Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial

Abstract

Background Concurrent chemotherapy plus radiation therapy (chemoRT) is the standard treatment for stage IIIA(N2) non-small cell lung cancer (NSCLC), a common disease entity. Phase II studies demonstrated feasibility of resection after chemoRT with encouraging survival rates. This phase III trial compared both approaches. Methods Patients with stage T1-3pN2M0 NSCLC were randomized before induction chemoRT (2 cycles of cisplatin and etoposide [PE] concurrent with 45 Gy RT). If no progression, arm 1 underwent resection, and arm 2 continued RT uninterrupted to 61 Gy. Two additional cycles of PE were given. The primary endpoint was overall survival (OS). Findings Progression-free survival for 396 eligible patients was superior in arm 1: median 12.8 versus 10.5 months, p=0.017, hazard ratio (HR) 0.77 (0.62,0.96); 5-yr 22.4% versus 11.1%. Median OS was 23.6 versus 22.2 months, p=0.24, HR 0.87 (0.70,1.10). Five-year survivals were arm 1, 27.2% and arm 2, 20.3%; odds ratio 0.63 (0.36,1.10, p=0.10). N0 status at thoracotomy predicted median OS of 33.5 months (5-year, 41.8%). Major chemoRT toxicities were neutropenia and esophagitis. Treatment-related death occurred in 16 (7.9%) patients on arm 1, of which 14 were post-pneumonectomy; and in 4 (2.1%) on arm 2. An exploratory analysis showed improved OS for patients who underwent lobectomy versus a matched cohort on chemoRT alone, but not for those undergoing pneumonectomy (matched similarly). Interpretation There was no significant survival advantage to surgery after chemoRT, despite improved PFS. Both chemoRT with definitive RT and chemoRT followed by resection (preferably lobectomy) are options for patients with stage IIIA(N2) NSCLC.

A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903)

“…[9][10][11][12] In particular, Albain et al recently reported a phase 3 study of concurrent chemoradiotherapy with or without surgical resection for stage IIIA, N2 NSCLC. 14 The median OS with and without surgery was 23.6 months and 22.2 months, respectively (P ¼ .24) and the median PFS was better in patients with surgery (12.8 months vs 10.5 months, P ¼ .017). In further exploratory analysis, the median OS was improved in the surgical group when a lobectomy was performed compared with a matched nonsurgical group (33.6 months vs 21.7 months, P ¼ .002).…”

A Model to Predict the Use of Surgical Resection for Advanced-Stage Non-Small Cell Lung Cancer Patients

“…However, the inclusion of surgical intervention into the treatment strategy for advanced-stage NSCLC has been reproducibly associated with improvements in survival [3][4][5][6][7][8]. Using data from population-based and institutional databases, we and others have demonstrated significantly longer cancer-specific and overall survival in advanced NSCLC patients treated with surgical intervention (alone or in combination) compared with nonsurgical modalities, including chemoradiotherapy, chemotherapy alone, radiotherapy alone, and no treatment (p < 0.001) [3][4][5][6].…”

“…Survival for advanced-stage NSCLC is only 4%, and outcomes are generally governed by response to systemic therapy [1]. Yet, the inclusion of surgical therapy into multimodality treatment regimens has been reproducibly associated with improved outcomes [3][4][5][6][7][8]15]. A recurrent criticism of these studies is that the observation of improved survival with surgical intervention is attributable to selection bias for patients with favorable characteristics (fewer comorbidities, lower-volume disease) rather the surgical treatment.…”

“…Our findings are not surprising, because these factors are known to favorably influence prognosis, reinforcing the concept that patients with an expectation of greater survival are offered higher-risk treatments. In fact, the independent relationship between lower metastatic status, nodal status, and younger age with longer survival is well established in clinical trials and also in previously created prediction models [7,[15][16][17].…”

Surgery for nonsmall cell lung cancer

“…Most phase II and III studies of induction chemotherapy or chemoradiation have shown prolonged survival compared with historical series and complete pathological response (i.e. no viable tumour) in 10-20% of patients [21,98,99].…”