lmprovement of 177Lu-octreotate treatment of small-intestine neuroendocrine tumors by hyperfractionation

Abstract

Neuroendocrine tumor incidence is steadily rising, and the late diagnosis often results in metastatic disease and current treatments mostly prolong life and in-crease quality of life without increasing cure rate. 177Lu-octreotate was recently approved for treatment of neuroendocrine tumors, but the dosage scheme should be optimized. The aim of this thesis was to study the effects of fractionated admin-istration of 177Lu-octreotate in the human GOT1 tumor mouse model.

GOT1 bearing mice were given 177Lu-octreotate as a single or fractionated admin-istration. The biodistribution and tumor volume response was followed with time. DNA and RNA were extracted from tumor tissue. DNA methylation was evaluated, and expression of genes involved in apoptosis determined.

Hyperfractionated administration gave a more pronounced anti-tumoral effect and longer progression-free survival than single administration with the same total amount of 177Lu-octreotate. The methylation analysis of genes and promoters re-vealed 177Lu-octreotate treatment specific responses across the groups. Altered expression of apoptosis related genes in regrown tumors was modest, with vary-ing commonalities between the groups. Hyperfractionation generally resulted in a different apoptotic gene expression pattern compared with single-administration in regrown tumors. Hyperfractionation led to higher absorbed dose to tumor and lower to kidneys than single-administration. Expression of genes related to apop-tosis in tumors were similar between groups early after high dose level of 177Lu-octreotate, but sometimes with a trend towards higher gene regulation for the hy-perfractionated groups. The pro apoptotic genes BAX, FAS, GADD45A and TNFRSF10B were significantly regulated at several early time-points for both high dose groups.

In conclusion, hyperfractionation of 177Lu-octreotate shows promise compared with single administration, and should be tested clinically.