Abstract
PurposePeptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA0,TYR3-octreotate ([177Lu]Lu-DOTA-TATE) and the mechanistic target of rapamycin (mTOR) inhibitor everolimus are both approved for the treatment of neuroendocrine tumours (NET). However, tumour progression is still frequent, and treatment strategies need further improvement. One possible approach could be to combine different therapy options. In this study, we investigated the toxicity of a combined treatment with everolimus and [177Lu]Lu-DOTA-TATE in female Lewis rats.MethodsAnimals received 200 MBq of [177Lu]Lu-DOTA-TATE once and/or 5 mg/kg body weight everolimus or placebo weekly for 16 weeks and were divided into four groups (group 1, placebo; group 2, everolimus; group 3, placebo + [177Lu]Lu-DOTA-TATE; group 4, everolimus + [177Lu]Lu-DOTA-TATE). Blood levels of creatinine and blood urea nitrogen (BUN) were assessed weekly to monitor nephrotoxicity, and a full blood count was performed at the time of euthanasia to monitor myelotoxicity. Additionally, renal function was analysed by sequential [99mTc]Tc-mercaptoacetyltriglycine ([99mTc]Tc-MAG3) scintigraphies. Histopathological examination was performed in all the kidneys using a standardized renal damage score (RDS).ResultsRats receiving everolimus showed a significantly lower increase in creatinine levels than those receiving placebo. Everolimus therapy reduced white blood count significantly, which was not observed for [177Lu]Lu-DOTA-TATE. Functional renal scintigraphies using [99mTc]Tc-MAG3 showed a compromised initial tracer uptake after PRRT and slower but still preserved excretion after everolimus. Histology showed no significant RDS differences between groups.ConclusionRenal scintigraphy is a highly sensitive tool for the detection of renal function impairment after a combination of everolimus and PRRT. Additional treatment with everolimus does not increase renal and haematological toxicity of PRRT with [177Lu]Lu-DOTA-TATE.
Highlights
Neuroendocrine tumours (NET) are a relatively rare entity of malignancies with increasing incidence and prevalence during the last decades [1, 2]
Strosberg et al reported significantly longer progression-free survival for patients with advanced, metastatic midgut NETs treated with [177Lu]LuDOTA-TATE in the randomized, multi-centric phase-III NETTER-1 trial [6], which led to the approval of [177Lu]Lu-DOTA-TATE by the FDA and EMA
analysis of variance (ANOVA) showed that everolimus was significantly associated with slower weight gain (p = 0.009), whereas there was no significant impact for [177Lu]LuDOTA-TATE (p = 0.133) or the combination of everolimus and [177Lu]Lu-DOTA-TATE (p = 0.809)
Summary
Neuroendocrine tumours (NET) are a relatively rare entity of malignancies with increasing incidence and prevalence during the last decades [1, 2]. Since everolimus is known to increase the radiosensitivity in solid tumours treated with external radiation therapy [7, 8], the effects of PRRT and everolimus might be potentiated. These considerations gave rise to the phase-I NETTLE study exploring the maximum tolerated dose of everolimus in a combined therapy with [177Lu]Lu-DOTA-TATE [9]. In a small cohort of patients who received a standard PRRT regime, no severe adverse effects where seen up to a daily administered dose of 7.5 mg everolimus. Using PRRT with [177Lu]Lu-DOTA-TATE, haematotoxicity is rare, and dose limiting nephrotoxicity can be reduced by co-administration of basic amino acids [6]. The aim of this work is to evaluate the toxicity of this combined treatment in a rat model using [99mTc]Tc-mercaptoacetyltriglycine ([99mTc]Tc-MAG3) scintigraphies for the longitudinal evaluation of renal function, laboratory chemical analyses (blood count, creatinine, blood urea nitrogen) to further assess nephro- and haematotoxicity as well as a histopathologic preparation and microscopic analysis of the kidneys to assess morphological damages to this organ
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