The efficacy and safety of induction chemotherapy combined with concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in nasopharyngeal carcinoma patients: a systematic review and meta-analysis

Background Induction chemotherapy (IC) combined with concurrent chemoradiotherapy (CCRT) has been recommended as the first-line therapy for locoregional nasopharyngeal carcinoma (NPC). Due to the different chemotherapeutic drugs used in the IC and CCRT, the results remain controversial. Methods PubMed, EMBASE, Web of Science, and Cochrane Library databases were systematically retrieved to search potentially eligible clinical trials up to Sep 11, 2019. Eligible studies were registered and prospective randomized controlled clinical trials. Results From 526 records, nine articles including seven randomized controlled clinical trials were eligible, with a total of 2311 locoregional advanced NPC patients. IC + CCRT had significantly lower risks of death (3-year hazard ratio [HR]: 0.70, 95% confidence interval [CI] 0.55–0.89, p = 0.003; 5-year HR: 0.77, 95% CI 0.62–0.94, p = 0.01), disease progression (3-year HR: 0.67, 95% CI 0.55–0.80, p < 0.001; 5-year HR: 0.70, 95% CI 0.58–0.83, p < 0.0001), distant metastasis (3-year HR: 0.58, 95% CI 0.45–0.74, p < 0.0001; 5-year HR: 0.69, 95% CI 0.55–0.87, p = 0.001) and locoregional relapse (3-year HR: 0.69, 95% CI 0.50–0.95, p = 0.02; 5-year HR: 0.66, 95% CI 0.51–0.86, p = 0.002) than CCRT. Compared with CCRT, IC + CCRT showed higher relative risks of grade 3 or more neutropenia, thrombocytopenia, nausea, vomiting and hepatotoxicity throughout the course of treatment, and higher relative risks of grade ≥ 3 thrombocytopenia and vomiting during CCRT. Conclusion IC combined with CCRT significantly improved the survival in locoregional advanced NPC patients. Moreover, toxicities were well tolerated during IC and CCRT. Further clinical trials are warranted to confirm the optimal induction chemotherapeutic regimen in the future.

1. IC combined with CCRT significantly improved the survival outcomes of patients with locoregional advanced NPC. 2. IC combined with CCRT showed higher relative risks of grade 3 or more neutropenia, thrombocytopenia, nausea, vomiting and hepatotoxicity throughout the course of treatment, and higher relative risks of grade 3 or more thrombocytopenia and vomiting during CCRT.

Background
Nasopharyngeal carcinoma (NPC) is one of head and neck tumors with an unbalanced endemic distribution and a high prevalence in Southeast Asia, Southeast China, and North Africa [1]. More than two decades ago, locoregionally advanced NPC had an unfavorable prognosis. Since the administration of concurrent chemoradiotherapy (CCRT), the survival outcomes have been significantly improved [2,3]. However, there are still over 20% of patients with locoregionally advanced NPC living for less than 5 years [3]. In the European Society for Medical Oncology (ESMO) clinical practice guideline, CCRT is suggested to treat locoregionally advanced NPC (category 1A), while induction chemotherapy (IC) combined with CCRT is recommended to stage IV NPC patients (category 2B) [4]. Nevertheless, this guideline has not been updated since 2012.
In the National Comprehensive Cancer Network (NCCN) clinical practice guideline for patients with locoregionally advanced NPC, the preferred recommendation is participating in clinical trials, while the category 2A and 2B recommendations are, respectively, IC followed by CCRT and CCRT alone [5].
In the past decade, considerable studies on IC for NPC have been carried out. Among these clinical trials, different chemotherapeutic drugs and different doses or cycles of the IC were administered. However, owing to multiple clinical trials showing different results, adding IC to CCRT remains controversial.
Accordingly, in this systematic review and metaanalysis, we compared the IC plus CCRT with CCRT alone in NPC patients to analyze the 3-year/5-year survival outcomes and grade ≥ 3 toxicities in the registered and prospective clinical studies.

Methods
This analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Metaanalyses guideline (PRISMA) [6].

Search strategy
A systematic literature search was performed in PubMed, EMBASE, Web of Science, and Cochrane Library databases to identify all relevant records up to Sep 11, 2019. Search terms included: "induction chemotherapy", "concurrent chemoradiotherapy", "nasopharyngeal carcinoma", and "randomized controlled trial or randomized clinical trial or clinical trial or trial". The references of relevant articles were manually searched for more clinical studies. The search records were uploaded into EndNote software (http://endnote.com/) for further review.

Selection criteria
All of the eligible clinical trials should meet the following inclusion criteria: (1) prospective studies in previously untreated patients with NPC, (2) all eligible studies were registered clinical trials and provided the registered numbers, (3) only randomized controlled clinical studies were eligible, (4) in randomized controlled studies, the experiment group was treated with IC combined with CCRT, and the control group was treated with CCRT alone, (5) neoadjuvant chemotherapy described in the articles was deemed as induction chemotherapy, (6) IC or CCRT combined with target therapy was excluded, (7) because of the absence of complete efficacy and safety data, conference abstracts were excluded, (8) studies were published in English. Any disagreements were resolved by discussion.

Data extraction and quality assessment
The primary outcome was overall survival (OS), failurefree survival (FFS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRFS), and the second outcome was toxicity. FFS was defined as the date of randomization to documented disease progression (the date of locoregional/distant failure or death from any cause, whichever occurred first). Two authors (BW and BX) independently extracted information from the full texts and supplementary materials. Any discrepancies were resolved by consensus. The following details were extracted from each eligible clinical trial: first author, publication year, inclusion period, registered number, study design, number of patients, mean age, median follow-up, therapeutic regimens, OS, FFS, DMFS, LRFS, survival rate, and adverse events. The Jadad scoring scale was used to evaluate the methodological quality of each eligible trial by two authors (BW and BX) [7].

Statistical analysis
Survival outcomes (OS, FFS, DMFS and LRFS) from randomized controlled studies were assessed by hazard ratio (HR) with 95% confidence interval (CI) using Cochrane Collaboration's Information Management System (RevMan) software (version 5.3). Toxicities were calculated as risk ratios (RRs) and 95% CIs. The chi-squared (χ 2 ) tests and I 2 statistic percentages were used to test and quantify the heterogeneity. A fixed-effects model (Mantel-Haenszel method) was adopted in the calculations if I 2 ≤ 50%, otherwise, a random-effect model was applied. When p < 0.05, the differences were considered statistically significant.

Grade ≥ 3 toxicities
For grade 3 or more adverse events during the IC and CCRT, two randomized controlled trails compared the IC plus CCRT group against the CCRT group [10, 11,  Fig. 6e-i).

Publication bias
Using the Jadad scoring scale, all enrolled trials were identified as high quality (a score of ≥3).

Discussion
In this meta-analysis, all survival data were significantly better in NPC patients treated with IC combined with CCRT than that in patients treated with CCRT alone.
We conducted this meta-analysis to estimate the efficacy and safety of IC combined with CCRT in NPC patients. There were several early meta-analyses indicating the benefits of IC in treating patients with locoregionally advanced NPC. However, most of the studies were published before 2018 (Table 3) [17][18][19][20][21]. Song synthesized only four randomized clinical studies and demonstrated that IC followed CCRT performed significant treatment effects in DMFS and progression-free survival (PFS) rather than OS and LRFS [18]. In a network meta-analysis conducted by Chen, the results showed that IC plus CCRT had a higher risk of locoregional recurrence than CCRT and found no significant improvement in OS [17]. Tan analyzed six randomized controlled studies and five observation studies and displayed significant improvement in OS and PFS without the analyses of DMFS and LRFS [21]. Moreover, the inclusion of retrospective studies might increase the bias of the analysis. Although Ouyang's pairwise meta-analysis confirmed the benefit in OS, PFS, DMFS and LRFS in NPC, patients in four of 10 included studies were treated with radiotherapy alone without concurrent chemotherapy [19]. Thus, we considered that the previous meta-analysis might not fully demonstrate the efficacy of IC + CCRT in the treatment of NPC compared with CCRT. In order to minimize the bias, we selected prospective and clinical registered randomized controlled clinical trials as the eligible studies.
Over 70% of newly diagnosed NPC patients were classified as locoregionally advanced diseases [22]. Although IMRT combined with concurrent chemotherapy improved the locoregional control, long-term survival outcomes were poor. Distant recurrence might be a major reason for the treatment failure in long-term survived patients [23][24][25]. The efficacy of IC in the IC + CCRT group was due to the lower incidence of distant metastatic recurrence than that in the CCRT group. In Li's study, patients from the IC plus CCRT group showed significantly better 5-year DMFS 88% versus 79.8%; p = 0.030) [11], while the corresponding figures reported by Yang et al. were 82.8% versus 73.1%, p = 0.014 [13].
However, another phase II clinical study showed that IC of cisplatin combined with paclitaxel and epirubicin followed with CCRT did not significantly improve OS and PFS compared with CCRT alone in NPC [8].  Moreover, a randomized phase II-III study reported induction gemcitabine, carboplatin, and paclitaxel combined with CCRT had no significant differences in OS, disease-free survival (DFS) and DMFS compared with CCRT alone in patients with locoregionally advanced NPC [9]. A previously prospective clinical study proved that gemcitabine combined with cisplatin might be better than fluorouracil plus cisplatin in the first-line treatment of recurrence/metastatic NPC [40]. A retrospective study showed no significant difference in survival outcomes between induction cisplatin plus gemcitabine and cisplatin in combination with fluorouracil and docetaxel for the treatment of locoregionally advanced NPC [41]. Several ongoing clinical studies might be leading to evaluate the benefit and risk of different induction chemotherapeutic regimens in patients with locoregionally advanced NPC. For instance, NCT03604965, NCT035 03136, and NCT02512315. The verification of the value of these treatment strategies is awaited.
Grade ≥ 3 adverse events were more frequent in the IC + CCRT group. During IC + CCRT, the most prominent grade ≥ 3 adverse events were neutropenia, thrombocytopenia, nausea, vomiting and hepatotoxicity. During CCRT, the most prominent grade 3 or more adverse events were thrombocytopenia, anemia and vomiting. However, these toxicities were uncomplicated, tolerated and manageable. We observed that there were no significant differences in radiotherapy related toxicities, comprising stomatitis (mucositis) and dermatitis, between the two groups. For late toxicities, Li et al. reported that the incidence of grade ≥ 3 late adverse events was 8.8% in the IC followed by CCRT group and 9.2% in the CCRT group [11]. Yang's study also showed similar rates of late toxicities between IC + CCRT and CCRT alone group and auditory toxicities were the most common late adverse events [13].
There are several limitations in this analysis. First, different regimens and cycles of IC and CCRT might influence the survival outcomes. Second, two/threedimensional conformal radiotherapy (2D/3D-CRT) and intensity modulated radiotherapy (IMRT) were included in the studies. Although the advent of IMRT had been demonstrated to promote a higher local tumor control rate [23], several studies had shown no significant advantage between 2D-CRT and IMRT in DMFS [24]. Third, late adverse events data were limited for further analyses. Fourth, as the EBV is an important prognostic factor, in this meta-analysis, there is no important biomarker data to suggest that which group of patients based on EBV DNA level has benefited from IC plus CCRT as compared to CCRT alone. Li′s trial is the only study in this meta-analysis that performed post-hoc subgroup analysis and demonstrated that patients with EBV ≥ 6000 copies/ml had FFS benefit when received IC followed by CCRT as compared to CCRT [11].

Conclusion
This systematic review and meta-analysis demonstrated that, compared with CCRT alone in patients with locoregionally advanced NPC, the addition of IC to CCRT achieved favorable survival rates, and could significantly improve survival outcomes, including OS, FFS, DMFS and LRFS. As the majority of eligible studies have taken place in endemic areas, the results might not be entirely applicable to patients in non-endemic regions (e.g. EBVpatients). Additionally, it should be further explored the best selection of patient subgroups who will get the most benefit from IC plus CCRT as well as the selection of the most effective regimens for induction chemotherapy.