Intra-arterial peptide-receptor radionuclide therapy for neuro-endocrine tumour liver metastases: an in-patient randomised controlled trial (LUTIA)

Abstract

Purpose: Peptide receptor radionuclide therapy (PRRT) using [¹⁷⁷Lu]Lu-DOTATATE has been shown to effectively prolong progression free survival in grade 1-2 gastroenteropancreatic neuroendocrine tumours (GEP-NET), but is less efficacious in patients with extensive liver metastases. The aim was to investigate whether tumour uptake in liver metastases can be enhanced by intra-arterial administration of [¹⁷⁷Lu]Lu-DOTATATE into the hepatic artery, in order to improve tumour response without increasing toxicity.

Methods: Twenty-seven patients with grade 1-2 GEP-NET, and bi-lobar liver metastases were randomized to receive intra-arterial PRRT in the left or right liver lobe for four consecutive cycles. The contralateral liver lobe and extrahepatic disease were treated via a "second-pass" effect and the contralateral lobe was used as the control lobe. Up to three metastases (> 3 cm) per liver lobe were identified as target lesions at baseline on contrast-enhanced CT. The primary endpoint was the tumour-to-non-tumour (T/N) uptake ratio on the 24 h post-treatment [¹⁷⁷Lu]Lu-SPECT/CT after the first cycle. This was calculated for each target lesion in both lobes using the mean uptake. T/N ratios in both lobes were compared using paired-samples t-test.

Findings: After the first cycle, a non-significant difference in T/N uptake ratio was observed: T/N_IA = 17·4 vs. T/N_control = 16·2 (p = 0·299). The mean increase in T/N was 17% (1·17; 95% CI [1·00; 1·37]). Of all patients, 67% (18/27) showed any increase in T/N ratio after the first cycle.

Conclusion: Intra-arterial [¹⁷⁷Lu]Lu-DOTATATE is safe, but does not lead to a clinically significant increase in tumour uptake.

Keywords: Efficacy; Intra-arterial; Neuroendocrine tumour; PRRT; Safety.

Fig. 1

A Intra-arterial administration was performed in either the left or the right hepatic artery, thereby exposing half of the liver to high concentration [¹⁷⁷Lu]Lu-DOTATATE. B [¹⁷⁷Lu]Lu-DOTATATE enters systemic circulation via the hepatic vein. C tumours in the contra-lateral lobe and extrahepatic disease are treated via systemic circulation, both via portal vein and hepatic artery (second-pass effect)

Fig. 2

Example procedure in a 64 years old male patient with grade I small-intestinal NET, with lymphatic, hepatic, pulmonary, orbital and skeletal metastases. The patient was randomized to intra-arterial PRRT infused from the left hepatic artery. A: baseline CECT depicting extensive bi-lobar disease; B: baseline [⁶⁸Ga]Ga-DOTATOC PET/CT maximum intensity projection depicting extensive metastatic disease; C: cone-beam CT showing the microcatheter placed in the left hepatic artery, and hypervascular tumours in the left liver lobe; D: post-treatment ¹⁷⁷Lu SPECT/CT, showing similar activity distribution compared to the baseline [⁶⁸Ga]Ga-DOTATOC PET/CT. The resulting T/N_IA ratio was 9.4, and the T/N_control ratio was 6.9. Both liver lobes showed stable disease at 3 and 6 months post-treatment follow-up imaging

Fig. 3

Flowchart of patient inclusion, treatment and analysis. Due to the in-patient randomization, no dedicated flowchart per treatment arm can be shown. One patient died due to disease progression after receiving the first cycle. One patient was referred for additional treatment before finishing four cycles of intra-arterial PRRT, and another patient was referred after the 3-month follow-up imaging. One patient voluntarily withdrew from the study after the first cycle. Twenty-four patients finished all four treatment cycles

Fig. 4

A Boxplot of the T/N uptake ratios observed in control and intra-arterially treated liver metastases, calculated on the 24 h post-treatment SPECT/CT after the first cycle (primary endpoint). B Uptake in intra-arterially treated liver metastases relative to control tumours. Mean relative change = 17% (p = 0·045, 95% CI [0·00, 0·31]). T/N = Tumour-to-non-tumour; IA = Intra-arterial

Fig. 5

Response of hepatic metastases after intra-arterial treatment. A: trend of mean diameter of liver metastases with confidence interval from baseline to 6 months post-treatment. B and C: Waterfall plots showing the relative change in diameter of all target lesions in each liver lobe compared to baseline. Intra-arterially treated lobes and control lobes are distributed rather uniformly across the plot, indicating no significant difference in response. Note: each subject is present in each waterfall plot twice, due to intra-patient comparison. IA = Intra-arterial

Fig. 6

Mean hepatic parameters during follow-up after intra-arterial administration of [¹⁷⁷Lu]Lu-DOTATATE show a slight decrease of pre-existent elevated liver enzymes and no indication of additional hepatic toxicity