Abstract
Background:
The clinical application has widespread disagreement on the different regimens of neoadjuvant chemotherapy (NCT) in the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC). We conducted a network meta-analysis (NMA) to evaluate the efficacy of the different NCT regimens in the treatment of NPC.
Methods:
A systematic literature search was performed using PubMed, Embase, and Cochran Library. Totally, 31 randomized controlled trials (RCTs) (n = 4062) met study selection criteria and were incorporated in this NMA study.
Results:
Our study showed that certain NCT regimens improved the prognosis of patients, and found out the relative best solution for each endpoint, such as paclitaxel, carboplatin, and gemcitabine for 1-year overall survival (OS) rate, cisplatin, calcium folinate, and 5-fluorouracil for 2-year OS rate, vinorelbine and cisplatin (NP) for 3-year OS rate, cyclophosphamide, cisplatin, and 5-fluorouracil for 5-year OS rate, NP for complete remission rate, cisplatin and gemcitabine for overall remission rate of the primary tumor. In addition, for certain grade 3 and above toxicity, the results of the NMA reflected certain NCT regimens can reduce toxicity of chemoradiotherapy (CRT) to a minimum, such as NP for anemia, mucositis, and thrombocytopenia, paclitaxel, epirubicin, and cisplatin for neutropenia and skin toxicity.
Conclusion:
Our NMA showed that certain cisplatin-based NCT regimens improved the prognosis of patients with NPC and reduced the toxicity of CRT. However, in view of survival rate and response rate, the best NCT regimen is not entirely consistent. Therefore, which NCT regimen will benefit most patients will need further explored.
Keywords: nasopharyngeal carcinoma, neoadjuvant chemotherapy, network meta-analysis
1. Introduction
Nasopharyngeal carcinoma (NPC), linked to Epstein–Barr virus (EBV), is the most common malignant tumor in head and neck, mainly distributing in southeast Asia, southern China, Hong Kong, and Taiwan.[1] Due to the abundant lymphatic network under the nasopharyngeal mucosa, NPC has a tendency to metastasize to lymph nodes early. Radiotherapy (RT) is used to be the recommended option for these patients; however, only 30% to 50% patients with NPC with RT are able to survive for 5 years, and if RT is not delivered timely, the recurrence rate of lymph nodes will be as high as 40%.[2] As a result, the combination of chemotherapy (CRT) and RT is hypothesized to be an effective therapy to improve the survival status of patients with NPC. But even so, the 5-year survival rate is only 40% to 50%.[3,4]
Neoadjuvant chemotherapy (NCT) was usually regarded as no benefit at first glance in the past, due to triggering an accelerated repopulation and even cross resistance after treatment. A recent meta-analysis demonstrated that NCT followed by concurrent chemoradiotherapy (CCRT) or RT could improve both overall survival (OS) and progression-free survival (PFS) for patients with locoregionally advanced NPC, compared with CCRT or RT.[5]
The clinical application has widespread disagreement on the different regimens of NCT in the treatment of locoregionally advanced NPC. Consequently, it remains unclear which NCT regimen benefits patients with NPC better. As such, the pairwise comparison meta-analysis is difficult to determine the superiority of a NCT regimen. It is more and more popular for network meta-analysis (NMA) to assess medical interventions, especially, although the head-to-head comparisons are lacking, NMA could provide an effective way to evaluate the relative effectiveness among all interventions and rank ordering of the interventions. Therefore, in the present study, we conducted an NMA to evaluate the efficacy of the different NCT regimens in the treatment of NPC.
2. Methods
2.1. Search strategy and selection criteria
Literature search was conducted in electronic databases by 2 independent reviewers. Multiple resources were searched accordingly for the purpose of preventing selection bias: the Cochrane Library, PubMed, and Embase. The following terms were applied: “nasopharyngeal neoplasm,” “NPC,” “neoadjuvant chemotherapy,” “induction chemotherapy,” “randomized controlled trial,” and “RCT.” The searching results were updated in May 2017. Studies were included if they were RCT combined with at least 1 NCT regimen with chemotherapy or RT. The reference lists of the included studies were reviewed as a supplement. No language limits were applied to literature search. Besides that patients in the included studies were diagnosed with NPC (stages I–IV) according to the criteria set by the American Joint Committee on Cancer, the World Health Organization, the International Union against Cancer, and the tumor node metastasis staging system.
2.2. Data extraction and quality assessment
Two investigators independently reviewed the articles and disagreements were resolved by discussion and consensus. We extracted the following information from each study: first author's surname, publication year, stages, number of patients, median age, and median follow-up; treatment regimens for each study; reported outcomes, including complete remission rate (CRR) or overall remission rate (ORR) of the primary tumor, OS and grade 3 and above toxicities. If the same study had been published for more than once, the one with longer follow-up duration would be preferred.
The quality was evaluated by the Jadad composite scale. This scale included the method of randomization (0–2 points), double blinding (0–2 points), and the description of dropouts (0–1 points).
2.3. Statistical analysis
The primary endpoint of this NMA was OS, defined as the time from random assignment to death. Secondary endpoints were grade 3 and above toxicities and CRR or ORR of the primary tumor.
The NMA was performed by STATA 13.1 (Stata Corporation, College Station, TX). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the random-effects model or fixed-effects model for investigating treatment effects. Z test was conducted to assess the significance of overall effect size. A P-value of <.05 was considered statistically significant.
After constructing a heterogeneity matrix, the frequentist method was applied to the fitted meta-regression model. The model covariates as the basic parameters and assumed that heterogeneity is independent of the comparison between effect sizes from multi-arm studies. Inconsistency refers to the differences between direct and various indirect effects estimated for the same comparison. We estimated the probability of a treatment being ranked at a specific place according to the outcome using “network rank.” The publication bias was evaluated by a “comparison-adjusted” funnel plots whose horizontal axis presents the difference between study-specific effect sizes and the corresponding comparison-specific summary effect. The funnel plot should be symmetrical near the zero line if there is no publication bias.
3. Results
3.1. Baseline characteristics of included studies
The initial database search broadly identified 290 studies. After reviewing the title and abstract, duplicate search results (n = 111), letters or reviews (31), and nonhuman studies (1) were excluded. From the remaining n = 147 full-text articles, non-RCT (n = 21), articles not associated with NPC or not related to the research topic (n = 80), retrospective study (n = 13), and not English or Chinese (n = 2) were further eliminated by the screening process. Ultimately, 31 RCTs[6–36] (n = 4062) met study selection criteria and were incorporated in this NMA study. Among the 31 RCTs, we summarized 16 NCT regimens. The screening and inclusion process is presented in Figure 1, and the baseline characteristics of the 31 included studies are summarized in Table 1.
Figure 1.
Flow chart shows the detailed procedures of study screening and exclusion criteria. Thirty-one studies were included in this network meta-analysis. RCT = randomized controlled trial.
Table 1.
Characteristics of published studies included in this network meta-analysis.
3.2. Evidence network
The evidence network is displayed in Figures 2 and 3. Connecting lines indicated direct comparison between the 2 interventions, and pairs of interventions without connection can be compared indirectly through NMA. The width of lines represents the number of trials. The size of nodes suggests the overall sample size of intervention.
Figure 2.
Evidence network of all enrolled studies in relation to short-term effects and survival outcomes in this network meta-analysis. (A) Network plot of complete remission rate (CRR) of primary tumor. (B) Network plot of overall remission rate (ORR) of primary tumor. (C) Network plot of 1-year overall survival (OS) rate. (D) Network plot of 2-year OS rate. (E) Network plot of 3-year OS rate. (F) Network plot of 5-year OS rate.
Figure 3.
Evidence network of all enrolled studies in relation to toxicities (≥grade 3) in this network meta-analysis. (A) Network plot of anemia. (B) Network plot of neutropenia. (C) Network plot of skin toxicity. (D) Network plot of mucositis toxicity.
3.3. Evaluating and presenting assumptions of NMA
The present NMA consisted of 1 triangular loop (RT/CRT-cisplatin and 5-fluorouracil [PF]-docetaxel and cisplatin [TP] loop). For indirect comparisons, node-splitting model was performed to estimated degree of inconsistency. Then we found inconsistency was not statistically significant (P > .05).
3.4. CRR and ORR of primary tumor
Nineteen RCTs reported CRR of primary tumor. In these RCTs, 1912 patients were involved, and 12 NCT regimens were included. The results of NMA found RT/CRT followed by TP, vinorelbine and cisplatin (NP), and cisplatin and gemcitabine (PG) regimens can improve CRR of the primary tumor. The ranking probabilities of the 3 regimens for the effects on CRR of the primary tumor were: 37.2% for NP regimen, 18.1% for DF regimen, and 16.4% for PG regimen. In addition, 14 RCTs reported ORR of primary tumor further. PG regimen improved CRR of the primary tumor significantly and the value of ranking probabilities was 37%. The ranking for CRR and ORR of primary tumor is illustrated in Figure 4.
Figure 4.
Ranking for the short-term effects in this network meta-analysis. (A) Complete remission rate (CRR) of primary tumor. (B) Overall remission rate (ORR) of primary tumor.
3.5. Overall survival rate
Data available regarding the survival outcomes were limited. Although certain literatures reported the results of metastasis-free survival, PFS, disease-free survival, and recurrence-free survival, the reporting and occurrence of these events were rare. Therefore, we could only choose the results of OS to evaluate the survival outcomes.
A total of 1916 patients in 8 RCTs containing 7 NCT regimens (cyclophosphamide, cisplatin, and 5-fluorouracil [CPF], TPF, bleomycin, 5-fluorouracil, and cisplatinum [BFC], bleomycin, epirubicin, and cisplatinum [BCE], cisplatin and epirubicin [PE], PF, and paclitaxel, carboplatin, and gemcitabine [GCP]) were included to compare the 1-year OS rate. All the NCT regimens except PF can improve 1-year OS rate. The results of probability ranking of the 8 interventions revealed that GCP regimen group was significantly higher than other 7 groups (ranking probabilities was 53.4%, Fig. 5A). The CIs of estimates for 1-year OS rate are shown in Table 2.
Figure 5.
Ranking for the survival outcomes in this network meta-analysis. (A) 1-year overall survival (OS) rate. (B) 2-year OS rate. (C) 3-year OS rate. (D) 5-year OS rate.
Table 2.
Combined odds ratio and 95% confidence interval for 1-year overall survival (OS) rate from network meta-analysis.
Eleven studies reported 2-year OS rate, and 9 NCT regimens (BCE, PFT, PF, PE, cisplatin, calcium folinate, and 5-fluorouracil [PLF], TP, BFC, GCP, and CPF) were included. In addition to PF and TP regimens, other 7 NCT regimens improved 2-year OS rate. Probability ranking revealed that the 2-year OS rate of PLF regimen group was significantly higher than other groups (ranking probabilities were 52.9% for PLF, 31.6% for CPF, 11.7% for TPF, 2.3% for GCP, 1.0% or BFC, 0.3% for BCE and 0.1% for PE, Fig. 5B). The CIs of estimates for 2-year OS rate are shown in Table 3.
Table 3.
Combined odds ratio and 95% confidence interval for 2-year overall survival (OS) rate from network meta-analysis.
Fifteen studies also reported 3-year OS rate, and 7 NCT regimens were considered to be able to improve 3-year OS rate of patients. NMA results demonstrated that NP regimens may be the patients’ 3-year OS rate of maximum benefit (ranking probability was 51.7%, Fig. 5C).
Nine RCTs reported 5-year OS rate, involving 6 NCT regimens and 1903 patients. We found 4 NCT regimens (CPF, BFC, PFP, PE, and PF regimen) improved the 5-year OS rate of patients with advanced NPC in different degree. Then the results of probability ranking revealed that the 5-year OS rate of CPF regimen group was significantly higher than other groups (ranking probability was 65.4%, Fig. 5D). The CIs of estimates for 5-year OS rate are shown in Table 4.
Table 4.
Combined odds ratio and 95% confidence interval for 5-year overall survival (OS) rate from network meta-analysis.
3.6. Grade 3 and above toxicity
Toxicities are the important indicators of drug evaluation. To address severe acute toxicities (≥grade 3), we compared toxicity rates among NCT groups and RT/CRT alone groups. This NMA evaluated the following most reported toxicities: anemia, thrombocytopenia, neutropenia, skin toxicity, and mucositis toxicity.
Six NCT regimens were included compared the incidence rate of anemia. Two regimens (TP and NP) were considered to decrease the incidence rate of anemia, while other 4 regimens (PF, paclitaxel, epirubicin, and cisplatin [CEP], GCP, and PG) increased the rate. Incidence rate was lowest in NP regimen (ranking probability was 75.4%).
Sixteen studies (n = 1774) provided data about neutropenia which occurred during the entire treatment and 6 NCT regimens (PF, CEP, TP, NP, GCP, and PG) were reported. The pooled incidence rates of neutropenia from 16 studies reflected CEP regimen had the lowest incidence rate (ranking probability was 55.8%).
The pooled incidence rates of thrombocytopenia for each treatment regimen from 13 studies, including 6 NCT regimens (PF, CEP, TP, NP, GCP, and PG). We found only NP regimen could reduce the risk of thrombocytopenia (ORs = −0.36, 95% CI −2.43 to 1.70).
In addition, we evaluated incidence rate of mucositis by comparing 6 NCT regimens (BCE, PF, CEP, TP, NP, and BFC). BCE, CEP, and NP regimens reduced the risk of mucositis. And NP regimen had the lowest incidence rate (ranking probability was 46.2%). Eleven studies reported incidence rate of skin toxicity, involving 6 NCT regimens (BCE, PF, CEP, TP, NP, and GCP). CEP regimen had the lowest incidence rate (ranking probability was 81.5%).
3.7. Publication bias
Figure 6 presented the funnel plot for the network. All the included studies symmetrically distribute around the vertical line (x = 0), indicating no significant publication bias in this NMA.
Figure 6.
Comparison-adjusted funnel plot for assessing publications bias. The red line suggests the null hypothesis that the study-specific effect sizes do not differ from the respective comparison-specific pooled effect estimates. Different colors represent different comparisons. (A) RT/CRT, (B) BCE-RT/CRT, (C) TPF-RT/CRT, (D) PF-RT/CRT, (E) DF-RT/CRT; (F) PE-RT/CRT, (G) CEP-RT/CRT, (H) TP-RT/CRT, (I) NP-RT/CRT, (J) PLF-RT/CRT, (K) BFC-RT/CRT, (L) CPF-RT/CRT, (M) PG-RT/CRT. BCE = bleomycin, epirubicin, and cisplatinum, BFC = bleomycin, 5-fluorouracil, and cisplatinum, CEP = paclitaxel, epirubicin, and cisplatin, CPF = cyclophosphamide, cisplatin, and 5-fluorouracil, CRT = chemoradiotherapy, DF = docetaxel and cisplatin, NP = vinorelbine and cisplatin, PE = cisplatin and epirubicin, PF = cisplatin and 5-fluorouracil, PG = cisplatin and gemcitabine, PLF = cisplatin, calcium folinate, and 5-fluorouracil, RT = radiotherapy, TP = docetaxel and cisplatin, TPF = docetaxel, cisplatin, and 5-fluorouracil.
4. Discussion
This NMA is the first study to evaluate the efficacy of the different NCT regimens in the treatment of NPC through direct and indirect statistical comparisons based on all available information from the included RCTs. Compared with RT/CRT alone, most of the NCT regimens can improve the long-term survival rate (1-year, 2-year, 3-year, and 5-year OS rate) of patients and CRR and ORR of primary tumor in different degrees. Meanwhile certain NCT regimens do not improve patient prognosis, and even cause serious toxicity.
As far as this research is concerned, we still not able to confirm the best NCT regimen, because the best regimen for various outcomes and toxicity is not entirely consistent. In spite of this, the NMA identified the relatively optimal NCT regimen based different prognostic indicators, such as GCP for 1-year OS rate, PLF for 2-year OS rate, NP for 3-year OS rate, CPF for 5-year OS rate, NP for CRR, and PG for ORR. In addition, for certain grade 3 and above toxicity, we found certain NCT regimens can reduce toxicity to a minimum, such as NP for anemia, mucositis, and thrombocytopenia, CEP for neutropenia and skin toxicity.
National Comprehensive Cancer Network recommends CCRT for locoregionally advanced NPC. On the contrary, according to clinical practice guidelines of European Society of Oncology, cisplatin-based NCT regimens are recommended for patients with advanced NPC.[37] And our NMA results also confirm and support the conclusion.
But the study limitations also should be acknowledged: only English and Chinese language studies were included might have led to potential publication bias; the exclusion of unpublished data was generally associated with an overestimation of the true effect; prognosis indexes failed to incorporate all of the NCT regimens, so that it is difficult to determine which regimen is optimal for the patients.
In conclusion, our NMA showed that certain cisplatin-based NCT regimens improved the prognosis of patients with NPC and reduced the toxicity of CRT. However, in view of survival rate and response rate, the best NCT regimen is not entirely consistent. Therefore, which NCT regimen will benefit most patients will need further explored.
Author contributions
Data curation: Le Wang, Li-Hua Ni, Lu Xu, Xiao-Long Wang, Guang Zeng.
Writing – original draft: Cheng Yuan, Shang-Wen Luo, Min Sun.
Writing – review & editing: Xin-Hua Xu.
Footnotes
Abbreviations: BCE = bleomycin, epirubicin, and cisplatinum, BFC = bleomycin, 5-fluorouracil, and cisplatinum, CEP = paclitaxel, epirubicin, and cisplatin, CI = confidence interval, CPF = cyclophosphamide, cisplatin, and 5-fluorouracil, CR = complete remission, CRT = chemoradiotherapy, CT = chemotherapy, DF = docetaxel and cisplatin, EBV = Epstein–Barr virus, GCP = paclitaxel, carboplatin, and gemcitabine, NCCN = National Comprehensive Cancer Network, NMA = network meta-analysis, NP = vinorelbine and cisplatin, NPC = nasopharyngeal carcinoma, OR = overall remission, ORs = odds ratios, OS = overall survival, PE = cisplatin and epirubicin, PF = cisplatin and 5-fluorouracil, PFP = carboplatin, 5-fluorouracil, and pingyangmycin, PFS = progression-free survival, PG = cisplatin and gemcitabine, PLF = cisplatin, calcium folinate, and 5-fluorouracil, RCT = randomized controlled trial, RT = radiotherapy, TP = docetaxel and cisplatin, TPF = docetaxel, cisplatin, and 5-fluorouracil.
CY, SWL, and LW contributed equally to this work.
Ethical approval was not necessary, because this article is a meta-analysis and it does not involve the participation of ethics committee.
This study was funded by Natural Science Foundation of Hubei Province, China (grant number 2014CFB312).
The authors have no conflicts of interest to disclose.
References
- [1].Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2006;15:1765–77. [DOI] [PubMed] [Google Scholar]
- [2].Li JG, Yuan X, Zhang LL, et al. A randomized clinical trial comparing prophylactic upper versus whole-neck irradiation in the treatment of patients with node-negative nasopharyngeal carcinoma. Cancer 2013;119:3170–6. [DOI] [PubMed] [Google Scholar]
- [3].Wang WY, Twu CW, Chen HH, et al. Long-term survival analysis of nasopharyngeal carcinoma by plasma Epstein-Barr virus DNA levels. Cancer 2013;119:963–70. [DOI] [PubMed] [Google Scholar]
- [4].Lee AW, Lin JC, Ng WT. Current management of nasopharyngeal cancer. Semin Radiat Oncol 2012;22:233–44. [DOI] [PubMed] [Google Scholar]
- [5].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;24:2136–46. [DOI] [PubMed] [Google Scholar]
- [6].Anonymous Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV (> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. Int J Radiat Oncol Biol Phys 1996;35:463–9. [DOI] [PubMed] [Google Scholar]
- [7].Casanova M, Ozyar E, Patte C, et al. International randomized phase 2 study on the addition of docetaxel to the combination of cisplatin and 5-fluorouracil in the induction treatment for nasopharyngeal carcinoma in children and adolescents. Cancer Chemother Pharmacol 2016;77:289–98. [DOI] [PubMed] [Google Scholar]
- [8].Chakrabandhu S, Chitapanarux I, Onchan W, et al. Neoadjuvant chemotherapy plus chemoradiation (NACT-CCRT) versus chemoradiation plus adjuvant chemotherapy (CCRT-ACT) for locally advanced nasopharyngeal cancer: 3-year results from a randomised trial. Eur J Cancer 2015;51:E2. [Google Scholar]
- [9].Chan AT, Hui E, Ma B, et al. A randomized phase II study of concurrent cisplatin-radiotherapy (RT) with or without neoadjuvant chemotherapy using docetaxel (Taxotere) and cisplatin in advanced nasopharyngeal carcinoma (NPC). 41st Annual Meeting of the American Society of Clinical Oncology (ASCO), Orlando, Florida, USA, 13-17 May, 2005. J Clin Oncol 2005;23: abstract no 5544. [Google Scholar]
- [10].Chan AT, Teo PM, Leung TW, et al. A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1995;33:569–77. [DOI] [PubMed] [Google Scholar]
- [11].Changqing C, Su W, Wanqing L, et al. Neoadjuvant chemotherapy (plus radiotherapy) in the treatment of patients with N2 nasopharyngeal carcinoma. Chin J Clin Oncol 1999;26:420–2. [Google Scholar]
- [12].Chen B. A clinical trial of neoadjuvant chemotherapy plus late-course hyperfractionated accelerated radiation therapy for nasopharyngeal carcinoma. J Gannan Med Coll 2003;23:408–9. [Google Scholar]
- [13].Chua DT, Sham JS, Wei WI, et al. Control of regional metastasis after induction chemotherapy and radiotherapy for nasopharyngeal carcinoma. Head Neck 2002;24:350–60. [DOI] [PubMed] [Google Scholar]
- [14].Fan RT, Guo YN, Wang JM, et al. Clinical study on short-term response of two kinds of associated concomitant radio-chemotherapy for advanced nasopharyngeal carcinoma [in Chinese]. Chin J Cancer Prev Treat 2008;15:1888–9. [Google Scholar]
- [15].Fountzilas G, Ciuleanu E, Bobos M, et al. Induction chemotherapy followed by concomitant radiotherapy and weekly cisplatin versus the same concomitant chemoradiotherapy in patients with nasopharyngeal carcinoma: a randomized phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluation. Ann Oncol 2012;23:427–35. [DOI] [PubMed] [Google Scholar]
- [16].Geara FB, Glisson BS, Sanguineti G, et al. Induction chemotherapy followed by radiotherapy versus radiotherapy alone in patients with advanced nasopharyngeal carcinoma: results of a matched cohort study. Cancer 1997;79:1279–86. [DOI] [PubMed] [Google Scholar]
- [17].Han S, Yu L, Zhang Z, et al. Evaluation of induction chemotherapy with vinorelbine plus cisplatin (NP) or docetaxel plus cisplatin (TP) combined with concurrent chemoradiotherapy for patients with locally advanced nasopharyngeal carcinoma [in Chinese]. Zhonghua Zhong Liu Za Zhi 2013;35:623–6. [PubMed] [Google Scholar]
- [18].Hareyama M, Sakata K, Shirato H, et al. A prospective, randomized trial comparing neoadjuvant chemotherapy with radiotherapy alone in patients with advanced nasopharyngeal carcinoma. Cancer 2002;94:2217–23. [DOI] [PubMed] [Google Scholar]
- [19].Hu FJ, Zhang HW, Xu BY. A prospective randomized study of neoadjuvant chemotherapy and radiotherapy in advanced nasopharyngeal carcinoma. Prac J Cancer 2002;17:304–6. [Google Scholar]
- [20].Huang S, Deng G, Huang G, et al. Efficacy of induction chemotherapy combined with concurrent chemoradiotherapy for advanced nasopharyngeal carcinoma [in Chinese]. Chin J Clin Oncol 2012;39:788–91. [Google Scholar]
- [21].Hui EP, Ma BB, Leung SF, et al. Randomized phase II trial of concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol 2009;27:242–9. [DOI] [PubMed] [Google Scholar]
- [22].l Z, y HUS, h B, et al. Induction chemotherapy combined with radiotherapy for advanced nasopharyngeal carcinoma. Acta Acad Med Militaris Tertiae 2004;24:006. [Google Scholar]
- [23].Li P, Liu C, Zhang H, et al. A clinical trial of neoadjuvant chemotherapy plus late-course hyperfractionated accelerated radiation therapy for nasopharyngeal carcinoma. J West China Univ Med Sci 2002;33:632–5. [Google Scholar]
- [24].Ling HH, Chen HW, Lin W. Effect of neoadjuvant chemotherapy combined with concurrent radiotherapy and chemotherapy for advanced nasopharyngeal carcinoma in early-to-middle adulthood. Chin J Cancer Prev Treat 2008;15:921–3. [Google Scholar]
- [25].Liu H, Peng KG, Shen XM, et al. Induction chemotherapy plus radiotherapy for advanced nasopharyngeal carcinoma. J Bengbu Med Coll 2002;27:316–8. [Google Scholar]
- [26].Long B, Tan B, Zhou X, et al. Effect of chemoradiotherapy on local advanced nasopharyngeal carcinoma [in Chinese]. Chin J Clin Oncol 2012;39:1556–8. [Google Scholar]
- [27].Ma J, Mai HQ, Hong MH, et al. Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 2001;19:1350–7. [DOI] [PubMed] [Google Scholar]
- [28].Pan J, Lin S, Wu J, et al. Long-term results of a prospective randomized study on nasopharyngeal carcinoma by radiotherapy combined with induction or concurrent chemotherapy. Chin J Rad Oncol 2000;9:221–4. [Google Scholar]
- [29].Gao JQ, Gao TS, Dong ZR. A prospective and randomized study of induction chemotherapy combined with concurrent chemoradiotherapy in the treatment for nasopharyngeal carcinoma stage T_(3∼4)N_ (2∼3)M_0. J Chin Oncol 2013;19:161–5. [Google Scholar]
- [30].Ruste SA, Dizon DS, Ramirez F, et al. Induction chemotherapy followed by concurrent chemoradiotherapy vs concurrent chemoradiotherapy followed by chemotherapy in the treatment of patients with advanced nasopharyngeal carcinoma. Phillippine J Int Med 2011;49:1–7. [Google Scholar]
- [31].Tan T, Lim WT, Fong KW, et al. Concurrent chemo-radiation with or without induction gemcitabine, carboplatin, and paclitaxel: a randomized, phase 2/3 trial in locally advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2015;91:952–60. [DOI] [PubMed] [Google Scholar]
- [32].Wu H, Yu ZH, Yang ZX, et al. Outcomes of induction chemotherapy plus radiotherapy in the treatment of advanced nasopharyngeal carcinoma. Guangdong Med J 2002;23:343–4. [Google Scholar]
- [33].Xie FY, Qi SN, Hu WH, et al. Comparison of efficacy of docetaxel combined cisplatin (TP regimen) and cisplatin combined 5-fluorouracil (PF regimen) on locally advanced nasopharyngeal carcinoma [in Chinese]. Ai Zheng 2007;26:880–4. [PubMed] [Google Scholar]
- [34].Xu T, Zhu G, He X, et al. A phase III randomized study comparing neoadjuvant chemotherapy with concurrent chemotherapy combined with radiotherapy for locoregionally advanced nasopharyngeal carcinoma: updated long-term survival outcomes. Oral Oncol 2014;50:71–6. [DOI] [PubMed] [Google Scholar]
- [35].Yang Q, Jin C, Zhang W. Induction chemotherapy and radiotherapy in the treatment of patients with IV (N3M0) stage nasopharyngeal carcinoma. J Preclin Med Coll Shandong Med Univ 2002;16:147–8. [Google Scholar]
- [36].Yau TK, Lee AW, Wong DH, et al. Treatment of Stage IV (A-B) nasopharyngeal carcinoma by induction-concurrent chemoradiotherapy and accelerated fractionation: impact of chemotherapy schemes. Int J Radiat Oncol Biol Phys 2006;66:1004–10. [DOI] [PubMed] [Google Scholar]
- [37].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):vii83–5. [DOI] [PubMed] [Google Scholar]