- Email: [email protected]
Reporting Quality of Randomized, Controlled Trials Evaluating Combined Chemoradiotherapy in Nasopharyngeal Carcinoma
Accepted Manuscript Reporting Quality of Randomised Controlled Trials Evaluating Combined Chemoradiotherapy in Nasopharyngeal Carcinoma Yu-Pei Chen, M.D., Lei Chen, M.D., Wen-Fei Li, M.D., Anne W.M. Lee, M.D., Jan B. Vermorken, MD, Ph.D., Joseph Wee, FRCR, Brian O’Sullivan, M.D., Avraham Eisbruch, M.D., Jin-Ching Lin, M.D., Hai-Qiang Mai, MD, Ph.D., Li Zhang, M.D., Ying Guo, M.D., Ai-Hua Lin, M.D., Ying Sun, Ph.D., Jun Ma, M.D. PII:
S0360-3016(17)30276-6
DOI:
10.1016/j.ijrobp.2017.01.214
Reference:
ROB 24052
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 9 November 2016 Revised Date:
7 January 2017
Accepted Date: 19 January 2017
Please cite this article as: Chen Y-P, Chen L, Li W-F, Lee AWM, Jan Vermorken B, Wee J, O’Sullivan B, Eisbruch A, Lin J-C, Mai H-Q, Zhang L, Guo Y, Lin A-H, Sun Y, Ma J, Reporting Quality of Randomised Controlled Trials Evaluating Combined Chemoradiotherapy in Nasopharyngeal Carcinoma, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/j.ijrobp.2017.01.214. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title page
Title: Reporting Quality of Randomised Controlled Trials Evaluating Combined
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Chemoradiotherapy in Nasopharyngeal Carcinoma
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Running title: Reporting Quality for NPC Trials
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Authors and Affiliations:
Yu-Pei Chen, M.D.,1* Lei Chen, M.D.,1* Wen-Fei Li, M.D.,1* Anne W.M. Lee, M.D.,2 Jan B.Vermorken, MD, Ph.D.,3 Joseph Wee, FRCR,4 Brian O’Sullivan, M.D.,5 Avraham Eisbruch, M.D.,6 Jin-Ching Lin, M.D.,7 Hai-Qiang Mai, MD, Ph.D.,8 Li
M.D.,1†
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Zhang, M.D.,9 Ying Guo, M.D.,10 Ai-Hua Lin, M.D.,11 Ying Sun, Ph.D.,1 Jun Ma,
1. Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State
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Key Laboratory of Oncology in South China, Collaborative Innovation Centre of
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Cancer Medicine, Guangzhou, People’s Republic of China 2. Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, People’s Republic of China 3. Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium 4. Department of Radiation Oncology, National Cancer Centre Singapore, Singapore 5. Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
ACCEPTED MANUSCRIPT 6. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States 7. Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung,
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Taiwan 8. Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre
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of Cancer Medicine, Guangzhou, People’s Republic of China
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9. Department of Medical Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre of Cancer Medicine, Guangzhou, People’s Republic of China
10. Clinical Trials Centre, Sun Yat-sen University Cancer Centre, State Key
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Laboratory of Oncology in South China, Collaborative Innovation Centre of Cancer Medicine, Guangzhou, People’s Republic of China 11. Department of Medical Statistics and Epidemiology, School of Public Health, Sun
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Yat-sen University, Guangzhou, People’s Republic of China
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* Yu-Pei Chen, Lei Chen, and Wen-Fei Li contributed equally to this work. †Corresponding author: Jun Ma, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of China. Tel.:+86-20-87343469
ACCEPTED MANUSCRIPT Fax:+86-20-87343295 E-mail: [email protected]
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Grant support This work was supported by grants from the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10); the Health &
Planned
Science
and
Technology
Project
of
Guangdong
Province
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the
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Medical Collaborative Innovation Project of Guangzhou City, China (201400000001);
(2013B020400004); and the Science and Technology Project of Guangzhou City, China (14570006).
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Acknowledgements
We thank the Clinical Trials Centre, Sun Yat-sen University Cancer Centre, for assistance in data interpretation. We thank Dr Jean-Pierre Pignon (Meta-analysis Unit,
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Biostatistics and Epidemiology Department, Institut Gustave Roussy, France) for his
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statistical assistance and helpful comments on this study.
Conflict of interest statement No potential conflicts of interest were disclosed.
ACCEPTED MANUSCRIPT Summary This study aimed to comprehensively assess the reporting quality of RCTs in NPC based on CONSORT statements. We found that the overall reporting quality for RCTs
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in NPC was unsatisfactory. Substantial selectivity and heterogeneity existed in reporting of certain crucial issues; further efforts are required to ensure stricter
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adherence to the CONSORT recommendations in publications of NPC trials.
ACCEPTED MANUSCRIPT Reporting Quality of Randomised Controlled Trials Evaluating Combined Chemoradiotherapy in Nasopharyngeal Carcinoma
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Purpose: Randomised controlled trials (RCTs) represent the gold standard for evidence-based medicine. This study aimed to comprehensively assess the reporting quality of RCTs in nasopharyngeal carcinoma (NPC), and to identify significant
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predictors of quality.
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Methods and Materials: Two investigators searched MEDLINE and EMBASE for RCTs published between January 1988 and December 2015 that assessed the effect of combined chemoradiotherapy for NPC. The overall quality of each report was assessed using a 28-point overall quality score (OQS) based on the 2010 Consolidated
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Standards of Reporting Trials (CONSORT) statement. To provide baseline data for further evaluation, we also investigated the reporting quality of certain important issues in detail, including key methodologic items (allocation concealment, blinding,
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events.
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intention-to-treat principle), endpoints, follow-up, subgroup analyses, and adverse
Results: We retrieved 24 relevant RCTs including 6,591 patients. Median 2010 OQS and were 15.5 (range, 10-24). Half of the items in the 2010 OQS were poorly reported in at least 40% of trials. Multivariable regression models revealed publication after 2010, high impact factor, were significant predictors of improved 2010 OQS. Additionally, many issues that we consider significant were not reported adequately. Conclusions: Despite publication of the CONSORT statement over a decade ago,
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ACCEPTED MANUSCRIPT overall reporting quality for RCTs in NPC was unsatisfactory. Additionally, substantial selectivity and heterogeneity exists in reporting of certain crucial issues. This survey provides the first prompt for NPC trial investigators to improve reporting
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quality based on the CONSORT statement; increased scrutiny and diligence by editors and peer reviewers is also required.
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Keywords: Randomised controlled trial; Nasopharyngeal carcinoma; Consolidated
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Standards of Reporting Trials statement; Reporting quality
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ACCEPTED MANUSCRIPT INTRODUCTION Randomised controlled trials (RCTs) remain the gold standard for evidence-based medicine. Published RCTs are the most important and direct resources for us to assess
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quality of trials, and poor RCT reporting can have detrimental consequences for routine clinical practice (1). The Consolidated Standards of Reporting Trials (CONSORT) statement was developed to ensure clarity and transparency in trial
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reporting (2); it was updated in 2001 and 2010 to incorporate new elements (3,4).
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Nasopharyngeal carcinoma (NPC) is uncommon in most populations but prevalent in Southeast Asia (5,6). Radiotherapy is the primary treatment; combined chemoradiotherapy has been being investigated in recent decades (7,8). Due to its rarity, a small number of RCTs have been reported for NPC. Therefore, good
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reporting quality is essential to ensure valid meta-analyses. Difficulties in patient recruitment and increasing therapeutic costs also necessitate high quality NPC trials. Thus, in this study, we aimed to assess the quality of overall reporting and certain
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important issues of published RCTs in NPC based on CONSORT statement.
METHODS AND MATERIALS We searched PUBMED and EMBASE to include all RCTs evaluating combined chemoradiotherapy for NPC published between January 1, 1988 and December 31, 2015 (Fig. 1). The overall reporting quality of the included RCTs was assessed using the overall quality score (OQS) (9-11) consisting of 28 items based on the most recent 2010 CONSORT statement (Table 1). A 19-item OQS based on the 2001 CONSORT
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ACCEPTED MANUSCRIPT was also used (Supplementary Table S1). Each item was scored: 1, reported; 0, not clearly stated/definitely not stated. Reporting of allocation concealment, blinding, and intention-to-treat principle (ITT) are considered important methodologic items for
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avoiding bias (9,10). To identify factors associated with reporting quality, we modelled OQS as outcome variables using linear regression; generalized estimating equations was employed (12). Details of study selection, the important issues (key
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methodologic factors, endpoints, follow-up, subgroup analyses and adverse events),
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and statistical analysis are shown in Supplementary Materials.
RESULTS
Twenty-four RCTs were found eligible. Their characteristics are summarized in Table
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2. A total of 6,591 patients were randomly assigned (median, 230; range, 65-803). Inter-rater agreements were substantial, good or perfect for most items (Table 1). The ratings according to the 2010 OQS are listed in Table 1. Median OQS was 15.5
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(range, 10-24) on a 0-28 scale, demonstrating that half of RCTs did not clearly report
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at least 46% of items. With respect to individual items, at least 40% of trials reported 14 of the 28 items poorly (Table 1). In multivariate analyses, publications after 2010 and impact factor (IF) of 4-10 retained independent significance variable that were associated with increased 2010 OQS (Table 3). The median 2001 OQS was 11 (range, 7-15), and the sole independent variable was publication after 2010 (Supplementary Tables S1 and S3). Considering reporting of key methodologic factors, analyses according to ITT
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ACCEPTED MANUSCRIPT were clearly performed in 15 (63%) RCTs (Supplementary Table S4). However, six (67%) of the other nine RCTs stated that the ITT principle was followed but did not analyze patients in a randomised manner, which could be misleading. Supplementary
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Tables S5-7 describe the the reporting of endpoints, follow-up, and subgroup analyses respectively. Of the 24 RCTs, only one of eight (13%) trials used interaction test. The
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median AERS was 7.5 (range, 3-11) on a 0-12 scale.
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adverse event reporting score (AERS) was shown in Supplementary Table S2. The
DISCUSSION
Despite publication of the CONSORT statement over a decade ago, overall reporting quality for RCTs in NPC was unsatisfactory. Substantial selectivity and heterogeneity
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exists in reporting of certain issues. Compared to the 2001 CONSORT statement, items added or redefined in the 2010 revision were usually reported poorly. Additionally, reporting of some items common to both the 2010/2001 OQS was
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neither uniform or complete (e.g., blinging, implementation of randomisation, etc;
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Table 1). The missing information could complicate interpretation, and low quality reporting of certain items such as key methodologic factors may even lead to potential misleading conclusions (9,10). Detailed reporting of these elements may not be viewed with importance, which results in a lack of awareness among authors and reviewers; limitations on word counts may contribute to incomplete reporting. More recent publications adhered better to the CONSORT statement, possibly reflecting increasing uptake of the guidelines (9-11,13).
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ACCEPTED MANUSCRIPT Reporting quality of key methodologic items was suboptimal as well. This may be due to the perception that the clinical features of RCTs are more interesting, particularly as many authors are clinicians. Despite not being reported in publications,
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certain methodological aspects are often adequately performed (14-16); the paucity of information for these items may reflect deliberate de-emphasis, rather than defective trial design. Besides, the reporting of other important issues were also unsatisfactory.
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Great effort is required to improve reporting quality for future publications according
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to the CONSORT items.
This study has several limitations. Compared to other oncology subspecialties (9,10), relatively few trials were available due to the relative rarity of NPC worldwide. In addition, this analysis was limited to information published in RCT reports.
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Another problem is that the OQS gives equal weight to each item on the CONSORT, which may overemphasize some less important items. To compensate for this, we investigated the reporting of certain important issues in details. Also, it should be
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noted that early studies usually got low scores in 2010 CONSORT, as expectations of
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journals and reviewers changed over the lengthy time frame. There are several ways to improve reporting quality: training, increasing the
adherence to CONSORT, or improving it. Training should target those aspects corresponding to items reported in poor quality. In this study, several journals have not adopted CONSORT yet, and more journals should be encouraged to endorse CONSORT to improve reporting of trials. Moreover, to make the current CONSORT friendlier could be helpful.
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ACCEPTED MANUSCRIPT In summary, reporting quality for NPC trials is unsatisfactory. Investigators should be more aware of the CONSORT items and use them in the reporting of trials;
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increased scrutiny and diligence by editors and peer reviewers is also required.
REFERENCES
1. Moher D, Pham B, Jones A, et al. Does quality of reports of randomised trials
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affect estimates of intervention efficacy reported in meta-analyses? Lancet
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1998;352:609-613.
2. Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting of randomized controlled trials. The consort statement. Jama 1996;276:637-639. 3. Moher D, Schulz KF, Altman D, et al. The consort statement: Revised
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recommendations for improving the quality of reports of parallel-group randomized trials. Jama 2001;285:1987-1991. 4. Schulz KF, Altman DG, Moher D, et al. Consort 2010 statement: Updated
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guidelines for reporting parallel group randomised trials. Bmj 2010;340:c332.
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5. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA: a cancer journal for clinicians 2011;61:69-90.
6. Wei KR, Zheng RS, Zhang SW, et al. Nasopharyngeal carcinoma incidence and mortality in china in 2010. Chinese journal of cancer 2014;33:381-387.
7. Chua ML, Wee JT, Hui EP, et al. Nasopharyngeal carcinoma. Lancet 2015. 8. Blanchard P, Lee A, Marguet S, et al. Chemotherapy and radiotherapy in nasopharyngeal carcinoma: An update of the mac-npc meta-analysis. Lancet
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ACCEPTED MANUSCRIPT Oncol 2015;16:645-655. 9. Lai R, Chu R, Fraumeni M, et al. Quality of randomized controlled trials reporting in the primary treatment of brain tumors. J Clin Oncol 2006;24:1136-1144.
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10. Toulmonde M, Bellera C, Mathoulin-Pelissier S, et al. Quality of randomized controlled trials reporting in the treatment of sarcomas. J Clin Oncol 2011;29:1204-1209.
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11. Peron J, Pond GR, Gan HK, et al. Quality of reporting of modern randomized
2012;104:982-989.
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controlled trials in medical oncology: A systematic review. J Natl Cancer Inst
12. Zeger SL, Liang KY, Albert PS. Models for longitudinal data: A generalized estimating equation approach. Biometrics 1988;44:1049-1060.
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13. Moher D, Jones A, Lepage L, et al. Use of the consort statement and quality of reports of randomized trials: A comparative before-and-after evaluation. Jama 2001;285:1992-1995.
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14. Devereaux PJ, Choi PT, El-Dika S, et al. An observational study found that
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authors of randomized controlled trials frequently use concealment of randomization and blinding, despite the failure to report these methods. J Clin
Epidemiol 2004;57:1232-1236.
15. Soares HP, Daniels S, Kumar A, et al. Bad reporting does not mean bad methods for randomised trials: Observational study of randomised controlled trials performed by the radiation therapy oncology group. Bmj 2004;328:22-24. 16. Pildal J, Chan AW, Hrobjartsson A, et al. Comparison of descriptions of allocation
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ACCEPTED MANUSCRIPT concealment in trial protocols and the published reports: Cohort study. Bmj
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2005;330:1049.
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ACCEPTED MANUSCRIPT FIGURE LEGENDS Figure 1. Flowchart of selection process of randomised controlled trial (RCT)
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articles.
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Table 1. Overall Quality of Reporting: Rating Using Items Based on the 2010 CONSORT Statement (n = 24) Item Criteria 1 Title
Description Identification as a randomised trial in the title
No. of Positive Trials 18
% 75
95% CI 56 to 94
Cohen’s κ Coefficient 1
Abstract structure
Structured summary of trial design, methods, results and conclusions
24
100
3
Background
Adequate description of the scientific background and explanation of
23
96
87 to 100
0.65
22
92
80 to 100
0.65
12
50
28 to 72
0.67
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2
rationale Objectives
Description of the specific objectives or the scientific hypotheses in the introduction
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4
NA*
Trial design
Description of trial design, including allocation ratio
6
Participants
Description of the eligibility criteria for participants
24
100
7
Settings and location
Description of the settings and locations where the data were collected
9
38
8
Interventions
Details of the interventions intended for each group
24
100
9
Outcomes
Definition of primary and secondary outcome measures, including how
16
67
46 to 87
0.80
and when they were assessed
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5
NA* 17 to 58
0.65 NA*
Sample size
Description of sample size calculation
19
79
62 to 97
0.86
11
Randomisation,
Definition of the method used to generate the random allocation
12
50
28 to 72
0.75
sequence generation
sequence
Randomisation,
Description of the type of randomisation; details of any restriction
17
71
51 to 90
0.90
Allocation
Description of the mechanism used to implement the random allocation
9
38
17 to 58
0.83
concealment
sequence to assure concealment until interventions were assigned
Implementation
Description of who generated the random allocation sequence, who
1
4
0 to 13
0.65
restriction 13
14
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12
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10
enrolled participants, and who assigned participants to interventions
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15
Blinding
Whether or not participants, those administering the interventions, or
1
4
0 to 13
0.65
24
100
11
46
24 to 67
0.92
those assessing the outcomes were blinded to group assignment; if relevant, description of the similarity of interventions Statistical methods
Description of the statistical methods used to compare groups for
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16
primary and secondary outcomes Ancillary analysis,
Description of the methods for additional analyses, such as subgroup
method
analyses and adjusted analyses
18
Diagram
A CONSORT diagram was presented to show the flow of participants
9
38
17 to 58
1
19
Participant flow
Details on the flow of participants through each stage of the trials
8
33
13 to 54
0.57
3 to 38
0.70
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17
NA*
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(number of patients randomly assigned, receiving intended treatment, and were analyzed for the primary outcome) Recruitment
Dates defining the periods of recruitment and follow-up
5
21
21
Baseline data
A table showing baseline demographic and clinical characteristics for
24
100
15
63
42 to 83
0.73
15
63
42 to 83
0.74
12
50
28 to 72
0.67
14
58
37 to 80
0.73
each group 22
Intent-to-treat analysis
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20
Number of patients in each group included in each analysis and whether
NA*
randomly assigned 23
Outcomes measures
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patients were analyzed according to the group to which they were
For each primary and secondary outcome, a summary of results for each
provided 24
Ancillary analyses
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group, the estimated effect size and its precision (e.g., 95% CI) are
Results of subgroup analyses and adjusted analyses, distinguishing prespecified from exploratory
25
Adverse event
Description of all important adverse events in each group, with
classification
classification
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26
Registration
Presentation of the registration number and name of trial registry
4
17
1 to 33
1
27
Protocol
Where the full trial protocol can be accessed
1
4
0 to 13
1
28
Funding
Sources of funding and other support
17
71
51 to 90
1
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Abbreviations: CONSORT, Consolidated Standards of Reporting Trials; NA, not available. * Cohen’s κ indices could not be calculated as the positive rates awarded by the two investigators were both 100% for these items.
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Table 2. Trial Characteristics No. of Studies (n = 24)
%
1988-2000
5
21
2001-2009
13
54
2010-2015
6
25
Asia
20
83
Europe & North America
4
17
Government/foundation
13
54
Partially funded by industry
3
13
Completely funded by industry
1
4
Funding not reported
7
29
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Characteristic Year of publication
Journal of Clinical Oncology
11
International Journal of Radiation
5
21
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Oncology, Biology, Physics
46
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Journal
3
13
5
21
<4
2
8
4-10
10
42
> 10
12
50
Cancer Other journals* Journal impact factor
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Sources of trial funding
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Region in which trials were conducted
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Phase II
2
8
III
22
92
Concomitant
6
25
Concomitant + adjuvant
5
25
Induction
9
38
Adjuvant
3
13
Positive
9
38
Negative
15
63
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Chemotherapy intervention
Sample size 230 (65-803)
< 200
9
200-400
11
> 400
4
38
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Median (Range)
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Primary outcome
46
17
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* Each journal published only one RCT. They were Lancet Oncology, Journal
Chinese Journal of Cancer.
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of the National Cancer Institute, Annals of Oncology, Medical Oncology, and
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Table 3. Publication Characteristics Associated with 2010 Overall Reporting Quality* Mean OQS (95% CI)
Univariate Analyses Estimate (95% CI)†
Before
15.4 (13.7 to 17.2)
Reference
After
18.7 (15.2 to 22.2)
1.9 (-0.1 to 6.3)
Asia
16.3 (14.4 to 18.2)
Reference
Europe & North America
16.0 (13.8 to 18.2)
-0.3 (-2.9 to 2.3)
No industry funding
17.4 (15.1 to 19.7)
Reference
Some industry funding
16.0 (11.3 to 20.7)
-2.0 (-7.9 to 3.8)
0.49
Unknown
14.3 (12.0 to 166)
-2.0 (-5.4 to 1.5)
0.26
0.056
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Sources of trial funding
16.6 (14.2 to 19.0)
> 10
16.3 (13.7 to 18.9)
Phase
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4-10
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Journal impact factor 14.0 (11.9 to 16.1)
Reference 4.1 (1.0 to 7.2)
Not included
Reference 0.009
4.6 (0.7 to 8.5)
0.021
1.8 (-0.1 to 2.9)
0.071
1.1 (-0.6 to 8.2)
0.092
III
16.0 (14.3 to 17.8)
-2.6 (-5.0 to -0.3)
Negative
14.1 (12.6 to 15.6)
Reference
Positive
18.1 (15.7 to 20.4)
3.40 (1.0 to 5.8)
15.3 (12.6 to 18.0)
Reference
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Not included
2.3 (0.6 to 4.1)
19.0 (NA)
Reference
Reference 0.028
-0.2 (-5.3 to 4.8)
0.92
Reference 0.005
2.7 (-0.5 to 6.0)
Sample size < 200
0.009
0.81
Reference
II
Primary outcome
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Region in which trials were conducted
<4
P
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Publication Characteristic Publication of 2010 CONSORT statement
Multivariable Analyses Estimate (95% CI)†
Not included
0.098
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200-400
16.5 (14.1 to 18.8)
0.8 (-1.6 to 3.2)
0.52
> 400
17.8 (12.7 to 22.8)
2.5 (-2.7 to 7.6)
0.35
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Abbreviations: CONSORT, Consolidated Standards of Reporting Trials; NA, not available. * Scale of 0 to 28. † The estimates indicate the benefit observed compared with the reference. Any positive value indicates incremental benefit compared with the reference, whereas any negative value indicates detriment compared with the reference.
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S0360-3016(17)30276-6
DOI:
10.1016/j.ijrobp.2017.01.214
Reference:
ROB 24052
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 9 November 2016 Revised Date:
7 January 2017
Accepted Date: 19 January 2017
Please cite this article as: Chen Y-P, Chen L, Li W-F, Lee AWM, Jan Vermorken B, Wee J, O’Sullivan B, Eisbruch A, Lin J-C, Mai H-Q, Zhang L, Guo Y, Lin A-H, Sun Y, Ma J, Reporting Quality of Randomised Controlled Trials Evaluating Combined Chemoradiotherapy in Nasopharyngeal Carcinoma, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/j.ijrobp.2017.01.214. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title page
Title: Reporting Quality of Randomised Controlled Trials Evaluating Combined
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Chemoradiotherapy in Nasopharyngeal Carcinoma
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Running title: Reporting Quality for NPC Trials
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Authors and Affiliations:
Yu-Pei Chen, M.D.,1* Lei Chen, M.D.,1* Wen-Fei Li, M.D.,1* Anne W.M. Lee, M.D.,2 Jan B.Vermorken, MD, Ph.D.,3 Joseph Wee, FRCR,4 Brian O’Sullivan, M.D.,5 Avraham Eisbruch, M.D.,6 Jin-Ching Lin, M.D.,7 Hai-Qiang Mai, MD, Ph.D.,8 Li
M.D.,1†
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Zhang, M.D.,9 Ying Guo, M.D.,10 Ai-Hua Lin, M.D.,11 Ying Sun, Ph.D.,1 Jun Ma,
1. Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State
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Key Laboratory of Oncology in South China, Collaborative Innovation Centre of
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Cancer Medicine, Guangzhou, People’s Republic of China 2. Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, People’s Republic of China 3. Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium 4. Department of Radiation Oncology, National Cancer Centre Singapore, Singapore 5. Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
ACCEPTED MANUSCRIPT 6. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States 7. Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung,
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Taiwan 8. Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre
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of Cancer Medicine, Guangzhou, People’s Republic of China
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9. Department of Medical Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre of Cancer Medicine, Guangzhou, People’s Republic of China
10. Clinical Trials Centre, Sun Yat-sen University Cancer Centre, State Key
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Laboratory of Oncology in South China, Collaborative Innovation Centre of Cancer Medicine, Guangzhou, People’s Republic of China 11. Department of Medical Statistics and Epidemiology, School of Public Health, Sun
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Yat-sen University, Guangzhou, People’s Republic of China
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* Yu-Pei Chen, Lei Chen, and Wen-Fei Li contributed equally to this work. †Corresponding author: Jun Ma, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of China. Tel.:+86-20-87343469
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Grant support This work was supported by grants from the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10); the Health &
Planned
Science
and
Technology
Project
of
Guangdong
Province
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the
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Medical Collaborative Innovation Project of Guangzhou City, China (201400000001);
(2013B020400004); and the Science and Technology Project of Guangzhou City, China (14570006).
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Acknowledgements
We thank the Clinical Trials Centre, Sun Yat-sen University Cancer Centre, for assistance in data interpretation. We thank Dr Jean-Pierre Pignon (Meta-analysis Unit,
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Biostatistics and Epidemiology Department, Institut Gustave Roussy, France) for his
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statistical assistance and helpful comments on this study.
Conflict of interest statement No potential conflicts of interest were disclosed.
ACCEPTED MANUSCRIPT Summary This study aimed to comprehensively assess the reporting quality of RCTs in NPC based on CONSORT statements. We found that the overall reporting quality for RCTs
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in NPC was unsatisfactory. Substantial selectivity and heterogeneity existed in reporting of certain crucial issues; further efforts are required to ensure stricter
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adherence to the CONSORT recommendations in publications of NPC trials.
ACCEPTED MANUSCRIPT Reporting Quality of Randomised Controlled Trials Evaluating Combined Chemoradiotherapy in Nasopharyngeal Carcinoma
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Purpose: Randomised controlled trials (RCTs) represent the gold standard for evidence-based medicine. This study aimed to comprehensively assess the reporting quality of RCTs in nasopharyngeal carcinoma (NPC), and to identify significant
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predictors of quality.
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Methods and Materials: Two investigators searched MEDLINE and EMBASE for RCTs published between January 1988 and December 2015 that assessed the effect of combined chemoradiotherapy for NPC. The overall quality of each report was assessed using a 28-point overall quality score (OQS) based on the 2010 Consolidated
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Standards of Reporting Trials (CONSORT) statement. To provide baseline data for further evaluation, we also investigated the reporting quality of certain important issues in detail, including key methodologic items (allocation concealment, blinding,
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events.
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intention-to-treat principle), endpoints, follow-up, subgroup analyses, and adverse
Results: We retrieved 24 relevant RCTs including 6,591 patients. Median 2010 OQS and were 15.5 (range, 10-24). Half of the items in the 2010 OQS were poorly reported in at least 40% of trials. Multivariable regression models revealed publication after 2010, high impact factor, were significant predictors of improved 2010 OQS. Additionally, many issues that we consider significant were not reported adequately. Conclusions: Despite publication of the CONSORT statement over a decade ago,
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ACCEPTED MANUSCRIPT overall reporting quality for RCTs in NPC was unsatisfactory. Additionally, substantial selectivity and heterogeneity exists in reporting of certain crucial issues. This survey provides the first prompt for NPC trial investigators to improve reporting
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quality based on the CONSORT statement; increased scrutiny and diligence by editors and peer reviewers is also required.
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Keywords: Randomised controlled trial; Nasopharyngeal carcinoma; Consolidated
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Standards of Reporting Trials statement; Reporting quality
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ACCEPTED MANUSCRIPT INTRODUCTION Randomised controlled trials (RCTs) remain the gold standard for evidence-based medicine. Published RCTs are the most important and direct resources for us to assess
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quality of trials, and poor RCT reporting can have detrimental consequences for routine clinical practice (1). The Consolidated Standards of Reporting Trials (CONSORT) statement was developed to ensure clarity and transparency in trial
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reporting (2); it was updated in 2001 and 2010 to incorporate new elements (3,4).
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Nasopharyngeal carcinoma (NPC) is uncommon in most populations but prevalent in Southeast Asia (5,6). Radiotherapy is the primary treatment; combined chemoradiotherapy has been being investigated in recent decades (7,8). Due to its rarity, a small number of RCTs have been reported for NPC. Therefore, good
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reporting quality is essential to ensure valid meta-analyses. Difficulties in patient recruitment and increasing therapeutic costs also necessitate high quality NPC trials. Thus, in this study, we aimed to assess the quality of overall reporting and certain
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important issues of published RCTs in NPC based on CONSORT statement.
METHODS AND MATERIALS We searched PUBMED and EMBASE to include all RCTs evaluating combined chemoradiotherapy for NPC published between January 1, 1988 and December 31, 2015 (Fig. 1). The overall reporting quality of the included RCTs was assessed using the overall quality score (OQS) (9-11) consisting of 28 items based on the most recent 2010 CONSORT statement (Table 1). A 19-item OQS based on the 2001 CONSORT
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ACCEPTED MANUSCRIPT was also used (Supplementary Table S1). Each item was scored: 1, reported; 0, not clearly stated/definitely not stated. Reporting of allocation concealment, blinding, and intention-to-treat principle (ITT) are considered important methodologic items for
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avoiding bias (9,10). To identify factors associated with reporting quality, we modelled OQS as outcome variables using linear regression; generalized estimating equations was employed (12). Details of study selection, the important issues (key
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methodologic factors, endpoints, follow-up, subgroup analyses and adverse events),
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and statistical analysis are shown in Supplementary Materials.
RESULTS
Twenty-four RCTs were found eligible. Their characteristics are summarized in Table
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2. A total of 6,591 patients were randomly assigned (median, 230; range, 65-803). Inter-rater agreements were substantial, good or perfect for most items (Table 1). The ratings according to the 2010 OQS are listed in Table 1. Median OQS was 15.5
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(range, 10-24) on a 0-28 scale, demonstrating that half of RCTs did not clearly report
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at least 46% of items. With respect to individual items, at least 40% of trials reported 14 of the 28 items poorly (Table 1). In multivariate analyses, publications after 2010 and impact factor (IF) of 4-10 retained independent significance variable that were associated with increased 2010 OQS (Table 3). The median 2001 OQS was 11 (range, 7-15), and the sole independent variable was publication after 2010 (Supplementary Tables S1 and S3). Considering reporting of key methodologic factors, analyses according to ITT
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ACCEPTED MANUSCRIPT were clearly performed in 15 (63%) RCTs (Supplementary Table S4). However, six (67%) of the other nine RCTs stated that the ITT principle was followed but did not analyze patients in a randomised manner, which could be misleading. Supplementary
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Tables S5-7 describe the the reporting of endpoints, follow-up, and subgroup analyses respectively. Of the 24 RCTs, only one of eight (13%) trials used interaction test. The
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median AERS was 7.5 (range, 3-11) on a 0-12 scale.
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adverse event reporting score (AERS) was shown in Supplementary Table S2. The
DISCUSSION
Despite publication of the CONSORT statement over a decade ago, overall reporting quality for RCTs in NPC was unsatisfactory. Substantial selectivity and heterogeneity
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exists in reporting of certain issues. Compared to the 2001 CONSORT statement, items added or redefined in the 2010 revision were usually reported poorly. Additionally, reporting of some items common to both the 2010/2001 OQS was
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neither uniform or complete (e.g., blinging, implementation of randomisation, etc;
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Table 1). The missing information could complicate interpretation, and low quality reporting of certain items such as key methodologic factors may even lead to potential misleading conclusions (9,10). Detailed reporting of these elements may not be viewed with importance, which results in a lack of awareness among authors and reviewers; limitations on word counts may contribute to incomplete reporting. More recent publications adhered better to the CONSORT statement, possibly reflecting increasing uptake of the guidelines (9-11,13).
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ACCEPTED MANUSCRIPT Reporting quality of key methodologic items was suboptimal as well. This may be due to the perception that the clinical features of RCTs are more interesting, particularly as many authors are clinicians. Despite not being reported in publications,
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certain methodological aspects are often adequately performed (14-16); the paucity of information for these items may reflect deliberate de-emphasis, rather than defective trial design. Besides, the reporting of other important issues were also unsatisfactory.
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Great effort is required to improve reporting quality for future publications according
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to the CONSORT items.
This study has several limitations. Compared to other oncology subspecialties (9,10), relatively few trials were available due to the relative rarity of NPC worldwide. In addition, this analysis was limited to information published in RCT reports.
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Another problem is that the OQS gives equal weight to each item on the CONSORT, which may overemphasize some less important items. To compensate for this, we investigated the reporting of certain important issues in details. Also, it should be
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noted that early studies usually got low scores in 2010 CONSORT, as expectations of
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journals and reviewers changed over the lengthy time frame. There are several ways to improve reporting quality: training, increasing the
adherence to CONSORT, or improving it. Training should target those aspects corresponding to items reported in poor quality. In this study, several journals have not adopted CONSORT yet, and more journals should be encouraged to endorse CONSORT to improve reporting of trials. Moreover, to make the current CONSORT friendlier could be helpful.
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ACCEPTED MANUSCRIPT In summary, reporting quality for NPC trials is unsatisfactory. Investigators should be more aware of the CONSORT items and use them in the reporting of trials;
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increased scrutiny and diligence by editors and peer reviewers is also required.
REFERENCES
1. Moher D, Pham B, Jones A, et al. Does quality of reports of randomised trials
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affect estimates of intervention efficacy reported in meta-analyses? Lancet
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1998;352:609-613.
2. Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting of randomized controlled trials. The consort statement. Jama 1996;276:637-639. 3. Moher D, Schulz KF, Altman D, et al. The consort statement: Revised
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recommendations for improving the quality of reports of parallel-group randomized trials. Jama 2001;285:1987-1991. 4. Schulz KF, Altman DG, Moher D, et al. Consort 2010 statement: Updated
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guidelines for reporting parallel group randomised trials. Bmj 2010;340:c332.
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5. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA: a cancer journal for clinicians 2011;61:69-90.
6. Wei KR, Zheng RS, Zhang SW, et al. Nasopharyngeal carcinoma incidence and mortality in china in 2010. Chinese journal of cancer 2014;33:381-387.
7. Chua ML, Wee JT, Hui EP, et al. Nasopharyngeal carcinoma. Lancet 2015. 8. Blanchard P, Lee A, Marguet S, et al. Chemotherapy and radiotherapy in nasopharyngeal carcinoma: An update of the mac-npc meta-analysis. Lancet
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ACCEPTED MANUSCRIPT Oncol 2015;16:645-655. 9. Lai R, Chu R, Fraumeni M, et al. Quality of randomized controlled trials reporting in the primary treatment of brain tumors. J Clin Oncol 2006;24:1136-1144.
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10. Toulmonde M, Bellera C, Mathoulin-Pelissier S, et al. Quality of randomized controlled trials reporting in the treatment of sarcomas. J Clin Oncol 2011;29:1204-1209.
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11. Peron J, Pond GR, Gan HK, et al. Quality of reporting of modern randomized
2012;104:982-989.
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controlled trials in medical oncology: A systematic review. J Natl Cancer Inst
12. Zeger SL, Liang KY, Albert PS. Models for longitudinal data: A generalized estimating equation approach. Biometrics 1988;44:1049-1060.
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13. Moher D, Jones A, Lepage L, et al. Use of the consort statement and quality of reports of randomized trials: A comparative before-and-after evaluation. Jama 2001;285:1992-1995.
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14. Devereaux PJ, Choi PT, El-Dika S, et al. An observational study found that
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authors of randomized controlled trials frequently use concealment of randomization and blinding, despite the failure to report these methods. J Clin
Epidemiol 2004;57:1232-1236.
15. Soares HP, Daniels S, Kumar A, et al. Bad reporting does not mean bad methods for randomised trials: Observational study of randomised controlled trials performed by the radiation therapy oncology group. Bmj 2004;328:22-24. 16. Pildal J, Chan AW, Hrobjartsson A, et al. Comparison of descriptions of allocation
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ACCEPTED MANUSCRIPT concealment in trial protocols and the published reports: Cohort study. Bmj
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2005;330:1049.
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ACCEPTED MANUSCRIPT FIGURE LEGENDS Figure 1. Flowchart of selection process of randomised controlled trial (RCT)
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articles.
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Table 1. Overall Quality of Reporting: Rating Using Items Based on the 2010 CONSORT Statement (n = 24) Item Criteria 1 Title
Description Identification as a randomised trial in the title
No. of Positive Trials 18
% 75
95% CI 56 to 94
Cohen’s κ Coefficient 1
Abstract structure
Structured summary of trial design, methods, results and conclusions
24
100
3
Background
Adequate description of the scientific background and explanation of
23
96
87 to 100
0.65
22
92
80 to 100
0.65
12
50
28 to 72
0.67
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2
rationale Objectives
Description of the specific objectives or the scientific hypotheses in the introduction
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4
NA*
Trial design
Description of trial design, including allocation ratio
6
Participants
Description of the eligibility criteria for participants
24
100
7
Settings and location
Description of the settings and locations where the data were collected
9
38
8
Interventions
Details of the interventions intended for each group
24
100
9
Outcomes
Definition of primary and secondary outcome measures, including how
16
67
46 to 87
0.80
and when they were assessed
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5
NA* 17 to 58
0.65 NA*
Sample size
Description of sample size calculation
19
79
62 to 97
0.86
11
Randomisation,
Definition of the method used to generate the random allocation
12
50
28 to 72
0.75
sequence generation
sequence
Randomisation,
Description of the type of randomisation; details of any restriction
17
71
51 to 90
0.90
Allocation
Description of the mechanism used to implement the random allocation
9
38
17 to 58
0.83
concealment
sequence to assure concealment until interventions were assigned
Implementation
Description of who generated the random allocation sequence, who
1
4
0 to 13
0.65
restriction 13
14
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12
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10
enrolled participants, and who assigned participants to interventions
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15
Blinding
Whether or not participants, those administering the interventions, or
1
4
0 to 13
0.65
24
100
11
46
24 to 67
0.92
those assessing the outcomes were blinded to group assignment; if relevant, description of the similarity of interventions Statistical methods
Description of the statistical methods used to compare groups for
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16
primary and secondary outcomes Ancillary analysis,
Description of the methods for additional analyses, such as subgroup
method
analyses and adjusted analyses
18
Diagram
A CONSORT diagram was presented to show the flow of participants
9
38
17 to 58
1
19
Participant flow
Details on the flow of participants through each stage of the trials
8
33
13 to 54
0.57
3 to 38
0.70
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17
NA*
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(number of patients randomly assigned, receiving intended treatment, and were analyzed for the primary outcome) Recruitment
Dates defining the periods of recruitment and follow-up
5
21
21
Baseline data
A table showing baseline demographic and clinical characteristics for
24
100
15
63
42 to 83
0.73
15
63
42 to 83
0.74
12
50
28 to 72
0.67
14
58
37 to 80
0.73
each group 22
Intent-to-treat analysis
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20
Number of patients in each group included in each analysis and whether
NA*
randomly assigned 23
Outcomes measures
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patients were analyzed according to the group to which they were
For each primary and secondary outcome, a summary of results for each
provided 24
Ancillary analyses
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group, the estimated effect size and its precision (e.g., 95% CI) are
Results of subgroup analyses and adjusted analyses, distinguishing prespecified from exploratory
25
Adverse event
Description of all important adverse events in each group, with
classification
classification
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26
Registration
Presentation of the registration number and name of trial registry
4
17
1 to 33
1
27
Protocol
Where the full trial protocol can be accessed
1
4
0 to 13
1
28
Funding
Sources of funding and other support
17
71
51 to 90
1
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Abbreviations: CONSORT, Consolidated Standards of Reporting Trials; NA, not available. * Cohen’s κ indices could not be calculated as the positive rates awarded by the two investigators were both 100% for these items.
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Table 2. Trial Characteristics No. of Studies (n = 24)
%
1988-2000
5
21
2001-2009
13
54
2010-2015
6
25
Asia
20
83
Europe & North America
4
17
Government/foundation
13
54
Partially funded by industry
3
13
Completely funded by industry
1
4
Funding not reported
7
29
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Characteristic Year of publication
Journal of Clinical Oncology
11
International Journal of Radiation
5
21
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Oncology, Biology, Physics
46
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Journal
3
13
5
21
<4
2
8
4-10
10
42
> 10
12
50
Cancer Other journals* Journal impact factor
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Sources of trial funding
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Region in which trials were conducted
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Phase II
2
8
III
22
92
Concomitant
6
25
Concomitant + adjuvant
5
25
Induction
9
38
Adjuvant
3
13
Positive
9
38
Negative
15
63
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Chemotherapy intervention
Sample size 230 (65-803)
< 200
9
200-400
11
> 400
4
38
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Median (Range)
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Primary outcome
46
17
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* Each journal published only one RCT. They were Lancet Oncology, Journal
Chinese Journal of Cancer.
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of the National Cancer Institute, Annals of Oncology, Medical Oncology, and
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Table 3. Publication Characteristics Associated with 2010 Overall Reporting Quality* Mean OQS (95% CI)
Univariate Analyses Estimate (95% CI)†
Before
15.4 (13.7 to 17.2)
Reference
After
18.7 (15.2 to 22.2)
1.9 (-0.1 to 6.3)
Asia
16.3 (14.4 to 18.2)
Reference
Europe & North America
16.0 (13.8 to 18.2)
-0.3 (-2.9 to 2.3)
No industry funding
17.4 (15.1 to 19.7)
Reference
Some industry funding
16.0 (11.3 to 20.7)
-2.0 (-7.9 to 3.8)
0.49
Unknown
14.3 (12.0 to 166)
-2.0 (-5.4 to 1.5)
0.26
0.056
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Sources of trial funding
16.6 (14.2 to 19.0)
> 10
16.3 (13.7 to 18.9)
Phase
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4-10
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Journal impact factor 14.0 (11.9 to 16.1)
Reference 4.1 (1.0 to 7.2)
Not included
Reference 0.009
4.6 (0.7 to 8.5)
0.021
1.8 (-0.1 to 2.9)
0.071
1.1 (-0.6 to 8.2)
0.092
III
16.0 (14.3 to 17.8)
-2.6 (-5.0 to -0.3)
Negative
14.1 (12.6 to 15.6)
Reference
Positive
18.1 (15.7 to 20.4)
3.40 (1.0 to 5.8)
15.3 (12.6 to 18.0)
Reference
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Not included
2.3 (0.6 to 4.1)
19.0 (NA)
Reference
Reference 0.028
-0.2 (-5.3 to 4.8)
0.92
Reference 0.005
2.7 (-0.5 to 6.0)
Sample size < 200
0.009
0.81
Reference
II
Primary outcome
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<4
P
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Publication Characteristic Publication of 2010 CONSORT statement
Multivariable Analyses Estimate (95% CI)†
Not included
0.098
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200-400
16.5 (14.1 to 18.8)
0.8 (-1.6 to 3.2)
0.52
> 400
17.8 (12.7 to 22.8)
2.5 (-2.7 to 7.6)
0.35
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Abbreviations: CONSORT, Consolidated Standards of Reporting Trials; NA, not available. * Scale of 0 to 28. † The estimates indicate the benefit observed compared with the reference. Any positive value indicates incremental benefit compared with the reference, whereas any negative value indicates detriment compared with the reference.
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