The role of concurrent chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma among endemic population: a meta-analysis of the phase iii randomized trials
- Li Zhang†1,
- Chong Zhao†2,
- Bijesh Ghimire1,
- Ming-Huang Hong3,
- Qing Liu3,
- Yang Zhang3,
- Ying Guo3Email author,
- Yi-Jun Huang4Email author and
- Zhong-Zhen Guan1
© Zhang et al; licensee BioMed Central Ltd. 2010
Received: 10 June 2010
Accepted: 15 October 2010
Published: 15 October 2010
The main objective of this meta-analysis was to determine the clinical benefit of concurrent chemoradiotherapy (CCRT) compared with radiation alone (RT) in the treatment of nasopharyngeal carcinoma (NPC) patients in endemic geographic areas.
Using a prospective meta-analysis protocol, two independent investigators reviewed the publications and extracted the data. Published randomized controlled trials (RCTs) in which patients with NPC in endemic areas were randomly assigned to receive CCRT or RT alone were included.
Seven trials (totally 1608 patients) were eligible. Risk ratios (RRs) of 0.63 (95% CI, 0.50 to 0.80), 0.76 (95% CI, 0.61 to 0.93) and 0.74 (95% CI, 0.62 to 0.89) were observed for 2, 3 and 5 years OS respectively in favor of the CCRT group. The RRs were larger than that detected in the previously reported meta-analyses (including both endemic and non-endemic), indicating that the relative benefit of survival was smaller than what considered before.
This is the first meta-analysis of CCRT vs. RT alone in NPC treatment which included studies only done in endemic area. The results confirmed that CCRT was more beneficial compared with RT alone. However, the relative benefit of CCRT in endemic population might be less than that from previous meta-analyses.
Nasopharyngeal carcinoma (NPC) is a common malignant disease of the head and neck with a high prevalence in Southern China and Southeast Asia. It is different from other head and neck cancers because of unique epidemiology, natural behavior and therapeutic considerations.
NPC is both a radiosensitive and chemosensitive tumor. Since the publication of the results of a multicentre randomized trial conducted in North America (Intergroup study 0099) , concurrent chemoradiotherapy (CCRT) has been accepted as standard in the treatment of patients with stage III and IV NPC gradually. However, the major concern remains in extrapolating the findings of the intergroup study to patient groups in the Asian context, where NPC is endemic. Several meta-analyses and a pooled data analysis [2–5] had shown an improvement of survival in NPC patients who received chemotherapy and radiotherapy (CR+RT) versus those received radiotherapy alone (RT). Unfortunately, it still remains unclear regarding the benefit of CCRT especially for endemic population in the previously published meta-analyses. This fact is all these meta-analyses included heterogeneous histological mix of patients, limited number of studies published, or complexity of study design (CCRT with or without adjuvant or neoadjuvant chemotherapy versus RT alone). In contrast, a number of clinical studies [6–18] mainly focus on the additional value of CCRT from endemic areas has been published in recent years.
To gain a better understanding of the potential benefit of CCRT in endemic population, we undertook a meta-analysis that pooled data from all published Phase III randomized controlled trials (RCTs) done in endemic areas focusing on the impact of CCRT comparing with RT alone on patients with locally advanced NPC. To our knowledge, this is the first meta-analysis that included only those randomized trials done in endemic areas to date. The pooled analysis of largest cohort (1608 patients) should provide a clearer understanding of the impact of CCRT on the natural history of this disease.
A prospective meta-analysis protocol including study aim, study selection criteria, literature search strategy, quality control of literature and statistical procedures was developed. The primary aim of present analysis was designed to evaluate how the CCRT influenced survival at 2, 3 and 5 years after treatment compared with RT alone in endemic area patients with locally advanced NPC. More specifically, the analysis was designed to examine the difference in patterns of failure (locoregional recurrence, distant metastasis) in CCRT and RT alone treatment group. In addition to the main meta-analysis, we also compared the survival difference between the CCRT with/without adjuvant chemotherapy (AC) and RT alone.
The selection criteria for eligible studies in this meta-analysis included published randomized controlled trials done in endemic area recruiting NPC patients of Asian origin. Patients were randomly assigned to receive radiotherapy alone or concurrent chemotherapy combined with radiotherapy. Patients receiving concurrent chemotherapy plus some form of adjuvant chemotherapy in addition to radiotherapy were also included in this analysis. The 1997 UICC TNM staging system was used for the staging of the primary tumor. CT or MRI was used as the main evaluation method and adequate doses of radiotherapy was given in both arms equivalent to at least 64Gy, with conventional fractionation to the primary lesion. Overall survival (OS) was the primary outcome measure for measuring the effect of treatment.
Literature Search Strategy
The meta-analysis aimed to include all the relevant published trials done in endemic areas. To conduct a search of the published literatures, multiple search tools by two independent investigators were used: 1.Computerized bibliographic databases: Electronic databases (MEDLINE, CANCERLIT, and EMBASE) were searched with the medical headlines such as Nasopharyngeal carcinoma, Concurrent chemoradiotherapy, radiotherapy, and randomized controlled trials, to identify potentially eligible trials. 2. Journal manual search and reference lists: The computer search was supplemented with manual search of reference lists of all available review articles, primary studies, abstracts from meetings, and bibliographies of books. 3. Conference proceedings of ASCO, ESMO/ECCO, ASTRO and ESTRO.
Application of literature quality
The trials were reviewed using a list of predefined pertinent issues that concerned the characteristics of patients and treatments. To assess the methodological quality of RCTs, we have examined the statistical design, the randomization process, the quality control process, the dropout rate and if potential bias was taken into account. All analyses followed the intention-to-treat principle. This meta-analysis was performed according to preferred reporting items for systematic reviews and meta-analyses - The PRISMA statement .
Method of data retrieves
Two independent investigators reviewed the publications and extracted the data. The following information was extracted from each article: 1. Basic information from papers such as, year of publication, journal name, and author name etc. 2. Characteristics of patients such as: age, sex, pathological types, stage, and study duration. 3. Information of study designation such as: sample size per group, study design, randomization scheme, inclusion criteria, and type of end point used. 4. Information of treatment such as: treatment modality, dose of RT, response rate of treatment, numbers of death, locoregional recurrence, distant metastasis, withdrawals, and so on. Available information was extracted and recorded to a data collection form and entered into electronic database.
The primary end point of this meta-analysis was OS, defined as the time from random assignment to death. Secondary end points were the incidence of local and/or regional recurrence (LRR) and distant metastasis (DM). Extraction of summary statistics from the Kaplan-Meier curve was performed according to standard methods for survival endpoints proposed by Parmar et al . Standard techniques for meta-analysis were used .
Results were expressed as relative risk (RR) with 95% confidence intervals (CIs). The RR of survival at 2, 3, and 5 years and RR of LRR or DM at 3 years were compared between the CCRT and RT alone groups. RR less than 1 indicated improved survival for the combined-modality treatment compared with radiotherapy alone. When the span of the 95% CI given did not include 1, the result was statistically significant. Before estimation of a RR, a statistical test for homogeneity was performed. A Dersimonian and Laird random effects model  was used in cases in which statistically significant heterogeneity between studies likely existed. If no significant heterogeneity was found, a fixed-effects model was used to calculate pooled RR and 95% CIs. All analyses were conducted using Review Manager Version 5.0.24 (Revman; the Cochrane Collaboration; Oxford, England).
Study identification and eligibility
Summary of studies included in the meta-analysis
No. of patients
Histology (WHO grade, No.)
Kwong et al,  2004
AJCC stage II -IV, any T, any N
2.5GyFx/5days/wk, primary site- 68Gy, Nodes- 66Gy, + 10Gy boost dose were given for pharyngeal extension and residual nodes
UFT 200 mg/day/7 days a wk
Alternating Cisplatin 100 mg/m2 day1 and 5FU 1 gm/m2/d day 1-3 and VBM regimen (Vincristine 2 mg, bleomycin 30 mg, MTX 150 mg/m2) every 3wks for 6 cycles.
Chan et al,  2005
AJCC stage II to IV, any T, any N, M0
66Gy in 33Fx per 6.5 wks + additional boost in case of parapharyngeal extension, residual neck nodes, and/or residual nasopharyngeal disease (Brachytherapy)
Cisplatin 40 mg/m2 in day1 weekly
Wee et al,  2005
100% grade II and III
AJCC stage II to IV, any T, any N
70Gy (2Gy/d in 5Fx/wk for 7 wks)
CDDP 25 mg/m2/d for 4 days, alternatively 30/30/40 mg/m2/d for 3 days if patient starts RT on Wednesday
CDDP 20 mg/m2/d × 4 days, 5FU 1000 mg/m2/d × 4 days
100% grade II
AJCC stage III and IV, any T, N2 or N3, M0
≥66Gy (2Gy/Fx/d, 5Fx/wk) + additional boosts to the parapharyngeal space, the primary or nodal sites when indicated not exceeding 20Gy
Cisplatin 100 mg/m2 × 3wks on days 1,22,43
CDDP 80 mg/m2 and 5FU 1000 mg/m2/d every 4 wks on days 71,99 and 127
Zhang et al,  2005
100% grade II and III
AJCC stage III and IV, any T, N2 or N3, M0
70-74Gy (2Gy/Fx/d, 5fx/wk) + additional boost in case of parapharyngeal extension, residual neck nodes and/or residual nasopharyngeal disease
6× Oxaliplatin 70 mg/m2 weekly
100% grade II
AJCC stage III and IV, T3-4, N0-1, M0
≥66Gy (2Gy/Fx/d, 5Fx/wk) + Additional boosts to the parapharyngeal space, the primary or nodal sites when indicated not exceeding 20Gy
Cisplatin 100 mg/m2 × 3wks on days 1,22,43
Cisplatin 80 mg/m2 and 5FU 1000 mg/m2/d on days 71,99 and 127
Chen et al,  2008
100% grade II and III
AJCC stage III and IVA-B, T1-4, N0-3,
≥68Gy (2Gy/Fx/d, 5Fx/wk) in 7 weeks + additional boost in case of parapharyngeal extension, residual neck nodes and/or residual nasopharyngeal disease
Cisplatin 40 mg/m2 day1 weekly × 7wks
Cisplatin 80 mg/m2 day1 and 5FU 800 mg/m2/d on days1-5 every 4wks for 3 cycles.
All 7 trials [10–18] were pooled together and 1608 patients were randomly assigned; of whom 773 received RT and 835 received combined modality treatment. For 3 years OS, the 6 trials [10–15] were included. Out of 6 studies, in three studies [10, 11, 14] including 573 patients, CCRT were compared with RT alone whereas in four studies [10, 12, 13, 15] including 774 patients, AC was added to CCRT.
Additionally, the RR for 3 years LRR of CCRT vs. RT alone [10, 11, 14] and the LRR of CCRT+ AC vs. RT alone [10, 12, 13, 15] were also calculated. LRR of CCRT without AC group had the RR of 0.74 (95% CI, 0.47 to 1.17) compared with RT alone. The group with CCRT plus AC showed the RR of 0.65 (95% CI, 0.45 to 0.95) (Figure.4).
The RR for DMR of CCRT vs. RT alone [10, 11, 14] and DMR of CCRT +AC vs. RT alone [10, 12, 13, 15] were also calculated. The CCRT group had the RR of 0.71 (95% CI, 0.51 to 0.99) compared with RT alone and the group with CCRT plus AC showed the RR of 0.71 (95% CI, 0.54 to 0.92) compared with RT alone (Figure. 5).
NPC is most common in Southern China and Southeast Asia, which accounts for the majority of NPC cases worldwide. The endemic type of NPC is generally different from western counterpart in pathological types, association with Epstein Barr Virus, natural history, and treatment. A meta-analysis which consists of patients purely from the endemic areas was long overdue.
This meta-analysis was designed to directly address the additional effect of chemotherapy concurrently combined with radiotherapy (CCRT) in endemic NPC population. These results suggested that the superior survival observed with CCRT compared with RT alone may be related significantly with improvement in the risk of distant metastasis.
Summary of the percentage of WHO type I tumors and outcome on overall survival
Patients with WHO type I tumors
Huncharek et al  2002*
Al-Sarraf et al 
Langendijk et al  2004#
Al-Sarraf et al 
Lin et al 
Chan et al 
Baujat et al  2006#
Al-Sarraf et al 
Chan et al 
Kwong et al 
b). Conc. +AC
Our study 2010§
Kwong et al 
Chan et al 
Wee et al 
Zhang et al 
Chen et al 
In this analysis, we also tried to find if there is any additional benefit for the patients receiving CCRT plus some kind of AC. Sub-group analyses showed that both locoregional recurrences and distant failure were improved in CCRT+AC arms compared with RT alone. Pooling the results of these studies, the RR of death with CCRT+AC was not significant (figure 3, P = 0.18). This lack of survival difference might be due to increased mortality related to the toxicities of chemotherapy, and possibly successful salvage after relapse. Increase of non-cancer deaths due to treatment-related, incidental, and unknown causes might have also narrowed the actual magnitude of survival gain [13, 15, 17, 18]. The role of adjuvant chemotherapy remains to be addressed by additional studies.
There was an indication from a previous trial by Lin et al  that the benefit of AC was associated with so called high-risk patients who met at least one of the following criteria: (1) nodal size >6 cm, (2) supraclavicular node metastases, (3) 1992 AJCC stage T4N2, (4) multiple neck node metastases with 1 node >4 cm. As our analysis did not include enough individual data, we could not analyze the effect of CCRT and AC vs. RT alone for the high-risk patients. We recommend that the future trials should be focused on the high risk patients.
One of the shortcomings of our meta-analysis is that all information came from published data instead of individual patient data, which might result in two sources of bias - publication bias and selection bias. We used funnel plot to estimate the publication bias. If the funnel plot is not symmetrical or not integrated then it suggests that the result may be biased. So we tested it by using the linear regression model proposed by Egger [23, 24]. In our studies the funnel plot was symmetrical, suggesting that publication bias was not significant. To avoid the selection bias, two independent investigators reviewed the publications and extracted the data. The heterogeneity between the individual studies was also evaluated.
This meta-analysis was performed in geographic areas where NPC is endemic [10–18]. It still remained unclear whether the results obtained from trials performed in these endemic areas could be extrapolated to non-endemic areas.
In conclusion, our meta-analysis based on published trials in endemic areas showed that the CCRT was the most effective treatment modality for the improvement of overall survival in locally advanced NPC. However, the relative benefit of CCRT in endemic population might be very different from previously published meta-analyses. In the future, treatment of NPC should be individualized, according to recognized prognostic factors, while recognizing the results of randomized trials of induction and concurrent CCRT.
We thank Benny C. Y. Zee, Ph.D. Director of center for clinical trial and comprehensive cancer trials unit, Professor of school of Public Health and Department of statistics, The Chinese University of Hong Kong, for his assistance in English editing and statistical recommendations.
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