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. 2022 Mar 18;17(3):e0265551. doi: 10.1371/journal.pone.0265551

A Bayesian network meta-analysis of the primary definitive therapies for locoregionally advanced nasopharyngeal carcinoma: IC+CCRT, CCRT+AC, and CCRT alone

Zhan-Jie Zhang 1, Liang-Liang Shi 1, Xiao-Hua Hong 1, Bo-Ya Xiao 2, Guo-He Lin 3, Quentin Liu 4, Bi-Cheng Wang 1,*
Editor: Sethu Thakachy Subha5
PMCID: PMC8932567  PMID: 35303014

Abstract

Background

The major aim of this Bayesian network analysis was to determine the optimal treatment strategy for locoregionally advanced nasopharyngeal carcinoma (LANPC).

Method

We systematically searched databases and extracted data from randomized clinical trials involving LANPC patients randomly assigned to receive induction chemotherapy followed by concurrent chemoradiotherapy (IC+CCRT), CCRT followed by adjuvant chemotherapy (CCRT+AC), or CCRT.

Results

In the network analysis, IC+CCRT was significantly better than CCRT alone for 5-year FFS (odds ratio [OR]: 1.63, 95% credible interval [CrI] 1.16–2.29), DMFS (OR: 1.56, 95% CrI 1.08–2.22), and LFRS (OR: 1.62, 95% CrI 1.02–2.59), but not OS (OR: 1.35, 95% CrI 0.92–2.00). Rank probabilities showed that IC+CCRT was ranked the best followed by CCRT+AC and CCRT for all 5-year outcomes. Although compared to IC+CCRT and CCRT, CCRT+AC did not significantly improve survival but had the highest 5-year survival rates.

Conclusions

IC+CCRT could be recommended as a front-preferred primary definitive therapy for patients with LANPC.

Introduction

Previous phase III clinical trials have confirmed that concurrent chemoradiotherapy (CCRT) is superior to radiotherapy (RT) for patients with locoregionally advanced NPC (LANPC) [1–3]. Therefore, in the 2011 and 2012 National Comprehensive Cancer Network (NCCN) guidelines, CCRT was suggested as a category 1 recommendation [4,5].

Since 2013, the category of evidence supporting CCRT for LANPC has been cut to 2B [6]. At the same time, CCRT followed by adjuvant chemotherapy (CCRT+AC) was given a 2A recommendation [6]. However, the cited studies do not fully support the use of CCRT+AC over CCRT, as the two trials demonstrated the superiority of CCRT+AC compared to RT but not CCRT [1,7]. Additionally, another two prospective clinical trials failed to show that the addition of AC to CCRT improved survival outcomes [8–10].

From 2015, more prospective and large randomized studies have illustrated the benefit of induction chemotherapy followed by CCRT (IC+CCRT) versus CCRT alone in the treatment of LANPC [11]. However, until 2018, the level of evidence for IC+CCRT in the NCCN guideline was adjusted from category 3 to category 2A [12]. Our recently published study also demonstrated that, compared with CCRT, IC+CCRT significantly reduced the risks of death in patients with LANPC (3-year OS hazard ratio [HR]: 0.70, 95% confidence interval [CI] 0.55–0.89; 5-year OS HR: 0.77, 95% CI 0.62–0.94) [13]. To date, when LANPC patients receive IC, gemcitabine/cisplatin or docetaxel/cisplatin/5-fluorouracil could be recommended as category 1 regimens [14,15].

According to the 2020 NCCN guideline, IC+CCRT, CCRT+AC, and CCRT alone are all the primary definitive therapies for LANPC. Nevertheless, the cited studies recommending the application of CCRT+AC have not been updated. Since the absence of a randomized trial directly comparing IC+CCRT to CCRT+AC and to explore the optimal therapeutic strategy for LANPC, we conducted this Bayesian network analysis to comprehensively compare the efficacies of IC+CCRT, CCRT+AC, and CCRT.

Methods

This study was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) extension statement for network meta-analysis [16].

Search strategy

A systematic search of articles was conducted on PubMed, EMBASE, Web of Science, and Cochrane Library for clinical trials comparing at least any two of the three types of treatments on Nov 1, 2020. All the identified trials and relevant reviews were identified through reference lists to ensure completeness. The search terms in PubMed, EMBASE, and Web of Science online databases were “induction OR neoadjuvant OR adjuvant” and “concurrent OR concomitant” and “cisplatin” and “chemotherapy OR chemoradiotherapy OR radiotherapy” and “nasopharyngeal” and “carcinoma OR cancer OR tumor” and “study OR trial”, while the search terms used in searching Cochrane Library included: “induction OR neoadjuvant OR adjuvant” and “concurrent OR concomitant” and “cisplatin” and “chemotherapy OR chemoradiotherapy OR radiotherapy” and “nasopharyngeal carcinoma OR nasopharyngeal cancer OR nasopharyngeal tumor”.

Selection criteria

Eligible trials were requested to satisfy the following “PICO” inclusion criteria: (P) patients were newly diagnosed with LANPC; (I+C) LANPC patients randomly received at least two of the three treatment strategies, including IC+CCRT, CCRT+AC, and CCRT; (O) full-text articles and data of survival rates were available. Additional criteria comprised: (1) CCRT was cisplatin-based conventional concomitant chemoradiotherapy; (2) trials should be officially registered prospective phase II-IV clinical studies; (3) target therapy was prohibited during the whole care process; (4) published language was English. Any discrepancies were resolved by discussion.

Outcomes

The primary endpoints were the rates of 5-year overall survival (OS) and failure-free survival (FFS). The secondary endpoints were 5-year rates of distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LRFS).

Data extraction and risk of bias assessment

Bi-Cheng Wang and Zhan-Jie Zhang independently extracted the survival rates of all outcomes and the data of basic study characteristics and treatment modalities. All raw data were directly collected from the eligible clinical trials without further modification or adjustment. Review Manager 5.3 software (Cochrane Collaboration’s Information Management System) was used to assess the risk of bias.

Data synthesis and statistical analysis

Bayesian network meta-analyses were built using the Bayesian Markov Chain Monte-Carlo (MCMC) sampling in WinBUGS or GeMTC. The random-effects model was proposed. The effect size was estimated with odds ratios (ORs) and 95% credible intervals (CrIs) using the available raw data extracted from the trials. ORs were computed on averages of the 100,000 iterations (four chains with a thinning interval of 10) after a training phase of 50,000 burn-ins. Node-splitting approach was performed to evaluate if there was inconsistency in the closed-loop. Pairwise meta-analyses were applied to evaluate incoherence between direct and indirect evidence. The probability of each treatment being the best among the three therapies was estimated by using the distribution of the ranking probabilities.

Pooled OS, FFS, DMFS, and LRFS rates and 95% CIs were analyzed by using STATA 14.0 software. The heterogeneity between rates was tested by I2 statistic percentages. Whether the heterogeneity was high (I2 > 50%) or low (I2 ≤ 50%), random effects were performed to reduce the bias.

Results

Basic information on eligible clinical trials

Through a literature search, 1664 records were identified, of which 802 were duplicated records and 838 were excluded based on screening titles and abstracts (Fig 1). After a full-text article assessment of 121 remaining studies, 12 studies within 9 randomized clinical trials were included in this Bayesian network analysis [9–11,17–25].

Fig 1. Flowchart of literature search and selection.

Fig 1

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The basic characteristics of all eligible trials were listed in Table 1. A total of 3140 randomly assigned LANPC patients were involved: 1321 received IC+CCRT, 411 received CCRT+AC, and 1408 received CCRT. 2/3-dimensional radiotherapy (2/3DRT) and intensity-modulated radiotherapy (IMRT) had been applied in these trials. The regimens of induction chemotherapy comprised cisplatin+epirubicin+paclitaxel, gemcitabine+carboplatin+paclitaxel, docetaxel+cisplatin+5-fluorouracil, mitomycin C+epirubicin+cisplatin+5-fluorouracil, gemcitabine+cisplatin, and cisplatin+5-fluorouracil. The adjuvant chemotherapy in both selected trials was cisplatin+5-fluorouracil. In NPC-0501 trial, we extracted data of two arms (patients received cisplatin plus 5-fluorouracil IC or AC) in order to reduce the risk of bias [25]. In addition, the concurrent chemotherapies included weekly and triweekly cisplatin strategies.

Table 1. Summary of the eligible trials in Bayesian network analysis.

Study Registered number No. of patients Stage Radiotherapy Induction chemotherapy Concurrent Chemotherapy Adjuvant chemotherapy
IC+CCRT vs CCRT
Fountzilas 2011 ACTRN12609000730202 141 AJCC 6th/IIb–IVb 2DRT/3DRT cisplatin, epirubicin and paclitaxel cisplatin 40 mg/m2, qw /
Tan 2015 CDR0000657121 172 UICC 1997/III-IVb 2DRT/IMRT gemcitabine, carboplatin and paclitaxel cisplatin 40 mg/m2, qw /
Frikha 2017 NCT00828386 83 -/T2b, T3, T4 and/or N1-N3, M0 IMRT/non-IMRT docetaxel, cisplatin and 5-fluorouracil cisplatin 40 mg/m2, qw /
Hong 2018 NCT00201396 479 AJCC 5th or UICC 1997/IVa–IVb 3DRT/IMRT mitomycin C, epirubicin, cisplatin and 5-fluorouracil cisplatin 30 mg/m2, qw /
Zhang 2019 NCT01872962 480 AJCC 7th/III–IVb IMRT gemcitabine and cisplatin cisplatin 100 mg/m2, q3w /
Sun 2016/Li 2019 NCT01245959 480 AJCC 7th or UICC 7th/III-IVb, except T3-4N0 IMRT docetaxel, cisplatin and 5-fluorouracil cisplatin 100 mg/m2, q3w /
Cao 2017/Yang 2019 NCT00705627 476 AJCC 6th or UICC 6th/III-IVb, except T3N0-1 2DRT/IMRT cisplatin and 5-fluorouracil cisplatin 80 mg/m2, q3w /
CCRT vs CCRT+AC
Chen 2012/Chen 2017 NCT00677118 508 AJCC 6th/III-IVb, except T3-4N0 2DRT/3DRT/IMRT / cisplatin 40 mg/m2, qw cisplatin and 5-fluorouracil
IC+CCRT vs CCRT+AC
Lee 2014 NCT00379262 321 AJCC 6th/III-IVb 2DRT/3DRT/IMRT cisplatin and 5-fluorouracil cisplatin 100 mg/m2, q3w cisplatin and 5-fluorouracil
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Abbreviation: IC, induction chemotherapy; CCRT, concurrent chemotherapy; AC, adjuvant chemotherapy; 2DRT, 2-dimensional radiotherapy; 3DRT, 3-dimensional radiotherapy; IMRT, intensity-modulated radiotherapy; AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control.

Although all eligible trials were well-randomized studies, the methodological quality of this analysis was at moderate risk for reporting bias owing to the open-label design (S2 Fig).

Bayesian network analyses of efficacy

We established a network to compare IC+CCRT, CCRT+AC, and CCRT (S1 Fig). Fig 2 summarizes the Bayesian analyses results for 5-year rates data of OS, FFS, DMFS, and LRFS. According to the results, IC+CCRT was statistically superior to CCRT in terms of 5-year FFS (OR 1.63, 95% CrI: 1.16–2.29), DMFS (OR 1.56, 95% CrI: 1.08–2.22), and LRFS (OR 1.62, 95% CrI: 1.02–2.59) but not statistically superior for OS (OR 1.35, 95% CrI: 0.92–2.00). CCRT+AC showed no significant difference in assessed outcomes compared with IC+CCRT and CCRT alone, and there were no significant differences for all survival outcomes.

Fig 2.

Fig 2

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Bayesian network analysis results for 5-year overall survival (A up), failure-free survival (A below), distant metastasis-free survival (B up), and locoregional recurrence-free survival (B below). Treatments in the rows were compared with those in the columns. Highlighting numbers, odds ratios (ORs) with significant differences. IC+CCRT, induction chemotherapy followed by concurrent chemoradiotherapy; CCRT+AC, concurrent chemoradiotherapy followed by adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy.

Ranking on 5-year survival indicated that IC+CCRT had the highest probabilities (OS: 62%; FFS: 82%; DMFS: 62%; LFRS: 80%) to be the preferred options, followed by CCRT+AC, and CCRT alone (Fig 3). For prolonging 5-year outcomes, CCRT had the lowest probability of being the preferred option.

Fig 3. Rank probabilities of each treatment based on the random-effects model.

Fig 3

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(A) 5-year overall survival; (B) 5-year failure-free survival; (C) 5-year distant metastasis-free survival; (D) 5-year locoregional recurrence-free survival.

Pooled analyses of survival rates

Fig 4 presented the pooled survival rates in the eligible trials. Among the three treatment strategies, the most efficient therapy for OS was CCRT+AC, followed by IC+CCRT and CCRT. According to this order, the pooled rates of 5-year OS were 83% (95% CI 78%-88%), 80% (95% CI 72%-87%), and 76% (95% CI 71%-81%) (Fig 4A). Pooled 5-year FFS rate was 75% (95% CI 70%-80%) in CCRT+AC versus 71% (95% CI 61%-80%) in IC+CCRT versus 63% (95% CI 54%-71%) in CCRT (Fig 4B).

Fig 4. Pooled results of single-arm data for each therapeutic strategy.

Fig 4

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(A) 5-year overall survival; (B) 5-year failure-free survival; (C) 5-year distant metastasis-free survival; (D) 5-year locoregional recurrence-free survival. A dotted line indicated the survival rate analyzed from all the data included in that figure.

The pooled analyzed results of secondary endpoints showed that CCRT+AC (5-year DMFS 85%, 95% CI 80%-89%; 5-year LRFS 91%, 95% CI 87%-94%) had the highest distant metastasis and locoregional recurrence controlled rates compared to IC+CCRT (5-year DMFS 83%, 95% CI 78%-88%; 5-year LRFS 86%, 95% CI 80%-92%) and CCRT alone (5-year DMFS 77%, 95% CI 73%-81%; 5-year LRFS 82%, 95% CI 75%-90%) (Fig 4C and 4D).

Discussion

Our study fully collected the prospective registered and randomized clinical trials and comprehensively analyzed the efficacies of IC+CCRT, CCRT+AC, and CCRT on LANPC. Based on our Bayesian network analysis, IC+CCRT ranked the best for all 5-year survival outcomes. In addition, CCRT+AC showed the highest response rates in the pooled analyses.

IC+CCRT vs CCRT

Multiple phase III clinical trials have confirmed the critical role of IC+CCRT in treating patients with LANPC. Compared with CCRT alone, IC+CCRT had better HRs in terms of OS, FFS, DMFS, and LRFS [13].

In Zhang’s study [21] published in 2019, gemcitabine plus cisplatin as IC combined with CCRT increased the 3-year OS rate to 94.6% versus 90.3% in CCRT group. IC could be well tolerated as 96.7% of the patients in IC+CCRT group completed three cycles of IC. In the newest NCCN guideline [15], gemcitabine and cisplatin regimen was recommended as a category 1 treatment for LANPC patients given IC+CCRT. In addition to this regimen, taxane (including docetaxel, paclitaxel, and nab-paclitaxel) plus cisplatin strategy is used in our hospital. A propensity-score matching analysis indicated that there were no significant differences in clinical outcomes and safety profiles between docetaxel plus cisplatin and gemcitabine plus cisplatin [26]. Therefore, we suggest taxane or gemcitabine plus cisplatin as a front IC option for LANPC patients.

In addition, Lv et al. conducted a randomized phase 3 clinical trial and compared lobaplatin plus 5-fluorouracil with cisplatin plus 5-fluorouracil in LANPC patients. According to the report, no significant differences were observed between cisplatin-based IC and lobaplatin-based IC in terms of OS (hazard ratio [HR] 0.90, 95% CI 0.55–1.45; p = 0.65) and progression-free survival (HR 0.98, 95% CI 0.69–1.39; p = 0.92) [27]. Thus, lobaplatin-based strategies might be another promising induction chemotherapies for patients with LANPC.

CCRT+AC vs CCRT

CCRT+AC failed to show the superiority compared to IC+CCRT or CCRT alone in the Bayesian analysis. However, the survival rates in patients received CCRT+AC were numerically highest. Since most data of CCRT+AC were contributed by Chen’s studies [9,10], that is the reason why CCRT+AC did not have higher ORs than the other two therapies. Although there were no significant differences between the groups in Chen’s clinical trial, the survival rates in CCRT+AC group were numerically higher than those in CCRT group. Kim and colleagues retrospectively detected the benefit of addition AC to CCRT and found that CCRT+AC showed higher 3-year OS (86% vs 80%, p = 0.894) and FFS (75% vs 66%, p = 0.018) rates against CCRT [28]. However, another retrospective study determined that patients with LANPC might not receive significant survival benefits from adding AC to CCRT (OS HR 0.77, 95% CI 0.37–1.57; FFS HR 1.26, 95% CI 0.69–2.28) [29]. Combined with our Bayesian network analysis, to date, there is still a lack of evidence to confirm the superiority of CCRT+AC compared to CCRT.

In 2021, Hui et al. detected the prediction function of plasma Epstein barr virus (EBV) deoxyribonucleic acid (DNA) and found that the patients with detectable post-radiotherapy plasma EBV DNA who experienced subsequent plasma EBV DNA clearance might be the potential target population of AC [30]. In further explorations, the ongoing phase II and III study, NRG-HN001, attempt to risk-stratify AC using post-radiotherapy plasma biomarker EBV DNA levels. The future results of NRG-HN001 might help us determine the suitable population and whether omitting AC will result in non-inferior survivals compared to patients treated with CCRT+AC.

IC+CCRT vs CCRT+AC

Large-scale phase III clinical trials that directly compare IC+CCRT with CCRT+AC are limited. NPC-0501 was the only prospective randomized study we identified [25]. Compared with cisplatin plus 5-fluorouracil AC arm (75%), cisplatin plus 5-fluorouracil IC arm had a similar 3-year FFS rate (79%), while cisplatin plus capecitabine arm showed a significantly higher 3-year FFS rate (81%). Therefore, different chemotherapeutic regimens might have impacts on responses. Moreover, NPC-0501 indicated that accelerated fractionation radiotherapy did not achieve more benefits but incurred higher toxicities against conventional fractionation radiotherapy. According to the retrospective results reported by Setakornnukul and colleagues, IC+CCRT was not superior to CCRT+AC (adjusted OS 3-year: 84% vs 81%; 5-year: 74% vs 70%) [31].

Based on the results of published studies and our analysis, IC+CCRT and CCRT+AC display comparable effects on LANPC patients. However, we would recommend IC+CCRT based on the improved probability of being the preferred regimen in all 5-year Bayesian models.

Limitations

(1) all enrolled clinical trials were open-label studies, which might increase the bias of evaluation; (2) only two trials provided the data for AC, leading to weak evidence for supporting the accurate efficacy of CCRT+AC on LANPC patients; (3) weekly and triweekly cisplatin regimens were conducted during CCRT, however, there is still a debate on the response rates of between the two treatment modalities (week NPC); (4) Analyses of individual patient data are lacking.

Conclusions

Among the three standard therapeutic strategies, IC+CCRT can be recommended as the preferred choice for previously untreated LANPC patients. Even if current studies suggest CCRT+AC is not inferior to IC+CCRT, evidence comparing CCRT+AC to the other two strategies remains limited.

Supporting information

S1 Checklist. PRISMA checklist.

(DOC)

Click here for additional data file. (64KB, doc)
S1 Fig. Network of the comparisons for the Bayesian network meta-analysis.

Network for 5-year overall survival (A), failure-free survival (B), distant metastasis-free survival (C), and locoregional recurrence-free survival (D). each circular node represents a type of treatment. The dot size is proportional to the total number of patients who received a regimen. Each line represents a head-to-head comparison and the line width is proportional to the number of clinical trials comparing the connected treatment strategies.

(DOCX)

Click here for additional data file. (111.4KB, docx)
S2 Fig. Risk of bias assessment in the analysis.

(DOCX)

Click here for additional data file. (249.2KB, docx)
S1 File

(DOCX)

Click here for additional data file. (14.6KB, docx)

Acknowledgments

We thank the members in the SNOWELL STUDIO for helping to improve the manuscript.

Data Availability

All included studies can be searched and downloaded from their official websites or PubMed. 1. Doi:10.1016/s1470-2045(11)70320-5. 2. Doi:10.1016/j.ejca.2017.01.002. 3. Doi:10.1016/s1470-2045(16)30410-7. 4. Doi:10.1093/annonc/mdr116. 5. Doi:10.1016/j.ijrobp.2015.01.002. 6. Doi:10.1093/annonc/mdx770. 7. Doi:10.1093/annonc/mdy249. 8. Doi:10.1056/NEJMoa1905287. 9. Doi:10.1002/ijc.32099. 10. Doi:10.1016/j.ejca.2016.12.039. 11. Doi:10.1016/j.ejca.2019.07.007. 12. Doi:10.1002/cncr.29208.

Funding Statement

This study was supported by the Hubei Provincial Natural Science Foundation (Grant number: 2020CFB397 to Bi-Cheng Wang) and the Independent Innovation Foundation of Wuhan Union Hospital (Grant number: 2019-109 to Bi-Cheng Wang). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Sethu Thakachy Subha

23 Feb 2022

PONE-D-21-23917

A Bayesian network analysis of the primary definitive therapies for locoregionally advanced nasopharyngeal carcinoma: IC+CCRT, CCRT+AC, and CCRT alone

PLOS ONE

Dear Dr. Wang,

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Reviewer #1: Yes

Reviewer #2: Yes

********** 

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********** 

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Reviewer #1: Dear PLOS ONE,

It's an honor to review an original manuscript collaborating with your system.

This manuscript was a hard work to provide a great contribution for practice changeable update and hope to apply updates in different guidelines as a better management in locoregional advanced head and neck cancer . A newly diagnosed unresectable locoregional advanced disease or unfit for surgery applied with concurrent systemic therapy followed by radiotherapy is preferred previously. This meta analysis describes and includes all evidence based different applied therapies with comparable selection criteria that established a clear outcome with recognized medical statistical methods. After this practice changeable updated work makes it easy to choose therapy and probably applicable to best care of these patients' kind. 

Thank you editorial board.

Kind regards;

Prem Raj Shrestha

+977984641180

Clinical Hematology and stem cell transplant unit, Department of Medicine

Civil service hospital

Minbhawan, New BaneswarKathmandu Nepal.

Reviewer #2: Zhang et al. present an extensive and rigorous study investigating the Bayesian network analysis involved in the primary definitive therapies for locoregionally advanced nasopharyngeal carcinoma. The question of induction chemotherapy versus adjuvant chemotherapy along with concurrent chemoradiotherapy is an important question to optimize the care of these patients with curable disease. While the experiments are well thought out and expertly executed, some areas of the manuscript require clarification before publication.

Title page

1. The fourth affiliation address “3 State Key Laboratory of Oncology in South China……” should be “4 State Key Laboratory of Oncology in South China……”.

Induction section

2. Paragraph 3: ‘However, it was not until 2018 that the level of evidence for IC+CCRT in the NCCN guideline was adjusted from category 3 to category 2A’ should be replaced by “However, until 2018, the level of evidence for IC+CCRT in the NCCN guideline was adjusted from category 3 to category 2A”.

3. Paragraph 4: “applying” should be replaced by “application”.

Methods section

4. Paragraph 3: “satisfied” should be replaced by “satisfy”.

5. Paragraph 4: “The primary endpoints were 5-year overall survival (OS) and failure-free survival (FFS) rates” could be replaced by “The primary endpoints were the rates of 5-year overall survival (OS) and failure-free survival (FFS)”.

Results section

6. Paragraph 2: “receive” should be replaced by “received”.

Discussion section

7. The study published by Lv et al. has compared lobaplatin plus 5-fluorouracil with cisplatin plus 5-fluorouracil in locoregionally advanced NPC patients. The authors could add the results to the “IC+CCRT vs CCRT” part. (Lancet Oncol. 2021 May;22(5):716-726.)

8. In terms of adjuvant chemotherapy, another study reported by Hui et al. has detected the function of plasma EBV DNA and explored the potential target population. The authors may consider discussing the detailed results in the “CCRT+AC vs CCRT” part. (Clin Cancer Res. 2021 May 15;27(10):2827-2836.)

********** 

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Reviewer #1: No

Reviewer #2: Yes: Yang Chen

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PLoS One. 2022 Mar 18;17(3):e0265551. doi: 10.1371/journal.pone.0265551.r002

Author response to Decision Letter 0

2 Mar 2022

Response to the reviewers’ comments

(PONE-D-21-23917)

To Reviewer #1

We truly appreciate the reviewer for considering that our manuscript provides a great contribution for the clinical practice in treating locoregionally advanced nasopharyngeal carcinoma patients.

To Reviewer #2

We truly appreciate the reviewer for finding our work “extensive and rigorous”. We thank the reviewer’s encouraging comments and very constructive recommendations. We thus addressed the points accordingly.

Title page

1. The fourth affiliation address “3 State Key Laboratory of Oncology in South China……” should be “4 State Key Laboratory of Oncology in South China……”.

Reply:

This is a very helpful comment. We are very sorry for the typing mistake. The number of the affiliation address has been corrected. The details are as followings:

Revised Title page (Page 1, line 13 in the revised manuscript):

1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

2 Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China

3 Department of Oncology, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China

4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China

Induction section

2. Paragraph 3: ‘However, it was not until 2018 that the level of evidence for IC+CCRT in the NCCN guideline was adjusted from category 3 to category 2A’ should be replaced by “However, until 2018, the level of evidence for IC+CCRT in the NCCN guideline was adjusted from category 3 to category 2A”.

Reply:

We thank the reviewer for the very constructive recommendation. The sentence has been adjusted according to the reviewer’s suggestion. The details are as followings:

Revised Introduction (Page 4, line 16-17 in the revised manuscript):

From 2015, more prospective and large randomized studies have illustrated the benefit of induction chemotherapy followed by CCRT (IC+CCRT) versus CCRT alone in the treatment of LANPC [11]. However, until 2018, the level of evidence for IC+CCRT in the NCCN guideline was adjusted from category 3 to category 2A [12]. Our recently published study also demonstrated that, compared with CCRT, IC+CCRT significantly reduced the risks of death in patients with LANPC (3-year OS hazard ratio [HR]: 0.70, 95% confidence interval [CI] 0.55-0.89; 5-year OS HR: 0.77, 95% CI 0.62–0.94) [13]. To date, when LANPC patients receive IC, gemcitabine/cisplatin or docetaxel/cisplatin/5-fluorouracil could be recommended as category 1 regimens [14, 15]

3. Paragraph 4: “applying” should be replaced by “application”.

Reply:

We thank the reviewer for this comment. We have replaced “applying” by “application” in the revised manuscript. The details are as followings:

Revised Introduction (Page 4, line 26 in the revised manuscript):

According to the 2020 NCCN guideline, IC+CCRT, CCRT+AC, and CCRT alone are all the primary definitive therapies for LANPC. Nevertheless, the cited studies recommending the application of CCRT+AC have not been updated. Since the absence of a randomized trial directly comparing IC+CCRT to CCRT+AC and to explore the optimal therapeutic strategy for LANPC, we conducted this Bayesian network analysis to comprehensively compare the efficacies of IC+CCRT, CCRT+AC, and CCRT.

Methods section

4. Paragraph 3: “satisfied” should be replaced by “satisfy”.

Reply:

This is a helpful comment. We have replaced “applying” by “application” in the revised manuscript. The details are as followings:

Revised Methods (Page 5, line 19 in the revised manuscript):

Selection criteria

Eligible trials were requested to satisfy the following “PICO” inclusion criteria: (P) patients were newly diagnosed with LANPC; (I+C) LANPC patients randomly received at least two of the three treatment strategies, including IC+CCRT, CCRT+AC, and CCRT; (O) full-text articles and data of survival rates were available. Additional criteria comprised: (1) CCRT was cisplatin-based conventional concomitant chemoradiotherapy; (2) trials should be officially registered prospective phase II-IV clinical studies; (3) target therapy was prohibited during the whole care process; (4) published language was English. Any discrepancies were resolved by discussion.

5. Paragraph 4: “The primary endpoints were 5-year overall survival (OS) and failure-free survival (FFS) rates” could be replaced by “The primary endpoints were the rates of 5-year overall survival (OS) and failure-free survival (FFS)”.

Reply:

We thank the reviewer for the recommendation. The sentence has been adjusted according to the reviewer’s suggestion. The details are as followings:

Revised Introduction (Page 5, line 28-29 in the revised manuscript):

Outcomes

The primary endpoints were the rates of 5-year overall survival (OS) and failure-free survival (FFS). The secondary endpoints were 5-year rates of distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LRFS).

Results section

6. Paragraph 2: “receive” should be replaced by “received”.

Reply:

Thank you for this helpful comment. We have replaced “receive” by “received” in the revised manuscript. The details are as followings:

Revised Results (Page 7, line 9 in the revised manuscript):

The basic characteristics of all eligible trials were listed in Table 1. A total of 3140 randomly assigned LANPC patients were involved: 1321 received IC+CCRT, 411 received CCRT+AC, and 1408 received CCRT. 2/3-dimensional radiotherapy (2/3DRT) and intensity-modulated radiotherapy (IMRT) had been applied in these trials. The regimens of induction chemotherapy comprised cisplatin+epirubicin+paclitaxel, gemcitabine+carboplatin+paclitaxel, docetaxel+cisplatin+5-fluorouracil, mitomycin C+epirubicin+cisplatin+5-fluorouracil, gemcitabine+cisplatin, and cisplatin+5-fluorouracil. The adjuvant chemotherapy in both selected trials was cisplatin+5-fluorouracil. In NPC-0501 trial, we extracted data of two arms (patients received cisplatin plus 5-fluorouracil IC or AC) in order to reduce the risk of bias [25]. In addition, the concurrent chemotherapies included weekly and triweekly cisplatin strategies.

Discussion section

7. The study published by Lv et al. has compared lobaplatin plus 5-fluorouracil with cisplatin plus 5-fluorouracil in locoregionally advanced NPC patients. The authors could add the results to the “IC+CCRT vs CCRT” part. (Lancet Oncol. 2021 May;22(5):716-726.)

Reply:

We thank the reviewer for this constructive suggestion. The results reported by Lv et al. has been discussed in the revised manuscript. The details are as followings:

Revised Discussion (Page 9, line 22-28 in the revised manuscript):

IC+CCRT vs CCRT

Multiple phase III clinical trials have confirmed the critical role of IC+CCRT in treating patients with LANPC. Compared with CCRT alone, IC+CCRT had better HRs in terms of OS, FFS, DMFS, and LRFS [13].

In Zhang’s study [21] published in 2019, gemcitabine plus cisplatin as IC combined with CCRT increased the 3-year OS rate to 94.6% versus 90.3% in CCRT group. IC could be well tolerated as 96.7% of the patients in IC+CCRT group completed three cycles of IC. In the newest NCCN guideline [15], gemcitabine and cisplatin regimen was recommended as a category 1 treatment for LANPC patients given IC+CCRT. In addition to this regimen, taxane (including docetaxel, paclitaxel, and nab-paclitaxel) plus cisplatin strategy is used in our hospital. A propensity-score matching analysis indicated that there were no significant differences in clinical outcomes and safety profiles between docetaxel plus cisplatin and gemcitabine plus cisplatin [26]. Therefore, we suggest taxane or gemcitabine plus cisplatin as a front IC option for LANPC patients.

In addition, Lv et al. conducted a randomized phase 3 clinical trial and compared lobaplatin plus 5-fluorouracil with cisplatin plus 5-fluorouracil in LANPC patients. According to the report, no significant differences were observed between cisplatin-based IC and lobaplatin-based IC in terms of OS (hazard ratio [HR] 0.90, 95% CI 0.55-1.45; p = 0.65) and progression-free survival (HR 0.98, 95% CI 0.69-1.39; p = 0.92) [27]. Thus, lobaplatin-based strategies might be another promising induction chemotherapies for patients with LANPC.

27. Lv X, Cao X, Xia WX, Liu KY, Qiang MY, Guo L, et al. Induction chemotherapy with lobaplatin and fluorouracil versus cisplatin and fluorouracil followed by chemoradiotherapy in patients with stage III-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(5):716-26. Epub 2021/04/16. doi: 10.1016/S1470-2045(21)00075-9. PubMed PMID: 33857411.

8. In terms of adjuvant chemotherapy, another study reported by Hui et al. has detected the function of plasma EBV DNA and explored the potential target population. The authors may consider discussing the detailed results in the “CCRT+AC vs CCRT” part. (Clin Cancer Res. 2021 May 15;27(10):2827-2836.)

Reply:

We are thankful for this comment. The results reported by Hui et al. has been added in the revised manuscript. The details are as followings:

Revised Discussion (Page 10, line 14-21 in the revised manuscript):

CCRT+AC vs CCRT

CCRT+AC failed to show the superiority compared to IC+CCRT or CCRT alone in the Bayesian analysis. However, the survival rates in patients received CCRT+AC were numerically highest. Since most data of CCRT+AC were contributed by Chen’s studies [9, 10], that is the reason why CCRT+AC did not have higher ORs than the other two therapies. Although there were no significant differences between the groups in Chen’s clinical trial, the survival rates in CCRT+AC group were numerically higher than those in CCRT group. Kim and colleagues retrospectively detected the benefit of addition AC to CCRT and found that CCRT+AC showed higher 3-year OS (86% vs 80%, p = 0.894) and FFS (75% vs 66%, p = 0.018) rates against CCRT [28]. However, another retrospective study determined that patients with LANPC might not receive significant survival benefits from adding AC to CCRT (OS HR 0.77, 95% CI 0.37-1.57; FFS HR 1.26, 95% CI 0.69-2.28) [29]. Combined with our Bayesian network analysis, to date, there is still a lack of evidence to confirm the superiority of CCRT+AC compared to CCRT.

In 2021, Hui et al. detected the prediction function of plasma Epstein barr virus (EBV) deoxyribonucleic acid (DNA) and found that the patients with detectable post-radiotherapy plasma EBV DNA who experienced subsequent plasma EBV DNA clearance might be the potential target population of AC [30]. In further explorations, the ongoing phase II and III study, NRG-HN001, attempt to risk-stratify AC using post-radiotherapy plasma biomarker EBV DNA levels. The future results of NRG-HN001 might help us determine the suitable population and whether omitting AC will result in non-inferior survivals compared to patients treated with CCRT+AC.

30. Hui EP, Ma BBY, Lam WKJ, Chan KCA, Mo F, Ai QH, et al. Dynamic Changes of Post-Radiotherapy Plasma Epstein-Barr Virus DNA in a Randomized Trial of Adjuvant Chemotherapy Versus Observation in Nasopharyngeal Cancer. Clin Cancer Res. 2021;27(10):2827-36. Epub 2021/03/12. doi: 10.1158/1078-0432.CCR-20-3519. PubMed PMID: 33692028.

To Editor

1. The title has been adjusted to meet the publication criteria. The details are as followings:

A Bayesian network meta-analysis of the primary definitive therapies for locoregionally advanced nasopharyngeal carcinoma: IC+CCRT, CCRT+AC, and CCRT alone

Zhan-Jie Zhang1, Liang-Liang Shi1, Xiao-Hua Hong1, Bo-Ya Xiao2, Guo-He Lin3, Quentin Liu4, Bi-Cheng Wang1,ξ

1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

2 Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China

3 Department of Oncology, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China

4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China

Attachment

Submitted filename: Response to Reviewers.doc

Click here for additional data file. (54.5KB, doc)

Decision Letter 1

Sethu Thakachy Subha

4 Mar 2022

A Bayesian network meta-analysis of the primary definitive therapies for locoregionally advanced nasopharyngeal carcinoma: IC+CCRT, CCRT+AC, and CCRT alone

PONE-D-21-23917R1

Dear Dr. Wang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Sethu Thakachy Subha, M.S

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Sethu Thakachy Subha

10 Mar 2022

PONE-D-21-23917R1

A Bayesian network meta-analysis of the primary definitive therapies for locoregionally advanced nasopharyngeal carcinoma: IC+CCRT, CCRT+AC, and CCRT alone

Dear Dr. Wang:

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on behalf of

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist. PRISMA checklist.

    (DOC)

    Click here for additional data file. (64KB, doc)
    S1 Fig. Network of the comparisons for the Bayesian network meta-analysis.

    Network for 5-year overall survival (A), failure-free survival (B), distant metastasis-free survival (C), and locoregional recurrence-free survival (D). each circular node represents a type of treatment. The dot size is proportional to the total number of patients who received a regimen. Each line represents a head-to-head comparison and the line width is proportional to the number of clinical trials comparing the connected treatment strategies.

    (DOCX)

    Click here for additional data file. (111.4KB, docx)
    S2 Fig. Risk of bias assessment in the analysis.

    (DOCX)

    Click here for additional data file. (249.2KB, docx)
    S1 File

    (DOCX)

    Click here for additional data file. (14.6KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.doc

    Click here for additional data file. (54.5KB, doc)

    Data Availability Statement

    All included studies can be searched and downloaded from their official websites or PubMed. 1. Doi:10.1016/s1470-2045(11)70320-5. 2. Doi:10.1016/j.ejca.2017.01.002. 3. Doi:10.1016/s1470-2045(16)30410-7. 4. Doi:10.1093/annonc/mdr116. 5. Doi:10.1016/j.ijrobp.2015.01.002. 6. Doi:10.1093/annonc/mdx770. 7. Doi:10.1093/annonc/mdy249. 8. Doi:10.1056/NEJMoa1905287. 9. Doi:10.1002/ijc.32099. 10. Doi:10.1016/j.ejca.2016.12.039. 11. Doi:10.1016/j.ejca.2019.07.007. 12. Doi:10.1002/cncr.29208.

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