Elsevier

The Lancet

Volume 368, Issue 9538, 2–8 September 2006, Pages 843-854
The Lancet

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Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis

https://doi.org/10.1016/S0140-6736(06)69121-6Get rights and content

Summary

Background

Several trials have studied the role of unconventional fractionated radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. The aim of this meta-analysis was to assess whether this type of radiotherapy could improve survival.

Methods

Randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic HNSCC were identified and updated individual patient data were obtained. Overall survival was the main endpoint. Trials were grouped in three pre-specified categories: hyperfractionated, accelerated, and accelerated with total dose reduction.

Findings

15 trials with 6515 patients were included. The median follow-up was 6 years. Tumours sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III–IV disease (International Union Against Cancer, 1987). There was a significant survival benefit with altered fractionated radiotherapy, corresponding to an absolute benefit of 3·4% at 5 years (hazard ratio 0·92, 95% CI 0·86–0·97; p=0·003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at 5 years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1·7% with total dose reduction at 5 years, p=0·02). There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6·4% at 5 years; p<0·0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (hazard ratio 0·78 [0·65–0·94] for under 50 year olds, 0·95 [0·83–1·09] for 51–60 year olds, 0·92 [0·81–1·06] for 61–70 year olds, and 1·08 [0·89–1·30] for over 70 year olds; test for trends p=0·007).

Interpretation

Altered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit.

Introduction

Head and neck squamous cell carcinomas are frequent tumours, with more than 550 000 new cases of oral cavity, oropharynx, hypopharynx, and larynx cancer every year worldwide.1 About 40% of patients have locally advanced disease at diagnosis. Surgery, radiation therapy, or both, have been used for decades to achieve locoregional control; the most commonly used schedule when radiotherapy is given alone is 2 Gy in a single fraction per day, 5 days a week, for 7 weeks. Despite these treatments, the prognosis of patients with head and neck squamous cell carcinomas with locally advanced disease remains poor, with 5-year survival rates of 30–35%.2

In the past decade, new radiotherapy regimens for the treatment of head and neck squamous cell carcinomas have been assessed. These regimens were designed to increase the dose-intensity by delivering a higher total dose in the same time,3, 4, 5, 6 the same total dose in 5–6 weeks instead of 7 weeks,6, 7, 8, 9, 10, 11, 12 or a smaller total dose given in 3–4 weeks.13, 14, 15, 16, 17 Reducing the total treatment time—ie, accelerating the treatment—should reduce the repopulation of tumour cells between sessions, resulting in improved locoregional control. In hyperfractionated regimens, two to three fractions are delivered each day, with a reduced dose per fraction equal to 1·1–1·2 Gy. The reduction of the dose per fraction might reduce the risk of late toxicity, despite an increased total dose. Acceleration and hyperfractionation can be combined, in particular for regimens in which overall treatment time is reduced.

In some randomised trials, altered fractionated radiotherapy has proved to be of benefit in locoregional control,3, 4, 5, 6, 9, 11, 17 although no benefit in survival was generally detected. The use of altered fractionated radiotherapy is associated with some increase in toxicity, mostly due to mucositis,6, 7, 8, 9, 17 and can add some practical constraints in radiotherapy departments3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17—eg, treatment two to three times a day or at a weekend—that need to be balanced by substantial benefit.

A meta-analysis of updated individual patient data is the most reliable way to assess whether altered fractionated radiotherapy could affect survival. This meta-analysis was undertaken by the MARCH (Meta-Analysis of Radiotherapy in Carcinomas of Head and neck) Collaborative Group. The main objective was to study the effect of altered fractionation in overall survival. A comparison between the effects of the three types of altered fractionated radiotherapy was also planned.

Section snippets

Selection of trials

The methods were specified in a protocol published in the Cochrane Library.18 The collaborative group's steering committee prespecified three groups of trials with different modifications of fractionation that correspond to three distinct biological questions. The first group (hyperfractionation) examined the effect of a higher total dose in the same overall time than in the reference arm.3, 4, 5, 6 The second group (accelerated group) represented a pure test of the effect of accelerating

Results

Of 26 potentially eligible randomised trials, nine were excluded: three were post-operative trials, one had biased randomisations, two used unconventional radiotherapy in the reference group, and three used hypofractionated radiotherapy in the experimental group (webappendix). Data from one eligible trial (212 patients) were lost.25 15 trials fulfilled all the inclusion criteria and data were available for 6515 patients.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 The length of follow-up

Discussion

This meta-analysis of individual patient data showed that different types of altered fractionated radiotherapy could improve the effectiveness of radiotherapy in head and neck squamous cell carcinomas, compared with conventional radiotherapy, with a small but significant benefit in survival and a more pronounced benefit in locoregional and local control. Our findings provide strong evidence that altered fractionated radiotherapy can improve survival in this disease. The survival benefit was

References (29)

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