Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis

Summary

Background

The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials.

Methods

For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival.

Findings

Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11 423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio [HR] 0·94, 95% CI 0·90–0·98; p=0·0033), with an absolute difference at 5 years of 3·1% (95% CI 1·3–4·9) and at 10 years of 1·2% (−0·8 to 3·2). We found a significant interaction (p=0·051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0·83, 0·74–0·92), with absolute differences at 5 years of 8·1% (3·4 to 12·8) and at 10 years of 3·9% (−0·6 to 8·4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1·22, 1·05–1·42; p=0·0098), with absolute differences at 5 years of −5·8% (−11·9 to 0·3) and at 10 years of −5·1% (−13·0 to 2·8).

Interpretation

This update confirms, with more patients and a longer follow-up than the first version of MARCH, that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested.

Funding

Institut National du Cancer; and Ligue Nationale Contre le Cancer.

Introduction

Modifications of radiotherapy fractionation have long been studied in various disease sites, including head and neck cancer. Altered fractionation radiotherapy is believed to be effective through two mechanisms that together improve the therapeutic ratio: the delivery of small fractions twice per day reduces the frequency of late toxicity, allowing for higher total doses of radiation to be delivered than can be achieved with conventional dosing; and the shortening of the overall treatment time limits tumour repopulation. Both strategies could improve tumour control. Many randomised trials have assessed these radiotherapy schedules and provided conflicting results regarding tumour control and survival, mostly because of trial heterogeneity and small sample sizes. However, these trials have confirmed that fractionation modifications were usually associated with more frequent acute side-effects but similar or less frequent late toxicity than conventional fractionation radiotherapy.1, 2, 3, 4

Research in context

Evidence before this study

The Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH) based on 15 trials and 6515 patients showed that altered fractionation radiotherapy is associated with improved overall survival and progression-free survival when compared with conventional fractionation radiotherapy. For this update, we searched PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov, and meeting proceedings, without language restriction, for published and unpublished “randomized trials” of “radiotherapy fractionation” in “head and neck cancer” published or presented between Jan 1, 2009, and July 15, 2015. Randomised trials comparing conventional fractionation radiotherapy with altered fractionation radiotherapy (with or without the same concomitant chemotherapy in both groups), or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone, in patients with non-metastatic squamous cell carcinoma were eligible as long as they had started randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010. For the trials previously included in the first round of MARCH, a follow-up update was requested.

Added value of this study

Individual patient data meta-analyses of randomised trials provide the highest level of evidence. This update of the MARCH meta-analysis almost doubled the number of patients and trials included, reaching 34 trials and 11 969 patients. The median follow-up was increased, and is now 7·9 years overall (IQR 5·3–12·1) and 10·4 years (5·7–15·2) for the 15 trials previously included in the MARCH meta-analysis. Data on acute and late toxicity were collected. Finally, a separate meta-analysis was done that compared altered fractionation radiotherapy and concomitant chemoradiotherapy. Altered fractionation radiotherapy was associated with a significant overall survival benefit compared with conventional fractionation. However, the overall survival benefit was restricted to the hyperfractionated group due to a significant interaction between type of fractionation and treatment effect. Progression-free survival was improved by altered fractionation radiotherapy, without a significant difference between type of fractionation, through an improvement in local and regional control. Acute mucositis and the need for a feeding tube during treatment were increased in the altered fractionation group but late toxicities were similar between the groups. Altered fractionation radiotherapy had significantly lower overall survival compared with conventional radiotherapy plus concomitant chemotherapy although the altered fractionation regimens of trials in this comparison were mainly accelerated radiotherapy, which has not been shown to increase survival compared with conventional fractionation.

Implications of all the available evidence

This updated meta-analysis confirms the efficacy of altered fractionation radiotherapy over conventional fractionation radiotherapy and the superiority of hyperfractionated radiotherapy over the other altered fractionation radiotherapy schedules. The effect of accelerated radiotherapy is limited to local control, whereas hyperfractionated radiotherapy seems to improve both local and regional control, and might therefore be preferred for patients with node-positive tumours. Hyperfractionated radiotherapy should therefore be regarded as a standard of care along with concomitant chemoradiotherapy for the treatment of locally advanced head and neck cancers. Head-to-head comparisons between hyperfractionated radiotherapy and concomitant chemoradiotherapy are scarce.

For squamous cell carcinoma of the head and neck, the Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH)¹ showed that altered fractionation radiotherapy is associated with improved overall survival and progression-free survival when compared with conventional fractionation radiotherapy. Trials were grouped according to the type of altered fractionation used: hyperfractionation, which used a higher total dose than the reference group, using twice daily fractions but with the same overall treatment time; moderate acceleration, in which the total dose was unchanged (±5%) but delivered more quickly (generally about 1 week faster) than in the reference group; and very accelerated radiotherapy with dose reduction, in which radiotherapy duration was shortened by 50% or more and total dose reduced by about 15% (range 11–23) compared with the reference groups. The meta-analysis¹ noted a significant interaction between treatment effect and altered fractionation regimens, the survival benefit being restricted to the hyperfractionation subgroup. The reasons for the superiority of hyperfractionation over other types of altered fractionation remained unclear, and hyperfractionation has not become a standard of care, mostly due to logistical issues, such as the difficulty to find two slots per day on machines or patient management between fractions, which favoured the delivery of concomitant chemoradiotherapy over hyperfractionation.

Because several new trials have been published since the original publication of MARCH, we provide an update, aiming to confirm and explain the superiority of hyperfractionation over the other altered fractionation regimens, to assess the benefit of altered fractionation within the context of concomitant chemotherapy or postoperative trials, and to provide a direct comparison of altered fractionation with conventional fractionation concomitant chemoradiotherapy.