Skip to main content
PLOS ONE logoLink to PLOS ONE
. 2018 May 2;13(5):e0196730. doi: 10.1371/journal.pone.0196730

The current status of clinical trials focusing on nasopharyngeal carcinoma: A comprehensive analysis of ClinicalTrials.gov database

Hao Peng 1, Lei Chen 1, Yu-Pei Chen 1, Wen-Fei Li 1, Ling-Long Tang 1, Ai-Hua Lin 2, Ying Sun 1, Jun Ma 1,*
Editor: Joseph S Pagano3
PMCID: PMC5931495  PMID: 29718970

Abstract

Purpose

Clinical Trials have emerged as the main force in driving the development of medicine. However, little is known about the current status of clinical trials regarding nasopharyngeal carcinoma (NPC). This study aimed at providing a comprehensive landscape of NPC-related trials on the basis of ClinicalTrials.gov database.

Patients and methods

We used the keyword “nasopharyngeal carcinoma” to search the ClinicalTrials.gov database and assessed the characteristics of these trials.

Results

Up to December 30, 2016, 462 eligible trials in total were identified, of which 222 (48.0%) recruited only NPC (NPC trials) and the other 240 (52.0%) recruited both NPC and other cancers (multiple cancer trials). Moreover, 47 (10.2%) were Epstein-Barr virus (EBV)-related trials and 267 (57.8%) focused on metastatic/recurrent disease. Compared with NPC trials, the multiple cancer trials had a higher percentage of phase 1 (26.7% vs. 6.7%, P < 0.001) studies and more patients with metastatic/recurrent disease (72.5% vs. 41.9%, P < 0.001). Notably, non-EBV trials had more phase 2 or 3 (78.4% vs. 48.8%, P < 0.001) and interventional studies (89.5% vs. 70.7%, P = 0.002) than EBV trials. Obviously, more phase 2/3 or 3 trials were conducted in patients with non-metastatic/recurrent disease (29.4% vs. 4.9%, P < 0.001); however, metastatic/recurrent trials were more likely to be anticancer (94.6% vs. 63.6%, P < 0.001).

Conclusions

The role of plasma EBV DNA in clinical trials is underestimated, and high-level randomized clinical trials should be performed for patients with metastatic/recurrent disease.

Introduction

Nasopharyngeal carcinoma (NPC) differs from other head and neck cancers for its epidemiology, clinical characteristics and therapy modality; it has an incidence rate of 20 per 100,000 persons in endemic regions such as South East Asia and Southern China [1], and radiotherapy has come as the only curative treatment as a result of the anatomic constraints and its sensitivity to irradiation. With the advancement of radiotherapy technique and combined therapy strategies of radiotherapy and chemotherapy over the last twenty years, outcomes for NPC have improved greatly, producing a 5-year overall survival rate of 84.7–87.4% [24]. However, control of advanced disease may be unsatisfactory, with an overall survival of 67–77% [5]. Furthermore, distant metastasis at initial diagnosis or after radical radiotherapy and recurrent NPC still remain the most serious challenges as the median overall survival of these patients is only 20 months [6]. Therefore, much effort are urgently needed to develop more effective treatment modalities.

Clinical trials have emerging as foundation of evidence-based medicine and the main force in driving the development of medicine. In September 2004, a consensus has been reached by the International Committee of Medical Journal Editors (ICMJE) that clinical trials should be registered in a public registry before recruiting patients to ensure transparency of the whole process. Later on, this policy was applied to all the clinical trials starting recruitment after July 1, 2005 [7]. ClinicalTrials.gov, developed and maintained by National Library of Medicine (NLM), is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. Currently, the ClinicalTrials.gov provides the most comprehensive source of information on ongoing and completed clinical studies worldwide.

As clinical trials usually represent the latest treatment modalities in the war against cancer, clinicians hope that these new drugs or technologies could be applied in clinical practice as soon as possible. Given the truth that we still lack a thorough understanding of current clinical studies regarding NPC, we therefore conducted this study aiming at providing a comprehensive landscape of NPC-related trials on the basis of ClinicalTrials.gov database and evaluating the characteristics of these studies.

Materials and methods

Data source and eligible study

Three oncologists (LC, YPC and WFL) at the Sun Yat-sen University Cancer Centre used the term “nasopharyngeal carcinoma” to search all the registered clinical trials in the ClinicalTrials.gov database separately. All the information of these searched clinical trials provided by the sponsors and/or collaborators were thoroughly gone through and kept. A fourth oncologist (HP) would review the data recorded by the three oncologists, and any disagreements were solved by consensus or referring to the fifth oncologist (JM) who has more than twenty years of experience in NPC clinical trials. Up to December 30, 2016, a total of 508 trials were identified. After carefully reviewing all the information presented by ClinicalTrials.gov database, 46 (9.1%) trials were excluded (Fig 1).

Fig 1. Flowchart of recruited NPC and multiple cancer trials registered with ClinicalTrials.gov by December 30, 2016.

Fig 1

Abbreviations: NPC = nasopharyngeal carcinoma.

Therefore, 462 (90.9%) trials were left for further analysis (S1 File). This study was approved by the Research Ethics Committee of Sun Yat-sen university cancer center.

Study variables

Before searching, we set up recording standards for each study variable and the following characteristics provided by ClinicalTrials.gov database were assessed: registered number, registered time, Epstein-Barr virus (EBV)-related trials (yes or no), time perspective (prospective or retrospective), tumor stage (non-metastasis/recurrent or metastasis/recurrent or both or health population), tumor category (nasopharyngeal carcinoma only or multiple), the phase of trial (none or phase 0/1 or phase 1/2 or phase 2/3 or phase 4), study type (interventional or observational), interventional phase (none or prior to radiotherapy or during radiotherapy or after radiotherapy or metastatic/recurrent disease), interventional measure (none or anticancer or non-anticancer), anticancer drug (none or chemotherapy or targeted therapy or radiotherapy or immunotherapy or other), endpoint classification (efficacy or safety or efficacy/safety or other), masking (none or open label or blind), allocation (none or randomized or non-randomized), study arm (none or one or two or more), funding source (industry or national cancer institute or other), study sample (< 50 or 50–100 or > 100), participant age (< 18y or ≥ 18y or both), region (Unite states/Canada or European or Asia or other) and center (one or two or more).

The definition of EBV-related trials was that pre-treatment plasma EBV DNA was one of the inclusion criteria or therapy targeted EBV-related antigens such as latent membrane protein 1 (LMP1). If a trial included both NPC and other kinds of cancer types, it would be grouped into a “multiple” category. With regard to interventional stage, the trial would be classified as “metastatic/recurrent disease” if only patients with recurrent/metastatic disease were recruited; otherwise, the trial was categorized according to the order of intervention and radiotherapy for newly diagnosed, non-disseminated disease. For retrospective or observational studies, the phase of trial, interventional stage, interventional measure, anticancer drug, masking, allocation and study arm were considered as “none”, and the endpoint classification was “other”. Funding sources were categorized as industry, national cancer institute (NCI) or other academic groups based on the sponsor or collaborators [8]. If an industry was listed as the sponsor or collaborators, the trial would be treated as funded by industry. When NCI was the lead sponsor or collaborators, the trial was considered as NCI-funded. Furthermore, the region of the trial mainly depends on the location of lead sponsor.

Statistical analysis

The characteristics of clinical trials were summarized by descriptive statistics: continuous variables were characterized as median and interquartile ranges (IQR) and categorical variables were reported as frequencies and percentages. Pearson Chi-square test was used to compare the characteristics difference between different kinds of NPC-related trials, and Fisher’s exact test would also be applied if indicated. Any missing value would be excluded from analysis. All statistical tests were performed using STATA version 13.0 (Stata Corporation LP, College Station, TX, USA), and a two-sided P < 0.05 was considered statistically significant.

Results

Basic characteristics of included trials

Among the 462 eligible trials, 222 (48.0%) were identified as NPC trials and the other 240 (52.0%) were multiple cancer trials. The distribution of these two kinds of trials according to registered time was summarized in Fig 2.

Fig 2. Distribution of NPC and multiple cancer trials according to registered year in ClinicalTrials.gov database.

Fig 2

Abbreviations: NPC = nasopharyngeal carcinoma.

Obviously, the number of NPC trials increased greatly after 2004, and the number of multiple cancer trials decreased and remained stable after 2011. The baseline characteristics of 462 trials were presented in Table 1. Although plasma EBV DNA has been documented to be a reliable biomarker in prognosis predicting and decisions making in NPC since 2004 [9], its role in clinical trials still remains slight (10.2%). Intriguingly, more than half of trials (57.8%) focused on metastatic or recurrent disease and only 40.5% recruited non-disseminated NPC at initiation diagnosis. Notably, the primary purpose of most trials (72%) was anticancer intervention, and much attention was paid to chemotherapy (30.7%) and targeted therapy (23.4%). Moreover, 51.3% of the trials were registered in Unite States (US)/Canada where NPC has a very low rate of incidence, and most of these studies were multiple cancer trials which mainly focused on other head and neck cancers.

Table 1. Basic characteristics of the 462 trials registered with ClinicalTrials.gov up to December 30, 2016.

Characteristics Number Percentage (%)
EBV-related trials
Yes 47 10.2
No 415 89.8
Time perspective
Prospective 447 96.5
Retrospective 15 3.5
Tumor stage
Non-metastasis/recurrent 187 40.5
Metastasis/recurrent 205 44.4
Both 62 13.4
Health population 8 1.7
Tumor category
NPC only 222 48.0
Multiple a 240 52.0
Phase
None 77 16.7
Phase 1 81 17.5
Phase 1/2 or 2 203 43.9
Phase 2/3 or 3 69 14.9
Phase 4 5 1.1
Missing value 27 5.9
Study type
Interventional 386 83.5
Observational 76 16.5
Interventional phase
None 76 16.5
Prior to radiotherapy 37 8.0
During radiotherapy 93 20.1
After radiotherapy 33 7.1
Metastatic/recurrent disease 195 42.2
Two or more phases 25 5.4
Missing value 3 0.7
Interventional measure
None 76 16.5
Anticancer 333 72.0
Non-anticancer b 53 11.5
Interventional drug
None 76 16.5
Chemotherapy 142 30.7
Targeted therapy 108 23.4
Radiotherapy 23 5.0
Immunotherapy 44 9.5
Other c 69 14.9
Endpoint classification
Efficacy 93 20.1
Safety 38 8.2
Efficacy/safety 254 55.0
Other d 77 16.7
Masking
None 77 16.7
Open label 348 75.3
Blind 37 8.0
Allocation
None 77 16.7
Randomized 152 32.9
Non-randomized 233 50.4
Study arm
None 77 16.7
One 229 49.6
Two 139 30.0
Three or more 17 3.7
Funding source
Industry 46 10.0
NCI 174 37.6
Other 242 52.4
Study sample
< 50 212 45.9
50~100 104 22.5
> 100 144 31.2
Missing value 2 0.4
Participant age (y)
< 18 1 0.2
≥ 18 418 90.5
Both 43 9.3
Region
US/Canada 237 51.3
European 26 5.6
Asia 195 42.2
Other e 4 0.9
Centers
One 299 64.7
Two 26 5.6
Three or more 137 29.7

Abbreviations: EBV = Epstein-Barr virus; NPC = nasopharyngeal carcinoma; NCI = national cancer institute; US = Unite States.

a Trials includes both nasopharyngeal carcinoma and other kinds of cancer types.

b Non-anticancer measures mainly include symptomatic treatment such as radiotherapy-induced oral mucositis.

c Other refers to surgical treatment or drugs dealing with chemotherapy or radiotherapy-related toxicities.

d Endpoint classifications of retrospective or prospectively observational study were considered as “other”.

e Other regions include Africa, South America, Oceania, North America other than US/Canada.

NPC trials and multiple cancer trials

Table 2 summarized the study characteristics of NPC trials and multiple cancer trials registered with ClinicalTrials.gov database. Difference in the number of EBV-related trials was apparent: NPC trials had an obviously higher rate of EBV-related trials (18.5% vs. 2.5%, P < 0.001) compared with multiple cancer trials. Moreover, NPC trials were more likely to focus on non-metastatic/recurrent disease at initiation diagnosis (55.0% vs. 27.1%, P < 0.001), while multiple cancer trials mainly recruited patients with metastatic/recurrent disease (55.0% vs. 32.0%, P < 0.001) and had more phase I studies (26.7% vs. 7.6%, P < 0.001). Unlike multiple cancer trials, NPC trials had a higher percentage of chemotherapy intervention (39.2% vs. 22.9%, P = 0.001). Furthermore, NPC trials were more likely to be funded by other academic groups (82.8% vs. 24.2%, P < 0.001) and had more large-scale studies (41.9% vs. 21.2%, P < 0.001) compared to multiple cancer trials. Obviously, most of NPC trials were conducted in Asia and multiple cancer trials in US/Canada.

Table 2. Characteristics difference between different trials registered with ClinicalTrials.gov up to December 30, 2016.

NPC Trials Multiple Cancer Trials EBV Trials Non-EBV Trials
(n = 222) (n = 240) (n = 41) (n = 181)
Characteristics No. (%) No. (%) P1 a No. (%) No. (%) P2 a
EBV-related trials < 0.001 -
Yes 41 (18.5) 6 (2.5) - -
No 181 (81.5 234 (97.5) - -
Time perspective 0.246 0.587
Prospective 217 (97.7) 230 (95.8) 41 (100) 176 (97.2)
Retrospective 5 (2.3) 10 (4.2) 0 (0) 5 (2.8)
Tumor stage < 0.001 < 0.001
Non-metastatic/recurrent 122 (55.0) 65 (27.1) 17 (41.5) 105 (58.0)
Metastatic/recurrent 73 (32.9) 132 (55.0) 13 (31.7) 60 (33.1)
Both 20 (9.0) 42 (17.5) 4 (9.8) 16 (8.9)
Health population 7 (3.1) 1 (0.4) 7 (17.0) 0 (0)
Phase b < 0.001 < 0.001
None 32 (14.4) 45 (18.8) 12 (29.3) 20 (11.0)
Phase 1 17 (7.6) 64 (26.7) 9 (21.9) 8 (4.4)
Phase 1/2 or 2 108 (48.6) 95 (39.6) 12 (29.3) 96 (53.0)
Phase 2/3 or 3 54 (24.3) 15 (6.3) 8 (19.5) 46 (25.4)
Phase 4 3 (1.4) 2 (0.8) 0 (0) 3 (1.7)
Study type 0.166 0.002
Interventional 191 (86.0) 195 (81.2) 29 (70.7) 162 (89.5)
Observational 31 (14.0) 45 (18.8) 12 (29.3) 19 (10.5)
Interventional phase c < 0.001 0.003
None 31 (14.0) 45 (18.8) 12 (29.3) 19 (10.5)
Prior to radiotherapy 32 (14.4) 5 (2.0) 2 (4.9) 30 (16.6)
During radiotherapy 50 (22.5) 43 (17.9) 5 (12.2) 45 (24.9)
After radiotherapy 22 (9.9) 11 (4.6) 7 (17.1) 15 (8.3)
Metastatic/recurrent disease 70 (31.5) 125 (52.1) 14 (34.1) 56 (30.9)
Two or more phases 15 (6.8) 10 (4.2) 1 (2.4) 14 (7.7)
Interventional measure 0.07 < 0.001
None 31 (14.0) 45 (18.8) 12 (29.3) 19 (10.5)
Anticancer 171 (77.0) 162 (67.5) 29 (70.7) 142 (78.5)
Non-anticancer 20 (9.0) 33 (13.7) 0 (0) 20 (11.0)
Interventional drug 0.001 < 0.001
None 31 (14.0) 45 (18.8) 12 (29.3) 19 (10.5)
Chemotherapy 87 (39.2) 55 (22.9) 10 (24.4) 77 (42.5)
Targeted therapy 46 (20.7) 62 (25.8) 7 (17.0) 39 (21.5)
Radiotherapy 13 (5.9) 10 (4.2) 0 (0) 13 (7.2)
Immunotherapy 23 (10.3) 21 (8.7) 12 (29.3) 11 (6.1)
Other 22 (9.9) 47 (19.6) 0 (0) 22 (12.2)
Endpoint classification < 0.001 0.018
Efficacy 35 (15.8) 58 (24.2) 5 (12.2) 30 (16.6)
Safety 11 (5.0) 27 (11.2) 3 (7.3) 8 (4.4)
Efficacy/safety 144 (64.8) 110 (45.8) 21 (51.2) 123 (68.0)
Other 32 (14.4) 45 (18.8) 12 (29.3) 20 (11.0)
Masking 0.337 0.02
None 32 (14.4) 45 (18.8) 12 (29.3) 20 (11.0)
Open label 174 (78.4) 174 (72.5) 27 (65.8) 147 (81.3)
Blind 16 (7.2) 21 (8.7) 2 (4.9) 14 (7.7)
Allocation < 0.001 0.008
None 32 (14.4) 45 (18.8) 12 (29.3) 20 (11.0)
Randomized 105 (47.3) 47 (19.6) 14 (34.1) 91 (50.3)
Non-randomized 85 (38.3) 148 (61.6) 15 (36.6) 70 (38.7)
Study arm < 0.001 0.019
None 32 (14.4) 45 (18.8) 12 (29.3) 20 (11.0)
One 83 (37.4) 146 (60.8) 15 (36.6) 68 (37.6)
Two 96 (43.2) 43 (17.9) 12 (29.3) 84 (46.4)
Three or more 11 (5.0) 6 (2.5) 2 (4.8) 9 (5.0)
Funding source < 0.001 < 0.001
Industry 25 (11.3) 21 (8.7) 0 (0) 25 (13.8)
NCI 13 (5.9) 161 (67.1) 6 (14.6) 7 (3.9)
Other 184 (82.8) 58 (24.2) 35 (85.4) 149 (82.3)
Study sample d < 0.001 0.01
< 50 72 (32.4) 140 (58.3) 18 (43.9) 54 (29.8)
50~100 57 (25.7) 47 (19.6) 3 (7.3) 54 (29.8)
>100 93 (41.9) 51 (21.2) 20 (48.8) 73 (40.4)
Region < 0.001 0.006
US/Canada 34 (15.3) 203 (84.6) 14 (34.1) 20 (11.0)
European 10 (4.5) 16 (6.7) 1 (2.4) 9 (5.0)
Asia 176 (79.3) 19 (7.9) 26 (63.5) 150 (82.9)
Other 2 (0.9) 2 (0.8) 0 (0) 2 (1.1)

Abbreviations: NPC = nasopharyngeal carcinoma; EBV = Epstein-Barr virus; NCI = national cancer institute; US = Unite States.

a P-Values were calculated using Pearson Chi-Square test or Fisher’s exact test if indicated.

b 8 trials in the NPC trials arm and 19 trials in the multiple cancer trials arm were missing; 8 trials in Non-EBV trials arm were missing.

c 2 trials in the NPC trials arm and 1 trial in multiple cancer trials arm were missing; 2 trials in Non-EBV trials arm were missing.

d 2 trials in multiple cancer trials arm were missing.

EBV and non-EBV trials

Apparently, multiple cancer trials registered in Unite States/Canada mainly focused on other head and neck cancers and EBV was not an inclusion criteria, we therefore excluded these trials when analyzing the characteristic difference between EBV and non-EBV trials (Table 2). EBV trials were less likely to recruit non-metastatic/recurrent disease (41.5% vs. 58.0%, P < 0.001) and had a higher percentage of health participants (17.0% vs. 0, P < 0.001). Besides, non-EBV trials had more phase 2 or 3 (78.4% vs. 48.8%, P < 0.001) and interventional studies (89.5% vs. 70.7%, P = 0.002). Also, the intervention of non-EBV trials mainly focused on chemotherapy (42.5% vs. 24.4%, P < 0.001) while EBV trials had an obviously higher rate of immunotherapy intervention (29.3% vs. 6.1%, P < 0.001). Furthermore, non-EBV trials were more likely to receive funding from industry (13.8% vs. 0, P < 0.001) and registered in Asia (82.9% vs. 63.5%, P = 0.006).

Metastatic/Recurrent and Non-metastatic/Recurrent trials

As prognosis of non-metastatic/recurrent nasopharyngeal carcinoma is much better than that of metastatic/recurrent disease, we therefore further compared the characteristics difference between trials recruiting non-metastatic/recurrent and metastatic/recurrent patients (Table 3). Obviously, more phase 2/3 or 3 trials were conducted in patients with non-metastatic/recurrent disease (29.4% vs. 4.9%, P < 0.001); however, metastatic/recurrent trials were more likely to be anticancer (94.6% vs. 63.6%, P < 0.001). Moreover, metastatic/recurrent trials had a higher percentage of targeted therapy (35.6% vs. 16.0%, P < 0.001) and immunotherapy (18.1% vs. 2.2%, P < 0.001) interventions compared with non-metastatic/recurrent trials. In addition, non-metastatic/recurrent trials intended to be funded by other academic groups (70.6% vs. 35.6%, P < 0.001), be conducted in Asia (58.3% vs. 29.8%, P < 0.001) and have large-scale samples of more than 100 (45.4% vs. 14.2%, P < 0.001).

Table 3. Characteristics of Metastatic/Recurrent and Non-metastatic/Recurrent trials registered with ClinicalTrials.gov up to December 30, 2016.

Metastatic/recurrent Trials Non-metastatic/recurrent Trials
(n = 205) (n = 187)
Characteristics No. (%) No. (%) Pa
Time perspective 0.032
Prospective 198 (96.6) 186 (99.5)
Retrospective 7 (3.4) 1 (0.5)
Phase b < 0.001
None 11 (5.4) 27 (14.4)
Phase 1 59 (28.8) 12 (6.4)
Phase 1/2 or 2 122 (59.5) 71 (38.0)
Phase 2/3 or 3 10 (4.9) 55 (29.4)
Phase 4 0 (0) 3 (1.6)
Study type 0.001
Interventional 195 (95.1) 160 (85.6)
Observational 10 (4.9) 27 (14.4)
Interventional measure < 0.001
None 10 (4.9) 27 (14.4)
Anticancer 194 (94.6) 119 (63.6)
Non-anticancer 1 (0.5) 41 (22.0)
Interventional drug < 0.001
None 10 (4.9) 27 (14.4)
Chemotherapy 65 (31.7) 70 (37.4)
Targeted therapy 73 (35.6) 30 (16.0)
Radiotherapy 6 (2.9) 15 (8.0)
Immunotherapy 37 (18.1) 4 (2.2)
Other 14 (6.8) 41 (22.0)
Endpoint classification < 0.001
Efficacy 35 (17.1) 52 (27.8)
Safety 24 (11.7) 5 (2.7)
Efficacy/safety 136 (66.3) 102 (54.5)
Other 10 (4.9) 28 (15.0)
Masking < 0.001
None 11 (5.4) 27 (14.4)
Open label 189 (92.2) 130 (69.6)
Blind 5 (2.4) 30 (16.0)
Allocation < 0.001
None 11 (5.4) 27 (14.4)
Randomized 34 (16.6) 109 (58.3)
Non-randomized 160 (78.0) 51 (27.3)
Funding source < 0.001
Industry 29 (14.2) 12 (6.4)
NCI 103 (50.2) 43 (23.0)
Other 73 (35.6) 132 (70.6)
Study sample < 0.001
< 50 129 (62.9) 59 (31.6)
50~100 47 (22.9) 43 (23.0)
>100 29 (14.2) 85 (45.4)
Region < 0.001
US/Canada 136 (66.3) 66 (35.3)
European 7 (3.4) 9 (4.8)
Asia 61 (29.8) 109 (58.3)
Other 1 (0.5) 3 (1.6)

Abbreviations: NCI = national cancer institute; US = Unite States.

a P-values were calculated using Pearson Chi-square test or Fisher’s exact test if indicated.

b Three trials in the metastatic/recurrent trials arm and 19 trials in non-metastatic/recurrent trials arm were missing.

Discussion

Clinical trials have play an irreplaceable role in changing clinical practice and decision making in medicine, especially for well-designed randomized clinical trials. NPC, known as a cancer rising from nasopharynx epithelium, is mainly prevalent in Southeast Asia, the Middle East and North Africa [1012]. Therefore, given the overall low incidence rate worldwide, NPC does not attract the attention of most researches and little is known about the current status of clinical trials regarding NPC. To the best of our knowledge, our study is the first one to report the landscape of NPC-related trials and assess the characteristics of these trials. Our findings suggested that NPC-related trials were predominantly early-phase trials with small samples less than 100 and mainly focused on chemotherapy and targeted therapy intervention. Surprisingly, metastatic/recurrent disease even occupied a greater part in these trials. Obviously, NPC trials were more likely to be performed in Asia while multiple cancer trials were mainly conducted in US/Canada.

Although multiple cancer trials recruited patients with NPC, the information of managing NPC they provided may be very limited because most of these trials were conducted in US/Canada where the incidence of NPC is extremely low and mainly focused on other head and neck cancers. Actually, there are few publications regarding NPC from this region. Notably, compared with NPC trials, the multiple cancer trials had a higher percentage of phase 1 (26.7% vs. 6.7%) studies and patients with metastatic/recurrent disease (72.5% vs. 41.9%). One reasonable explanation is that these trials were conducted to test new drugs or new treatment modalities in patients with metastatic/recurrent who failed standard therapy. Hence, these trials were more likely to have small samples of less than 50 (58.3% vs. 32.4%) and to be single arm (60.8% vs. 37.4%) and non-randomized (61.6% vs. 38.3%).

NPC has been established as an EBV-associated cancer for a long time [1315]. Subsequently, the prognostic value of plasma EBV DNA has been widely proven both in non-disseminated [9, 1623] and metastatic/recurrent disease [24, 25]. Moreover, plasma EBV DNA could also stratify patients into different risk groups and guide individualized treatment [2628]. Therefore, plasma EBV DNA could be a reliable biomarker and should play an important role when designing clinical trials. However, results of our study reveal only 10.2% of the trials are EBV-related, and the distribution of these trials (Fig 3) remind us that the number increased only after 2014 but was still small. One of the main reasons is that there is no uniform standard in detecting the plasma EBV DNA level worldwide and hospitals would get different results if different test reagents are used, which makes it hard to perform multicenter collaborations. Therefore, EBV trials has a lower percentage of phase 2/3 (48.8% vs. 78.4%) and interventional (70.7% vs. 89.5%) studies. Future trials are urgently warranted to focus on the standardization of detecting plasma EBV DNA.

Fig 3. Distribution of EBV-related trials according to registered year in ClinicalTrials.gov database up.

Fig 3

Abbreviations: EBV = Epstein-Barr virus.

Although primary metastasis at initial diagnosis accounts for only 4.4% to 6% of all NPC patients [2931] and excellent therapeutic outcomes have been achieve for advanced NPC, distant metastasis and recurrence after radiotherapy still remain a huge challenge. Our study showed that 205 trials regarding metastatic/recurrent disease were performed; however, most of these trials were conducted in US/Canada and were multiple cancer trials mainly focusing on other head and neck cancers. Furthermore, these trials were more likely to be early-phase, non-randomized and small-scale (< 50) compared with trials recruiting non-metastatic/recurrent patients. Therefore, we still lack high-level evidence of managing metastatic/recurrent disease. Actually, a recent study carried out by Zhang et al. [32] is the only phase 3 randomized trial focusing on metastatic/recurrent disease in endemic era. Hence, more attention should be paid to this subpopulation to optimize clinical practice.

Limitations of this study should also be acknowledged. First, ClinicalTrials.gov database does not include all clinical trials because investigators and sponsors may register their studies at other registrations. This may be embedded in the small number of trials from European. Second, some investigators or sponsors may input unconsciously wrong information in this database which would complicate our conclusions as the NLM cannot verify the trial information sponsors provided on ClinicalTrials.gov. Moreover, we did not assess the final results of these trials because part of these trials are still ongoing or not reporting the results.

Conclusions

Overall, our study firstly provides a best-possible overview of current clinical trials regarding NPC and demonstrated that the number is still insufficient especially for high-level, randomized phase 3 trials. The role of plasma EBV DNA in clinical trials is far from its value in clinical practice although numerous studies have established its value in prognosis prediction, risk stratification and decision making. Moreover, more randomized clinical trials should be performed for patients with metastatic/recurrent disease because we still lack high-level evidence in treating these patients.

Supporting information

S1 File. Summary of the 462 included clinical trials.

(XLSX)

Acknowledgments

We sincerely thanked the Sun Yat-sen University Cancer Center for providing the Research Data Deposit site for storing the data of current study (RDDA2017000152).

Data Availability

All relevant data are found within the paper and its Supporting Information file.

Funding Statement

This work was supported by grants from the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10); the Health & Medical Collaborative Innovation Project of Guangzhou City, China (201400000001) and the Science and Technology Project of Guangzhou City, China (14570006). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.Razak AR, Siu LL, Liu FF, Ito E, O’Sullivan B, Chan K. Nasopharyngeal carcinoma: the next challenges. Eur J Cancer. 2010; 46:1967–1978. doi: 10.1016/j.ejca.2010.04.004 . [DOI] [PubMed] [Google Scholar]
  • 2.Sun X, Su S, Chen C, Han F, Zhao C, Xiao W, 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; 110:398–403. doi: 10.1016/j.radonc.2013.10.020 . [DOI] [PubMed] [Google Scholar]
  • 3.Yang L, Hong S, Wang Y, Chen H, Liang S, Peng P, et al. Development and External Validation of Nomograms for Predicting Survival in Nasopharyngeal Carcinoma Patients after Definitive Radiotherapy. Sci Rep. 2015; 5:15638 doi: 10.1038/srep15638 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Zhang MX, Li J, Shen GP, Zou X, Xu JJ, Jiang R, et al. Intensity-modulated radiotherapy prolongs the survival of patients with nasopharyngeal carcinoma compared with conventional two-dimensional radiotherapy: A 10-year experience with a large cohort and long follow-up. Eur J Cancer. 2015; 51:2587–2595. doi: 10.1016/j.ejca.2015.08.006 . [DOI] [PubMed] [Google Scholar]
  • 5.Yi JL, Gao L, Huang XD, Li SY, Luo JW, Cai WM, et al. Nasopharyngeal carcinoma treated by radical radiotherapy alone: Ten-year experience of a single institution. Int J Radiat Oncol Biol Phys. 2006; 65:161–168. doi: 10.1016/j.ijrobp.2005.12.003 . [DOI] [PubMed] [Google Scholar]
  • 6.Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet. 2005; 365:2041–2054. doi: 10.1016/S0140-6736(05)66698-6 . [DOI] [PubMed] [Google Scholar]
  • 7.De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med. 2004; 351:1250–1251. doi: 10.1056/NEJMe048225 . [DOI] [PubMed] [Google Scholar]
  • 8.Anderson ML, Chiswell K, Peterson ED, Tasneem A, Topping J, Califf RM. Compliance with results reporting at ClinicalTrials.gov. N Engl J Med. 2015; 372:1031–1039. doi: 10.1056/NEJMsa1409364 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, et al. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med. 2004; 350:2461–2470. doi: 10.1056/NEJMoa032260 . [DOI] [PubMed] [Google Scholar]
  • 10.Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev. 2006; 15: 1765–1777. doi: 10.1158/1055-9965.EPI-06-0353 . [DOI] [PubMed] [Google Scholar]
  • 11.Shanmugaratnam K, Chan SH, de-The G, Goh JE, Khor TH, Simons MJ, et al. Histopathology of nasopharyngeal carcinoma: correlations with epidemiology, survival rates and other biological characteristics. Cancer. 1979; 44:1029–1044. . [DOI] [PubMed] [Google Scholar]
  • 12.Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol. 2002; 12:421–429. . [DOI] [PubMed] [Google Scholar]
  • 13.Chang YS, Tyan YS, Liu ST, Tsai MS, Pao CC. Detection of Epstein-Barr virus DNA sequences in nasopharyngeal carcinoma cells by enzymatic DNA amplification. J Clin Microbiol. 1990; 28:2398–2402. . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Chen CL, Wen WN, Chen JY, Hsu MM, Hsu HC. Detection of Epstein-Barr virus genome in nasopharyngeal carcinoma by in situ DNA hybridization. Intervirology. 1993; 36:91–98. doi: 10.1159/000150327 . [DOI] [PubMed] [Google Scholar]
  • 15.Tsai ST, Jin YT, Su IJ. Expression of EBER1 in primary and metastatic nasopharyngeal carcinoma tissues using in situ hybridization. A correlation with WHO histologic subtypes. Cancer. 1996; 77:231–236. doi: 10.1002/(SICI)1097-0142(19960115)77:2<231::AID-CNCR2>3.0.CO;2-P . [DOI] [PubMed] [Google Scholar]
  • 16.Chan AT, Lo YM, Zee B, Chan LY, Ma BB, Leung SF, et al. Plasma Epstein-Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst. 2002; 94:1614–1619. . [DOI] [PubMed] [Google Scholar]
  • 17.Leung SF, Chan AT, Zee B, Ma B, Chan LY, Johnson PJ, et al. Pretherapy quantitative measurement of circulating Epstein-Barr virus DNA is predictive of posttherapy distant failure in patients with early-stage nasopharyngeal carcinoma of undifferentiated type. Cancer. 2003; 98:288–291. doi: 10.1002/cncr.11496 . [DOI] [PubMed] [Google Scholar]
  • 18.Leung SF, Chan KC, Ma BB, Hui EP, Mo F, Chow KC, et al. Plasma Epstein-Barr viral DNA load at midpoint of radiotherapy course predicts outcome in advanced-stage nasopharyngeal carcinoma. Ann Oncol. 2014; 25:1204–1208. doi: 10.1093/annonc/mdu117 . [DOI] [PubMed] [Google Scholar]
  • 19.Leung SF, Zee B, Ma BB, Hui EP, Mo F, Lai M, et al. Plasma Epstein-Barr viral deoxyribonucleic acid quantitation complements tumor-node-metastasis staging prognostication in nasopharyngeal carcinoma. J Clin Oncol. 2006; 24:5414–5418. doi: 10.1200/JCO.2006.07.7982 . [DOI] [PubMed] [Google Scholar]
  • 20.Lin JC, Chen KY, Wang WY, Jan JS, Liang WM, Tsai CS, et al. Detection of Epstein-Barr virus DNA in the peripheral-blood cells of patients with nasopharyngeal carcinoma: relationship to distant metastasis and survival. J Clin Oncol. 2001; 19:2607–2615. doi: 10.1200/JCO.2001.19.10.2607 . [DOI] [PubMed] [Google Scholar]
  • 21.Lin JC, Wang WY, Liang WM, Chou HY, Jan JS, Jiang RS, et al. Long-term prognostic effects of plasma epstein-barr virus DNA by minor groove binder-probe real-time quantitative PCR on nasopharyngeal carcinoma patients receiving concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2007; 68:1342–1348. doi: 10.1016/j.ijrobp.2007.02.012 . [DOI] [PubMed] [Google Scholar]
  • 22.Ma BB, King A, Lo YM, Yau YY, Zee B, Hui EP, et al. Relationship between pretreatment level of plasma Epstein-Barr virus DNA, tumor burden, and metabolic activity in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2006; 66:714–720. doi: 10.1016/j.ijrobp.2006.05.064 . [DOI] [PubMed] [Google Scholar]
  • 23.Peng H, Guo R, Chen L, Zhang Y, Li WF, Mao YP, et al. Prognostic Impact of Plasma Epstein-Barr Virus DNA in Patients with Nasopharyngeal Carcinoma Treated using Intensity-Modulated Radiation Therapy. Sci Rep. 2016; 6:22000 doi: 10.1038/srep22000 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.An X, Wang FH, Ding PR, Deng L, Jiang WQ, Zhang L, et al. Plasma Epstein-Barr virus DNA level strongly predicts survival in metastatic/recurrent nasopharyngeal carcinoma treated with palliative chemotherapy. Cancer. 2011; 117:3750–3757. doi: 10.1002/cncr.25932 . [DOI] [PubMed] [Google Scholar]
  • 25.Jin Y, Cai XY, Cai YC, Cao Y, Xia Q, Tan YT, et al. To build a prognostic score model containing indispensible tumour markers for metastatic nasopharyngeal carcinoma in an epidemic area. Eur J Cancer. 2012; 48:882–888. doi: 10.1016/j.ejca.2011.09.004 . [DOI] [PubMed] [Google Scholar]
  • 26.Du XJ, Tang LL, Chen L, Mao YP, Guo R, Liu X, et al. Neoadjuvant chemotherapy in locally advanced nasopharyngeal carcinoma: Defining high-risk patients who may benefit before concurrent chemotherapy combined with intensity-modulated radiotherapy. Sci Rep. 2015; 5:16664 doi: 10.1038/srep16664 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Peng H, Chen L, Li WF, Guo R, Zhang Y, Zhang F, et al. Prognostic Value of Neoadjuvant Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma with Low Pre-treatment Epstein-Barr Virus DNA: a Propensity-matched Analysis. J Cancer. 2016; 7:1465–1471. doi: 10.7150/jca.15736 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Twu CW, Wang WY, Chen CC, Liang KL, Jiang RS, Wu CT, et al. Metronomic adjuvant chemotherapy improves treatment outcome in nasopharyngeal carcinoma patients with postradiation persistently detectable plasma Epstein-Barr virus deoxyribonucleic acid. Int J Radiat Oncol Biol Phys. 2014; 89:21–29. doi: 10.1016/j.ijrobp.2014.01.052 . [DOI] [PubMed] [Google Scholar]
  • 29.Lee AW, Poon YF, Foo W, Law SC, Cheung FK, Chan DK, et al. Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976–1985: overall survival and patterns of failure. Int J Radiat Oncol Biol Phys. 1992; 23:261–270. . [DOI] [PubMed] [Google Scholar]
  • 30.Sham JS, Choy D, Choi PH. Nasopharyngeal carcinoma: the significance of neck node involvement in relation to the pattern of distant failure. Br J Radiol. 1990; 63:108–113. doi: 10.1259/0007-1285-63-746-108 . [DOI] [PubMed] [Google Scholar]
  • 31.Teo PM, Kwan WH, Lee WY, Leung SF, Johnson PJ. Prognosticators determining survival subsequent to distant metastasis from nasopharyngeal carcinoma. Cancer. 1996; 77:2423–2431. doi: 10.1002/(SICI)1097-0142(19960615)77:12<2423::AID-CNCR2>3.0.CO;2-N . [DOI] [PubMed] [Google Scholar]
  • 32.Zhang L, Huang Y, Hong S, Yang Y, Yu G, Jia J, 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; 388:1883–1892. doi: 10.1016/S0140-6736(16)31388-5 . [DOI] [PubMed] [Google Scholar]

Associated Data

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

Supplementary Materials

S1 File. Summary of the 462 included clinical trials.

(XLSX)

Data Availability Statement

All relevant data are found within the paper and its Supporting Information file.


Articles from PLoS ONE are provided here courtesy of PLOS

RESOURCES