Abstract
Large cell neuroendocrine carcinomas (LCNEC) represent approximately 3% of all lung cancers. Due to this rarity, little knowledge exists about their outcome, prognosis or optimal treatment strategy. The objective of this study is to evaluate the outcomes of patients undergoing lung resection for LCNEC to identify the factors affecting survival and recurrence to help refine the optimal treatment strategy. We retrospectively reviewed 116 patients who underwent lung resection at 8 centers between 2000 and 2015. We excluded 18 patients: pNX(3), stage IV(5), R1-2(10). Univariate and multivariate analysis were performed to identify factors influencing disease-specific survival, overall survival and recurrence. The variables included age, gender, smoking habit, previous malignancy, ECOG performance status, symptoms at diagnosis, extent of resection, extent of lymphadenectomy, tumor location, tumor size, pT, pleura invasion, pN, pStage and neo/adjuvant treatments. Kaplan-Meier, Cox regression and ROC curve were used. A total of 98 patients (M/F:60/38) were analyzed with a median age of 66 years (IQR=58-72). Prior to resection, 11 (11%) received induction therapy. Resections included pneumonectomy (8), bilobectomy (3), lobectomy (76) and sublobar (11) with an associated lymph node sampling (N=52, 55%) and lymphadenectomy (N=43, 45%). Adjuvant therapy was delivered in 28 (30%). Pathologic stages were I (N=40, 41%), II (N=33, 34%) and IIIA (N=25, 25%). Median follow-up was 62 (IQR=19-120) months. The 5-year disease-specific and overall survival rates were 51.6% and 42.7%. On univariate analysis, pT was associated with disease-specific and overall survival (p=0.011, p=0.028). Similarly pT was also associated on multivariate analysis with disease-specific and overall survival (p=0.044, p=0.034). The recurrence rate was 55% (2% local, 10% regional, 32% systemic, 11% not-specified). The median disease-free interval was 16 (IQR=6-80) months. Local-regional recurrence wasn’t associated with any factor on univariate analysis. Systemic recurrence was correlated with tumor size (p=0.002), pT (p=0.003) and pStage (p=0.024) on univariate analysis. Tumor size was an independent prognostic factor of systemic recurrence on multivariate analysis (p=0.001) with a threshold value of 3 cm (AUC=0.712). The 5-year disease-free survival for systemic recurrence in tumors < 3 cm or ≥3 cm was 75.4% and 37.8% (p=0.001). The 5-year disease-specific survival was 56.7% and 47.3% (p=0.088). Treatment of LCNEC with predominately surgical resection results in a respectable 5-year survival. However, a high proportion of systemic recurrence occurs. Tumors ≥3 cm have a higher rate of systemic recurrence and lower rate of survival suggesting that adjuvant chemotherapy may be indicated for completely resected LCNEC ≥3 cm.
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