Elsevier

The Lancet

Volume 355, Issue 9208, 18 March 2000, Pages 949-955
The Lancet

Articles
Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data*,

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Summary

Background

Despite more than 70 randomised trials, the effect of chemotherapy on non-metastatic head and neck squamous-cell carcinoma remains uncertain. We did three meta-analyses of the impact of survival on chemotherapy added to locoregional treatment.

Methods

We updated data on all patients in randomised trials between 1965 and 1993. We included patients with carcinoma of the oropharynx, oral cavity, larynx, or hypopharynx.

Findings

The main meta-analysis of 63 trials (10 741 patients) of locoregional treatment with or without chemotherapy yielded a pooled hazard ratio of death of 0·90 (95% CI 0·85–0·94, p<0·0001), corresponding to an absolute survival benefit of 4% at 2 and 5 years in favour of chemotherapy. There was no significant benefit associated with adjuvant or neoadjuvant chemotherapy. Chemotherapy given concomitantly to radiotherapy gave significant benefits, but heterogeneity of the results prohibits firm conclusions. Meta-analysis of six trials (861 patients) comparing neoadjuvant chemotherapy plus radiotherapy with concomitant or alternating radiochemotherapy yielded a hazard ratio of 0·91 (0·79–1·06) in favour of concomitant or alternating radiochemotherapy. Three larynx-preservation trails (602 patients) compared radical surgery plus radiotherapy with neoadjuvant chemotherapy plus radiotherapy in responders or radical surgery and radiotherapy in non responders. The hazard ratio of death in the chemotherapy arm as compared with the control arm was 1·19 (0·97–1·46).

Interpretation

Because the main meta-analysis showed only a small significant survival benefit in favour of chemotherapy, the routine use of chemotherapy is debatable. For larynx preservation, the non-significant negative effect of chemotherapy in the organ-preservation strategy indicates that this procedure must remain investigational.

Introduction

About 400 000 head and neck squamous-cell carcinomas are diagnosed worldwide annually,1 most of which are locally advanced at presentation.2 Surgery and/or radiotherapy are the mainstay of locoregional treatment,3 and are often followed by chemotherapy especially in locally advanced disease. Chemotherapy induces tumour responses, but is toxic and costly. It is therefore important to know whether its addition leads to clinical benefits. Over 70 randomised trials in more than 12 000 patients have compared locoregional treatment plus chemotherapy versus the logoregional treatment alone. However, most of these trials were too small to detect even a moderate effect on survival. Yet chemotherapy is routinely used in locally advanced disease.4 In the absence of a large (over 1000-2000 patients) randomised trial, the most reliable way to evaluate chemotherapy is to do a meta-analysis based on updated individual data. The Meta-Analysis of Chemotherapy on Head and Neck Cancer (MACH-NC) collaborative group reports such an overview here.

Section snippets

Methods

The methods were specified in a protocol (available on request from JPP).

Results

The trials we included are detailed in The Lancet's website with a short description of the excluded trials (http://www.thelancet.com) The trials' references and a sensitivity analyses can also be found there.

Larynx preservation

The third meta-analysis included patients with locally advanced laryngeal or hypopharyngeal carcinomas and compared radical surgery plus radiotherapy with a neoadjuvant combination of cisplatin and fluorouracil followed by radiotherapy in responders or radical surgery plus radiotherapy in non-responders. The three trials identified (table 3) included 602 patients, with a median follow-up of 5·7 years.

The pooled hazard ratio (1·19, 0·97–1·46, figure 6) showed a non-significant trend (p=0·1) in

Discussion

In the first meta-analysis on the addition of chemotherapy to locoregional treatment, the most important result was a small, but statistically significant, overall benefit in survival with chemotherapy (the absolute benefit at 2 and 5 years was 4%). This size of effect of chemotherapy in head and neck squamous-cell carcinoma is similar to that observed in non-small-cell lung cancer.11 Prespecified analyses of the timing of chemotherapy suggested no significant benefit of adjuvant or neoadjuvant

References (13)

There are more references available in the full text version of this article.

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Collaborators listed at end of paper

References 70 and 71 (see website) have WR Bezwoda as a co-author. One of Dr Bezwoda's other studies has recently beed audited negatively. References 70 and 71 contributed 58 and 27 patients to the meta-analysis. The authors have informed us that the overall hazard ratio in the meta-analysis is the same with or without these data. In the concomitant group, the hazard ratio changes from 0·81 to 0·83, but is anyway not statistically significant—Ed.

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