- Email: [email protected]
A Bayesian network meta-analysis comparing concurrent chemoradiotherapy followed by adjuvant chemotherapy, concurrent chemoradiotherapy alone and radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma
Annals of Oncology Advance Access published October 29, 2014 1
A Bayesian network meta-analysis comparing concurrent chemoradiotherapy followed by adjuvant chemotherapy, concurrent chemoradiotherapy alone and radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma
A.H. Lin3, Y. Sun1, J. Ma1 1
State Key Laboratory of Oncology in South China, Department of Radiation
Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China 2
Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People’s
Republic of China 3
Department of Medical Statistics and Epidemiology, School of Public Health, Sun
Yat-sen University, Guangzhou, People’s Republic of China Correspondence to: Prof. Jun Ma, State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of China. Tel.:+86-20-87343469, Fax:+86-20-87343295, E-mail: [email protected] †
These authors contributed equally to this work.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
Y.P. Chen1,†, Z.X. Wang2,†, L. Chen1,†, X. Liu1, L.L. Tang1, Y.P. Mao1, W.F. Li1,
2
ABSTRACT Background: Given the lack of studies, whether the addition of adjuvant chemotherapy (AC) to concurrent chemoradiotherapy (CCRT) is superior to CCRT alone for locoregionally advanced nasopharyngeal carcinoma (NPC) remains unclear. The main objective of this Bayesian network meta-analysis was to determine
Patients and methods: We systematically searched databases and extracted data from randomized controlled trials involving NPC patients randomly assigned to receive CCRT+AC, CCRT, or radiotherapy (RT). Overall survival (OS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) with hazard ratios (HRs) were investigated. A Bayesian network for different outcomes was established to incorporate all evidence. Multiple treatment comparisons based on the network integrated the efficacy of CCRT+AC, CCRT, and RT. Results: Eight studies involving 2144 patients were analyzed. In the network meta-analysis, CCRT+AC and CCRT were both significantly better than RT alone for all outcomes, except that no significant difference was found between CCRT and RT for LRFS. Though ranking probabilities showed that CCRT+AC was ranked superior to CCRT for OS, LRFS and DMFS, no significant differences were found between CCRT+AC and CCRT for all outcomes (OS: HR = 0.86, 95% credible interval [CrI] 0.60–1.16; LRFS: HR = 0.72, 95%CrI 0.43–1.15; DMFS: HR = 0.86, 95%CrI 0.62–1.16).
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
the efficacy of CCRT+AC as compared with CCRT alone.
3
Conclusions: No significant improvement was found following CCRT+AC compared with CCRT alone. Whether the omission of additional AC can reduce toxic effects without adversely affecting survival in patients with locoregionally advanced NPC should be further explored, in addition to the precise patient status that would benefit from AC following CCRT.
nasopharyngeal carcinoma, network meta-analysis
Key Message: "It remains unclear whether the addition of adjuvant chemotherapy (AC) to concurrent chemoradiotherapy (CCRT) is superior to CCRT alone for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). This Bayesian network meta‐analysis shows no significant improvement found following CCRT+AC compared with CCRT alone. Whether omitting additional AC can reduce toxic effects without adversely affecting survival should be further explored."
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
Key words: concurrent chemoradiotherapy, adjuvant chemotherapy, radiotherapy,
4
Nasopharyngeal carcinoma (NPC) has uneven worldwide distribution and high prevalence in Southeast Asia and North Africa [1]. Radiotherapy (RT) is the primary treatment modality for early-stage patients, but control of locoregionally advanced NPC with RT alone is usually unsatisfactory [2]. Combining chemotherapy and RT is a reasonable strategy for improving the prognosis of locoregionally advanced NPC. A recent meta-analysis [3] showed that concurrent chemoradiotherapy (CCRT) was more beneficial for NPC patients than RT alone, while another meta-analysis showed that neoadjuvant chemotherapy effectively enhanced overall survival (OS) and reduced the distant metastasis rate (DMR), and that adjuvant chemotherapy (AC) aided in improving control of the NPC locoregional recurrence rate (LRR) [4]. The Intergroup 0099 Study (IGS) was the first randomized controlled trial (RCT) to achieve a significant improvement in the 3-year OS for stage III–IVB NPC patients by adding concurrent-adjuvant chemotherapy to conventional RT [5]. Since then, the National Comprehensive Cancer Network (NCCN) has recommended RT with concurrent-adjuvant chemotherapy for locoregionally advanced NPC. However, there
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
INTRODUCTION
5
have been serious concerns regarding the applicability of the IGS results, and the outcomes of several RCTs attempting to verify CCRT+AC efficacy were conflicting [6-13]. Moreover, despite the well-demonstrated efficacy of CCRT for locoregionally advanced NPC, whether adding AC to CCRT is better for locoregionally advanced NPC than CCRT alone has not been confirmed, as we lack trials for direct comparison.
trial comparing CCRT+AC with CCRT alone in endemic area, where short-term evaluation found no significant difference between failure-free survival and OS [14]. Therefore, this network meta-analysis is important because it would provide useful information on comparisons of CCRT+AC, CCRT, and RT by integrating direct and indirect methods to demonstrate the additional value of AC and to verify its efficacy in treating locoregionally advanced NPC. MATERIALS AND METHODS Supplementary material The study inclusion criteria, literature search strategy, quality control and data extraction methods, and associated references are described in the supplementary Methods, available at Annals of Oncology online. Statistical analysis The primary endpoint of our network meta-analysis was OS; the secondary endpoints were locoregional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). The survival endpoint results are expressed as hazard ratios (HRs). Traditional pairwise meta-analyses were conducted first. Details
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
To the best of our knowledge, our previous reported study is the first head to head
6
on endpoints and direct meta-analysis are described in the supplementary Methods, available at Annals of Oncology online. Estimated survival curves for OS, LRFS and DMFS were plotted using the method detailed by Parmar et al. [15]. To address severe acute toxicities (≥Grade 3), we compared toxicity rates between CCRT and RT with the χ2 test.
random effects model proposed by Woods and colleagues. Treatment effects were estimated by posterior means with corresponding 95% credible intervals (CrIs), which can be interpreted similarly to conventional 95% confidence intervals (CIs). The main difference between the fixed and random effects model is that the latter considers between-study variance, thereby producing wider CrIs, and is preferred in the presence of heterogeneity. We used Bayesian deviance information criterion (DIC) statistics to compare the two models. The DIC provides a measure of model fit that penalizes model complexity, with lower values suggesting a simpler model and differences of 2–5 considered important. The probability of each treatment being the best, second best, and third best was estimated based on its posterior probabilities. The Bayesian network meta-analyses results were compared with pairwise meta-analyses results to evaluate inconsistency. Also, significant inconsistency was indicated if node-splitting analysis derived P < 0.05. Details on methods of Bayesian network meta-analysis and associated references are described in the supplementary Methods, available at Annals of Oncology online. RESULTS
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
The network meta-analyses were built in WinBUGS. We applied both the fixed and
7
Eligible studies During selection (supplementary Figure S1, available at Annals of Oncology online), we excluded the study by Chen et al. [16] as it involved stage II NPC patients, and excluded the study by Lin et al. [17] for not meeting the eligibility criterion of unpredictable treatment assignment [18]. As Kwong et al. [6] used uracil+tegafur
meta-analysis, but was included in an additional meta-analysis that did not restrict the agents used, and the results are described in the supplementary Results (available at Annals of Oncology online). Thus, 8 studies were considered eligible [5, 7-14, 19-22]. The study by Lee et al. was first published in 2005 [8] and updated in 2010 with the 5-year OS data [9]. The same updates were made to the studies of Lee et al. [10, 11], Chen et al. [12, 13], Chan et al. [19, 20], and Zhang et al. [21, 22]. In the study by Lee et al. [10, 11], patients were divided into four treatment groups: conventional fractionation (CF); CF with concurrent-adjuvant chemotherapy; accelerated fractionation (AF); and AF with concurrent-adjuvant chemotherapy. The benefit of AF has not yet been confirmed [11], and the two groups that were treated with AF were excluded as they did not meet our inclusion criterion for the use of CF. Table 1 lists the baseline characteristics of all included studies. These pooled 8 studies involved 2144 randomly assigned patients: 840 received CCRT+AC, 490 received CCRT, and 814 received RT alone. The OS was available for all trials (to include all 193 available patients in the study by Al-Sarraf et al. [5], we obtained the corresponding observed minus expected number of deaths [O-E] and variance from a
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
instead of platinum in concurrent chemotherapy, it was excluded from this network
8
previous meta-analysis based on individual patient data [18]). The LRFS and DMFS were available for only 7 studies [7-14, 19-22] (for the study by Chan et al. [19, 20], we could obtain corresponding O-E and variance from the individual patient data meta-analysis [18]). Al-Sarraf et al. reported only the absolute number of locoregional and distant failures of 147 patients [5]; information on the time to event was not
the assessment of the quality of all eligible RCTs. Direct meta-analysis Supplementary Figure S2, available at Annals of Oncology online presents all direct meta-analyses. Compared with RT alone, CCRT+AC (P < 0.0001, HR = 0.64, 95%CI = 0.53–0.76) and CCRT (P = 0.005, HR = 0.66, 95%CI = 0.49–0.88) benefited OS significantly; there was no significant difference between CCRT+AC and CCRT. CCRT+AC was associated with lower locoregional recurrence risk as compared with RT alone (P = 0.01, HR = 0.59, 95%CI = 0.40–0.89); there was no significant difference between CCRT+AC and CCRT, and CCRT and RT alone. There was significantly reduced distant failure in patients who received CCRT+AC (P = 0.002, HR = 0.67, 95%CI = 0.52–0.87) and CCRT (P = 0.02, HR = 0.68, 95%CI = 0.50–0.95) as compared with RT alone. No significant difference in DMFS was found between CCRT+AC and CCRT. There was no between-study effect size heterogeneity in all comparisons for all endpoints. To determine whether excluding the trial by Al-Sarraf et al. [5] would affect our conclusions on locoregional and distant failures, we performed direct meta-analyses of LRR and DMR for CCRT+AC versus RT that
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
available. Supplementary Table S1, available at Annals of Oncology online describes
9
included that study. The results are expressed as relative risk (RR) with 95%CIs using the Mantel–Haenszel method, and the conclusions remained valid (supplementary Figure S3, available at Annals of Oncology online). Network meta-analysis of efficacy We established a network to compare CCRT+AC, CCRT, and RT alone
summarizes the multiple treatment meta-analyses results for OS, LRFS, and DMFS. The respective sets of HRs and corresponding 95% CrIs from the fixed and random effects models had good consistency despite the relatively wider CrIs of the latter (Figure 1A, 1C, 1E). Moreover, we confirmed good coherence between direct and indirect comparisons for all endpoints; node-splitting analysis indicated no significant inconsistency (all P > 0.05). Based on the DIC (Figure 1A, 1C, 1E), the fixed effects model fit the data better than the random effects model, with relatively lower DIC values for all endpoints (though the differences were all between 1 and 2), indicating that heterogeneity might not be obvious. Furthermore, as both models yielded consistent conclusions, we applied the fixed effects model for the rest of the study. Except the CCRT and RT LRFS, CCRT+AC and CCRT outcomes were both significantly better than RT alone. However, CCRT+AC and CCRT shared equivalent efficacy, and there were no significant differences for all treatment outcomes (OS, LRFS, DMFS) (Figure 1A, 1C, 1E). Figure 1B, 1D, and 1F shows the probability of each treatment being ranked the
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
(Supplementary Figure S4, available at Annals of Oncology online). Figure 1
10
best, second best, and third best, and the cumulative probabilities for the most efficacious treatments were as follows (OS, LRFS, DMFS): CCRT+AC (84%, 90%, 85%), CCRT (16%, 10%, 15%), RT (0%, 0%, 0%). Supplementary Figure S5, available at Annals of Oncology online depicts the estimated survival curves for all endpoints.
Supplementary Table S2, available at Annals of Oncology online summarizes the severe acute toxicities (≥Grade 3) of the studies included in this network meta-analysis. In the initial phase, severe adverse events occurred more often following CCRT compared to RT alone. No significant differences existed between the CCRT+AC and CCRT arms in the initial phase of the study by Chen et al. [14]. In the adjuvant phase, the commonly recorded severe acute toxicities were neutropenia (14.1%), nausea/vomiting (13.4%), leukopenia (13.3%), and mucositis (12.0%). Additional network meta-analysis The additional network meta-analysis results, which included the study by Kwong et al. [6], are described in the supplementary Results, supplementary table S3 and S4, and supplementary Figure S6, S7, and S8, available at Annals of Oncology online. The conclusions remained valid after including the abovementioned study, but there was effect size heterogeneity in the direct comparisons of CCRT+AC versus CCRT for DMFS. DISCUSSION Multiple treatment comparison is a powerful method for investigating RCT
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
Severe acute toxicities
11
networks, and has been used for head and neck squamous cell carcinoma [23]. Our Bayesian network meta-analysis is the first study to compare CCRT+AC, CCRT, and RT efficacy for locoregionally advanced NPC through direct and indirect statistical comparisons based on all available information from the included RCTs. As HR was the only summary statistic allowing for both censoring and time to an event, we
consistency between direct and network meta-analyses of these endpoints. Compared with RT alone, CCRT+AC had a significant treatment effect on OS, LRFS, and DMFS; CCRT had a significant treatment effect on OS and DMFS, but did not improve locoregional control significantly. However, there was no significant difference between CCRT+AC and CCRT for all endpoints, indicating that AC following CCRT did not improve treatment outcome remarkably. All included studies involving AC used the IGS regimen for the adjuvant phase, adopting cisplatin and fluorouracil (PF regimen) as recommended [5]. A phase III study [24] showed that this combination improved the response rate but not the survival rate as compared with either agent individually, indicating that the adjuvant PF regimen may be insufficiently effective for eradicating micrometastases and improving OS in head and neck cancers and NPC. The well-recognized favorable results for CCRT may also have diluted any potential benefit of AC for controlling locoregional recurrence and distant metastases. Moreover, given the acute toxic effects during CCRT, adjuvant therapy compliance was similar (52–61%) and relatively poor in the CCRT+AC RCT [14], which may have affected the efficacy of AC. The actual magnitude of the AC
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
assessed OS, LRFS, and DMFS with HR and its 95%CI or CrI, confirming good
12
survival benefit may also have been reduced due to the toxicities of chemotherapy, possibly successful salvage after relapse, and increased non-cancer deaths [8, 10, 12]. As expected, RT ranked worst for OS, LRFS, and DMFS. As for CCRT+AC and CCRT, the former ranked superior to the latter for all treatment outcomes. However, in network meta-analysis, even if the effect size differences among treatments were
produced without a clear statistical meaning. It would be misleading if clinical decisions regarding the therapeutic regimens selected were mainly dependent on it. In fact, CCRT+AC and CCRT did not differ significantly for all outcomes in our study. Also, it was noteworthy that the survival curves for CCRT+AC and CCRT were gradually separated by a slight difference in approximately the first 2–3 years, but later became relatively smoother and closer, with slightly smaller absolute differences at 5 years than at 3 years (Supplementary Figure S5, available at Annals of Oncology online). This trend may have been due to the more common occurrence of locoregional recurrence and distant metastasis in the early years after RT [12], and it has been hypothesized that AC may only prolong the latency of locoregional recurrence and distant metastasis occurrence instead of improving their long-term control effectively [13]. Overall, a dialectical and comprehensive view on the choice between CCRT+AC and CCRT in the clinic is required. Currently, the 2014 NCCN recommends CCRT followed by AC for locoregionally advanced NPC (Category 2A); CCRT alone is also an option (Category 2B) (http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf). The
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
small and non-significant, a probability of treatment ranking would have been
13
National Cancer Institute also recommends CCRT+AC for locoregionally advanced NPC((http://www.cancer.gov/cancertopics/pdq/treatment/nasopharyngeal/HealthProfe ssional). However, the European Society for Medical Oncology recommends CCRT alone for locoregionally advanced NPC, and indicates that the benefit of 3 cycles of adjuvant cisplatin–fluorouracil is uncertain and that it has a substantial toxic effect
relatively fewer toxic effects without additional adjuvant therapy; (2) more satisfactory compliance; (3) relatively lower expense. Although the CCRT and RT LRFS were not significantly different in our study, improved radiation techniques such as intensity-modulated RT may have compensated for it. Regardless, a trend towards a higher rate of efficacy for CCRT+AC compared with CCRT alone was observed. Certain patient statuses might therefore benefit most from additional AC following CCRT. The subgroup analysis by Lee et al. [9] showed that among NPC patients with T1–4N2–3M0 disease, CCRT+AC mainly benefited patients with T1–2N2–3 disease. A retrospective study [26] showed that CCRT+AC mainly benefited intermediate-risk patients (T2b–3N0–2M0), with significant benefit in 5-year OS as compared with RT or CCRT alone. Recently, it was reported that unfavorable Epstein–Barr virus DNA response midpoint of RT was an adverse prognosticator for treatment outcome in advanced-stage NPC [27], and may serve as an indicator for the addition of adjuvant therapy to initial treatment. Overall, CCRT+AC appears to benefit patients who meet certain selection criteria, and further studies are required to define this patient population.
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
[25]. Compared with CCRT+AC, CCRT alone has the following advantages: (1)
14
The study limitations also should be acknowledged: extracted all information from published data other than individual patient data, which may have resulted in publication and reporting bias. Some of this unreported individual patient information may have aided better evaluation of the quality of an RCT. Moreover, without access to individual patient data, missing information on certain prognostic factors and
in the study by Al-Sarraf et al. [5]. To minimize the risk of bias, we restricted inclusion criteria, searched and reviewed the publications comprehensively, and two independent investigators extracted the data and assessed RCT quality. Excluding the study by Al-Sarraf et al. [5] from the LRFS and DMFS analysis might have affected the validity of our findings, although our conclusions remained valid following additional direct meta-analyses of LRR and DMR that included that trial. In conclusion, our network meta-analysis shows that there was no significant survival improvement following CCRT+AC as compared with CCRT alone. The long-term follow-up results of our trial [14], which would be instructive, is awaiting to be reported. Whether the omission of additional AC can reduce toxic effects without adversely affecting survival outcomes for patients with locoregionally advanced NPC should be further explored. In addition, the specific patient statuses that would benefit from AC following CCRT deserve further investigation. ACKNOWLEDGEMENTS We thank the anonymous reviewers for their insightful comments and great efforts to improve this manuscript.
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
endpoints could have affected our analysis, e.g., LRFS and DMFS were not available
15
FUNDING The authors received no external funding for this meta-analysis. CONFLICT OF INTEREST The authors have declared no conflicts of interest.
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
16
REFERENCES 1.
Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet 2005; 365: 2041-2054.
2.
Ma J, Mai HQ, Hong MH et al. Is the 1997 AJCC staging system for
nasopharyngeal carcinoma prognostically useful for Chinese patient populations? Int J Radiat Oncol Biol Phys 2001; 50: 1181-1189. Zhang L, Zhao C, Ghimire B et al. 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. BMC Cancer 2010; 10: 558. 4.
OuYang PY, Xie C, Mao YP et al. Significant efficacies of neoadjuvant and
adjuvant chemotherapy for nasopharyngeal carcinoma by meta-analysis of published literature-based randomized, controlled trials. Ann Oncol 2013; 24: 2136-2146. 5.
Al-Sarraf M, LeBlanc M, Giri PG et al. Chemoradiotherapy versus radiotherapy
in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998; 16: 1310-1317. 6.
Kwong DL, Sham JS, Au GK et al. Concurrent and adjuvant chemotherapy for
nasopharyngeal carcinoma: a factorial study. J Clin Oncol 2004; 22: 2643-2653. 7.
Wee J, Tan EH, Tai BC et al. Randomized trial of radiotherapy versus concurrent
chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 2005; 23: 6730-6738. 8.
Lee AW, Lau WH, Tung SY et al. Preliminary results of a randomized study on
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
3.
17
therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group. J Clin Oncol 2005; 23: 6966-6975. 9.
Lee AW, Tung SY, Chua DT et al. Randomized trial of radiotherapy plus
concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced
10. Lee AW, Tung SY, Chan AT et al. Preliminary results of a randomized study (NPC-9902 Trial) on therapeutic gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2006; 66: 142-151. 11. Lee AW, Tung SY, Chan AT et al. A randomized trial on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma. Radiother Oncol 2011; 98: 15-22. 12. Chen Y, Liu MZ, Liang SB et al. Preliminary results of a prospective randomized trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of china. Int J Radiat Oncol Biol Phys 2008; 71: 1356-1364. 13. Chen Y, Sun Y, Liang SB et al. Progress report of a randomized trial comparing long-term survival and late toxicity of concurrent chemoradiotherapy with adjuvant chemotherapy versus radiotherapy alone in patients with stage III to IVB nasopharyngeal carcinoma from endemic regions of China. Cancer 2013; 119:
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
nasopharyngeal carcinoma. J Natl Cancer Inst 2010; 102: 1188-1198.
18
2230-2238. 14. Chen L, Hu CS, Chen XZ et al. Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. Lancet Oncol 2012; 13: 163-171.
meta-analyses of the published literature for survival endpoints. Stat Med 1998; 17: 2815-2834. 16. Chen QY, Wen YF, Guo L et al. Concurrent chemoradiotherapy vs radiotherapy alone in stage II nasopharyngeal carcinoma: phase III randomized trial. J Natl Cancer Inst 2011; 103: 1761-1770. 17. Lin JC, Jan JS, Hsu CY et al. Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival. J Clin Oncol 2003; 21: 631-637. 18. Baujat B, Audry H, Bourhis J et al. Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 2006; 64: 47-56. 19. Chan AT, Teo PM, Ngan RK et al. Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial. J Clin Oncol 2002; 20: 2038-2044. 20. Chan AT, Leung SF, Ngan RK et al. Overall survival after concurrent
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
15. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform
19
cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2005; 97: 536-539. 21. Zhang L, Zhao C, Peng PJ et al. Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol 2005; 23: 8461-8468.
comparing radiotherapy with or without weekly oxaliplatin for locoregionally advanced nasopharyngeal carcinoma. Ann Oncol 2013; 24: 2131-2136. 23. Blanchard P, Hill C, Guihenneuc-Jouyaux C et al. Mixed treatment comparison meta-analysis of altered fractionated radiotherapy and chemotherapy in head and neck cancer. J Clin Epidemiol 2011; 64: 985-992. 24. Jacobs C, Lyman G, Velez-Garcia E et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992; 10: 257-263. 25. Chan AT, Gregoire V, Lefebvre JL et al. Nasopharyngeal cancer: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 Suppl 7: vii83-85. 26. Cheng SH, Tsai SY, Yen KL et al. Prognostic significance of parapharyngeal space venous plexus and marrow involvement: potential landmarks of dissemination for stage I-III nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2005; 61: 456-465. 27. Leung SF, Chan KC, Ma BB et al. Plasma Epstein-Barr viral DNA load at
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
22. Wu X, Huang PY, Peng PJ et al. Long-term follow-up of a phase III study
20
midpoint of radiotherapy course predicts outcome in advanced-stage nasopharyngeal carcinoma. Ann Oncol 2014; 25: 1204-1208.
Figure legends Figure 1. Network meta-analysis results for (A, B) overall survival, (C, D)
C, E) Upper triangles denote pooled hazard ratios (HRs); treatments in the rows were compared with those in the columns. In each HR cell, the first and second lines contain the HRs from the fixed and random effects models, respectively. Numbers in parentheses indicate the corresponding 95% credible intervals. Red numbers, HRs with Bayesian P < 0.05. Lower triangles denote the Bayesian deviance information criterion (DIC) statistics from the fixed and random effects models. (B, D, F) Probabilities of each treatment ranking best, and second and third best based on the fixed effects model. CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; RT, radiotherapy.
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
locoregional recurrence-free survival, and (E, F) distant metastasis-free survival. (A,
21
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
Median No. of
follow-up patients
Chemotherapy
Inclusion
Study
Stage
Radiotherapy
period (months)
Concurrent
Adjuvant
CCRT+AC vs. RT Al-Sarraf et al.
193
1989-1995 32.4
1998 Wee et al.
221
1997-2003 38.4
2005
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
Table 1. Summary of studies included in the network meta-analysis
AJCC
1.8-2.0Gy/fx/d, 5fx/wk, to
3* DDP 100 mg/m2
4* DDP 80 mg/m2(day 1) +FU
III-IV
66-70 Gy
(days 1,22, 43）
1,000mg/m2 (days 1-4 civ)
AJCC II-IV, 70Gy (2Gy/fx/d, 5fx/wk
DDP 25 mg/m2/d
DDP 20 mg/m2/d for 4days, +FU
any T, any for 7wks)
for 4days,
1000 mg/m2/d for 4 days
N
alternatively
30/30/40mg/m2/d for 3days Lee et al. 2005,2010
348
1999-2004 70.8
AJCC
≥66Gy (2Gy/fx/d,
III-IV, any
5fx/wk), +additional boosts (days 1,22,43)
3* DDP 100 mg/m2
q4wk DDP 80 mg/m2 +FU 1000 mg/m2/d (days 71,99 and
for parapharyngeal space,
N3, M0
primary or nodal sites when indicated not exceeding 20Gy
Lee et al.
93
1999-2004 75.6
2006,2011
2008,2013
2002-2005 70
q4wk DDP 80 mg/m2 +FU
≥66Gy (2Gy/fx/d, 5
III-IV,
fx/wk), +additional boosts (days 1,22,43)
1000 mg/m2/d (days 71, 99 and
T3-4, N0-1,
for parapharyngeal space,
127)
M0
primary or nodal sites when not
exceeding
20Gy 316
127)
AJCC
indicated
Chen et al.
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
T, N2 or
3* DDP 100 mg/m2
AJCC
≥68Gy (2Gy/fx/d,
7* DDP 40 mg/m2
3* q4wk DDP 80 mg/m2 (day 1)
III-IV,
5fx/wk for 7 weeks), +
(day 1) weekly
+FU 800 mg/m2/d (days 1-5 )
T1-4, N0-3,
additional boost in case of
M0
parapharyngeal extension,
residual nasopharyngeal disease CCRT vs. RT Chan et al.
350
1994-1997 66
2002,2005
AJCC II-IV, 66Gy,+additional boost
8* DDP 40 mg/m2
any T, any in case of parapharyngeal
(day 1) weekly
N, M0
extension, residual neck nodes, and/or residual nasopharyngeal disease (brachytherapy)
Zhang et al. 2005,2013
115
2001-2003 114
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
residual neck nodes and
AJCC
70-74Gy(2Gy/fx/d, 5fx/wk)
6* Oxaliplatin 70
III-IV, any
+additional boost in case
mg/ m2 weekly
T, N2 or
of parapharyngeal
N3, M0
extension, residual neck
None
None
nasopharyngeal disease CCRT+AC vs. CCRT Chen et al.
508
2012
2006-2010 38
AJCC
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
nodes and/or residual
2.0–2.27Gy/fx/day,5 fx/wk, 7* DDP 40 mg/m2
III-IV, any to 60–66 Gy, irradiation to (day 1) weekly T, any N, 50 Gy for potential sites a M0, except T3–4N0
3* q4wk DDP 80 mg/m2 (day 1) +FU 800 mg/m2/d (days 1-5 )
CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; RT, radiotherapy; AJCC, American Joint Committee on Cancer; fx, fraction; DDP, cisplatin; FU, fluorouracil; civ, continuous intravenous; q4wk, every 4 weeks. a
Intensity-modulated radiotherapy and 3D conformal radiotherapy were adopted for partial patients.
A Bayesian network meta-analysis comparing concurrent chemoradiotherapy followed by adjuvant chemotherapy, concurrent chemoradiotherapy alone and radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma
A.H. Lin3, Y. Sun1, J. Ma1 1
State Key Laboratory of Oncology in South China, Department of Radiation
Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China 2
Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People’s
Republic of China 3
Department of Medical Statistics and Epidemiology, School of Public Health, Sun
Yat-sen University, Guangzhou, People’s Republic of China Correspondence to: Prof. Jun Ma, State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of China. Tel.:+86-20-87343469, Fax:+86-20-87343295, E-mail: [email protected] †
These authors contributed equally to this work.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
Y.P. Chen1,†, Z.X. Wang2,†, L. Chen1,†, X. Liu1, L.L. Tang1, Y.P. Mao1, W.F. Li1,
2
ABSTRACT Background: Given the lack of studies, whether the addition of adjuvant chemotherapy (AC) to concurrent chemoradiotherapy (CCRT) is superior to CCRT alone for locoregionally advanced nasopharyngeal carcinoma (NPC) remains unclear. The main objective of this Bayesian network meta-analysis was to determine
Patients and methods: We systematically searched databases and extracted data from randomized controlled trials involving NPC patients randomly assigned to receive CCRT+AC, CCRT, or radiotherapy (RT). Overall survival (OS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) with hazard ratios (HRs) were investigated. A Bayesian network for different outcomes was established to incorporate all evidence. Multiple treatment comparisons based on the network integrated the efficacy of CCRT+AC, CCRT, and RT. Results: Eight studies involving 2144 patients were analyzed. In the network meta-analysis, CCRT+AC and CCRT were both significantly better than RT alone for all outcomes, except that no significant difference was found between CCRT and RT for LRFS. Though ranking probabilities showed that CCRT+AC was ranked superior to CCRT for OS, LRFS and DMFS, no significant differences were found between CCRT+AC and CCRT for all outcomes (OS: HR = 0.86, 95% credible interval [CrI] 0.60–1.16; LRFS: HR = 0.72, 95%CrI 0.43–1.15; DMFS: HR = 0.86, 95%CrI 0.62–1.16).
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
the efficacy of CCRT+AC as compared with CCRT alone.
3
Conclusions: No significant improvement was found following CCRT+AC compared with CCRT alone. Whether the omission of additional AC can reduce toxic effects without adversely affecting survival in patients with locoregionally advanced NPC should be further explored, in addition to the precise patient status that would benefit from AC following CCRT.
nasopharyngeal carcinoma, network meta-analysis
Key Message: "It remains unclear whether the addition of adjuvant chemotherapy (AC) to concurrent chemoradiotherapy (CCRT) is superior to CCRT alone for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). This Bayesian network meta‐analysis shows no significant improvement found following CCRT+AC compared with CCRT alone. Whether omitting additional AC can reduce toxic effects without adversely affecting survival should be further explored."
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
Key words: concurrent chemoradiotherapy, adjuvant chemotherapy, radiotherapy,
4
Nasopharyngeal carcinoma (NPC) has uneven worldwide distribution and high prevalence in Southeast Asia and North Africa [1]. Radiotherapy (RT) is the primary treatment modality for early-stage patients, but control of locoregionally advanced NPC with RT alone is usually unsatisfactory [2]. Combining chemotherapy and RT is a reasonable strategy for improving the prognosis of locoregionally advanced NPC. A recent meta-analysis [3] showed that concurrent chemoradiotherapy (CCRT) was more beneficial for NPC patients than RT alone, while another meta-analysis showed that neoadjuvant chemotherapy effectively enhanced overall survival (OS) and reduced the distant metastasis rate (DMR), and that adjuvant chemotherapy (AC) aided in improving control of the NPC locoregional recurrence rate (LRR) [4]. The Intergroup 0099 Study (IGS) was the first randomized controlled trial (RCT) to achieve a significant improvement in the 3-year OS for stage III–IVB NPC patients by adding concurrent-adjuvant chemotherapy to conventional RT [5]. Since then, the National Comprehensive Cancer Network (NCCN) has recommended RT with concurrent-adjuvant chemotherapy for locoregionally advanced NPC. However, there
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
INTRODUCTION
5
have been serious concerns regarding the applicability of the IGS results, and the outcomes of several RCTs attempting to verify CCRT+AC efficacy were conflicting [6-13]. Moreover, despite the well-demonstrated efficacy of CCRT for locoregionally advanced NPC, whether adding AC to CCRT is better for locoregionally advanced NPC than CCRT alone has not been confirmed, as we lack trials for direct comparison.
trial comparing CCRT+AC with CCRT alone in endemic area, where short-term evaluation found no significant difference between failure-free survival and OS [14]. Therefore, this network meta-analysis is important because it would provide useful information on comparisons of CCRT+AC, CCRT, and RT by integrating direct and indirect methods to demonstrate the additional value of AC and to verify its efficacy in treating locoregionally advanced NPC. MATERIALS AND METHODS Supplementary material The study inclusion criteria, literature search strategy, quality control and data extraction methods, and associated references are described in the supplementary Methods, available at Annals of Oncology online. Statistical analysis The primary endpoint of our network meta-analysis was OS; the secondary endpoints were locoregional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). The survival endpoint results are expressed as hazard ratios (HRs). Traditional pairwise meta-analyses were conducted first. Details
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
To the best of our knowledge, our previous reported study is the first head to head
6
on endpoints and direct meta-analysis are described in the supplementary Methods, available at Annals of Oncology online. Estimated survival curves for OS, LRFS and DMFS were plotted using the method detailed by Parmar et al. [15]. To address severe acute toxicities (≥Grade 3), we compared toxicity rates between CCRT and RT with the χ2 test.
random effects model proposed by Woods and colleagues. Treatment effects were estimated by posterior means with corresponding 95% credible intervals (CrIs), which can be interpreted similarly to conventional 95% confidence intervals (CIs). The main difference between the fixed and random effects model is that the latter considers between-study variance, thereby producing wider CrIs, and is preferred in the presence of heterogeneity. We used Bayesian deviance information criterion (DIC) statistics to compare the two models. The DIC provides a measure of model fit that penalizes model complexity, with lower values suggesting a simpler model and differences of 2–5 considered important. The probability of each treatment being the best, second best, and third best was estimated based on its posterior probabilities. The Bayesian network meta-analyses results were compared with pairwise meta-analyses results to evaluate inconsistency. Also, significant inconsistency was indicated if node-splitting analysis derived P < 0.05. Details on methods of Bayesian network meta-analysis and associated references are described in the supplementary Methods, available at Annals of Oncology online. RESULTS
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
The network meta-analyses were built in WinBUGS. We applied both the fixed and
7
Eligible studies During selection (supplementary Figure S1, available at Annals of Oncology online), we excluded the study by Chen et al. [16] as it involved stage II NPC patients, and excluded the study by Lin et al. [17] for not meeting the eligibility criterion of unpredictable treatment assignment [18]. As Kwong et al. [6] used uracil+tegafur
meta-analysis, but was included in an additional meta-analysis that did not restrict the agents used, and the results are described in the supplementary Results (available at Annals of Oncology online). Thus, 8 studies were considered eligible [5, 7-14, 19-22]. The study by Lee et al. was first published in 2005 [8] and updated in 2010 with the 5-year OS data [9]. The same updates were made to the studies of Lee et al. [10, 11], Chen et al. [12, 13], Chan et al. [19, 20], and Zhang et al. [21, 22]. In the study by Lee et al. [10, 11], patients were divided into four treatment groups: conventional fractionation (CF); CF with concurrent-adjuvant chemotherapy; accelerated fractionation (AF); and AF with concurrent-adjuvant chemotherapy. The benefit of AF has not yet been confirmed [11], and the two groups that were treated with AF were excluded as they did not meet our inclusion criterion for the use of CF. Table 1 lists the baseline characteristics of all included studies. These pooled 8 studies involved 2144 randomly assigned patients: 840 received CCRT+AC, 490 received CCRT, and 814 received RT alone. The OS was available for all trials (to include all 193 available patients in the study by Al-Sarraf et al. [5], we obtained the corresponding observed minus expected number of deaths [O-E] and variance from a
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
instead of platinum in concurrent chemotherapy, it was excluded from this network
8
previous meta-analysis based on individual patient data [18]). The LRFS and DMFS were available for only 7 studies [7-14, 19-22] (for the study by Chan et al. [19, 20], we could obtain corresponding O-E and variance from the individual patient data meta-analysis [18]). Al-Sarraf et al. reported only the absolute number of locoregional and distant failures of 147 patients [5]; information on the time to event was not
the assessment of the quality of all eligible RCTs. Direct meta-analysis Supplementary Figure S2, available at Annals of Oncology online presents all direct meta-analyses. Compared with RT alone, CCRT+AC (P < 0.0001, HR = 0.64, 95%CI = 0.53–0.76) and CCRT (P = 0.005, HR = 0.66, 95%CI = 0.49–0.88) benefited OS significantly; there was no significant difference between CCRT+AC and CCRT. CCRT+AC was associated with lower locoregional recurrence risk as compared with RT alone (P = 0.01, HR = 0.59, 95%CI = 0.40–0.89); there was no significant difference between CCRT+AC and CCRT, and CCRT and RT alone. There was significantly reduced distant failure in patients who received CCRT+AC (P = 0.002, HR = 0.67, 95%CI = 0.52–0.87) and CCRT (P = 0.02, HR = 0.68, 95%CI = 0.50–0.95) as compared with RT alone. No significant difference in DMFS was found between CCRT+AC and CCRT. There was no between-study effect size heterogeneity in all comparisons for all endpoints. To determine whether excluding the trial by Al-Sarraf et al. [5] would affect our conclusions on locoregional and distant failures, we performed direct meta-analyses of LRR and DMR for CCRT+AC versus RT that
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
available. Supplementary Table S1, available at Annals of Oncology online describes
9
included that study. The results are expressed as relative risk (RR) with 95%CIs using the Mantel–Haenszel method, and the conclusions remained valid (supplementary Figure S3, available at Annals of Oncology online). Network meta-analysis of efficacy We established a network to compare CCRT+AC, CCRT, and RT alone
summarizes the multiple treatment meta-analyses results for OS, LRFS, and DMFS. The respective sets of HRs and corresponding 95% CrIs from the fixed and random effects models had good consistency despite the relatively wider CrIs of the latter (Figure 1A, 1C, 1E). Moreover, we confirmed good coherence between direct and indirect comparisons for all endpoints; node-splitting analysis indicated no significant inconsistency (all P > 0.05). Based on the DIC (Figure 1A, 1C, 1E), the fixed effects model fit the data better than the random effects model, with relatively lower DIC values for all endpoints (though the differences were all between 1 and 2), indicating that heterogeneity might not be obvious. Furthermore, as both models yielded consistent conclusions, we applied the fixed effects model for the rest of the study. Except the CCRT and RT LRFS, CCRT+AC and CCRT outcomes were both significantly better than RT alone. However, CCRT+AC and CCRT shared equivalent efficacy, and there were no significant differences for all treatment outcomes (OS, LRFS, DMFS) (Figure 1A, 1C, 1E). Figure 1B, 1D, and 1F shows the probability of each treatment being ranked the
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
(Supplementary Figure S4, available at Annals of Oncology online). Figure 1
10
best, second best, and third best, and the cumulative probabilities for the most efficacious treatments were as follows (OS, LRFS, DMFS): CCRT+AC (84%, 90%, 85%), CCRT (16%, 10%, 15%), RT (0%, 0%, 0%). Supplementary Figure S5, available at Annals of Oncology online depicts the estimated survival curves for all endpoints.
Supplementary Table S2, available at Annals of Oncology online summarizes the severe acute toxicities (≥Grade 3) of the studies included in this network meta-analysis. In the initial phase, severe adverse events occurred more often following CCRT compared to RT alone. No significant differences existed between the CCRT+AC and CCRT arms in the initial phase of the study by Chen et al. [14]. In the adjuvant phase, the commonly recorded severe acute toxicities were neutropenia (14.1%), nausea/vomiting (13.4%), leukopenia (13.3%), and mucositis (12.0%). Additional network meta-analysis The additional network meta-analysis results, which included the study by Kwong et al. [6], are described in the supplementary Results, supplementary table S3 and S4, and supplementary Figure S6, S7, and S8, available at Annals of Oncology online. The conclusions remained valid after including the abovementioned study, but there was effect size heterogeneity in the direct comparisons of CCRT+AC versus CCRT for DMFS. DISCUSSION Multiple treatment comparison is a powerful method for investigating RCT
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
Severe acute toxicities
11
networks, and has been used for head and neck squamous cell carcinoma [23]. Our Bayesian network meta-analysis is the first study to compare CCRT+AC, CCRT, and RT efficacy for locoregionally advanced NPC through direct and indirect statistical comparisons based on all available information from the included RCTs. As HR was the only summary statistic allowing for both censoring and time to an event, we
consistency between direct and network meta-analyses of these endpoints. Compared with RT alone, CCRT+AC had a significant treatment effect on OS, LRFS, and DMFS; CCRT had a significant treatment effect on OS and DMFS, but did not improve locoregional control significantly. However, there was no significant difference between CCRT+AC and CCRT for all endpoints, indicating that AC following CCRT did not improve treatment outcome remarkably. All included studies involving AC used the IGS regimen for the adjuvant phase, adopting cisplatin and fluorouracil (PF regimen) as recommended [5]. A phase III study [24] showed that this combination improved the response rate but not the survival rate as compared with either agent individually, indicating that the adjuvant PF regimen may be insufficiently effective for eradicating micrometastases and improving OS in head and neck cancers and NPC. The well-recognized favorable results for CCRT may also have diluted any potential benefit of AC for controlling locoregional recurrence and distant metastases. Moreover, given the acute toxic effects during CCRT, adjuvant therapy compliance was similar (52–61%) and relatively poor in the CCRT+AC RCT [14], which may have affected the efficacy of AC. The actual magnitude of the AC
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
assessed OS, LRFS, and DMFS with HR and its 95%CI or CrI, confirming good
12
survival benefit may also have been reduced due to the toxicities of chemotherapy, possibly successful salvage after relapse, and increased non-cancer deaths [8, 10, 12]. As expected, RT ranked worst for OS, LRFS, and DMFS. As for CCRT+AC and CCRT, the former ranked superior to the latter for all treatment outcomes. However, in network meta-analysis, even if the effect size differences among treatments were
produced without a clear statistical meaning. It would be misleading if clinical decisions regarding the therapeutic regimens selected were mainly dependent on it. In fact, CCRT+AC and CCRT did not differ significantly for all outcomes in our study. Also, it was noteworthy that the survival curves for CCRT+AC and CCRT were gradually separated by a slight difference in approximately the first 2–3 years, but later became relatively smoother and closer, with slightly smaller absolute differences at 5 years than at 3 years (Supplementary Figure S5, available at Annals of Oncology online). This trend may have been due to the more common occurrence of locoregional recurrence and distant metastasis in the early years after RT [12], and it has been hypothesized that AC may only prolong the latency of locoregional recurrence and distant metastasis occurrence instead of improving their long-term control effectively [13]. Overall, a dialectical and comprehensive view on the choice between CCRT+AC and CCRT in the clinic is required. Currently, the 2014 NCCN recommends CCRT followed by AC for locoregionally advanced NPC (Category 2A); CCRT alone is also an option (Category 2B) (http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf). The
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
small and non-significant, a probability of treatment ranking would have been
13
National Cancer Institute also recommends CCRT+AC for locoregionally advanced NPC((http://www.cancer.gov/cancertopics/pdq/treatment/nasopharyngeal/HealthProfe ssional). However, the European Society for Medical Oncology recommends CCRT alone for locoregionally advanced NPC, and indicates that the benefit of 3 cycles of adjuvant cisplatin–fluorouracil is uncertain and that it has a substantial toxic effect
relatively fewer toxic effects without additional adjuvant therapy; (2) more satisfactory compliance; (3) relatively lower expense. Although the CCRT and RT LRFS were not significantly different in our study, improved radiation techniques such as intensity-modulated RT may have compensated for it. Regardless, a trend towards a higher rate of efficacy for CCRT+AC compared with CCRT alone was observed. Certain patient statuses might therefore benefit most from additional AC following CCRT. The subgroup analysis by Lee et al. [9] showed that among NPC patients with T1–4N2–3M0 disease, CCRT+AC mainly benefited patients with T1–2N2–3 disease. A retrospective study [26] showed that CCRT+AC mainly benefited intermediate-risk patients (T2b–3N0–2M0), with significant benefit in 5-year OS as compared with RT or CCRT alone. Recently, it was reported that unfavorable Epstein–Barr virus DNA response midpoint of RT was an adverse prognosticator for treatment outcome in advanced-stage NPC [27], and may serve as an indicator for the addition of adjuvant therapy to initial treatment. Overall, CCRT+AC appears to benefit patients who meet certain selection criteria, and further studies are required to define this patient population.
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
[25]. Compared with CCRT+AC, CCRT alone has the following advantages: (1)
14
The study limitations also should be acknowledged: extracted all information from published data other than individual patient data, which may have resulted in publication and reporting bias. Some of this unreported individual patient information may have aided better evaluation of the quality of an RCT. Moreover, without access to individual patient data, missing information on certain prognostic factors and
in the study by Al-Sarraf et al. [5]. To minimize the risk of bias, we restricted inclusion criteria, searched and reviewed the publications comprehensively, and two independent investigators extracted the data and assessed RCT quality. Excluding the study by Al-Sarraf et al. [5] from the LRFS and DMFS analysis might have affected the validity of our findings, although our conclusions remained valid following additional direct meta-analyses of LRR and DMR that included that trial. In conclusion, our network meta-analysis shows that there was no significant survival improvement following CCRT+AC as compared with CCRT alone. The long-term follow-up results of our trial [14], which would be instructive, is awaiting to be reported. Whether the omission of additional AC can reduce toxic effects without adversely affecting survival outcomes for patients with locoregionally advanced NPC should be further explored. In addition, the specific patient statuses that would benefit from AC following CCRT deserve further investigation. ACKNOWLEDGEMENTS We thank the anonymous reviewers for their insightful comments and great efforts to improve this manuscript.
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
endpoints could have affected our analysis, e.g., LRFS and DMFS were not available
15
FUNDING The authors received no external funding for this meta-analysis. CONFLICT OF INTEREST The authors have declared no conflicts of interest.
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
16
REFERENCES 1.
Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet 2005; 365: 2041-2054.
2.
Ma J, Mai HQ, Hong MH et al. Is the 1997 AJCC staging system for
nasopharyngeal carcinoma prognostically useful for Chinese patient populations? Int J Radiat Oncol Biol Phys 2001; 50: 1181-1189. Zhang L, Zhao C, Ghimire B et al. 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. BMC Cancer 2010; 10: 558. 4.
OuYang PY, Xie C, Mao YP et al. Significant efficacies of neoadjuvant and
adjuvant chemotherapy for nasopharyngeal carcinoma by meta-analysis of published literature-based randomized, controlled trials. Ann Oncol 2013; 24: 2136-2146. 5.
Al-Sarraf M, LeBlanc M, Giri PG et al. Chemoradiotherapy versus radiotherapy
in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998; 16: 1310-1317. 6.
Kwong DL, Sham JS, Au GK et al. Concurrent and adjuvant chemotherapy for
nasopharyngeal carcinoma: a factorial study. J Clin Oncol 2004; 22: 2643-2653. 7.
Wee J, Tan EH, Tai BC et al. Randomized trial of radiotherapy versus concurrent
chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 2005; 23: 6730-6738. 8.
Lee AW, Lau WH, Tung SY et al. Preliminary results of a randomized study on
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
3.
17
therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group. J Clin Oncol 2005; 23: 6966-6975. 9.
Lee AW, Tung SY, Chua DT et al. Randomized trial of radiotherapy plus
concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced
10. Lee AW, Tung SY, Chan AT et al. Preliminary results of a randomized study (NPC-9902 Trial) on therapeutic gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2006; 66: 142-151. 11. Lee AW, Tung SY, Chan AT et al. A randomized trial on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma. Radiother Oncol 2011; 98: 15-22. 12. Chen Y, Liu MZ, Liang SB et al. Preliminary results of a prospective randomized trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of china. Int J Radiat Oncol Biol Phys 2008; 71: 1356-1364. 13. Chen Y, Sun Y, Liang SB et al. Progress report of a randomized trial comparing long-term survival and late toxicity of concurrent chemoradiotherapy with adjuvant chemotherapy versus radiotherapy alone in patients with stage III to IVB nasopharyngeal carcinoma from endemic regions of China. Cancer 2013; 119:
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
nasopharyngeal carcinoma. J Natl Cancer Inst 2010; 102: 1188-1198.
18
2230-2238. 14. Chen L, Hu CS, Chen XZ et al. Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. Lancet Oncol 2012; 13: 163-171.
meta-analyses of the published literature for survival endpoints. Stat Med 1998; 17: 2815-2834. 16. Chen QY, Wen YF, Guo L et al. Concurrent chemoradiotherapy vs radiotherapy alone in stage II nasopharyngeal carcinoma: phase III randomized trial. J Natl Cancer Inst 2011; 103: 1761-1770. 17. Lin JC, Jan JS, Hsu CY et al. Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival. J Clin Oncol 2003; 21: 631-637. 18. Baujat B, Audry H, Bourhis J et al. Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 2006; 64: 47-56. 19. Chan AT, Teo PM, Ngan RK et al. Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial. J Clin Oncol 2002; 20: 2038-2044. 20. Chan AT, Leung SF, Ngan RK et al. Overall survival after concurrent
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
15. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform
19
cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2005; 97: 536-539. 21. Zhang L, Zhao C, Peng PJ et al. Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol 2005; 23: 8461-8468.
comparing radiotherapy with or without weekly oxaliplatin for locoregionally advanced nasopharyngeal carcinoma. Ann Oncol 2013; 24: 2131-2136. 23. Blanchard P, Hill C, Guihenneuc-Jouyaux C et al. Mixed treatment comparison meta-analysis of altered fractionated radiotherapy and chemotherapy in head and neck cancer. J Clin Epidemiol 2011; 64: 985-992. 24. Jacobs C, Lyman G, Velez-Garcia E et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992; 10: 257-263. 25. Chan AT, Gregoire V, Lefebvre JL et al. Nasopharyngeal cancer: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 Suppl 7: vii83-85. 26. Cheng SH, Tsai SY, Yen KL et al. Prognostic significance of parapharyngeal space venous plexus and marrow involvement: potential landmarks of dissemination for stage I-III nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2005; 61: 456-465. 27. Leung SF, Chan KC, Ma BB et al. Plasma Epstein-Barr viral DNA load at
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
22. Wu X, Huang PY, Peng PJ et al. Long-term follow-up of a phase III study
20
midpoint of radiotherapy course predicts outcome in advanced-stage nasopharyngeal carcinoma. Ann Oncol 2014; 25: 1204-1208.
Figure legends Figure 1. Network meta-analysis results for (A, B) overall survival, (C, D)
C, E) Upper triangles denote pooled hazard ratios (HRs); treatments in the rows were compared with those in the columns. In each HR cell, the first and second lines contain the HRs from the fixed and random effects models, respectively. Numbers in parentheses indicate the corresponding 95% credible intervals. Red numbers, HRs with Bayesian P < 0.05. Lower triangles denote the Bayesian deviance information criterion (DIC) statistics from the fixed and random effects models. (B, D, F) Probabilities of each treatment ranking best, and second and third best based on the fixed effects model. CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; RT, radiotherapy.
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
locoregional recurrence-free survival, and (E, F) distant metastasis-free survival. (A,
21
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
Median No. of
follow-up patients
Chemotherapy
Inclusion
Study
Stage
Radiotherapy
period (months)
Concurrent
Adjuvant
CCRT+AC vs. RT Al-Sarraf et al.
193
1989-1995 32.4
1998 Wee et al.
221
1997-2003 38.4
2005
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
Table 1. Summary of studies included in the network meta-analysis
AJCC
1.8-2.0Gy/fx/d, 5fx/wk, to
3* DDP 100 mg/m2
4* DDP 80 mg/m2(day 1) +FU
III-IV
66-70 Gy
(days 1,22, 43）
1,000mg/m2 (days 1-4 civ)
AJCC II-IV, 70Gy (2Gy/fx/d, 5fx/wk
DDP 25 mg/m2/d
DDP 20 mg/m2/d for 4days, +FU
any T, any for 7wks)
for 4days,
1000 mg/m2/d for 4 days
N
alternatively
30/30/40mg/m2/d for 3days Lee et al. 2005,2010
348
1999-2004 70.8
AJCC
≥66Gy (2Gy/fx/d,
III-IV, any
5fx/wk), +additional boosts (days 1,22,43)
3* DDP 100 mg/m2
q4wk DDP 80 mg/m2 +FU 1000 mg/m2/d (days 71,99 and
for parapharyngeal space,
N3, M0
primary or nodal sites when indicated not exceeding 20Gy
Lee et al.
93
1999-2004 75.6
2006,2011
2008,2013
2002-2005 70
q4wk DDP 80 mg/m2 +FU
≥66Gy (2Gy/fx/d, 5
III-IV,
fx/wk), +additional boosts (days 1,22,43)
1000 mg/m2/d (days 71, 99 and
T3-4, N0-1,
for parapharyngeal space,
127)
M0
primary or nodal sites when not
exceeding
20Gy 316
127)
AJCC
indicated
Chen et al.
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
T, N2 or
3* DDP 100 mg/m2
AJCC
≥68Gy (2Gy/fx/d,
7* DDP 40 mg/m2
3* q4wk DDP 80 mg/m2 (day 1)
III-IV,
5fx/wk for 7 weeks), +
(day 1) weekly
+FU 800 mg/m2/d (days 1-5 )
T1-4, N0-3,
additional boost in case of
M0
parapharyngeal extension,
residual nasopharyngeal disease CCRT vs. RT Chan et al.
350
1994-1997 66
2002,2005
AJCC II-IV, 66Gy,+additional boost
8* DDP 40 mg/m2
any T, any in case of parapharyngeal
(day 1) weekly
N, M0
extension, residual neck nodes, and/or residual nasopharyngeal disease (brachytherapy)
Zhang et al. 2005,2013
115
2001-2003 114
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
residual neck nodes and
AJCC
70-74Gy(2Gy/fx/d, 5fx/wk)
6* Oxaliplatin 70
III-IV, any
+additional boost in case
mg/ m2 weekly
T, N2 or
of parapharyngeal
N3, M0
extension, residual neck
None
None
nasopharyngeal disease CCRT+AC vs. CCRT Chen et al.
508
2012
2006-2010 38
AJCC
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014
nodes and/or residual
2.0–2.27Gy/fx/day,5 fx/wk, 7* DDP 40 mg/m2
III-IV, any to 60–66 Gy, irradiation to (day 1) weekly T, any N, 50 Gy for potential sites a M0, except T3–4N0
3* q4wk DDP 80 mg/m2 (day 1) +FU 800 mg/m2/d (days 1-5 )
CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; RT, radiotherapy; AJCC, American Joint Committee on Cancer; fx, fraction; DDP, cisplatin; FU, fluorouracil; civ, continuous intravenous; q4wk, every 4 weeks. a
Intensity-modulated radiotherapy and 3D conformal radiotherapy were adopted for partial patients.