The study aimed to update previously published data, including recent trials, and to separately analyse the benefit of concomitant plus adjuvant chemotherapy
Results of the updated Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group meta-analysis of individual patient data also including recent clinical trials, published in theLancet Oncology, show concomitant chemotherapy to radiotherapy significantly improves survival in patients with locoregionally advanced nasopharyngeal carcinoma.
Nasopharyngeal carcinoma (NPC) has a high endemic incidence (more common in eastern Asia, northern Africa and Alaska), is pathogenetically correlated with Epstein-Barr Virus (EBV) and is usually appreciated as a separate clinical entity from other forms of head and neck cancer. Despite an aggressive natural locoregional course of disease and high risk of distant metastases, many patients are cured with standard therapy. Radiotherapy is the cornerstone of initial treatment due to the radiosensitive NPC behavior. The first MAC-NPC meta-analysis showed an overall survival benefit related to concomitant chemotherapy. Since then, additional trials have been done, allowing a study of the interaction between the timing of chemotherapy and the effect on various endpoints in more detail.
The study aimed to update previously published data, including recent trials, and to separately analyse the benefit of concomitant plus adjuvant chemotherapy. Authors accessed data from PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov, and various event resources. Data included had to be from trials that compared radiotherapy alone with radiotherapy plus chemotherapy for locoregional NPC, or 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. Unpublished and published trials were allowed as long as they met the criteria.
The primary endpoint was overall survival (OS). All trial results were combined and analysed using a fixed-effects model. The authors contacted the study investigators and requested individual patient data for patient and tumour characteristics, date of randomisation and treatment group allocation, dates of failures and death, treatment details, and acute and late toxicities for each trial. Information was updated for previously analysed trials whenever possible. All data were analysed on an intention-to-treat basis.
Data from 19 trials and 4806 patients were analysed; of these patients 74% were male and 63% were under 50. The median follow-up was 7.7 years.
The addition of chemotherapy to radiotherapy improved OS (hazard ratio [HR] 0·79, p<0·0001). An absolute benefit in OS at 5 years was found to be 6,3%.
Further analysis showed that concomitant plus adjuvant chemotherapy (HR 0·65) and concomitant without adjuvant chemotherapy (HR 0·80) had a significant improvement in OS, which was not the case for either adjuvant chemotherapy alone (HR 0·87) or induction chemotherapy alone (HR 0·96).
The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0·0001): progression-free survival (PFS, HR 0·75), locoregional control (HR 0·73), distant control (HR 0·67), and cancer mortality (HR 0·76).The strengths of this meta-analysis are its size and the use of individual patient data, which allowed detailed checking and re-analysis of each trial that was subsequently validated by the trial investigator. At the time of the update, seven trials had a follow-up longer than 10 years. The large number of patients allowed for subgroup and subset analyses to be done with adequate power while respecting the intention-to-treat principle. Sensitivity analyses show that the results are robust.
The major limitations of this study are the heterogeneity of trial designs and chemotherapy regimens, and the use of outdated radiotherapy technique in more than three-quarters of the patients with data available. The analysis of long-term toxicities was restricted due to the quality of the data and the low number of events. Data on dose intensity and cumulative dose of cisplatin were not collected so an analysis of the effect of chemotherapy dose on outcome could not be done.
Results of this individual patient data meta-analysis confirm the benefits of the addition of chemotherapy to radiotherapy in nasopharyngeal carcinoma. The greatest benefit was found in the group of patients who received concomitant chemotherapy with radiotherapy in terms of significant and clinically relevant improvements in OS and PFS, and reductions in locoregional failure, distant failure, and mortality related to nasopharyngeal carcinoma. The data also shows a significant link between chemotherapy timing and OS and PFS in favour of concomitant therapy. However, the benefits of induction or adjuvant chemotherapy in the context of concomitant chemo-radiation still need further assessment. The study was funded by French Ministry of Health (Programme d'actions intégrées de recherche VADS) and Ligue Nationale Contre le Cancer. The investigator meeting was organised with the help of Sanofi-Aventis.
Blanchard P, Lee A, Marguet S, et al. Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis; http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2970126-9/fulltext
The Lancet Oncology 2015;16(6):645-655.