Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis

doi:10.1016/S1470-2045(15)70126-9

The Lancet Oncology

Volume 16, Issue 6, June 2015, Pages 645-655

https://doi.org/10.1016/S1470-2045(15)70126-9 Get rights and content

Summary

Background

A previous individual patient data meta-analysis by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group to assess the addition of chemotherapy to radiotherapy showed that it improves overall survival in nasopharyngeal carcinoma. This benefit was restricted to patients receiving concomitant chemotherapy and radiotherapy. The aim of this study was to update the meta-analysis, include recent trials, and to analyse separately the benefit of concomitant plus adjuvant chemotherapy.

Methods

We searched PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov, and meeting proceedings to identify published or unpublished randomised trials assessing radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma and obtained updated data for previously analysed studies. The primary endpoint of interest was overall survival. All trial results were combined and analysed using a fixed-effects model. The statistical analysis plan was pre-specified in a protocol. All data were analysed on an intention-to-treat basis.

Findings

We analysed data from 19 trials and 4806 patients. Median follow-up was 7·7 years (IQR 6·2–11·9). We found that the addition of chemotherapy to radiotherapy significantly improved overall survival (hazard ratio [HR] 0·79, 95% CI 0·73–0·86, p<0·0001; absolute benefit at 5 years 6·3%, 95% CI 3·5–9·1). The interaction between treatment effect (benefit of chemotherapy) on overall survival and the timing of chemotherapy was significant (p=0·01) in favour of concomitant plus adjuvant chemotherapy (HR 0·65, 0·56–0·76) and concomitant without adjuvant chemotherapy (0·80, 0·70–0·93) but not adjuvant chemotherapy alone (0·87, 0·68–1·12) or induction chemotherapy alone (0·96, 0·80–1·16). The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0·0001): progression-free survival (HR 0·75, 95% CI 0·69–0·81), locoregional control (0·73, 0·64–0·83), distant control (0·67, 0·59–0·75), and cancer mortality (0·76, 0·69–0·84).

Interpretation

Our results confirm that the addition of concomitant chemotherapy to radiotherapy significantly improves survival in patients with locoregionally advanced nasopharyngeal carcinoma. To our knowledge, this is the first analysis that examines the effect of concomitant chemotherapy with and without adjuvant chemotherapy as distinct groups. Further studies on the specific benefits of adjuvant chemotherapy after concomitant chemoradiotherapy are needed.

Funding

French Ministry of Health (Programme d'actions intégrées de recherche VADS), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Introduction

Nasopharyngeal carcinoma is distinct from other head and neck carcinomas; it has a specific geographical distribution, is associated with the Epstein-Barr virus, has an aggressive natural locoregional history, and has a high risk of distant metastases.¹ Nevertheless, high proportions of patients are cured with standard therapy, even in cases of locoregionally advanced disease. Radiotherapy is the cornerstone of initial treatment due to the radiosensitive behaviour of nasopharyngeal carcinoma and its deep-seated location. The landmark Intergroup 0099 (INT-0099) trial² and the first Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC)³ showed that there was an overall survival benefit related to concomitant chemotherapy. However, this meta-analysis included only eight trials and 1753 patients, and combined results from trials of concomitant plus adjuvant chemotherapy and concomitant chemotherapy alone. Since those publications, additional trials have been done, including replications of the INT-0099 trial, allowing a study of the interaction between the timing of chemotherapy and the effect on various endpoints in more detail. The aim of this study was to update the meta-analysis, include recent trials, and to analyse separately the benefit of concomitant plus adjuvant chemotherapy.

Section snippets

Selection criteria and search strategy

This updated meta-analysis was done according to a pre-specified protocol. To be eligible, trials had to compare radiotherapy alone with radiotherapy plus chemotherapy, or to compare a treatment strategy with one chemotherapy timing (ie, radiotherapy plus concomitant chemotherapy, radiotherapy plus induction chemotherapy, or radiotherapy plus adjuvant chemotherapy) with the same treatment strategy plus chemotherapy at another timing. They had to be randomised and include patients with untreated

Results

Eight trials (1753 patients)2, 12, 13, 14, 15, 16, 17, 18 were included in our previous meta-analysis. This study includes 4806 patients from 19 trials (appendix), including one unpublished trial (VUMCA-95: International Nasopharynx Cancer Study Group, NCT00180973). Median follow-up was 7·7 years (IQR 6·2–11·9). Only two trials12, 19 (585 patients) had a median follow-up shorter than 5 years, and seven trials2, 16, 17, 18, 20, 21, 22 (1681 patients) had a median follow-up longer than 10 years.

Discussion

This updated individual patient data meta-analysis of the role of chemotherapy in nasopharyngeal carcinoma confirms the benefits associated with the use of chemotherapy in addition to radiotherapy, including significant and clinically relevant improvements in overall survival and progression-free survival, and reductions in locoregional failure, distant failure, and nasopharyngeal carcinoma-related mortality. The findings further support the use of concomitant chemotherapy; there is a

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ArticlesChemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Selection criteria and search strategy

Results

Discussion

Semin Radiat Oncol

Int J Radiat Oncol Biol Phys

Control Clin Trials

Prog Cardiovasc Dis

Lancet

J Clin Epidemiol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Lancet Oncol

Radiother Oncol

Ann Oncol

Ann Oncol

Oral Oncol

Int J Radiat Oncol Biol Phys

Eur J Cancer

Chemoradiotherpy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup Study 0099

J Clin Oncol

Articles
Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis