Elsevier

The Lancet Oncology

Volume 13, Issue 7, July 2012, Pages 671-678
The Lancet Oncology

Articles
Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301)

https://doi.org/10.1016/S1470-2045(12)70139-0Get rights and content

Summary

Background

It is unknown whether combined chemoradiotherapy improves overall survival in elderly patients with locally advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess whether radiotherapy plus carboplatin results in longer survival than radiotherapy alone in elderly patients with NSCLC.

Methods

This was a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Patients older than 70 years with unresectable stage III NSCLC were randomly assigned to chemoradiotherapy (60 Gy plus concurrent low-dose carboplatin [30 mg/m2 per day, 5 days a week for 20 days]) or radiotherapy alone, using a minimisation method with biased-coin assignment balancing on Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), stage (IIIA vs IIIB), and institution. The primary endpoint was overall survival, which was analysed for the eligible population and stratified by ECOG performance status, stage, and institution. The trial was stopped early as a result of the second planned interim analysis. This study is registered with UMIN Clinical Trials Registry, number C000000060, and ClinicalTrials.gov, number NCT00132665.

Findings

200 patients were enrolled from Sept 1, 2003 to May 27, 2010: 100 in the chemoradiotherapy group and 100 in the radiotherapy group. The second planned interim analysis was done 10 months after completion of patient accrual. At this time, median follow-up for censored cases was 19·4 months (IQR 10·3–33·5). In accordance with the prespecified stopping rule, the JCOG data and safety monitoring committee recommended early publication of this trial because the difference in overall survival favoured the chemoradiotherapy group. Median overall survival for the chemoradiotherapy and radiotherapy alone groups were 22·4 months (95% CI 16·5–33·6) and 16·9 months (13·4–20·3), respectively (hazard ratio 0·68, 95·4% CI 0·47–0·98, stratified log-rank test one-sided p value=0·0179). More patients had grade 3–4 haematological toxic effects in the chemoradiotherapy group than in the radiotherapy alone group, including leucopenia (61 [63·5%] vs none), neutropenia (55 [57·3%] vs none), and thrombocytopenia (28 [29·2%] vs two [2·0%]). Grade 3 infection was more common with chemoradiotherapy (12 patients [12·5%]) than with radiotherapy (four patients [4·1%]). Incidences of grade 3–4 pneumonitis and late lung toxicity were similar between groups. There were seven treatment-related deaths: three of 100 patients (3·0%) in the chemoradiotherapy group and four of 100 (4·0%) in the radiotherapy group.

Interpretation

For a select group of elderly patients with locally advanced NSCLC, combination chemoradiotherapy provides a clinically significant benefit over radiotherapy alone, and should be considered for this population.

Funding

Ministry of Health, Labour, and Welfare of Japan.

Introduction

Lung cancer is mainly a disease of the elderly. More than two-thirds of lung cancer cases occur in people 65 years or older, and the median age at diagnosis is 71 years.1 Therefore, it has become increasingly important to establish an effective treatment for elderly patients with lung cancer. At present, the standard treatment for patients with locally advanced non-small-cell lung cancer (NSCLC) is concurrent chemoradiotherapy.2, 3 However, few clinical trials have been designed to specifically study the treatment of elderly patients with stage III NSCLC, and it remains unclear whether combined chemoradiotherapy is suitable for elderly patients.

A previous randomised study by our group—the Japan Clinical Oncology Group 9812 trial (JCOG9812)4—was undertaken to assess whether daily low-dose carboplatin plus radiotherapy had a greater effect on survival than radiotherapy alone in elderly patients with unresectable locally advanced NSCLC. JCOG9812 was stopped early after treatment-related deaths occurred in four of 46 enrolled patients, three of whom were in the chemoradiotherapy group. We retrospectively assessed radiotherapy quality and noted that only 18 of 45 evaluable patients (40%) had radiotherapy fields that were protocol-compliant in terms of tumour coverage or normal lung restrictions. Additionally, two of the four treatment-related deaths were considered to be associated with protocol violations—ie, radiation fields that included more than half of the ipsilateral lung.

In view of these findings, JCOG introduced radiotherapy quality-assurance programmes in 2002.5 Although only 46 patients were enrolled in JCOG9812, median overall survival seemed to be better with combination chemotherapy (18·2 months) than with radiotherapy alone (14·1 months).4 Therefore, we initiated a new phase 3 trial (JCOG0301) with a design similar to JCOG9812 but that included a radiotherapy quality-assurance programme.

Section snippets

Study design and patients

This trial was a multicentre, randomised, phase 3 study. The study protocol was approved by the JCOG clinical trials review committee and the institutional review board of each participating institution before study initiation. Eligibility criteria were the following: cytologically or histologically confirmed NSCLC; age 71 years or older with a condition that precluded cisplatin-based combination chemotherapy (cisplatin therapy is considered inappropriate for all patients 75 years or older;

Results

From Sept 1, 2003, to May 27, 2010, 200 patients from 27 institutions were enrolled in this study: 100 in the chemoradiotherapy group and 100 in the radiotherapy alone group. A flow diagram is shown in figure 1. Three patients did not meet eligibility criteria subsequent to enrolment because of contralateral hilar node metastases or a wider than expected radiation field; one patient in the chemoradiotherapy group was not treated and was excluded from efficacy and safety analyses, two patients

Discussion

This randomised, controlled, phase 3 trial aimed to assess whether chemoradiotherapy led to better survival than radiotherapy alone in elderly patients with locally advanced NSCLC. Thoracic radiotherapy with daily low-dose carboplatin was associated with significantly longer survival than radiation alone. This trial is, to the best of our knowledge, the first study to show that combined chemoradiotherapy can improve the outcome of stage III NSCLC in elderly patients. Concurrent

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