Table 5.

Key Papers Describing Adjuvant Therapy in Pulmonary LCNEC.

Study	Study Design	Patient population	Total Patients	Treatment	Outcomes	Other
Iyoda et al. (83)	Prospective, one arm nonrandomized clinical study, compared to historical control group.	LCNEC after surgical resection (majority of patients underwent lobectomy)	15 LCNEC	Etoposide / Cisplatin	2 year OS 88.9% in the adjuvant chemotherapy group vs 65.2% in the control group. 5 year OS 88.9% in adjuvant chemotherapy group versus 47.4% in control group.
Kenmotsu et al. (84)	Prospective, one arm phase II trial	Stage I-IIIA completely resected pulmonary HGNEC (both SCLC and LCNEC)	40 (23 LCNEC and 17 SCLC)	Irinotecan / Cisplatin	3 year OS 86% among 23 LCNEC patients and 75% among 17 SCLC patients.
Kenmotsu et al. (85)	Prospective randomized, open-label, phase III study	Stage I-IIIA completely resected pulmonary HGNEC (both SCLC and LCNEC)	221 (74 LCNEC and 78 SCLC, 39 combined SCLC and 20 combined LCNEC)	Etoposide/Cisplatin (111 patients) vs Irinotecan / Cisplatin (110 patients)	No significance difference in 3 year RFS between treatments arms (Etoposide/Cisplatin arm 65.4% and Irinotecan/Cisplatin arm was 69%). Also no significant difference between treatment arms in subgroups of LCNEC and SCLC.
Rossi et al. (86)	Retrospective review	Pure pulmonary LCNEC who underwent surgical resection	83	Variable	5 year OS 27.6%, stage I, 33%, stage II, 23% and stage III, 8%. Of 13 patients who received adjuvant chemotherapy patients with SCLC based treatment (cisplatin/etoposide) had improved overall survival compared to other NSCLC based treatments.
Veronesi et al. (87)	Retrospective review	Consecutive patients with surgical resection of pulmonary LCNEC	144	Variable	5 year OS was 42.5%; for stage I, 52%, stage II, 59%, and stage III, 20%. Patients with stage I disease who received chemotherapy tended to survive longer than those who received no chemotherapy (p = 0.077).
Iyoda et al. (88)	Retrospective review	LCNEC patients with surgical resection of primary tumors	72	Variable	5 year DFS was 42.7%, 5 year OS for patients with recurrent tumors was 12.5%. Receiving platinum based adjuvant chemotherapy was associated with lower rate of tumor recurrence as compared to non-platinum based adjuvant chemotherapy.
Sarkaria et al. (89)	Retrospective Review	Resected LCNEC	100	Variable	Median OS was 3.4 years. 20 of 71 patients with stage I-II resected disease received platinum based chemotherapy. The 5 year OS was 37% for patients who did not receive platinum based chemotherapy and 51% for patients who received it.
Saji et al. (90)	Retrospective Review	Resected LCNEC or mixed LCNEC	45	Variable	2 year OS was 89.2% and 5 year OS was 69.4%. 5 year survival rates of patients who underwent perioperative adjuvant chemotherapy was significantly higher (87.5%) than those who underwent surgery alone (58.8%).
Kujtan et al. (91)	Retrospective review	Stage I LCNEC	1232 (957 surgical resection alone, 275 both surgery and systemic chemotherapy)	Variable	OS in univariate 30 day analysis was significantly improved in patients who received chemotherapy across the whole cohort. 5 year OS was significantly improved in patients who received both surgery and systemic chemotherapy as compared to those who received chemotherapy alone (64.5% versus 48.4%).
Raman et al. (92)	Retrospective review	Stage I LCNEC	2642	Variable	5 year OS was 53%, univariable analysis showed a significant increase in OS with adjuvant therapy for stage I LCNEC compared with no adjuvant therapy. In subgroup analysis of stage IA patients (n=2055) there was no significant survival benefit for adjuvant therapy, however significant survival benefit was present in stage IB patients (N= 587).
Shen et al. (58)	Retrospective review	Surgically resected LCNEC	94	Variable	Of 75 patients who received adjuvant chemotherapy patients who received platinum /etoposide base regimens had improved DFS as compared to NSCLC regiments.

RFA, recurrence free survival; OS, overall survival; LCNEC, Large cell neuroendocrine carcinoma; SCLC, Small cell Lung Cancer; DFS, Disease free survival; NSCLC, Non-small cell lung cancer.