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. 2019 Feb 19;24(4):505–512. doi: 10.1634/theoncologist.2018-0522

A Pairwise Meta‐Analysis of Induction Chemotherapy in Nasopharyngeal Carcinoma

Pu‐Yun OuYang a,†, Xiao‐Min Zhang a,†, Xing‐Sheng Qiu b,†, Zhi‐Qiao Liu a, Lixia Lu a, Yuan‐Hong Gao a,‡, Fang‐Yun Xie a,*,‡
PMCID: PMC6459258  PMID: 30782977

The role of induction chemotherapy in nasopharyngeal carcinoma remains controversial. This meta‐analysis of 10 randomized controlled trials confirmed its significant benefit in overall survival, progression free survival, locoregional and distant controls.

Keywords: Induction chemotherapy, Meta‐analysis, Nasopharyngeal carcinoma, Randomized controlled trials

Abstract

Background.

Locoregionally advanced nasopharyngeal carcinoma has high risk of distant metastasis and mortality. Induction chemotherapy is commonly administrated in clinical practice, but the efficacy was quite controversial in and out of randomized controlled trials. We thus conducted this pairwise meta‐analysis.

Materials and Methods.

Trials that randomized patients to receive radiotherapy or concurrent chemoradiotherapy with or without induction chemotherapy were identified via searches of PubMed, MEDLINE, and ClinicalTrials.gov.

Results.

A total of ten trials (2,627 patients) were included. The pooled hazard ratios (HRs) based on fixed effect model were 0.68 (95% confidence interval [CI] 0.56–0.80, p < .001) for overall survival (OS) and 0.70 (95% CI 0.61–0.79, p < .001) for progression‐free survival (PFS), which strongly favored the addition of induction chemotherapy. The absolute 5‐year survival benefits were 8.47% in OS and 10.27% in PFS, respectively. In addition, based on the available data of eight trials, induction chemotherapy showed significant efficacy in reducing locoregional failure rate (risk ratio [RR] = 0.81, 95% CI 0.68–0.96, p = .017) and distant metastasis rate (RR = 0.69, 95% CI 0.58–0.82, p < .001).

Conclusion.

This pairwise meta‐analysis confirms the benefit in OS, PFS, and locoregional and distant controls associated with the addition of induction chemotherapy in nasopharyngeal carcinoma.

Implications for Practice.

According to the results of this meta‐analysis of ten trials, induction chemotherapy can prolong overall survival and progression‐free survival and improve locoregional and distant controls for nasopharyngeal carcinoma.

Introduction

Nasopharyngeal carcinoma is squamous‐cell cancer that occurs in the epithelial lining of nasopharynx. The nonspecific nature of nasal and aural symptoms accounts for locoregionally advanced disease in nearly 70% of patients upon initial diagnosis [1]. Although advanced intensity‐modulated radiotherapy has improved locoregional control [2] and the administration of concurrent chemotherapy leads to significant benefit in progression‐free survival and overall survival [3], these patients still have high risk of distant metastasis and mortality [4]. Accordingly, induction chemotherapy is commonly added before radiotherapy in clinical practice, to shrink tumor volume, lower tumor burden, and reduce the radiation dose to organs at risk [5]. But unfortunately, none of early randomized controlled trials [6], [7], [8], [9] that assessed various combinations of induction chemotherapy before radiotherapy alone actually demonstrated improvement in overall survival, despite suggestions of better disease control.

Interestingly, a randomized phase II comparison of concurrent chemoradiotherapy with or without induction docetaxel and cisplatin by Hui and colleagues [10] found excellent improvement in 3‐year overall survival from 68% to 94% (p = .0066) and progression‐free survival from 60% to 88% (p = .11). However, the small number of participants, the insignificant improvement of progression‐free survival, and the inferiority of progression‐free survival and overall survival in the control group to reports from other cancer centers [11] made the trial finding controversial. In contrast, two subsequent randomized controlled trials [12], [13] did not confirm any survival benefit from induction chemotherapy. Recently, Sun and colleagues [14] tested an induction regimen consisting of docetaxel, cisplatin, and fluorouracil in a phase III randomized trial with 480 participants and reported significant benefit of overall survival, failure‐free survival, and distant failure‐free survival when the triplet combination was added to concurrent chemoradiotherapy. Additionally, the same induction regimen again significantly improved progression‐free survival and marginally prolonged overall survival of patients from nonendemic area with a higher dose intensity [15]. Another phase III trial of 476 patients from southern China [16] also observed higher disease‐free survival among the patients who received induction cisplatin plus fluorouracil followed by concurrent chemoradiotherapy, but similar overall survival, locoregional relapse‐free survival, and distant metastasis‐free survival compared with those who received concurrent chemoradiotherapy alone.

Therefore, the efficacy of induction chemotherapy in nasopharyngeal carcinoma remains investigational, and it is of immense importance to perform this pairwise meta‐analysis.

Materials and methods

Search Strategy and Selection Criteria

The following computerized bibliographic databases were used to search relevant literature: PubMed, MEDLINE, and clinicaltrials.gov. The search was further supplemented by reference lists of all available review articles and primary studies. Search terms were nasopharyngeal carcinoma or cancer, induction or neoadjuvant chemotherapy, and radiotherapy. To be eligible, trials had to compare induction chemotherapy plus radiotherapy or concurrent chemoradiotherapy with radiotherapy or concurrent chemoradiotherapy alone. They had to be randomized and include patients with untreated nonmetastatic nasopharyngeal carcinoma.

Data Extraction and Quality Control

Data on study design, year, number of patients, staging information, follow‐up duration, treatment protocol, endpoints, response to treatment, and failure patterns were extracted independently by two investigators (P.Y.O.Y and X.M.Z). To quantify study quality according to Jadad/Oxford quality scoring system [17], we examined the randomization procedure, estimation of sample size, allocation concealment blinding of outcome assessor, loss to follow‐up, dropout, and if the intention‐to‐treat analysis was followed. Any discrepancies in extracting data were resolved by consensus and consulting another investigator (X.S.Q.).

Statistical Analysis

The main endpoints were overall survival (time from random assignment to death from any cause) and progression‐free survival (time from random assignment to locoregional failure, distant metastasis, or death from any cause). Secondary endpoints were locoregional failure rate and distant metastasis rate. Hazard ratios (HRs) with 95% confidence intervals (CIs) were directly pooled for overall survival and progression‐free survival if reported in an individual trial. If not, these were estimated as elucidated by Tierney and colleagues [18]. Additionally, pooled overall survival and progression‐free survival curves were plotted, and absolute differences between induction chemotherapy arm and control arm were calculated as suggested by Pignon and colleagues [19]. Pooled risk ratios (RRs) with 95% CIs were assessed using the Mantel‐Haenszel method [20] for locoregional failure rate and distant metastasis rate.

Potential heterogeneity across studies was detected by χ2 test and I2 statistic, and significant heterogeneity was defined as a χ2 p value <.1 or an I2 statistic >50% [21]. Estimation was carried out based on the random‐effects model in the presence of heterogeneity and the fixed‐effects model in the absence of heterogeneity. Finally, publication bias was assessed using Begg's test [22], Egger's test [23] and/or visual inspection of a funnel plot. The Duval and Tweedie nonparametric “trim and fill” procedure [24] was also performed to further assess the possible effect of publication bias.

Statistical analyses were performed using Stata version 12.0 (Statacorp, College Station, TX). A two‐sided p value <.05 was considered significantly different for all analyses except heterogeneity tests.

Results

Trial Characteristics

After literature search and trials selection (supplemental online Fig. 1), a total of ten trials [6], [7], [8], [9], [10], [12], [13], [14], [15], [16] (Jadad score in supplemental online Table 1) were available for analysis, including 2,627 patients. The major characteristics are shown in Table 1. Three trials (226 patients) [9], [10], [15] enrolled less than 100 participants; two trials (224 patients) [9], [12] did not exclude early stage patients; and another two trials (814 patients) [7], [14] had a median follow‐up shorter than 3 years. Moreover, six trials (1,418 patients) [10], [12], [13], [14], [15], [16] used intensity‐modulated radiotherapy technique and delivered concurrent chemotherapy of cisplatin for both induction chemotherapy arm and control arm. Five trials (942 patients) [10], [12], [13], [14], [15] investigated the effect of taxane‐based induction chemotherapy.

Table 1. Summary of included studies.

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Abbreviations: 2DRT, two‐dimensional radiotherapy; 3DCRT, three‐dimensional conformal radiotherapy; 5FU, 5‐fluorouracil; AUC, area under the curve; BLM, bleomycin; DDP, cisplatin; f, fraction; FU, fluorouracil; IMRT, intensity‐modulated radiotherapy; LN, lymph node; q3w, every 3 weeks; RT, radiotherapy; UICC, Union for International Cancer Control.

Overall Survival and Progression‐Free Survival

Original HRs with 95% CIs were reported in three trials (626 patients) for overall survival [10], [14], [15] and in five trials (1,274 patients) for progression‐free survival [10], [13], [14], [15], [16]. In the absence of significant heterogeneity (I2 = 34.5%, p = .132 for overall survival; I2 = 0.0%, p = .794 for progression‐free survival), pooled HRs based on fixed effect model strongly favored the additional treatment of induction chemotherapy in significantly improving overall survival (HR = 0.68, 95% CI 0.56–0.80, p < .001) and progression‐free survival (HR = 0.70, 95% CI 0.61–0.79, p < .001; (Fig. 1A). The absolute 5‐year survival benefit was 8.47% in overall survival (Fig. 1B) and 10.27% in progression‐free survival (Fig. 1C), respectively. Begg's test (p = .857 for overall survival; p = .367 for progression‐free survival) or Egger's test (p = .743 for overall survival; p = .314 for progression‐free survival) did not indicate the existence of obvious publication bias.

Figure 1.

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Forest plot and estimated survival curves. (A): Forest plot for overall survival and progression free survival. (B): Estimated overall survival curve by induction chemotherapy. (C): Estimated progression free survival curve by induction chemotherapy.

Abbreviations: CI, confidence interval; HR, hazard ratio; IC, induction chemotherapy; O‐E, observed minus estimated number of events.

Locoregional Failure Rate and Distant Metastasis Rate

Two trials [15], [16] did not report the number of locoregional failure or distant metastasis. Out of 2,070 patients, 401 (19.4%) had locoregional failure and 420 (20.3%) had distant failure. Induction chemotherapy reduced the risk of locoregional failure (RR = 0.81, 95% CI 0.68–0.96, p = .017) and distant metastasis (RR = 0.69, 95% CI 0.58–0.82, p < .001; Fig. 2). Heterogeneity between trials was not observed for locoregional failure rate (I2 = 33.8%, p = .158) or distant metastasis rate (I2 = 0.0%, p = .655). Begg's test (p = .536) or Egger's test (p = .351) indicated no existence of obvious publication bias for distant metastasis rate. Visual inspection of the Begg's funnel plot for locoregional failure rate revealed asymmetry (supplemental online Fig. 2A), although the degree of asymmetry was not statistically significant by Begg's test (p = .063). But the Egger's test (p = .035) raised the possibility of publication bias. Accordingly, a sensitivity analysis was undertaken using the trim and fill method to adjust the estimate of effect size for potential asymmetry. The imputed trials produced a symmetrical funnel plot (supplemental online Fig. 2B). The pooled analysis incorporating the hypothetical trials continued to show a marginally significant advantage of induction chemotherapy in lowering the locoregional failure rate (RR = 0.76, 95% CI, 0.57–0.99, p = .047).

Figure 2.

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Forest plot for locoregional failure rate and distant metastasis rate.

Abbreviations: CI, confidence interval; IC, induction chemotherapy; RR, risk ratio.

Grade 3 or Higher Acute Toxicities

During induction chemotherapy, the most common grade 3 or higher acute toxicities were neutropenia (35.7%), hair loss (31.9%), nausea/vomiting (17.4%), and leukopenia (10.7%). The induction chemotherapy arm had significantly higher proportion of grade 3 or higher thrombocytopenia than the control arm (p < .001). Other acute toxicities were similar between both arms (Table 2).

Table 2. Grade 3 or higher acute toxicities.

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Abbreviations: CI, confidence interval; NA, not available.

Discussion

The efficacy of induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma has been reviewed in several meta‐analyses [3], [25], [26], [27], [28], [29], [30], but the findings exerted limited effect on treatment decision. First, small proportions of participants were administered with the most recommended concurrent chemoradiotherapy in these meta‐analyses [3], [25], [26], [27], [28], [29]. Certainly, meta‐analysis could not be intact, and bias was possibly caused, when the randomized controlled trials of induction chemotherapy followed by radiotherapy versus radiotherapy alone were absent. [30]. Besides, as the radiation technique has updated from two‐dimensional radiotherapy to more advanced intensity‐modulated radiotherapy, whether the according survival advantage achieved from the newly radiation technique [2] can cover the survival benefits of induction chemotherapy remains investigational. Additionally, because nasopharyngeal carcinoma is extremely endemic in southern China [31] but less common in other areas [32], the lack of recent data from the most endemic area and the largest population may cause bias when evaluating the efficacy of induction chemotherapy. Notably, the first application of taxane‐based induction chemotherapy showed a great absolute 3‐year overall survival benefit of 26.4% [10]; however, the encouraging outcome of taxane‐based induction chemotherapy was not confirmed in another trial with different populations [12]. Both trials [10], [12] led to significant heterogeneity in the prior pairwise meta‐analysis [25]. Recently, two large‐scale phase III trials [14], [16] reported the results of induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in the endemic population. Therefore, an updated meta‐analysis is warranted.

Our pairwise meta‐analysis synthesized all the head‐to‐head randomized controlled comparisons of radiotherapy or concurrent chemoradiotherapy with or without induction chemotherapy. Overall, 54.0% (1,418 patients) of the 2,627 patients received concurrent chemoradiotherapy, and trials of these patients carried a total weight of 46.29% and 45.31% when evaluating the pooled HR of overall survival and progression‐free survival, respectively. In our meta‐analysis, 37.3% of patients (981 patients) were treated with intensity‐modulated radiotherapy, 36.2% (462 patients) of patients in the investigational arm were administrated with taxane‐based induction chemotherapy, and 53.7% of patients (1,412 patients) were from mainland China. The balanced distribution of patients’ characteristics resulted in no evidence of obvious heterogeneity and made our findings more convincing. Although the Egger's test indicated possible publication bias for locoregional failure rate, the subsequent sensitivity analysis using the trim and fill method denied this possibility, and the efficacy of induction chemotherapy in locoregional control was ultimately unchanged. On the contrary, the inappropriate enrollment of the trial by Chan and colleagues [33] in the individual patient data meta‐analysis [3] may have covered the independent role of induction chemotherapy, and the absence of data from recent trials [13], [14], [15], [16] could significantly bias the findings of prior meta‐analyses [3], [25], [26], [27], [29]. For example, significant heterogeneity was observed in the previous pairwise meta‐analysis [25] when evaluating the effect of induction chemotherapy on locoregional control without including these trials [13], [14], [16]. Moreover, confidence of the meta‐analysis by Tan and colleagues [30] was likely to be reduced, because the included nonrandomized comparative studies are ranked lower in the evidence hierarchy.

The absolute 5‐year survival benefit from the addition of induction chemotherapy was 8.47% in overall survival and 10.27% in progression‐free survival in our meta‐analysis, which was higher than the absolute benefit from concurrent chemotherapy (5.3% in overall survival and 6.6% in progression‐free survival) or adjuvant chemotherapy (3.3% in overall survival and 6.1% in progression‐free survival) alone, but was inferior to concurrent plus adjuvant chemotherapy (12.4% in overall survival and 12.4% in progression‐free survival), as estimated in the individual patient data meta‐analysis [3]. The sequence of the comparison was consistent with the findings of the recent network meta‐analysis [29]. But notably, the high absolute benefit of the combination of concurrent plus adjuvant chemotherapy derived entirely from the comparison with radiotherapy alone in that meta‐analysis [3]. Consequently, induction chemotherapy has in fact been a satisfactory treatment approach with definite survival benefit. Hence, the remaining question is to find out the best treatment of the three approaches: induction plus concurrent chemotherapy, concurrent plus adjuvant chemotherapy, or induction plus concurrent plus adjuvant chemotherapy. The preliminary results of trial NPC‐0501 [34] indicated that induction plus concurrent chemotherapy seemed to be better than concurrent plus adjuvant chemotherapy. Further validation (NCT01797900) is awaited. But no studies have investigated the triplet combination of induction, concurrent, and adjuvant chemotherapy.

In the real‐world clinical practice, however, the efficacy of induction chemotherapy was minimal, as observed in different populations [35], [36], [37], [38], [39]. Perhaps a more precise selection of real high‐risk patients based on prognostic tools (e.g., tumor volume [40], Epstein‐Barr virus deoxyribonucleic acid [41], or nomogram [42], [43], [44], [45]) and application of new chemotherapy regimens [34], [46] might be the promising strategies for induction chemotherapy in the future.

This study used published values rather than individual patient data, which could affect the accuracy of the estimates. Locoregional failure rate and distant metastasis rate were evaluated using risk ratios, which failed to allow for both censoring and time to an event. Furthermore, the exact number of locoregional failure and distant metastasis was not reported in two trials [15], [16], which might be the main cause of the presence of publication bias suggested by Egger's test when estimating the pooled locoregional failure rate. Although the trim and fill adjusted analysis finally confirmed no publication bias, the effect of induction chemotherapy on locoregional failure rate changed to be marginally significant after incorporating the hypothetical trials.

Conclusion

This pairwise meta‐analysis confirms the benefit in overall survival, progression‐free survival, and locoregional and distant controls associated with the addition of induction chemotherapy in nasopharyngeal carcinoma.

See http://www.TheOncologist.com for supplemental material available online.

Acknowledgments

This work was supported by the Sun Yat‐sen University Clinical Research 5010 Program (2015020), the National Natural Science Foundation of China (81672665), the Sci‐Tech Project Foundation of Guangdong Province (2016A020215087), and the Natural Science Foundation of Guangdong Province (2015A030313024).

†

Co‐first authors

‡

Co‐senior authors

Footnotes

For Further Reading: Petr Szturz, Kristien Wouters, Naomi Kiyota et al. Weekly Low‐Dose Versus Three‐Weekly High‐Dose Cisplatin for Concurrent Chemoradiation in Locoregionally Advanced Non‐Nasopharyngeal Head and Neck Cancer: A Systematic Review and Meta‐Analysis of Aggregate Data. The Oncologist 2017;22:1056–1066.

Implications for Practice: Given concurrently with conventional radiotherapy in locally advanced head and neck cancer, high‐dose three‐weekly cisplatin has often been replaced with weekly low‐dose infusions to increase compliance and decrease toxicity. The present meta‐analysis suggests that both approaches might be equal in efficacy, both in the definitive and postoperative settings, but differ in toxicity. However, some toxicity data can be influenced by unbalanced representation, and the conclusions are not based on adequately sized prospective randomized studies. Therefore, low‐dose weekly cisplatin should not be used outside clinical trials but first prospectively studied in adequately sized phase III trials versus the high‐dose three‐weekly approach.

Author Contributions

Conception/design: Pu‐Yun OuYang, Yuan‐Hong Gao, Fang‐Yun Xie

Provision of study material or patients: Pu‐Yun OuYang, Xiao‐Min Zhang, Xing‐Sheng Qiu

Collection and/or assembly of data: Pu‐Yun OuYang, Xiao‐Min Zhang, Xing‐Sheng Qiu, Zhi‐Qiao Liu

Data analysis and interpretation: Pu‐Yun OuYang

Manuscript writing: Pu‐Yun OuYang, Lixia Lu

Final approval of manuscript: Pu‐Yun OuYang, Xiao‐Min Zhang, Xing‐Sheng Qiu, Zhi‐Qiao Liu, Lixia Lu, Yuan‐Hong Gao, Fang‐Yun Xie

Disclosures

The authors indicated no financial relationships.

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