Table 8.

First Line Therapy in Metastatic Extra-Pulmonary LCNEC (most studies report outcomes for cohorts with combined SCNEC and LCNEC).

Study	Study Design	Patient population	Total Patients	Treatment	Outcomes	Other
Li et al. (107)	Prospective Phase II single arm study	Metastatic gastroenteropancreatic neuroendocrine carcinoma	40 (20 SCNEC, 8 LCNEC, 7 MANEC, 5 NET w/ elevated Ki-67)	Irinotecan/Cisplatin followed by octreotide LAR maintenance	32 patients evaluable for tumor response, ORR 45%, DCR 70% Median OS 12.8 months
Alifieris et al. (108)	Prospective Phase II single arm study	Advanced neuroendocrine carcinoma of the colon or small bowel	22 patients	First line capecitabine, irinotecan, oxaliplatin plus bevacizumab, for 6 cycles, if disease responding or stable, patients received maintenance therapy with pazopanib and capecitabine.	19 patients evaluable, ORR 47.4% (3 CR, 6 PR) Median PFS 13 months, median OS was 29 months
Mitry et al. (109)	Retrospective review	Gastroenteropancreatic neuroendocrine tumors	52 patients (41 poorly differentiated neuroendocrine carcinoma)	Etoposide/Cisplatin was given in 29/41 of poorly differentiated patients	Median OS for poorly differentiated tumors was 2.3 months ORR for patients with poorly differentiated disease was 41.5%
Terashima et al. (110)	Retrospective review	Advanced extra-pulmonary neuroendocrine carcinomas	41 patients	18 patients received Etoposide/Cisplatin 22 patients received Irinotecan/Cisplatin	Median OS was 9.2 months Patients who received Etoposide/Cisplatin had median OS of 7.3 months vs 14.0 months with Irinotecan/Cisplatin
Du et al. (111)	Retrospective review	High-grade gastrointestinal neuroendocrine neoplasm	11 (included both primary metastatic disease and patients who recurred after initial therapy)	Irinotecan combined with 5-fluorouracil and leucovorin	PR in 7 patients (ORR 63.6%) Median OS was 13.0 months
Yamaguchi et al. (112)	Retrospective review	Unresectable or recurrent neuroendocrine carcinomas of the digestive system	258, 206 patients received first line irinotecan (N=160) or etoposide (N=46) based regimens	Variable, most common regimens irinotecan/cisplatin, etoposide/cisplatin, and 5-FU based regimens	Median OS was 11.5 months ORR in irinotecan/cisplatin 50%, median OS 13 months, etoposide/cisplatin ORR 28%, median OS 7.3 months
Bongiovanni etl a. (113)	Retrospective review	Metastatic gastroenteropancreatic neuroendocrine carcinoma	19 patients (13 SCNEC, 7 LCNEC)	Most common regimen etoposide/cisplatin	Median OS was 13.5 months Patients with BMI ≥25 kg/m2 had a poor prognosis as did patients with Ki-67 >55%

NET, Neuroendocrine tumor; OS, overall survival; LCNEC, Large cell neuroendocrine carcinoma; SCNEC, Small cell neuroendocrine carcinoma; Long-acting release, LAR; MANEC, mixed adenoneuroendocrine carcinoma; BMI, Body mass index; ORR, overall response rate.