Inflammatory markers and long term hematotoxicity of holmium-166-radioembolization in liver-dominant metastatic neuroendocrine tumors after initial peptide receptor radionuclide therapy

Abstract

Purpose: In patients with neuroendocrine tumor liver metastases, additional tumor reduction can be achieved by sequential treatment with [166Ho]-radioembolization after peptide receptor radionuclide therapy (PRRT). The aim of this study was to analyze hematotoxicity profiles, (i.e. lymphocyte and neutrophile toxicity) and the prognostic value of neutrophil-to-lymphocyte ratio (NLR) and thrombocyte-to-lymphocyte ratio (TLR).

Methods: All patients included in the prospective HEPAR PLuS study were included in this study. Blood testing was performed at baseline (before radioembolization) and at regular intervals during 1-year follow-up. Radiological response was assessed at 3, 6, 9, and 12 months according to RECIST 1.1. Logistic regression was used to analyze the prognostic value of NLR and TLR on response.

Results: Thirty-one patients were included in the toxicity analysis; thirty were included in the response analysis. Three weeks after radioembolization, a significant decrease in lymphocyte count (mean change - 0.26 × 109/L) was observed. Ten patients (32.2%) experienced grade 3-4 lymphocyte toxicity. This normalized at 6 weeks and 3 months after treatment, while after 6 months a significant increase in lymphocyte count was observed. An increase in NLR and TLR at 3 weeks, compared to baseline, significantly predicted response at 3 months (AUC = 0.841 and AUC = 0.839, respectively) and at 6 months (AUC = 0.779 and AUC = 0.765). No significant relation with survival was found.

Conclusions: Toxicity after sequential treatment with PRRT and [166Ho]-radioembolization is limited and temporary, while significant additional benefit can be expected. Change in NLR and TLR at 3-weeks follow-up may be valuable early predictors of response. Trial registration ClinicalTrials.gov, NCT02067988. Registered 20 February 2014, https://ichgcp.net/clinical-trials-registry/NCT02067988 .

Keywords: Hematologic toxicity; Holmium-166; Inflammatory markers; Lutetium-177-dotatate; NET; NLR; Neuroendocrine neoplasm; Neuroendocrine tumor; PRRT; Radioembolization; TLR.

Conflict of interest statement

ML has acted as consultant for BTG/Boston Scientific and Terumo/Quirem Medical, and receives research support by Novatis/AAA. AB has acted as consultant for BTG/Boston Scientific and Terumo/Quirem Medical. All other authors declare that they have no conflicts of interest.

© 2022. The Author(s).

Figures

Fig. 1

Laboratory test trends indicating hematologic toxicity. Points indicate median change compared to baseline. FU follow-up

Fig. 2

Trends in absolute NLR and TLR after [166Ho]-radioembolization, with a significant peak 3 weeks after treatment. FU follow-up

Fig. 3

Differences in relative change in NLR and TLR at 3-weeks follow-up after [166Ho]-radioembolization plotted against response according to RECIST 1.1 at 3 months (top-left and top-right) and 6 months (bottom-left and bottom-right)

Fig. 4

ROC curves of relative change in NLR and TLR from baseline at 3-weeks follow-up in predicting objective response at 3 months (top row) and 6 months (bottom row), according to RECIST 1.1. AUC area under the curve

Fig. 5

A male patient with hepatic neuroendocrine tumor metastases, with the largest lesion measuring 60 mm at screening (A), was treated with whole-liver [166Ho]-radioembolization (B). After 3 months partial response was observed, with the largest lesion measuring 41 mm (C). A clear peak in NLR and TLR can be observed at 3 weeks follow-up (D). FU follow-up

Fig. 6

Difference in overall survival and progression-free survival in patients with or without extrahepatic disease (excluding lymph node involvement)