, leading to longer survival and improved quality of life. Side effects of PRRNT are typically seen in the kidneys and bone marrow. These, however, are usually mild provided adequate protective measures are undertaken. Despite the large body of evidence regarding efficacy and clinical safety, PRRNT is still considered an investigational treatment and its implementation must comply with national legislation, and ethical guidelines concerning human therapeutic investigations. This guidance was formulated based on recent literature and leading experts’ opinions. It covers the rationale, indications and contraindications for PRRNT, assessment of treatment response and patient follow-up. This document is aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRNT and to deliver the treatment in a safe and effective manner. This document is largely based on the book published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic Energy Agency

Development of a potent DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours

Radiolabelled somatostatin-based antagonists show a higher uptake in tumour-bearing mouse models than agonists of similar or even distinctly higher receptor affinity. Very similar results were obtained with another family of G protein-coupled receptor ligands, the bombesin family. We describe a new conjugate, RM2, with the chelator DOTA coupled to D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH(2) via the cationic spacer 4-amino-1-carboxymethyl-piperidine for labelling with radiometals such as (111)In and (68)Ga

Neoadjuvant targeting of glioblastoma multiforme with radiolabeled DOTAGA-substance P--results from a phase I study

Complete surgical resection beyond tumor margins cannot be achieved in glioblastoma multiforme (GBM) because of infiltrative nature. In several cancers, neoadjuvant treatment has been implemented to reduce the risk of tumor cell spreading during resection. In GBM, the objective of a neoadjuvant approach is reduction of tumor cells within the main tumor mass and beyond in the infiltration zone. Such an approach can only be performed if elevated intracranial pressure can be medically controlled. In a previous study with recurrent gliomas, we showed that local intratumoral injection of radiolabeled DOTAGA-substance P substantially inhibited further growth and led to radionecrotic transformation of the tumor (CCR 2006). We have now examined this modality as neoadjuvant treatment for GBM, primarily assessing feasibility, toxicity, the extent of resection, and functional outcome. After diagnosis of GBM, 17 patients were included in a prospective phase I study. Repetitive intratumoral injections of radiolabeled DOTAGA-substance P were performed, followed by surgical resection. Chemical synthesis, radiolabeling, and local injection of the peptidic vector [90Yttrium]-DOTAGA-substance P were described previously. Neoadjuvant injection of [90Y]-DOTAGA-substance P was feasible without decompensation of intracranial pressure. Prolonged application of corticosteroids was identified as the main risk factor for side effects. Fifteen patients stabilized or improved their functional status. The mean extent of resection in subsequent surgery was 96%. Neoadjuvant therapy of GBM using locally injected radiolabeled DOTAGA-substance P was feasible and of low toxicity. The high extent of resection and concomitant irradiation of tumor cells in the infiltration zone may be prognostically relevant