Risk factors and survival associated with lung cancer recurrence after curative-intent surgery: beyond TNM pathological staging

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Background: Lung cancer recurrence following curative-intent surgery remains a challenge for multi-disciplinary care teams. Currently, tumor, node, metastasis (TNM) staging is the main determinant of long-term outcomes and candidacy for perioperative therapies. The purpose of this study was to identify risk factors beyond TNM staging associated with lung cancer recurrence as well as overall survival following recurrence. Methods: A retrospective institutional database, designed for this cohort study, identified patients who underwent surgery for non-small cell lung cancer (NSCLC) and were found to be disease free in postoperative follow-up from 2004-2014. Patient characteristics, diagnostics, and operations were compared by recurrence of disease using chi squared and analysis of variance (ANOVA) tests. Multivariable Cox proportional hazard models identified factors associated with disease recurrence and patient survival. Kaplan-Meier analysis was performed to compare 5-year overall survival rates in patients with and without disease recurrence. Results: There were 1,195 patients with NSCLC who underwent surgery with 394 (33%) developing recurrence during follow up. Five year recurrence rates by pathologic staging were as follows: stage Ia 29%, stage Ib 39%, stage IIa 47%, stage IIb 59%, and stage III 57%. Risk factors associated with recurrence included wedge resection [hazard ratio (HR) 1.36, P=0.03], lymphovascular invasion (LVI) (HR 1.55, P=0.01), and visceral pleural invasion (VPI) (HR 1.43, P=0.008). Higher standardized uptake value (SUV) from preoperative positron emission tomography (PET) scans were also associated with higher recurrence rates (P=0.004). Overall 5-year survival for patients without recurrence was 72.2% compared to 47.4% (P<0.001). Minimally invasive modalities during the initial operation were associated with increased survival in patients who developed recurrence (HR 0.56, P=0.001) whereas squamous histology (HR 1.46, P=0.04), bilobectomy (HR 3.26, P=0.002) and sleeve lobectomy (HR 9.15, P=0.049) were associated with worse survival. Conclusions: Approximately, one third of patients experience recurrence after complete surgical resection of NSCLC. Recurrence and site of recurrence directly impact long-term survival. Risk factors for recurrence include wedge resection, LVI, VPI, and SUVmax, which add additional information beyond TNM staging to help prognosticate and potentially improve patient selection for emerging perioperative therapies or clinical trials.

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