Efficacy of mFOLFIRINOX chemotherapy for treatment of high-grade G3 neuroendocrine tumors and gastroenteropancreatic neuroendocrine carcinomas

Background. Gastroenteropancreatic (GEP) neuroendocrine carcinomas (NEC) are rare tumors. Despite the differences in genetic characteristics, treatment principles for GEP-NECs are extrapolated from lung NECs. A small retrospective study demonstrated potential effectiveness of the mFOLFIRINOX regimen.

Aim. To evaluate the efficacy of mFOLFIRINOX ± somatostatin analogues in treatment of inoperable or metastatic G3 Ki-67 ≥55 % GEP-NECs and neuroendocrine tumors (NETs) in a prospective cohort.

Materials and methods. A prospective single-center phase II trial with the Simon’s two-stage design was conducted. The primary endpoint was disease control (DC) ≥6 months. The statistical hypothesis was that the mFOLFIRINOX regimen would increase the disease control rate from 50 % (historical control) to 70 %. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). In the 1^st stage, 16 patients were planned for enrollment. If ≥9 patients achieved DC ≥6 months, the cohort would be expanded to 39 patients. Inclusion criteria: patients ≥18 years with histologically confirmed G3 Ki-67 ≥55 % GEP-NEC or NET, ECOG performance status 0–2. Patient enrollment took place between 2019 to February of 2024.

Results. Sixteen patients were included in the study (12 men, 4 women). The most common primary tumor sites were the stomach (8 patients, 50 %) and pancreas (5 patients, 31.3 %). Large-cell NEC was diagnosed in 10 patients (62.5 %), small-cell NEC in 1 patient (6.3 %), and G3 NET in 5 patients (31.3 %). Median Ki-67 index was 70 % (range 40–95 %). Stage IV disease was diagnosed in 15 patients (93.7 %), and 1 patient (6.3 %) had unresectable gastric NEC. The liver was the most frequent site of metastases (n = 11, 68.8 %), with isolated liver involvement in 9 patients (56.3 %). ECOG performance status was 0–1 in 15 patients (93.7 %). The majority (n = 14, 87.5 %) of patients received mFOLFIRINOX as 1^st line treatment. Positive expression of somatostatin receptors SSTR2A / 5 was found in 7 patients (43.7 %), who additionally received somatostatin analogues. ORR was 62.5 % (n = 10), and stable disease was observed in 37.5 % (n = 6) of patients. Disease control ≥6 months was achieved in 93.7 % of patients (n = 15). With a median follow-up of 13.2 months, median PFS was 10.8 months (95 % confidence interval 7.57–14.1). One serious adverse event (myocardial infarction) was reported. No grade V toxicity was observed.

Conclusion. mFOLFIRINOX chemotherapy demonstrated promising results in treatment of G3 Ki-67 ≥55 % GEP NECs and NETs. The primary endpoint was met, and the study is ongoing.