Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity

Abstract

PurposePeptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome.MethodsThe study group comprised 200 consecutive patients with metastasized somatostatin receptor-positive neuroendocrine tumours progressing on standard therapy or not suitable for other therapeutic options. A treatment cycle consisted of 7.4 GBq 177Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3–20% in 121 (60.5%) and >20% in 16 (8%).ResultsIn 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22–30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39–53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity.ConclusionsDosimetry-based therapy with 177Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

Safety and outcomes of 177Lu‐DOTATATE for neuroendocrine tumours: experience in New South Wales, Australia

“…The estimated median PFS of our patient cohort was lower than rates published in recent studies and could potentially be explained by differences in tumour characteristics. In general, a higher proportion of patients in this evaluation had non‐GEP NET primary sites and tumours with a high Ki‐67 proliferation index, which are associated with poorer PFS, than the published literature.…”

“…Our cohort consisted of a heterogenous population with a range of ages and primary tumour sites. For patients who met all protocol selection criteria, the estimated median OS of 50.7 months was consistent with OS rates from recent large ( n > 50) Australian and international studies . Characteristics associated with better survival were a low Ki‐67 proliferation index and GEP NET primary site.…”

“…Results from the phase III NETTER‐1 trial, published in January 2017, showed that PRRT treatment with 177 Lu‐DOTATATE significantly improved progression‐free survival (PFS) and suggested an overall survival (OS) benefit, when compared with treatment with octreotide long‐acting repeatable in patients with well‐differentiated, metastatic midgut NET . Results from case series have mostly focused on gastroenteropancreatic NET (GEP NET) and have also been encouraging …”

Radiation dosimetry of [131I]ICF01012 in rabbits: Application to targeted radionuclide therapy for human melanoma treatment

“…can also be used to address TRT to cells overexpressing an antigen or a cognate receptor . For example, 177 Lu‐DOTA‐octreotate peptides, somatostatin receptor ligands, are clinically relevant for neuroendocrine tumor treatments . Other specificities can be achieved with small molecules like melanin ligands belonging to the arylcarboxamide family, first developed for melanoma imaging …”

Trastuzumab cotreatment improves survival of mice with PC‐3 prostate cancer xenografts treated with the GRPR antagonist 177Lu‐DOTAGA‐PEG2‐RM26

“…Lutetium‐177 is a β − ‐emitter with half‐life of 6.71 days and maximum energy of 0.5 MeV, resulting in a maximal tissue penetration of <2 mm, most suitable for irradiation of small lesions. The accompanying gamma photons (113 keV, 6.4% and 208 keV, 11%) of 177 Lu allow for single photon emission computed tomography (SPECT) acquisition, favoring the application of this attractive radioisotope in a theranostic setting . A systematic search for the most suitable chelator for coupling to the biomolecule of interest, namely PEG 2 ‐RM26, is expected to help optimize the final radioligand profile.…”