Elsevier

The Lancet

Volume 386, Issue 9998, 12–18 September 2015, Pages 1049-1056
The Lancet

Articles
Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial

https://doi.org/10.1016/S0140-6736(15)60294-XGet rights and content

Summary

Background

One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes.

Methods

We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m2 cisplatin and 85 mg/m2 docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771.

Findings

From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7–22·9) in the chemoradiotherapy group and 11·6 months (8·4–15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6–50·0) with radiotherapy, compared with 26·2 months (19·9–52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery.

Interpretation

Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer.

Funding

Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

Introduction

Locally advanced stage III non-small-cell lung cancer is the most advanced stage at which cure can be achieved, but more than 60% of patients eventually die from their disease.1 For patients with stage IIIA/N2 disease, two standard treatment options are offered: definitive concurrent chemoradiotherapy2, 3 or surgery combined with chemotherapy. For the latter, randomised trials and meta-analyses have shown that adjuvant or neoadjuvant chemotherapy improves survival compared with surgery alone.4, 5

The Swiss cooperative group, SAKK, did a phase 2 trial of neoadjuvant chemotherapy with an intensive third-generation regimen that included cisplatin and docetaxel. The pathological complete response rate was 16%, and median overall survival was 27 months.6 This and several other studies showed that the most relevant determinants of favourable outcome were complete resection of the tumour and downstaging of the mediastinal nodes, from N2 to N1 or N0.7, 8 Neoadjuvant radiotherapy added to chemotherapy might improve mediastinal downstaging and the rate of complete resection, but the role of this approach in patients with surgically treated stage IIIA/N2 non-small-cell lung cancer has not been assessed in a phase 3 trial. Several phase 2 trials of neoadjuvant chemoradiotherapy, some including patients with stage IIIB non-small-cell lung cancer, have shown promising results.8, 9, 10 We did a randomised trial to test the hypothesis that incorporation of neoadjuvant radiotherapy would improve the local response rate and complete resection rate and, therefore, prolong event-free and, potentially, overall survival.

Section snippets

Patients

Patients were enrolled in 23 centres in Switzerland, Germany, and Serbia. Eligible patients had pathologically proven, locally advanced T1–3N2M0, stage IIIA/N2 non-small-cell lung cancer, according to the sixth edition of the TNM classification. Staging was done by PET-CT and brain MRI. N2 involvement had to be proven by mediastinoscopy or endobronchial ultrasonography, endoscopic ultrasonography, or bronchoscopy with transbronchial fine-needle aspiration. Patients with histological or

Results

From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group (figure 1). The trial was stopped after the third interim analysis and 134 events, on the advice of the independent data monitoring board, because the futility boundary had been crossed. At the time of data cutoff, the median follow-up time was 52·4 months (IQR 32·0–85·2).

The baseline characteristics of patients were well balanced in the two study groups (

Discussion

We completed a randomised phase 3 trial to assess the role of preoperative radiotherapy after induction chemotherapy in patients with IIIA/N2 non-small-cell lung cancer. The addition of radiotherapy did not improve event-free or overall survival, but the overall survival achieved with neoadjuvant chemotherapy and surgery were excellent.16 We applied rigorous initial staging requiring pathological proof of N2-involvement in all patients. However, technical resectability was defined pragmatically

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