Background: Treatment of neuro-endocrine tumors (NETs) is often challenging, given the heterogeneity of primary tumor sites, the individual disease complexity and the variety of treatment options. If patients are progressive during first-line treatment with somatostatin analogues (SSA), peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors. The NETTER-1 trial has demonstrated a pronounced positive effect on progression-free-survival of PRRT compared to high dose SSA, with a strong tendency towards overall survival benefit. In our PRRT cohort, many patients are pretreated with targeted agents, due to requirements for reimbursement within the Belgian healthcare system. The mTOR-inhibitor everolimus is approved for treatment of primary pancreatic NET and non-functional gastrointestinal or pulmonary NET. The multiple tyrosine kinase inhibitor sunitinib is approved for pancreatic NETs. Both targeted agents significantly improve progression-free survival, but they can entail several side effects, including bone marrow depression. There is currently only limited data regarding the optimal sequence of approved treatments in NET after failure of first line SSA.
Aim: Our aim was to determine the influence of pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of PRRT. We hypothesized that previous treatment with these agents could potentiate the subacute hematotoxicity of PRRT. This might also be clinically relevant for long term effects, since subacute hematotoxicity after PRRT has been shown to be a risk factor for late hematotoxicity (persistent hematological dysfunction and/or leukemia), one of the major side effects of PRRT.
Materials and methods: We performed a single-center retrospective study in which we analyzed consecutive patients treated with 177Lutetium-DOTATATE PRRT (1 to 4 cycles of 7.4 GBq), between November 2013 and July 2018. 177 Lutetium is a β-particle emitting radionuclide, with a mean penetration range of 0.7 mm in tissue (maximum penetration range of 2.2 mm), which is sufficient to kill targeted tumor cells and tumor cells in the vicinity (~20 cell diameters), with a limited effect on more distant normal cells. DOTATATE is a peptide that binds with high affinity to the somatostatin receptors overexpressed in NETs. Patients were assigned to two groups according to their pretreatment: no targeted agents (N=41), or pretreated (with everolimus, sunitinib or both; N=41). The end point was subacute hematotoxicity, defined as the nadir value in the timeframe from first administration until 3 months after the last administration, using the CTCAE 4.03 classification.
Results: The primary tumor site was gastroenteropancreatic in 80% of the patients. No statistically significant differences in severe acute hematotoxicity were seen in the pretreated group vs. the naïve group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), nor platelets (grade 3/4: 15% vs. 15%). Limitations of this study are its retrospective nature, potential bias in the lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events.
Conclusion: In a cohort of patients pretreated with everolimus and/or sunitinib, we could not demonstrate a significant negative influence of everolimus or sunitinib pretreatment on the subacute hematotoxicity of 177Lu-DOTATATE PRRT. With regard to the optimal sequence of approved treatments in NET after failure of first line SSAs, this study does not provide arguments to place everolimus and/or sunitinib treatment after PRRT.