Association of Chemoradiotherapy Regimens and Survival Among Patients With Nasopharyngeal Carcinoma: A Systematic Review and Meta-analysis | Head and Neck Cancer | JAMA Network Open | JAMA Network
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Figure 1.  Overall Survival With Hazard Ratios (HRs) by Timing of Chemotherapy
Overall Survival With Hazard Ratios (HRs) by Timing of Chemotherapy

The center of each square is the HR for individual trial comparison, with the corresponding horizontal line showing the 95% CIs. The size of the square is proportional to the number of deaths from the trial. The center of the first 4 diamonds is the HR for different timings of chemotherapy, and the extremities are the 95% CIs. The center of the diamond at the bottom represents the overall pooled HR, with the extremities of the diamond showing the 95% CI. AC indicates adjuvant chemotherapy; AF, accelerated fractionation; AOCOA, Asian-Oceanian Clinical Oncology Association; CCRT, concomitant chemoradiotherapy; CF, conventional fractionation; GORTEC, Head and Neck Radiation Oncology Group; HeCOG, Hellenic Cooperative Oncology Group; IC, induction chemotherapy; INT-0099, Southwest Oncology Group (SWOG)–coordinated Intergroup trial (also known as SWOG 8892); NPC, nasopharyngeal carcinoma; PWHQEH, Prince of Wales Hospital, Queen Elizabeth Hospital; QMH, Queen Mary Hospital (2 × 2 design, counted twice in the analysis); SQNP, Singapore Naso-Pharynx; TCOG, Taiwan Cooperative Oncology Group; and VUMCA, International Nasopharynx Cancer Study Group.

Figure 2.  Progression-Free Survival With Hazard Ratios (HRs) by Timing of Chemotherapy
Progression-Free Survival With Hazard Ratios (HRs) by Timing of Chemotherapy

The center of each square is the HR for individual trial comparison, with the corresponding horizontal line showing the 95% CI. The size of the square is proportional to the number of relapses or deaths from the trial. The center of the first 4 diamonds is the HR for different timings of chemotherapy, and the extremities are the 95% CIs. The center of the diamond at the bottom represents the overall pooled HR, with the extremities of the diamond showing the 95% CI. AC indicates adjuvant chemotherapy; AF, accelerated fractionation; AOCOA, Asian-Oceanian Clinical Oncology Association; CCRT, concomitant chemoradiotherapy; CF, conventional fractionation; GORTEC, Head and Neck Radiation Oncology Group; HeCOG, Hellenic Cooperative Oncology Group; IC, induction chemotherapy; INT-0099, SWOG (Southwest Oncology Group)–coordinated Intergroup trial (also known as SWOG 8892); NPC, nasopharyngeal carcinoma; PWHQEH, Prince of Wales Hospital, Queen Elizabeth Hospital; QMH, Queen Mary Hospital (2 × 2 design, counted twice in the analysis); SQNP, Singapore Naso-Pharynx; TCOG, Taiwan Cooperative Oncology Group; and VUMCA, International Nasopharynx Cancer Study Group.

Figure 3.  Distant Metastasis–Free Survival With Hazard Ratios (HRs) by Timing of Chemotherapy
Distant Metastasis–Free Survival With Hazard Ratios (HRs) by Timing of Chemotherapy

The center of each square is the HR for individual trial comparison, with the corresponding horizontal line showing the 95% CI. The size of the square is proportional to the number of distance metastasis from the trial. The center of the first 4 diamonds is the HR for different timings of chemotherapy, and the extremities are the 95% CIs. The center of the diamond at the bottom represents the overall pooled HR, with the extremities of the diamond showing the 95% CI. AC indicates adjuvant chemotherapy; AF, accelerated fractionation; AOCOA, Asian-Oceanian Clinical Oncology Association; CCRT, concomitant chemoradiotherapy; CF, conventional fractionation; GORTEC, Head and Neck Radiation Oncology Group; HeCOG, Hellenic Cooperative Oncology Group; IC, induction chemotherapy; INT-0099, SWOG (Southwest Oncology Group)–coordinated Intergroup trial (also known as SWOG 8892); NPC, nasopharyngeal carcinoma; PWHQEH, Prince of Wales Hospital, Queen Elizabeth Hospital; QMH, Queen Mary Hospital (2 × 2 design, counted twice in the analysis); SQNP, Singapore Naso-Pharynx; TCOG, Taiwan Cooperative Oncology Group; and VUMCA, International Nasopharynx Cancer Study Group.

Figure 4.  Locoregional Recurrence-Free Survival With Hazard Ratios (HRs) by Timing of Chemotherapy
Locoregional Recurrence-Free Survival With Hazard Ratios (HRs) by Timing of Chemotherapy

The center of each square is the HR for individual trial comparison, with the corresponding horizontal line showing the 95% CI. The size of the square is proportional to the number of locoregional recurrences from the trial. The center of the first 4 diamonds is the HR for different timings of chemotherapy, and the extremities are the 95% CIs. The center of the diamond at the bottom represents the overall pooled HR, with the extremities of the diamond showing the 95% CI. AC indicates adjuvant chemotherapy; AF, accelerated fractionation; CCRT, concomitant chemoradiotherapy; CF, conventional fractionation; GORTEC, Head and Neck Radiation Oncology Group; IC, induction chemotherapy; INT-0099, SWOG (Southwest Oncology Group)–coordinated Intergroup trial (also known as SWOG 8892); NPC, nasopharyngeal carcinoma; PWHQEH, Prince of Wales Hospital, Queen Elizabeth Hospital; QMH, Queen Mary Hospital; SQNP, Singapore Naso-Pharynx; TCOG, Taiwan Cooperative Oncology Group; and VUMCA, International Nasopharynx Cancer Study Group.

Table.  Summary of Studies Included in the Meta-analysis
Summary of Studies Included in the Meta-analysis
1.
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Pan  JJ, Ng  WT, Zong  JF,  et al.  Proposal for the 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy.  Cancer. 2016;122(4):546-558. doi:10.1002/cncr.29795PubMedGoogle ScholarCrossref
3.
Mao  YP, Xie  FY, Liu  LZ,  et al.  Re-evaluation of 6th edition of AJCC staging system for nasopharyngeal carcinoma and proposed improvement based on magnetic resonance imaging.  Int J Radiat Oncol Biol Phys. 2009;73(5):1326-1334. doi:10.1016/j.ijrobp.2008.07.062PubMedGoogle ScholarCrossref
4.
Yi  JL, Gao  L, Huang  XD,  et al.  Nasopharyngeal carcinoma treated by radical radiotherapy alone: ten-year experience of a single institution.  Int J Radiat Oncol Biol Phys. 2006;65(1):161-168. doi:10.1016/j.ijrobp.2005.12.003PubMedGoogle ScholarCrossref
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Sun  X, Su  S, Chen  C,  et al.  Long-term outcomes of intensity-modulated radiotherapy for 868 patients with nasopharyngeal carcinoma: an analysis of survival and treatment toxicities.  Radiother Oncol. 2014;110(3):398-403. doi:10.1016/j.radonc.2013.10.020PubMedGoogle ScholarCrossref
6.
Chua  MLK, Wee  JTS, Hui  EP, Chan  ATC.  Nasopharyngeal carcinoma.  Lancet. 2016;387(10022):1012-1024. doi:10.1016/S0140-6736(15)00055-0PubMedGoogle ScholarCrossref
7.
Lee  AW, Sze  WM, Au  JS,  et al.  Treatment results for nasopharyngeal carcinoma in the modern era: the Hong Kong experience.  Int J Radiat Oncol Biol Phys. 2005;61(4):1107-1116. doi:10.1016/j.ijrobp.2004.07.702PubMedGoogle ScholarCrossref
8.
Blanchard  P, Lee  A, Marguet  S,  et al; MAC-NPC Collaborative Group.  Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis.  Lancet Oncol. 2015;16(6):645-655. doi:10.1016/S1470-2045(15)70126-9PubMedGoogle ScholarCrossref
9.
Li  WF, Chen  NY, Zhang  N,  et al.  Concurrent chemoradiotherapy with/without induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: long-term results of phase 3 randomized controlled trial.  Int J Cancer. 2019;145(1):295-305. doi:10.1002/ijc.32099PubMedGoogle ScholarCrossref
10.
Vermorken  JB, Remenar  E, van Herpen  C,  et al; EORTC 24971/TAX 323 Study Group.  Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer.  N Engl J Med. 2007;357(17):1695-1704. doi:10.1056/NEJMoa071028PubMedGoogle ScholarCrossref
11.
Posner  MR, Hershock  DM, Blajman  CR,  et al; TAX 324 Study Group.  Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer.  N Engl J Med. 2007;357(17):1705-1715. doi:10.1056/NEJMoa070956PubMedGoogle ScholarCrossref
12.
Pointreau  Y, Garaud  P, Chapet  S,  et al.  Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation.  J Natl Cancer Inst. 2009;101(7):498-506. doi:10.1093/jnci/djp007PubMedGoogle ScholarCrossref
13.
Zhang  L, Huang  Y, Hong  S,  et al.  Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.  Lancet. 2016;388(10054):1883-1892. doi:10.1016/S0140-6736(16)31388-5PubMedGoogle ScholarCrossref
14.
Zhang  Y, Chen  L, Hu  GQ,  et al.  Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma  [published online May 31, 2019].  N Engl J Med. doi:10.1056/NEJMoa1905287PubMedGoogle Scholar
15.
Chen  L, Hu  CS, Chen  XZ,  et al.  Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial.  Lancet Oncol. 2012;13(2):163-171. doi:10.1016/S1470-2045(11)70320-5PubMedGoogle ScholarCrossref
16.
Moher  D, Liberati  A, Tetzlaff  J, Altman  DG; PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.  BMJ. 2009;339:b2535. doi:10.1136/bmj.b2535PubMedGoogle ScholarCrossref
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Liberati  A, Altman  DG, Tetzlaff  J,  et al.  The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.  Ann Intern Med. 2009;151(4):W65-W94. doi:10.7326/0003-4819-151-4-200908180-00136PubMedGoogle Scholar
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19.
Parmar  MK, Torri  V, Stewart  L.  Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints.  Stat Med. 1998;17(24):2815-2834. doi:10.1002/(SICI)1097-0258(19981230)17:24<2815::AID-SIM110>3.0.CO;2-8PubMedGoogle ScholarCrossref
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Fang  F, Zhang  Y, Tang  J,  et al.  Association of corticosteroid treatment with outcomes in adult patients with sepsis: a systematic review and meta-analysis.  JAMA Intern Med. 2019;179(2):213-223. doi:10.1001/jamainternmed.2018.5849PubMedGoogle ScholarCrossref
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24.
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27.
International Nasopharynx Cancer Study Group; VUMCA I Trial.  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(3):463-469. doi:10.1016/S0360-3016(96)80007-1PubMedGoogle ScholarCrossref
28.
Chua  DT, Sham  JS, Choy  D,  et al; Asian-Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group.  Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma.  Cancer. 1998;83(11):2270-2283. doi:10.1002/(SICI)1097-0142(19981201)83:11<2270::AID-CNCR6>3.0.CO;2-TPubMedGoogle ScholarCrossref
29.
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(8):2217-2223. doi:10.1002/cncr.10473PubMedGoogle ScholarCrossref
30.
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(5):1350-1357. doi:10.1200/JCO.2001.19.5.1350PubMedGoogle ScholarCrossref
31.
Cao  SM, Yang  Q, Guo  L,  et al.  Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase III multicentre randomised controlled trial.  Eur J Cancer. 2017;75:14-23. doi:10.1016/j.ejca.2016.12.039PubMedGoogle ScholarCrossref
32.
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(2):427-435. doi:10.1093/annonc/mdr116PubMedGoogle ScholarCrossref
33.
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(2):242-249. doi:10.1200/JCO.2008.18.1545PubMedGoogle ScholarCrossref
34.
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(5):952-960. doi:10.1016/j.ijrobp.2015.01.002PubMedGoogle ScholarCrossref
35.
Frikha  M, Auperin  A, Tao  Y,  et al; GORTEC.  A randomized trial of induction docetaxel-cisplatin-5FU followed by concomitant cisplatin-RT versus concomitant cisplatin-RT in nasopharyngeal carcinoma (GORTEC 2006-02).  Ann Oncol. 2018;29(3):731-736. doi:10.1093/annonc/mdx770PubMedGoogle ScholarCrossref
36.
Hong  RL, Hsiao  CF, Ting  LL,  et al.  Final results of a randomized phase III trial of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in patients with stage IVA and IVB nasopharyngeal carcinoma—Taiwan Cooperative Oncology Group (TCOG) 1303 Study.  Ann Oncol. 2018;29(9):1972-1979. doi:10.1093/annonc/mdy249PubMedGoogle ScholarCrossref
37.
Jin  YN, Yao  JJ, Wang  SY,  et al.  The effect of adding neoadjuvant chemotherapy to concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma and undetectable pretreatment Epstein-Barr virus DNA.  Transl Oncol. 2017;10(4):527-534. doi:10.1016/j.tranon.2017.03.007PubMedGoogle ScholarCrossref
38.
Chi  KH, Chang  YC, Guo  WY,  et al.  A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients.  Int J Radiat Oncol Biol Phys. 2002;52(5):1238-1244. doi:10.1016/S0360-3016(01)02781-XPubMedGoogle ScholarCrossref
39.
Rossi  A, Molinari  R, Boracchi  P,  et al.  Adjuvant chemotherapy with vincristine, cyclophosphamide, and doxorubicin after radiotherapy in local-regional nasopharyngeal cancer: results of a 4-year multicenter randomized study.  J Clin Oncol. 1988;6(9):1401-1410. doi:10.1200/JCO.1988.6.9.1401PubMedGoogle ScholarCrossref
40.
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41.
Kwong  DL, Sham  JS, Au  GK,  et al.  Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study.  J Clin Oncol. 2004;22(13):2643-2653. doi:10.1200/JCO.2004.05.173PubMedGoogle ScholarCrossref
42.
Chan  AT, Leung  SF, Ngan  RK,  et al.  Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma.  J Natl Cancer Inst. 2005;97(7):536-539. doi:10.1093/jnci/dji084PubMedGoogle ScholarCrossref
43.
Chen  QY, Wen  YF, Guo  L,  et al.  Concurrent chemoradiotherapy vs radiotherapy alone in stage II nasopharyngeal carcinoma: phase III randomized trial.  J Natl Cancer Inst. 2011;103(23):1761-1770. doi:10.1093/jnci/djr432PubMedGoogle ScholarCrossref
44.
Lin  JC, Jan  JS, Hsu  CY, Liang  WM, Jiang  RS, Wang  WY.  Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival.  J Clin Oncol. 2003;21(4):631-637. doi:10.1200/JCO.2003.06.158PubMedGoogle ScholarCrossref
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    Original Investigation
    Oncology
    October 18, 2019

    Association of Chemoradiotherapy Regimens and Survival Among Patients With Nasopharyngeal Carcinoma: A Systematic Review and Meta-analysis

    Author Affiliations
    • 1Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
    • 2Department of Radiation Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
    • 3Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
    • 4Big Data Decision Institute, Jinan University, Guangzhou, Guangdong, China
    • 5Department of Catheterization Laboratory, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People’s Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
    • 6Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
    • 7Department of Head and Neck Cancer, Guangdong Provincial People’s Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
    • 8Guangdong Provincial People’s Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
    • 9Key Laboratory of Molecular Imaging, Chinese Academy of Sciences, Beijing, China
    JAMA Netw Open. 2019;2(10):e1913619. doi:10.1001/jamanetworkopen.2019.13619
    Key Points español 中文 (chinese)

    Question  Is induction chemotherapy or adjuvant chemotherapy associated with additional survival benefit in locoregionally advanced nasopharyngeal carcinoma?

    Findings  In a systematic review and meta-analysis of 28 randomized clinical trials of 8036 patients, concurrent chemoradiotherapy was associated with substantial improvement in survival outcomes for patients with locoregionally advanced nasopharyngeal carcinoma. Survival benefit was also associated with the addition of induction chemotherapy but not adjuvant chemotherapy to concurrent chemoradiotherapy.

    Meaning  For locoregionally advanced nasopharyngeal carcinoma, concurrent chemoradiotherapy should be recommended as the standard treatment strategy, with the addition of induction chemotherapy but not adjuvant chemotherapy.

    Abstract

    Importance  The role of induction chemotherapy (IC) or adjuvant chemotherapy (AC) in the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC) remains controversial.

    Objectives  To update meta-analyses on the association of survival outcomes with IC and AC regimens in patients with locoregionally advanced NPC and assess whether the current evidence is conclusive by a trial sequential analysis (TSA) approach.

    Data Sources  PubMed, Embase, and Web of Science were searched for articles published from inception until June 1, 2019.

    Study Selection  Randomized clinical trials that assessed the efficacy of radiotherapy with or without chemotherapy among previously untreated patients and patients with nondistant metastatic NPC.

    Data Extraction and Synthesis  Data were extracted by 2 investigators from each trial independently and synthesized by the 2 investigators. All trial results were combined and analyzed by a fixed- or random-effects model.

    Main Outcomes and Measures  Overall survival (OS), progression-free survival (PFS), distant metastasis–free survival (DMFS), and locoregional recurrence-free survival (LRFS).

    Results  A total of 8036 patients (median age, 46.5 years; 5872 [73.1%] male) from 28 randomized clinical trials were included in the analysis. Pooled analyses revealed that concurrent chemoradiotherapy (CCRT) was significantly associated with improved OS, PFS, DMFS, and LRFS compared with radiotherapy across all subgroups. The TSA confirmed the treatment outcomes of CCRT compared with radiotherapy. The additional IC regimen was associated with an improvement in OS (hazard ratio [HR], 0.84; 95% CI, 0.74-0.95), PFS (HR, 0.73; 95% CI, 0.64-0.84), DMFS (HR, 0.67; 95% CI, 0.59-0.78), and LRFS (HR, 0.74; 95% CI, 0.64-0.85). These findings were consistent in subgroup analyses of multicenter trials with sample sizes greater than 250, years of survival rate of 5 or greater, median follow-up longer than 5 years, or low risk of bias. However, the additional AC regimen was not associated with a survival benefit in OS (HR, 0.98; 95% CI, 0.78-1.23), PFS (HR, 0.86; 95% CI, 0.70-1.07), DMFS (HR, 0.84; 95% CI, 0.64-1.10), or LRFS (HR, 0.80, 95% CI, 0.59-1.09). The TSA provided sound evidence on the additional benefit of IC but not AC.

    Conclusions and Relevance  These data suggest a significant association of survival outcomes with CCRT in patients with locoregionally advanced NPC. The addition of IC instead of AC could achieve survival benefits. The potential therapeutic gain of AC should be explored in the future.

    Introduction

    Nasopharyngeal carcinoma (NPC) is characterized by distinct geographic distribution and is particularly prevalent in East and Southeast Asia.1 In endemic areas, more than 70% of patients present with advanced (stage III-IV) disease at the time of diagnosis.2,3 Despite advances in diagnosis and multimodality treatment, approximately 30% of high-risk patients experience tumor recurrence, with distant metastasis as the primary source of treatment failure.4,5 Radiotherapy remains the primary treatment modality because of the anatomical location and radiosensitivity.6 Control of early-stage disease with radiotherapy is usually successful, with 5-year overall survival (OS) of 87% to 96%; however, the outcome of locoregionally advanced disease is unsatisfactory, with 5-year OS of 67% to 77%.7 Platinum-based concomitant chemotherapy (CCRT) is now the standard treatment for locoregionally advanced NPC, which can significantly reduce local and distant failure.8

    Additional cycles of chemotherapy, such as the addition of induction chemotherapy (IC) or adjuvant chemotherapy (AC) to CCRT or radiotherapy, may improve distant control in patients at high risk of distant failure.9 Induction chemotherapy offers the advantages of early eradication of micrometastases, tumor downstaging, and good tolerability.9 Cisplatin, fluorouracil, and docetaxel is the recommended induction regimen for head and neck cancer because of its superiority over cisplatin and fluorouracil.10-12 Gemcitabine and cisplatin have been established as the first-line treatment of choice over cisplatin and fluorouracil for patients with recurrent or metastatic disease.13 A recent randomized phase 3 trial found that additional gemcitabine and cisplatin IC has excellent efficacy and decreased toxicity.14 As for AC, cisplatin and fluorouracil are the recommended regimen for locoregionally advanced NPC. However, approximately 60% of patients could not complete the 3 cycles of AC after CCRT.15 Although dozens of randomized clinical trials (RCTs) have been conducted, the results were mixed. Therefore, the additional value of IC or AC is still controversial. The treatment guidelines allow for multiple treatment options. On the basis of the foregoing reasons, we decided to perform a meta-analysis, including recent eligible trials, to mainly explore the role of IC, CCRT, and AC regimens in the treatment of locoregionally advanced NPC and to examine whether and when the current evidence is sufficient and whether additional research by the trial sequential analysis (TSA) approach is needed.

    Methods

    This meta-analysis was approved by the First Affiliated Hospital of Jinan University Institutional Review Board. The methods and reporting of this systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.16,17

    Eligibility Criteria

    The eligible trials met the following PICOS (participants, interventions, comparisons, outcomes, and study design) criteria. The participants were patients with previously untreated, non–distant metastatic, newly histologically confirmed NPC. The interventions and comparisons consisted of radiotherapy plus chemotherapy compared with radiotherapy or a treatment regimen with 1 chemotherapy time compared with the same treatment strategy with chemotherapy at another time. At least 1 of the following outcomes could be extracted directly from the contents of the article or indirectly by the methods of Tierney et al18: time-to-event data, including OS, progression-free survival (PFS), distant metastasis–free survival (DMFS), and locoregional recurrence-free survival (LRFS). Only RCTs were included for analysis. This meta-analysis was limited to human studies published in English. For multiple articles from the same institution, articles that reported on different populations during nonoverlapping intervals or trials by different authors were included. Only the latest update was included if there were 2 or more articles about the same trial in the same patient population.

    Search Strategy and Study Selection

    We searched PubMed, Embase, and Web of Science for all eligible RCTs from inception to June 1, 2019. The search strategy is presented in eTable 1 in the Supplement. Two independent investigators (B.Z. and M.M.L.) first screened the titles and abstracts to determine whether the citation met the eligibility criteria. They screened the full text for potentially relevant trials when both agreed that a citation met the eligibility criteria. Disagreements between the investigators were resolved by consensus and, if necessary, consultation with a third investigator (Q.Y.C.).

    Data Collection

    The 2 independent investigators (B.Z. and M.M.L.) extracted data from the selected RCTs by standardized collection forms and created tables for the trial characteristics and treatment outcomes. Disagreements between the 2 investigators were resolved by consensus and, if necessary, consultation with a third investigator (Q.Y.C.). In particular, if the hazard ratios (HRs) and 95% CIs were available directly in a trial, then the values were used. If not, extraction of summary statistics from an individual trial was performed according to the methods detailed by Parmar et al.19

    Assessment of the Quality of Studies

    The 2 independent investigators (B.Z. and M.M.L.) performed risk assessment using the Cochrane Collaboration risk of bias tool.20 The selected RCTs were assessed for (1) random sequence generation (selection bias), (2) allocation concealment (selection bias), (3) blinding of participants and personnel (performance bias), (4) blinding of outcome assessment (detection bias), (5) incomplete outcome data (attrition bias), (6) selective reporting (reporting bias), and (7) other sources of bias. Each domain was assessed as of low, unclear, or high risk of bias. The highest risk of bias for any criterion was used to reflect the overall risk of bias. Trials were judged to have low risk of bias when all items were assessed to be low risk, trials were judged to have moderate risk of bias when 1 or more items were assessed to be of unclear risk, and trials were judged to have high risk of bias when 1 or more items were assessed to be of high risk.

    Outcomes of Interest

    The primary outcomes were OS, PFS, DMFS, and LRFS. Overall survival was defined as the time from randomization until death from any cause. Progression-free survival was defined as the time from randomization to first progression (locoregional or distant) or death from any cause. Distant metastasis–free survival was defined as the time from randomization to first distant metastasis. Locoregional recurrence-free survival was defined as the time from randomization to locoregional recurrence. If both locoregional failure and distant failure occurred at the same time, patients were considered to have an event for distant failure only. The secondary outcomes were the rates of severe (grade 3-5) toxic effects.

    Statistical Analysis

    All statistical analyses were performed by RevMan software, version 5.3.3 (Cochrane Collaboration) and Stata software, version 14.0 (StataCorp), and the fixed- or random-effects model was used for analyses. Dichotomous variables were analyzed by the Mantel-Haenszel method and expressed as HRs with 95% CIs. A 2-tailed P < .05 was considered to be statistically significant.

    Statistical heterogeneity was assessed by the χ2 test and the I2 test, with χ2P < .10 or an I2 greater than 50% considered substantial.21 The possibility of publication bias was assessed by visual estimate of funnel plot and by the Egger test or Begg test when at least 10 trials were pooled.22 We conducted prespecified subgroup analyses, which were planned for the following variables: (1) chemotherapy regimens (with or without IC, CCRT, or AC); (2) study center design (single-center or multicenter); (3) publication year (before 2015 vs after 2015); (4) sample size (>250 vs ≤250); (5) period of recruitment (>5 vs ≤5 years); (6) survival rate (≤3 vs ≥5 years); (7) World Health Organization histologic type (including type I or not); (8) tumor stage (including stage II or not); (9) median follow-up (>60 vs ≤60 months); and (10) risk of bias (low bias vs moderate or high bias). A fixed-effects or random-effects model was used to estimate odds ratios (ORs) for the comparison of severe toxic effects between 2 groups.

    Cumulative meta-analyses are at risk of producing type I error caused by sparse data and repeated significance testing of accumulating data, whereas the TSA can reduce the risk of type I error and estimate the a priori information size (APIS) needed for achieving a preset power level, drawing benefit boundaries and harm boundaries, and calculating futility.23,24 The TSA was conducted to explore whether cumulative data are adequately powered to reach a sound conclusion and whether further studies are needed.25 The TSA was performed using Stata software, version 14.0, with the random-effects model. The APIS was calculated and the monitoring boundaries were computed by the O’Brien-Fleming approach.26 An optimal information size was considered as a 2-sided 5% risk of a type I error, 20% risk of a type II error (power of 80%), and a priori relative risk reduction of 20%. The mean survival rate and loss to follow-up of patients in the selected studies were calculated for the APIS. Cumulative random-effects meta-analysis with Lan-DeMets bounds was used to calculate TSA-adjusted 95% CIs.

    Results
    Study Selection and Study Characteristics

    A total of 28 RCTs9,14,27-52 (8036 patients; median age, 46.5 years; 5872 [73.1%] male) were selected for this current meta-analysis. A flowchart of study selection is presented in eFigure 1 in the Supplement. The inclusion criteria and exclusion criteria for selecting trials are presented in eTable 2 in the Supplement.

    The characteristics of the included trials are summarized in the Table. Most trials were conducted in endemic areas in East and Southeast Asia, mainly in China (eFigure 2 in the Supplement). A total of 13 comparisons9,14,27-37 (4222 patients) investigated IC, including 4 trials27-30 (1209 patients) with the addition of IC to radiotherapy and 9 trials9,14,31-37 (3013 patients) with the addition of IC to CCRT in the treatment group. Four comparisons38-41 (1001 patients) investigated AC, including 2 trials40,41 (618 patients) with the addition of CCRT in the groups. Seven comparisons41-46 (1598 patients, 1 trial with 2 comparisons) investigated CCRT, including 1 trial41 (111 patients) with the addition of AC in both groups and 1 trial46 (400 patients) with the addition of IC in both groups. Eight comparisons41,47-52 (1437 patients, 1 trial with 2 comparisons) investigated CCRT plus AC vs radiotherapy. The median follow-up ranged from 30 to 128.4 months. Most trials (17 [61%] of 28) were multicenter trials. Patients from 16 trials (57%) had stage III or IV cancer, and the remaining 12 trials (43%) had patients with stage II cancer. Patients from 16 trials (57%) had a World Health Organization histologic type II or III cancer, and patients from 11 trials (39%) had a World Health Organization histologic type I cancer.

    Risk of Bias of Eligible Studies

    Among the 28 selected trials, 17 (61%) were judged as having overall low risk of bias because these trials met all criteria (eFigure 3 and eFigure 4 in the Supplement).

    Primary Clinical End Points and Trial Sequential Analysis

    We collected data regarding the survival outcomes from 13 trials for IC, 6 trials for CCRT, 4 trials for AC, and 7 trials for CCRT plus AC. Of these, data regarding the LRFS for IC were unavailable from the Asian-Oceanian Clinical Oncology Association,28 Hellenic Cooperative Oncology Group,32 and Singapore 200434 trials, and data regarding the PFS for CCRT were unavailable from the trial Guangzhou 2001.45 The results demonstrated that the addition of chemotherapy to radiotherapy was significantly associated with improved OS (HR, 0.76; 95% CI, 0.69-0.84; TSA-adjusted 95% CI, 0.69-0.84), PFS (HR, 0.72; 95% CI, 0.66-0.79; TSA-adjusted 95% CI, 0.66-0.79), DMFS (HR, 0.68; 95% CI, 0.62-0.75; TSA-adjusted 95% CI, 0.60-0.75), and LRFS (HR, 0.71; 95% CI, 0.64-0.79; TSA-adjusted 95% CI, 0.63-0.79) (Figure 1, Figure 2, Figure 3, and Figure 4). Low to moderate heterogeneity among trials was observed for OS (I2 = 34%, P = .03) and PFS (I2 = 36%, P = .02), whereas no significant heterogeneity was found among trials for DMFS (I2 = 21%, P = .14) and LRFS (I2 = 0%, P = .50).

    Notably, the IC group was significantly associated with OS (HR, 0.84; 95% CI, 0.74-0.95; TSA-adjusted 95% CI, 0.74-0.95), PFS (HR, 0.73; 95% CI, 0.64-0.84; TSA-adjusted 95% CI, 0.64-0.84), DMFS (HR, 0.67; 95% CI, 0.59-0.78; TSA-adjusted 95% CI, 0.58-0.77), and LRFS (HR, 0.74; 95% CI, 0.64-0.85; TSA-adjusted 95% CI, 0.61-0.86) (Figure 1, Figure 2, Figure 3, and Figure 4). Furthermore, in the CCRT group, we observed significantly prolonged OS (HR, 0.66; 95% CI, 0.51-0.85; TSA-adjusted 95% CI, 0.51-0.85), PFS (HR, 0.73; 95% CI, 0.57-0.93; TSA-adjusted 95% CI, 0.57-0.93), DMFS (HR, 0.69; 95% CI, 0.56-0.85; TSA-adjusted 95% CI, 0.48-0.85), and LRFS (HR, 0.70; 95% CI, 0.56-0.87; TSA-adjusted 95% CI, 0.53-0.98) (Figure 1, Figure 2, Figure 3, and Figure 4). However, AC was not associated with additional survival benefit for OS (HR, 0.98; 95% CI, 0.78-1.23; TSA-adjusted 95% CI, 0.78-1.24), PFS (HR, 0.86; 95% CI, 0.70-1.07; TSA-adjusted 95% CI, 0.70-1.07), DMFS (HR, 0.84; 95% CI, 0.64-1.10; TSA-adjusted 95% CI, 0.58-1.22), or LRFS (HR, 0.80; 95% CI, 0.59-1.09; TSA-adjusted 95% CI, 0.59-1.09) (Figure 1, Figure 2, Figure 3, and Figure 4). The combined CCRT plus AC was associated with survival benefit compared with radiotherapy in terms of OS (HR, 0.63; 95% CI, 0.53-0.74; TSA-adjusted 95% CI, 0.54-0.74), PFS (HR, 0.64; 95% CI, 0.51-0.80; TSA-adjusted 95% CI, 0.51-0.80), DMFS (HR, 0.62; 95% CI, 0.51-0.76; TSA-adjusted 95% CI, 0.47-0.81), and LRFS (HR, 0.61; 95% CI, 0.48-0.79; TSA-adjusted 95% CI, 0.45-0.83) (Figure 1, Figure 2, Figure 3, and Figure 4).

    For treatment outcomes of IC, CCRT, and CCRT plus AC, the cumulative z curve crossed the conventional boundaries (z = 1.96) and the monitoring boundaries for TSA, whereas for the outcomes of AC, the z curve did not cross the both boundaries. Hence, the TSA showed firm evidence on the treatment outcomes of IC, CCRT, and CCRT plus AC but absence of evidence on the treatment outcomes of AC. The required APIS of the TSA is shown in eFigures 5, 6, 7, and 8 in the Supplement.

    Subgroup Analyses

    Subgroup analyses on the IC regimen found a significant association of IC plus radiotherapy with improvement in all end points compared with radiotherapy (OS: HR, 0.87; 95% CI, 0.74-1.03; PFS: HR, 0.73; 95% CI, 0.63-0.85; DMFS: HR, 0.71; 95% CI, 0.58-0.88; and LRFS: HR, 0.75; 95% CI, 0.62-0.90) and a significant association of IC plus CCRT in all end points compared with CCRT (OS: HR, 0.81; 95% CI, 0.68-0.96; PFS: HR, 0.73; 95% CI, 0.63-0.83; DMFS: HR, 0.64; 95% CI, 0.53-0.78; LRFS: HR, 0.73; 95% CI, 0.58-0.91) (eTable 4 in the Supplement). However, these associations were influenced by study center design, sample size, period of recruitment, tumor stage, and study bias. Single-center trials with sample sizes of 250 or less, period of recruitment longer than 5 years, tumor stage II, or high bias were less likely to find additional survival benefits. However, multicenter trials with sample sizes greater than 250, survival rate of 5 years or longer, median follow-up time longer than 60 months, and low bias have provided data suggestive of a benefit from adding IC to the treatment regimen for locoregionally advanced NPC. Subgroup analyses under various conditions demonstrated no additional survival benefit associated with AC in any end point. We observed persistent survival benefits associated with CCRT and CCRT plus AC vs radiotherapy for all end points analyzed. Low heterogeneity within subgroups was observed for any end point.

    Publication Bias

    We found no evidence of publication bias based on visual inspection of funnel plots in terms of IC, CCRT, AC, and CCRT plus AC based on an analysis of pooled trials with sample sizes greater than 10 (eFigure 9 in the Supplement) or according to the Egger test or Begg test.

    Serious Adverse Events

    eTable 5 in the Supplement lists the severe (grades 3-5) toxic effects of chemoradiotherapy. The severe toxic effects of the AC regimen could not be analyzed because of unavailable or inadequate data. Primary toxic effects included hematologic toxic effects and digestive system toxic effects. Both IC plus CCRT and CCRT plus AC were associated with the highest frequency of acute toxic effects. The late toxic effects were mainly associated with radiotherapy.

    Discussion
    Summary of Main Findings

    This updated and comprehensive meta-analysis (comprising 28 RCTs with 8036 patients) of the role of chemotherapy regimens in NPC confirmed the benefits associated with the addition of chemotherapy to radiotherapy, including significant and clinically relevant improvements in all outcomes. The results of this study support the use of CCRT as the standard treatment for locoregionally advanced NPC, which was significantly associated with improvement in survival. The addition of IC but not AC to radiotherapy or CCRT could achieve prolonged OS, PFS, DMFS, and LRFS. The TSA provided firm evidence on the additional benefit associated with IC. However, the benefits associated with the addition of AC still lack evidence, which suggests more high-quality RCTs are needed.

    Comparison With Other Studies

    Compared with the previous meta-analyses listed in eTable 3 in the Supplement, this study has analyzed more trials and patients and has included data on toxic effects in the analysis insofar as was possible. Although this meta-analysis is similar to the one by You et al,53 there are some differences. You et al53 found that CCRT plus AC was associated with a better survival benefit compared with CCRT and IC plus CCRT for LRFS, whereas our study found no additional benefit associated with AC plus CCRT for all end points. In addition, this updated meta-analysis answered a question about whether the current evidence is inconclusive and conducted subgroup analyses to identify sources of heterogeneity to interpret the inconsistent findings of previous trials.

    Management of advanced NPC remains challenging for practitioners. Concurrent chemoradiotherapy has been adopted as the standard treatment for locoregionally advanced NPC, which is supported by previous meta-analyses (eTable 3 in the Supplement). Our study with TSA confirmed the association of CCRT with improvement in OS, PFS, DMFS, and LRFS compared with radiotherapy alone. Part of the current controversy regarding supportive evidence for combination treatment relates to the roles of IC and AC. Meta-analyses published in 2015 or earlier8,54-57 reported no significant differences between IC plus CCRT and CCRT with respect to OS and conflicting findings in PFS (eTable 3 in the Supplement). This finding might be because the meta-analyses included trials reported before 2013 but did not include trials using new IC regimens (eg, gemcitabine, cisplatin, and paclitaxel; cisplatin, fluorouracil, and docetaxel; and gemcitabine and cisplatin). Meta-analyses published after 201558-61 indicated significant benefits associated with adding IC to CCRT in prolonging survival outcomes (eTable 3 in the Supplement). Therefore, optimizing the IC regimen may be another orientation currently and in the future. Subgroup analyses showed additional benefit associated with adding IC to CCRT in multicenter trials or trials with sample sizes greater than 250, survival rates of 5 years or longer, median follow-up longer than 5 years, or low risk of bias. In contrast, single-center trials or trials with small sample sizes, tumor stage II, or high risk of bias were not significant with respect to the additional benefits of IC. These key points may be why we found inconsistent findings in previous meta-analyses (listed in eTable 3 in the Supplement). The TSA provided sound evidence on the additional value of IC. However, patients with advanced NPC comprise many subgroups, and not all of them could benefit from additional IC. Epstein-Barr virus DNA and imaging biomarkers were incorporated as selection factors for clinical trials of IC to determine who could benefit from the treatment.62

    In this meta-analysis, AC was not associated with any additional benefit in any of the end points, not only in the pooled analyses but also in the subgroup analyses. This finding was also supported by the preliminary results of meta-analyses (eTable 3 in the Supplement).8,54,57,63,64 Although some retrospective studies65-67 found an improvement in survival and fewer patients with distant metastases when 2 or more cycles of AC regimen were delivered, additional AC was poorly tolerated, with 55% to 75% adherence at best, and patients were at risk of more chemotherapy-related toxic effects.15 Although most trials used the cisplatin and fluorouracil AC regimen for advanced NPC, this combination perhaps benefitted only those with lower burden of distant tumor.40 Notably, only 4 trials38-41 investigated AC, of which 2 trials38,39 added AC to radiotherapy and 2 trials40,41 added AC to CCRT. The TSA produced an absence of evidence that AC alone could provide additional benefit. The required sample sizes ranged from 1698 to 2453 for the end points, which indicates that additional trials are needed.

    Strengths and Limitations

    Our meta-analysis has several strengths. We performed a comprehensive search of several databases and sources to identify eligible trials. We adopted strict methods following the recommendations of the Cochrane Collaboration and PRISMA statement, including but not limited to a prepublished protocol, an up-to-date literature search and independent study selection, data extraction, and risk-of-bias assessment by at least 2 investigators. To our knowledge, this is the largest conventional meta-analysis. The large number of patients allowed for subgroup analyses to be performed with adequate power. We performed subgroup analyses in various aspects to find out the potential sources of heterogeneity and ensure the reliability and soundness of our findings. Moreover, we considered comprehensive time-to-event data of OS, PFS, DMFS, and LRFS to evaluate the benefits of IC, CCRT, AC, and CCRT plus AC regimens. When reporting an RCT with survival-type data, the appropriate summary statistics are the log HR and its variance. Hence, we used the outcome measure HR (calculated if unavailable) instead of the OR or relative risk to express the outcomes, which takes into account the number and timing of events and the time until last follow-up for each patient who has not experienced an event (ie, has been censored). Although our review uniquely aims to examine whether and when sufficient evidence of the additional survival benefit of IC and AC has been accrued, repeated meta-analyses with accumulating trial data could lead to random errors or false-positive results if multiple tests are not accounted for. We reduced the risk of random error in the updated meta-analysis by the TSA approach to increase the robustness of the analyses; to our knowledge, this method has not been used in existing meta-analyses on chemotherapy regimens for locoregionally advanced NPC.

    Limitations of this study should be acknowledged. First, we could not evaluate the effects of various radiotherapy strategies, including 2-dimensional radiotherapy, 3-dimensional conformal radiotherapy, and intensity-modulated radiotherapy, on the heterogeneity among trials. Some previously published trials used outdated conventional or 2-dimensional radiotherapy. Second, unlike the individual patient data meta-analysis, we could not identify the interaction between treatment effect on survival end point and the timing of chemotherapy. Third, patients with stage II or World Health Organization type I cancer were included, but they represent few patients with NPC in both clinical practice and trials (Table).

    Conclusions

    This updated meta-analysis with TSA confirmed the benefits associated with the addition of chemotherapy to radiotherapy for patients with locoregionally advanced NPC; the greatest benefit was found in those groups with concomitant administration, suggesting that CCRT should be the standard treatment. The addition of IC instead of AC to CCRT was associated with an additional survival benefit. However, the additional value of the AC regimen to CCRT needs further assessment.

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    Article Information

    Accepted for Publication: September 3, 2019.

    Published: October 18, 2019. doi:10.1001/jamanetworkopen.2019.13619

    Correction: This article was corrected on November 13, 2019, to fix an error in the Results.

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Zhang B et al. JAMA Network Open.

    Corresponding Authors: Jie Tian, MD, PhD, Key Laboratory of Molecular Imaging, Chinese Academy of Sciences, No. 95 Zhongguancun E Rd, Beijing 100190, China (jie.tian@ia.ac.cn); Shui Xing Zhang, MD, PhD, Department of Radiology, The First Affiliated Hospital of Jinan University, No. 613 Huangpu W Rd, Tianhe District, Guangzhou, Guangdong 510627, China (shui7515@126.com).

    Author Contributions: Drs B. Zhang and Li contributed equally to this work. Drs B. Zhang and S. X. Zhang had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: B. Zhang, Li, W. H. Chen, Zhao, S. X. Zhang.

    Acquisition, analysis, or interpretation of data: B. Zhang, Li, W. H. Chen, W. Q. Chen, Dong, Gong, Q. Y. Chen, L. Zhang, Mo, Luo, Tian.

    Drafting of the manuscript: B. Zhang.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: B. Zhang, W. Q. Chen, Gong.

    Obtained funding: B. Zhang, S. X. Zhang.

    Administrative, technical, or material support: B. Zhang, Dong, Q. Y. Chen, L. Zhang, Mo, S. X. Zhang.

    Supervision: B. Zhang, Tian, S. X. Zhang.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This research was supported by grants 81571664 (Dr S. X. Zhang), 81871323 (Dr S. X. Zhang), and 81801665 (Dr B. Zhang) from the National Natural Science Foundation of China; grant 2018B030311024 from the National Natural Science Foundation of Guangdong Province (Dr S. X. Zhang); grant 201707010328 from the Scientific Research General Project of Guangzhou Science Technology and Innovation Commission (Dr S. X. Zhang); and grant 2016M600145 from the China Postdoctoral Science Foundation (Dr S. X. Zhang).

    Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

    Additional Contributions: Jiang Hu, BS (Nanchang Foryodoo Technology Co Ltd, Nanchang, China), assisted in editing the manuscript and was not compensated for the work.

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