Elsevier

The Lancet

Volume 362, Issue 9388, 20 September 2003, Pages 933-940
The Lancet

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Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6&7 randomised controlled trial

https://doi.org/10.1016/S0140-6736(03)14361-9Get rights and content

Summary

Background

Although head and neck cancer can be cured by radiotherapy, the optimum treatment time for locoregional control is unclear. We aimed to find out whether shortening of treatment time by use of six instead of five radiotherapy fractions per week improves the tumour response in squamous-cell carcinoma.

Methods

We did a multicentre, controlled, randomised trial. Between January, 1992, and December, 1999, of 1485 patients treated with primary radiotherapy alone, 1476 eligible patients were randomly assigned five (n=726) or six (n=750) fractions per week at the same total dose and fraction number (66–68 Gy in 33–34 fractions to all tumour sites except well-differentiated T1 glottic tumours, which were treated with 62 Gy). All patients, except those with glottic cancers, also received the hypoxic radiosensitiser nimorazole. Analysis was by intention to treat.

Findings

More than 97% of the patients received the planned total dose. Median overall treatment times were 39 days (sixfraction group) and 46 days (five-fraction group). Overall 5-year locoregional control rates were 70% and 60% for the six-fraction and five-fraction groups, respectively (p=0·0005). The whole benefit of shortening of treatment time was seen for primary tumour control (76 vs 64% for six and five fractions, p=0·0001), but was non-significant for neck-node control. Six compared with five fractions per week improved preservation of the voice among patients with laryngeal cancer (80 vs 68%, p=0·007). Disease-specific survival improved (73 vs 66% for six and five fractions, p=0·01) but not overall survival. Acute morbidity was significantly more frequent with six than with five fractions, but was transient.

Interpretation

The shortening of overall treatment time by increase of the weekly number of fractions is beneficial in patients with head and neck cancer. The six-fractions-weekly regimen has become the standard treatment in Denmark.

Introduction

Squamous-cell carcinoma of the head and neck is predominantly a locoregional disease, and the primary treatment methods are surgery and radiotherapy.1 Head and neck cancer can be cured by radiation, but tumours might be heterogeneous for intrinsic cellular radiosensitivity. This heterogeneity results in variation in the total dose needed to control the tumour, the presence of tumour hypoxia with the consequential hypoxic radioresistance, and tumour-cell proliferation during treatment.1, 2, 3, 4

In Denmark, there is a long-standing tradition of using primary radiotherapy to treat all laryngeal and pharyngeal carcinomas, and some tumours in the oral cavity, to induce optimum tumour control and to cause minimum normal-tissue complications. The treatment is coordinated by the Danish Head and Neck Cancer Study Group (DAHANCA). So far, DAHANCA has completed two national protocols that used hypoxic radiosensitisers, which significantly improved locoregional tumour control when combined with radiotherapy of pharyngeal and supraglottic laryngeal carcinoma.5, 6 Subsequently, the standard treatment in these groups of patients was selected as the best regimen from the DAHANCA 5 study—ie, conventional fractionation to 66–68 Gy (2 Gy per fraction in five fractions per week) together with the hypoxic radiosensitiser nimorazole.

A cause of treatment resistance could be radiation-induced accelerated proliferation of clonogenic tumour cells. A reduction in the chance of tumour control through the lengthening of treatment time has been clinically and biologically documented.4, 7 Furthermore, in several clinical studies, reduction in the total treatment time has improved tumour control.8, 9 A shorter treatment time may be accomplished by applying a higher dose per fraction, but this change will disproportionately increase the rate of late complications. A shorter treatment time is thus feasible only if the weekly number of radiation fractions is increased.

Repopulation and hypoxia can reasonably be assumed to be independent factors, and, thus, the optimum option is a reduced treatment time with use of concomitant hypoxic modification in relevant tumours. We assessed the suitability of five versus six weekly radiotherapy fractions, given to the same total dose, in unselected patients.

Section snippets

Protocol design and patients' eligibility

From January, 1992, to December, 1999, we enrolled patients into a randomised controlled trial that comprised of two subprotocols: DAHANCA 6, which included all glottic carcinomas, and DAHANCA 7, which included tumours of the supraglottic larynx, pharynx, and oral cavity. The only difference in the two subprotocols was that DAHANCA 6 dealt only with the fractionation effect, whereas the DAHANCA 7 also included treatment with the hypoxic radiosensitiser nimorazole.

Pretreatment assessment

Results

1485 patients were recruited, 791 in the DAHANCA 7 protocol and 694 in the DAHANCA 6 protocol. Nine were not eligible and, thus, 1476 assessable patients were included in the analysis (figure 1).

1229 patients were men and 247 women, with a median age at randomisation of 62 years (range 20–88). The distribution of patients' and tumour characteristics were similar in the two groups at baseline (Table 1). 750 patients were assigned six fractions per week, and 726 five fractions per week. This

Discussion

Accelerated radiotherapy applied to squamous-cell carcinoma of the head and neck yields better locoregional control than does a conventional schedule with identical dose and fractionation. This finding is in agreement with several similar but smaller randomised studies.10, 11, 12, 13, 14

In trials in which shorter treatment times were applied, but the total dose was also reduced,15, 16, 17, 18 a better or equivalent tumour response in the accelerated fractionation group was found. Accelerated

References (30)

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