Radiation therapy (RT) plays an important role in the management of locally advanced non–small-cell lung cancer (NSCLC). In the neoadjuvant (preoperative) setting, thoracic RT with concurrent chemotherapy (CT) can be an effective means for downstaging mediastinal disease and improving the likelihood of complete resection. In the adjuvant (postoperative) setting, RT may decrease the risk of locoregional recurrence for patients with high-risk disease such as pathologic N2 involvement and/or positive margins. Modern techniques of radiation treatment planning and delivery have improved the safety profile and efficacy of thoracic RT.
Neoadjuvant Concurrent CT and RT
In patients with stage IIIA, locally advanced NSCLC, neoadjuvant RT with concurrent CT (CT/RT) can play an important role in downstaging mediastinal disease and increasing the likelihood of an R0 resection. Neoadjuvant CT/RT has been studied systematically in the past several decades in the cooperative group setting. The Southwestern Oncology Group (SWOG) conducted a phase-II study (SWOG 88-05) of preoperative RT to 45 Gy with two cycles of concurrent “EP50/50” chemotherapy (cisplatin 50 mg/m2 on days 1, 8, 29, and 36 and etoposide 50 mg/m2 on days 1–5 and days 29–33) in 126 patients with stage IIIA/B NSCLC with either biopsy-proven positive N2 or N3 nodes, or T4 primary lesions.1 Patients with a response or stable disease proceeded to surgery. The clinical response rate to neoadjuvant therapy was 59%, and the resectability rate was 85% for patients with stage IIIA and 80% for patients with stage IIIB disease. The pathologic complete response rate was 21%. With a median follow-up of 2.4 years, the 3-year overall survival was 26%. While the locoregional recurrence rate was a promising 11%, the distant recurrence rate was 61%. Of interest, the strongest predictor of survival was clearance of mediastinal nodal (N2) disease by neoadjuvant treatment. The study reported a 3-year overall survival of 44% in patients with complete clearance of nodal disease (ypN0) and 18% in patients without nodal clearance (ypN+). Outcomes were particularly poor in patients with N3 disease by the presence of contralateral lymph nodes with a 3-year overall survival of 0%. However, the 3-year overall survival in patients with N3 disease due to the presence of supraclavicular lymph nodes was 35%. Treatment was relatively well tolerated, but concurrent CT/RT did result in grade 4 toxicity in 13% of patients and grade 5 toxicity in 10% of patients. However, this trial was conducted in an era when RT was delivered using fluoroscopic planning instead of modern computed tomography-based approaches.
Given the promising results of SWOG 88-05, this trimodality approach was compared against concurrent CT/RT alone in the Intergroup 0139 trial. This trial randomized 396 patients with initially unresectable T1-3, pathologic N2 NSCLC to preoperative concurrent CT/RT followed by surgery versus concurrent CT/RT alone.2 Treatment in the trimodality arm was similar to the SWOG 88-05 regimen and included 45 Gy of preoperative RT ...