Oncological outcomes from trimodality therapy receiving definitive doses of neoadjuvant chemoradiation (≥60 Gy) and factors influencing consideration for surgery in stage III non-small cell lung cancer

Abstract

Purpose: Guidelines for locally advanced non-small cell lung cancer (LA-NSCLC) recommend definitive chemoradiation therapy (CRT) for cN2-N3 disease, reserving surgery for patients with minimal nodal involvement at presentation. The current literature suggests that surgery after CRT for stage III NSCLC can improve freedom-from-recurrence (FFR) but has not consistently demonstrated an improvement in overall survival, perhaps partly due to the low (45-50.4 Gy) preoperative doses delivered that result in low rates of mediastinal nodal clearance. We therefore analyzed factors associated with trimodality therapy receipt and determined outcomes in patients with LA-NSCLC who were treated with definitive doses (≥60 Gy) of neoadjuvant CRT prior to surgery.

Methods and materials: We retrospectively analyzed 355 consecutive patients with LA-NSCLC who were treated with curative intent between January 2000 and December 2013. The Kaplan-Meier method was used to estimate the overall survival and FFR of patients who were initially planned to receive trimodality treatment but never underwent surgery (unplanned bimodality) compared with those who were never considered to be surgical candidates (planned bimodality) and those who underwent surgical resection after CRT (trimodality). Cox proportional hazards regression with forward selection was used for multivariate analyses, and the Fisher exact test was used to test contingency tables.

Results: Patients who received trimodality therapy had a longer median survival than those with unplanned or planned bimodality therapy at 59.9, 20.1, and 17.3 months, respectively (P < .001). The survival benefit with surgery persisted in patients with stage IIIB (P < .001) and N3 (P = .010) nodal disease when mediastinal nodal clearance was achieved. FFR was also improved with surgical resection (P = .001). Race (P < .001), stage (P < .001), performance status (P < .001), age (P < .001), and diagnosis of chronic obstructive pulmonary disease (P = .009) were significant indicators that influenced both the decision to initially choose trimodality therapy at consultation and to actually perform surgical resection.

Conclusions: Trimodality treatment significantly improves survival and FFR in patients with LA-NSCLC when definitive doses of radiation with neoadjuvant chemotherapy are employed. We identified important demographic features that predict the use of surgical intervention in patients with stage III NSCLC.

Figure 1

(A) Overall survival in the 3 patient cohorts: Trimodality (dark solid line), unplanned bimodality (dark dashed line), and planned bimodality (light dashed line). Hazard ratio (HR) comparing the trimodality and unplanned bimodality cohorts: HR, 0.688; 95% CI, 0.595-0.796; P < .001. Inset shows overall survival as a function of surgery type (lobectomy: dark dashed line; pneumonectomy: light dashed line) in patients who underwent trimodality treatment: P = .513; (B) Intention-to-treat overall survival curves comparing all trimodality patients (unplanned bimodality+trimodality; dark solid line) and planned bimodality cohort (light solid line). HR, 0.643; 95% CI, 0.505-0.819; P < .001.

Figure 2

Five-year overall survival in the 3 patient cohorts (trimodality [solid line], unplanned bimodality [dark dashed line], and planned bimodality [light dashed line]; P < .001), stratified by (A) stage IIIA and (B) stage IIIB. Inset shows overall survival in patients with clinical N3 disease (P = .014).

Figure 3

Five-year freedom from recurrence in the 3 patient cohorts (planned trimodality [solid line], unplanned bimodality [dark dashed line], planned bimodality [light dashed line]; P < .001).