Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study

Summary

Background

Four cycles of etoposide plus cisplatin and accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard of care for limited-stage small-cell lung cancer (SCLC). Irinotecan plus cisplatin significantly improved overall survival compared with etoposide plus cisplatin for extensive-stage SCLC. We compared these regimens for overall survival of patients with limited-stage SCLC.

Methods

We did this phase 3 study in 36 institutions in Japan. Eligibility criteria included age 20–70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and adequate organ functions. Eligible patients with previously untreated limited-stage SCLC received one cycle of etoposide plus cisplatin (intravenous etoposide 100 mg/m² on days 1–3; intravenous cisplatin 80 mg/m² on day 1) plus AHTRT (1·5 Gy twice daily, 5 days a week, total 45 Gy over 3 weeks). Patients without progressive disease following induction therapy were randomised (1:1 ratio, using a minimisation method with biased-coin assignment balancing on ECOG performance status [0 vs 1], response to induction chemoradiotherapy [complete response plus near complete response vs partial response and stable disease], and institution) to receive either three further cycles of consolidation etoposide plus cisplatin or irinotecan plus cisplatin (intravenous irinotecan 60 mg/m² on days 1, 8, 15; intravenous cisplatin 60 mg/m² on day 1). Patients, physicians, and investigators were aware of allocation. The primary endpoint was overall survival after randomisation; primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00144989, and the UMIN Clinical Trials Registry, number C000000095.

Findings

281 patients were enrolled between Sept 1, 2002, and Oct 2, 2006. After induction etoposide plus cisplatin and AHTRT, 258 patients were randomised to consolidation etoposide plus cisplatin (n=129) or irinotecan plus cisplatin (n=129). In the etoposide plus cisplatin group, median overall survival was 3·2 years (95% CI 2·4–4·1). In the irinotecan and cisplatin group, median overall survival was 2·8 years (95% CI 2·4–3·6); overall survival did not differ between the two groups (hazard ratio 1·09 [95% CI 0·80–1·46], one-sided stratified log-rank p=0·70). The most common adverse events of grade 3 or 4 were neutropenia (120 [95%] in the etoposide plus cisplatin group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [10%]). There was one treatment-related adverse event leading to death in each group (radiation pneumonitis in the etoposide plus cisplatin group; brain infarction in the irinotecan plus cisplatin group).

Interpretation

Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC.

Funding

National Cancer Center and the Ministry of Health, Labour, and Welfare of Japan.

Introduction

The shift from non-filter to filter tobacco has resulted in a decrease in small-cell and squamous-cell lung cancer, and an increase in adenocarcinoma of the lung.¹ Currently, small-cell lung cancer (SCLC) accounts for 13% of all lung cancer, and about a third of patients with SCLC have limited-stage disease—ie, disease confined to the hemithorax.²

Combination chemotherapy is the cornerstone of SCLC treatment, and meta-analyses3, 4 have shown that addition of thoracic radiotherapy to combination chemotherapy significantly improves the survival of patients with limited-stage SCLC. Several randomised trials5, 6, 7 have shown that early use of concurrent thoracic radiotherapy results in improved overall survival compared with sequential or late use when etoposide and cisplatin are used as combination chemotherapy. The US intergroup phase 3 study⁸ showed that accelerated hyperfractionated thoracic radiotherapy (AHTRT) with etoposide plus cisplatin for limited-stage SCLC resulted in significantly improved overall survival compared with standard fractionation, once-daily irradiation, with 5-year survival of 26% and 16%, respectively. Thus, etoposide plus cisplatin and AHTRT is now the standard of care in patients with limited-stage SCLC. However, many patients with limited-stage SCLC experience tumour recurrence and die from the disease, showing the need for improved therapy.

The Japan Clinical Oncology Group (JCOG) previously undertook a randomised phase 3 trial⁹ (JCOG9511) comparing irinotecan plus cisplatin with etoposide plus cisplatin in patients with extensive-stage SCLC. Response and overall survival were significantly better for patients treated with irinotecan than those treated with etoposide. The result prompted us to explore the use of irinotecan and cisplatin in limited-stage SCLC. A phase 2 study¹⁰ showed that irinotecan and cisplatin after concurrent etoposide plus cisplatin plus AHTRT for limited-stage SCLC was safe with acceptable side-effects, and the 3-year survival of 38% of patients was encouraging.

Therefore, we did a randomised phase 3 trial to compare overall survival of patients with limited-stage SCLC given three cycles of irinotecan plus cisplatin or etoposide plus cisplatin after one cycle of induction etoposide plus cisplatin and concurrent AHTRT.