Depending on the allocation after randomization, Lu-177-dotatate will be infused in either the left or the right hepatic artery, following catheterization using the Seldinger-technique.

The lobe that is not treated intra-arterially, will act as the intravenously treated lobe, due to the first-pass effect.

Neuroendocrine Tumors

Liver Metastases

Intra-arterial infusion of Lu-177-DOTATATE

Lutetium Lu 177-DOTATATE

Antoni van Leeuwenhoek Cancer Institute

Erasmus MC

University Medical Center Utrecht

Intra-arterial Lutetium-177-dotatate for Treatment of Patients With Neuro-endocrine Tumor Liver Metastases

To assess if there is a difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe. The T/N activity concentration will be measured on SPECT/CT. The primary endpoint will be assessed after the first treatment cycle. For each liver lobe up to three tumors (i.e. all >3 cm) will be selected based on size (i.e. the largest lesions without central necrosis). The weighted average activity per voxel of these lesions will be divided by the normal liver tissue mean activity per voxel (i.e. a VOI with 3 cm diameter will be placed in the normal liver tissue) to calculate the T/N ratio. The T/N activity ratios of the second, third, and final treatment cycle will be assessed as secondary endpoint. Intra- and inter-patient differences will be studied.

Difference in absolute values of mean tumor and healthy liver absorbed dose (in Gy) on post-treatment SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe: Dosimetry will be performed to measure mean tumor and healthy liver absorbed dose. Dosimetry will be performed on post-treatment SPECT/CT, which is performed 24 hours after administration of 177Lu-dotatate. The absolute absorbed dose in the IA treated liver lobe will be compared to the IV treated lobe.

-Difference in post-treatment tumor response between the intra-arterial treated liver lobe and the intravenous treated liver lobe: The tumors are measured on CT and scored according to the Southwest Oncology Group (SWOG) solid tumor response criteria, RECIST 1.1, and mRECIST criteria. Scoring systems will be applied on the patient and liver level, separately.
Because the eventual maximal shrinkage of the tumors may take months after completion of the therapy, we added the tumor response class 'minimal response (MR)', pertaining to a decrease in summed squares of tumor diameter more than 25% but less than 50%.

To assess if there is a dose-response relation between tumor absorbed dose and post-treatment tumor response: The tumor absorbed dose in both the IA and IV treated liver lobe will be calculated based on SPECT/CT as mentioned above. Tumor response will be measured on post-treatment follow-up imaging. With these parameters, a possible dose-response relation will be evaluated.

To assess safety and toxicity according to the common toxicity criteria on adverse events (CTCAE) version 4.03. The grade of toxicity refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE. Especially myelo-toxicity, renal toxicity and hepatic toxicity will be evaluated.

To assess if there is sufficient uptake of 177Lu-dotatate in extrahepatic lesions (comparison will be made with historical data): The 177Lu-dotatate uptake of the extrahepatic lesions (e.g. pancreas, intestine) will be calculated on post-treatment SPECT/CT. These results will be compared to historical data in order to evaluate if these extrahepatic tumor sites show sufficient uptake.

To assess if there is sufficient uptake of 177Lu-dotatate in the contralateral lobe (comparison will be made with historical data): The 177Lu-dotatate uptake of the contralateral lobe will be calculated on post-treatment SPECT/CT. These results will be compared to historical data in order to evaluate if the other lobe shows sufficient uptake.

To assess if there is a difference in kidney uptake of 177Lu-dotate between the IA treated patients and historical controls: Kidney uptake will be calculated on post-treatment SPECT/CT and compared to historical controls in order to assess differences in uptake.

Marnix Lam

Prof. dr. M.G.E.H. Lam

This study uses a with-in subject randomization between intra-arterial treatment via the left or right hepatic artery.

Patients will receive 200mCi dose of 177Lu Dotatate

177Lu-DOTATATE

Excel Diagnostics and Nuclear Oncology Center

177Lutetium-DOTA-Octreotate Therapy in Somatostatin Receptor-Expressing Neuroendocrine Neoplasms

Overall response will be determined by Progression Free Survival (PFS). PFS will be calculated as a function of time from start of therapy to time of overall disease progression. Patients will be censored at the date of last contact

lutetium/vomiting

Intra-arterial Lutetium-177-dotatate for Treatment of Patients With Neuro-endocrine Tumor Liver Metastases

177Lutetium-DOTA-Octreotate Therapy in Somatostatin Receptor-Expressing Neuroendocrine Neoplasms

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