The results of this dose escalation study suggest increasing hematological toxicities with increasing [90Y-DOTA]-TOC activities. Especially the high dose protocol was associated with a low but present risk of grade 4 hematotoxicities and a higher risk of kidney toxicities. Remarkably, the post hoc analyses suggested a potentially longer survival under the low dose protocol.
Hematotoxicity is an acute toxicity that can be due to irradiation from 90Y-DOTA]-TOC circulating through the body or binding to somatostatin receptors on bone marrow cells  or due to the small fraction of free 90Y that is administered during treatment cycles and that integrates into the bone matrix . The present study suggests higher risk of anemia, leukopenia and thrombocytopenia at higher administered activities of 90Y-DOTA]-TOC. These results might represent a step towards preventing severe hematotoxicity by tailoring the applied 90Y-DOTA]-TOC activities, e.g. in patients with preexisting hematological toxicities.
Renal toxicity, on the other hand, is a late toxicity of 90Y-DOTA]-TOC. It is mainly due to the glomerular filtration and the tubular retention of the radiopeptide and its fragments and usually develops several months or years after treatment. Renal toxicity still represents the dose limiting toxicity in somatostatin based radiopeptide therapy. Renal toxicity rates between 0% and 24% have been reported for treatment with the radiopeptides 90Y-DOTA]-TOC and 177Lu-DOTA]-TOC [21–26]. These studies have used different inclusion criteria, especially regarding the baseline kidney function; they have used different treatment protocols, different follow-up schemes and different definitions of renal toxicity. Intra-study comparisons are highly warranted to allow for a comparison of the benefits and harms of both radiopeptides. The present results, however, suggest that fractionated low dose protocols might help to reduce this main toxicity of 90Y-DOTA]-TOC.
High dose 90Y-DOTA]-TOC therapy was introduced in our department in 1999 and had become the standard treatment regime, as the extent of short-term hematological and renal toxicities had shown to be acceptable . The high dose protocol, in comparison to more fractionated dosage protocols, specifically allowed for a significant reduction of travelling efforts for patients recruited from Europe, North America, South America, Africa and Asia. Due to the systematic evaluation of the long-term outcome of all patients treated with 90Y-DOTA]-TOC  we were now able to also analyze the long-term outcome after the different dosage protocols. These present results reveal that fractionated low dose protocols might help to reduce the toxicity and improve the survival after 90Y-DOTA]-TOC.
Strengths of the present study include the comprehensive recruitment of 365 patients, the sufficiently long follow-up to detect renal toxicities months or years after [90Y-DOTA]-TOC treatment and the use of competing risk models to assess the long-term toxicities of [90Y-DOTA]-TOC.
The longer survival under the low dose protocol, nevertheless, represents an unexpected finding. However, in the present study survival was not a primary outcome. Furthermore, treatment allocation occurred in a non-randomized fashion, as naturally, the clinical introduction of a novel anti-cancer drug is done in a dose escalation study. Dose escalation studies may principally underestimate the outcome of patients receiving the initial dosage regime due to recruitment of very advanced cases to initially receive a new drug or due to advances in supportive care during the enrollment period. Still, in the present analysis, which was adjusted for all baseline characteristics and the cumulative administered activity, the longest survival was found for the initial dosage step. A randomized trial is warranted in order to confirm the results on survival and long-term toxicity of fractionated versus high dose 90Y-DOTA]-TOC therapy. Such a prospective trial should use the ECOG status , the ENETS grading system  and RECIST criteria  to investigate potential differences in response as well as differences in the time-to-progression at different dosage schemes. Furthermore, such a trial should examine a possible correlation of pre-existing diabetes, hypertension and proteinuria on kidney toxicity after 90Y-DOTA]-TOC.
In conclusion, herein we describe the outcome after clinical introduction and dose escalation of [90Y-DOTA]-TOC for somatostatin receptor targeted therapy in patients with metastasized neuroendocrine tumors. This study compares survival, acute toxicities and long-term toxicities of the different [90Y-DOTA]-TOC dosage protocols applied. Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicity. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results on the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve the overall survival.