Peptide receptor radionuclide therapy plus somatostatin analogues for a neuroendocrine tumour combined and maintenance treatment

Abstract

Neuroendocrine tumours (NETs) constitute a diverse group of cancers characterized by heterogeneous biological hallmarks and variable behaviour, from slow-growing and indolent tumours to aggressive and rapidly fatal cancers [1]. Somatostatin analogues (SSAs) provide the first line of systemic treatment of the gastro-entero-pancreatic-NETs (GEP-NETs), through the expression of somatostatin receptors (SSTRs) by NETs cells that bind the SSAs. The SSAs control the symptoms related to hormone hypersecretion in symptomatic GEP-NETs patients, inhibiting tumour angiogenesis and consequently its growth. This improves both progression-free survival (PFS) and overall survival (OS) [2]. Another option for the treatment of advanced, metastatic, well-differentiated and SSTRs-positive NETs is given by the peptide receptor radionuclide therapy (PRRT), which has been successfully applied since the 1990s [1]. The treatment for patients with progressive metastatic NETs, usually consisting of 4 cycles of 7.4 GBq (200 mCi) of [177Lu] DOTApeptide at 8 weekly intervals, has proven to be safe, effective and with low side-effects [1]. A number of studies have shown a significant clinical benefit in NETs patients following PRRT. Brabander et al. confirmed a promising therapeutic outcome in 443 metastatic NETs’ patients that expressed SSTRs [3]. The overall efficacy data showed good response rates, with, respectively, a PFS and OS of 29 and 63 months (64 months of median follow-up time and range 58–70 months). Until now, however, the data on OS and PFS have been established only for either SSAs or PRRT treatment, while their synergistic effect has been highlighted only recently. In 2014, Ezzidin and colleagues reported on 74 metastatic GEP-NETs patients treated with PRRT, observing a PFS and OS of, respectively, 26 and 55 months [4]. In their protocol, short-acting somatostatin analogues needed to be paused for 1 day before the administration of [177Lu]Octreotate, while for long-acting analogues, the suspension lasted for a minimum of 4 weeks before PRRT [4]. Furthermore, a better efficacy of [177Lu]DOTATATE plus Octreotide-LAR (30 mg) vs. Ocreotide-LAR (60 mg) alone in the treatment of metastatic, progressive, and SSTRspositive GEP-NETs has been demonstrated by the Netter-1 study [5]. In the [177Lu]DOTATATE therapy group, the patients continued receiving SSAs approximately 24 h after each [177Lu]DOTATATE cycle, then monthly after fulfilment of all four treatments [5]. Crucially, the study reported a median PFS of 28.4 months in a combined treatment group vs. 8.5 of a control group (follow-up period of about 40 months), while the median OS in the combined treatment group was not reached. The effectiveness of the combined SSAs plus PRRT therapy was also confirmed in a 2017 study [6], addressing the survival rate of 79 patients with metastatic NET and positive SSTRs imaging. In addition, the SSAs’ administration was delivered 1 month after the last cycle of PRRT and then maintained during the follow-up, resulting in an OS of 55 months, a PFS of 39 months, and an event-free survival of 33 months. As a further development, a recent article by Yordanova [7] highlighted for the first time the concept of PRRT plus SSAs as “Combined and Maintenance Therapy”. Here, the patients achieved a 91 months OS when treated with PRRT plus SSAs as a combination and/or maintenance therapy; the median follow-up period was 43.5 months. In contrast, those treated with PRRT had only 47 months of OS. These * Salvatore Antonio Pignata [email protected]