Elsevier

The Lancet Oncology

Volume 10, Issue 8, August 2009, Pages 785-793
The Lancet Oncology

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Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial

https://doi.org/10.1016/S1470-2045(09)70172-XGet rights and content

Summary

Background

Stage IIIB non-small-cell lung cancer (NSCLC) is usually thought to be unresectable, and is managed with chemotherapy with or without radiotherapy. However, selected patients might benefit from surgical resection after neoadjuvant chemotherapy and radiotherapy. The aim of this multicentre, phase II trial was to assess the efficacy and toxicity of a neoadjuvant chemotherapy and radiotherapy followed by surgery in patients with technically operable stage IIIB NSCLC.

Methods

Between September, 2001, and May, 2006, patients with pathologically proven and technically resectable stage IIIB NSCLC were sequentially treated with three cycles of neoadjuvant chemotherapy (cisplatin with docetaxel), immediately followed by accelerated concomitant boost radiotherapy (44 Gy in 22 fractions) and definitive surgery. The primary endpoint was event-free survival at 12 months. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030810.

Findings

46 patients were enrolled, with a median age of 60 years (range 28–70). 13 (28%) patients had N3 disease, 36 (78%) had T4 disease. All patients received chemotherapy; 35 (76%) patients received radiotherapy. The main toxicities during chemotherapy were neutropenia (25 patients [54%] at grade 3 or 4) and febrile neutropenia (nine [20%]); the main toxicity after radiotherapy was oesophagitis (ten patients [29%]; nine grade 2, one grade 3). 35 patients (76%) underwent surgery, with pneumonectomy in 17 patients. A complete (R0) resection was achieved in 27 patients. Peri-operative complications occurred in 14 patients, including two deaths (30-day mortality 5·7%). Seven patients required a second surgical intervention. Pathological mediastinal downstaging was seen in 11 of the 28 patients who had lymph-node involvement at enrolment, a complete pathological response was seen in six patients. Event-free survival at 12 months was 54% (95% CI 39–67). After a median follow-up of 58 months, the median overall survival was 29 months (95% CI 16·1–NA), with survival at 1, 3, and 5 years of 67% (95% CI 52–79), 47% (32–61), and 40% (24–55).

Interpretation

A treatment strategy of neoadjuvant chemotherapy and radiotherapy followed by surgery is feasible in selected patients. Toxicity is considerable, but manageable. Survival compares favourably with historical results of combined treatment for less advanced stage IIIA disease.

Funding

Swiss Group for Clinical Cancer Research (SAKK) and an unrestricted educational grant by Sanofi-Aventis (Switzerland).

Introduction

Management of locally advanced non-small cell lung cancer (NSCLC) remains a challenge.1, 2 Both local relapses and distant metastases are frequent, with 5-year survival of 3–17% for inoperable disease.3, 4, 5, 6, 7 Staging has historically subdivided stage III disease into clinical stage IIIA, thought to be potentially amenable to surgery, and stage IIIB, treated by definitive radiotherapy or radiochemotherapy. Clinical trials have repeatedly shown better outcomes with combined chemotherapy and radiotherapy, albeit with substantially increased acute toxicity.8, 9

In stage IIIA resectable disease, neoadjuvant chemotherapy seems to improve outcome.10, 11, 12, 13, 14, 15 Recent third-generation induction chemotherapy regimens have shown response rates of up to 60%.16, 17 The most important prognostic factors associated with prolonged survival were pathological mediastinal18, 19, 20 and tumour downstaging,13, 21 and complete resection.16, 18 Several trials assessing induction chemoradiotherapy followed by surgery have also included patients with stage IIIB disease. Retrospective subgroup analyses of these trials, particularly Southwest Oncology Group (SWOG) 8805,18 suggest that patients with operable stage IIIB NSCLC have outcomes similar to those with stage IIIA disease.

Progress in anaesthesia coupled with improved surgical techniques by specialised thoracic surgery units has enabled surgical limits to be expanded. Among patients with locally advanced stage IIIB NSCLC, there is a subgroup whose tumours are technically amenable to complete resection, such as localised N3 or T4 disease with involvement of the carina, the pulmonary artery, vertebral bodies, or the vena cava. Recent surgical series suggested encouraging survival rates in patients with stage IIIB disease after induction chemoradiotherapy.22, 23, 24, 25

Based on previous experience in patients with stage IIIA and N2 disease,16, 19 and in patients with operable stage IIIB disease,26 we aimed to improve outcomes in patients with operable stage IIIB disease by use of an integrated trimodality approach of neoadjuvant chemotherapy, using a modern platinum-based chemotherapy combined with docetaxel, immediately followed by accelerated concomitant boost radiotherapy (44 Gy in 22 fractions over 3 weeks) and surgical resection. To improve tolerability, a rapid sequential rather than concurrent chemoradiotherapy scheme was chosen. Our aim was to show that such an approach is feasible and safe, and to assess the outcome of selected patients presenting with locally advanced stage IIIB disease.

Section snippets

Patients

This open-label, multicentre, prospective phase II trial by the Swiss Group for Clinical Cancer Research (SAKK) was done in seven participating medical centres. Patients with potentially operable stage IIIB3 (T1–4, N3, M0 or T4, N0–3, M0) NSCLC were eligible for inclusion. N3 disease was considered technically operable when resection could be attempted with standard thoracotomy without additional sternotomy. Presence of malignant pleural or pericardial effusion or supraclavicular lymph-node

Results

Between September, 2001, and May, 2006, 46 patients with potentially resectable stage IIIB NSCLC were enrolled. Two patients were retrospectively considered ineligible due to the presence of metastatic disease at baseline, but all results are reported on an intention-to-treat basis including these patients. The baseline patient characteristics are shown in table 1. Most patients had good performance status. Squamous-cell carcinoma was the predominant histology (43%). Stage distribution at

Discussion

The data presented here suggest that treatment with chemotherapy and radiotherapy followed by surgery is feasible in selected patients with stage IIIB NSCLC, and might provide long-term survival and cure.

About a third of patients with newly diagnosed NSCLC present with locally advanced disease, 10–15% as stage IIIB disease.3 The optimum management of these patients remains controversial: American Society of Clinical Oncology and other treatment guidelines recommend definitive chemotherapy and

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