Adjuvant therapy for lung neuroendocrine neoplasms

Table 1 Summary of current available guidelines for the use of adjuvant therapy in the treatment of stage I, II, and III typical carcinoid and atypical carcinoid

Stage; Subgroup	Guidelines
	CommNETS/NANETS	ENETS	NCCN	ESMO
I; TC	Surgery without AT	Surgery without AT	Surgery without AT	Surgery without AT
I; AC	Surgery without AT	Surgery without AT	Surgery without AT	Surgery without AT
II; TC	Surgery without AT	Surgery without AT	Surgery without AT	Surgery without AT
II; AC	Surgery without AT	Surgery without AT	Surgery without AT	Surgery without AT
III; TC	Surgery without AT	Surgery without AT	Surgery without AT	Surgery without AT
III; AC	Surgery without AT	Chemotherapy may be considered in patients with positive lymph nodes	Chemotherapy may be considered. RT is not recommended	Chemotherapy with or without radiation therapy may be considered in patients who are at high risk of relapse, (ex: N2 patients)

AT: Adjuvant therapy; AC: Atypical carcinoid; ENETS: European Neuroendocrine Tumor Society; ESMO: European Society of Medical Oncology; CommNETS: Commonwealth Neuroendocrine Tumour Research Collaboration, NANETS: North American Neuroendocrine Endocrine Tumor Society; NCCN: National Comprehensive Cancer Network; NR: No recommendations; TC: Typical carcinoid.

Table 2 Summary of the available studies examining the use of adjuvant therapy in the treatment of stage I, II, and III typical carcinoid and atypical carcinoid

Study information; Stage and Subgroup	Ref.
	Westin et al[23], 2017	Wegner et al[21], 2019	Gosain et al[22], 2019	Nussbaum et al[24], 2015	Anderson et al[25], 2017	Herde et al[26], 2018	Chong et al[27], 2014	Buonerba et al[29], 2010
AT	Chemotherapy	Chemotherapy, radiation or chemoradiation	Chemotherapy	Chemotherapy	Chemotherapy	Chemoradiation or radiation alone	Chemoradiation	Chemotherapy; SSA
Study	Retrospective; NCDB	Retrospective; NCDB	Retrospective; NCDB	Retrospective; NCDB	Retrospective; NCDB	Retrospective; Single Institution	Retrospective; Single Institution	Case Report
Subgroup	TC/AC	TC/AC	TC/AC	TC	AC	TC/AC	TC/AC	AC
Stage	IIB,III	I,II,III	I,II,III	IIB,III	I,II,III	I,II,III	IIB,IIIA	I
Other	node +	NA	NA	node +	Comparing node + and node -	NA	NA	NA
I; TC	NA	Surgery without AT3	Surgery without AT	NA	NA	AT in patients with adverse pathologic features9	NA	NA
I; AC	NA	Surgery without AT3	Surgery without AT@ (5-yr OS of 84% in obs vs 52% AT; P < 0.01)	NA	Surgery without AT in node - (OS at 12 and 60 mo in AT 86.7% and 73.3%, vs obs 87.9% and 72.3% P = 0.54).	AT in patients with adverse pathologic features9	NA	Chemotherapy followed by SSA; 10-yr PFS
II; TC	Surgery without AT (inferior OS with AT)1	Surgery without AT3	Surgery without AT	Surgery without AT5,6 (5-yr OS 81.9% obs, vs 69.7% AT; P = 0.042)	NA	AT in patients with adverse pathologic features9	chemotherapy may be beneficial in a subset of patients8	NA
II; AC	Surgery without AT (no OS benefit)2	Surgery without AT3	Surgery without AT (5-yr survival of 81% in obs vs 55% AT; P = 0.34).	NA	Surgery without AT in node +7	AT in patients with adverse pathologic features9	chemotherapy may be beneficial in a subset of patients8	NA
III; TC	Surgery without AT (inferior OS with AT)1	Surgery without AT4	Surgery without AT	Surgery without AT5,6 (5-yr OS 81.9% obs, vs 69.7% AT; P = 0.042)	NA	AT in patients with adverse pathologic features9	chemotherapy may be beneficial in a subset of patients8	NA
III; AC	Surgery without AT (no OS benefit)2	Surgery without AT4	Surgery without AT but trend towards benefit (46% in obs vs 54% AT; P = 0.24)	NA	Surgery without AT in node +7	AT in patients with adverse pathologic features9	chemotherapy may be beneficial in a subset of patients8	NA

¹Stage IIB, III grouped together and was associated with inferior OS (HR: 3.8; 95%CI: 1.9-7.0; P = 0.004).

²Stage IIB, III grouped together with no befit in OS (HR: 1.1; 95%CI: 0.68-1.78; P = 0.6).

³TC and AC stage I and II tumors grouped together to show a median survival of 114 months versus 117 months with observation (P = 0.30).

⁴TC and AC stage III tumors favored observation with a median survival of 79 mo vs 63 mo (P = 0.89).

⁵Adjuvant treatment showed a harmful effect.

⁶When baseline patient features were matched a statistical difference in OS no longer existed but there was a towards detriment (69.7% vs 80.9%; P = 0.096).

⁷Node + stage II and III grouped together; OS at 12 and 60 mo in AT 98.9% and 47.9%, vs obs 98.4% and 67.1%; P = 0.46.

⁸Stage IIB and IIIA grouped together; at 2-yr follow up, there was a 28% recurrence rate for those with local regional disease.

⁹Stage I, II, III AC and TC grouped together; overall AT showed a 20% recurrence rate.

AT: Adjuvant therapy; AC: Atypical carcinoid; Obs: Observation; OS: Overall survival; NA: Not applicable; NCDB: National cancer database; PFS: Progression free survival; SSA: Somatostatin analogue; TC: Typical carcinoid.