Elsevier

Radiotherapy and Oncology

Volume 52, Issue 2, 1 August 1999, Pages 137-148
Radiotherapy and Oncology

Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial

https://doi.org/10.1016/S0167-8140(99)00087-0Get rights and content

Abstract

Background and method: A randomised controlled trial in locally advanced non-small cell lung cancer (NSCLC), compared CHART which employs 36 fractions of 1.5 Gy 3 times per day to give 54 Gy in 12 consecutive days with conventional radiotherapy–30 fractions of 2 Gy to a total dose of 60 Gy in 6 weeks. A total of 563 patients were entered between April 1990 and April 1995. This report is based upon the data updated to 1 April 1998.

Results: The analysis of the mature data shows that the benefits previously reported have been maintained. Overall there was a 22% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2 year survival of 9% from 20 to 29% (P=0.008) and a 21% reduction in the relative risk of local progression (P=0.033). In the large subgroup of patients with squamous cell cancer which accounted for 81% of the cases, there was a 30% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2 year survival of 13% from 20 to 33% (P=0.0007) and a 27% reduction in the relative risk of local progression (P=0.012). Furthermore, in squamous carcinoma there was a 25% reduction in the relative risk of local and/or distant progression (P=0.025) and 24% reduction in the relative risk of metastasis (P=0.043). There was no evidence that CHART gave more or less benefit in any other subgroup.

Conclusion: This analysis of mature data confirms that CHART is superior to conventional radiotherapy in achieving local tumour control and survival in locally advanced NSCLC. This demonstrates the importance of cellular repopulation as a cause of failure in the radiotherapy of NSCLC. The reduction in the risk of metastasis confirms that improved local tumour control, even in lung cancer, can reduce the incidence of metastasis. This trial shows that control of local tumour can lead to an improvement in long term survival.

Introduction

Continuous hyperfractionated accelerated radiotherapy (CHART) was introduced in January 1985 in an attempt to overcome proliferation of tumour cells during a conventional course of radiotherapy and to minimise long-term normal tissue morbidity by the use of many small fractions [9], [23].

In a pilot study of 76 patients with non-small cell lung cancer (NSCLC), there was improved primary tumour control and survival compared with historical controls [24]. A multicentre randomised trial was designed in 1989 to run in parallel with a similar study in head and neck cancer. In both, CHART was compared with conventional radiotherapy and there was a 2:1 randomisation in favour of CHART in order to facilitate the use of this regimen in groups of patients. Endpoints were: survival, disease-free interval, local tumour control, metastasis-free interval and morbidity. An interim report on both trials was prepared immediately after closure of entry in April 1995 and the definitive results of the trial in NSCLC were published in July 1997 [26], [27]. In this publication, we give further analyses of the data which has matured over two further years.

Section snippets

Patients and methods

The design, eligibility, radiotherapy and assessments, together with the endpoints and analysis has been described in detail [18], [27]. In summary, eligible patients were those who showed a WHO performance status of 0 or 1, and presented pathologically proven, inoperable NSCLC, considered suitable for radical radiotherapy. During the first phase of radiotherapy a large volume was irradiated which included the mediastinum and the primary tumour together with a 1 cm margin. The ipsilateral hilar

Results

From 1 April 1990 to 31 March 1995, 563 patients with NSCLC were entered by 13 centres–Clatterbridge, Merseyside (122); Beatson, Glasgow (71); Mount Vernon, Northwood (70); Weston Park, Sheffield (52); Nottingham (50); Royal Marsden, London/Surrey (40); Carl Gustav Carus, Dresden (39); Velindre, Cardiff (34); Cookridge, Leeds (33); Bristol (24); Umea, Sweden (14); St Mary's, Portsmouth (11) and Jonkoping, Sweden (3).

The trial profile is shown in Fig. 1. Four patients, two randomised to each

Discussion

This analysis of the mature data shows that improvement in survival and in local tumour control previously reported have been maintained [27]. Considering all patients the estimated benefits with regard to disease free and metastasis free intervals did not reach conventional levels of significance. However in the 81% of patients entered into this trial who had squamous cancer there was not only a reduction of 30% in the relative risk of death (P=0.0007) and 27% in the relative risk of local

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