Chinese patent medicine Fei-Liu-Ping ointment as an adjunctive treatment for non-small cell lung cancer: Protocol for a systematic review

Abstract

Introduction
Fei-Liu-Ping ointment has been widely applied as adjunctive drug in the treatment of non-small cell lung cancer (NSCLC). However, there has been no systematic review of research findings regarding the efficacy of this treatment. Here, we provide a protocol for assessing the effectiveness and safety of Fei-Liu-Ping ointment in the treatment of NSCLC.

Methods and analysis
The electronic databases to be searched will include MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Excerpt Medica Database (EMBASE), China National Knowledge Infrastructure (CNKI), China Scientific Journal Database (VIP), Wanfang Database and Chinese Biomedical Literature Database (CBM). Papers in English or Chinese published from inception to 2016 will be included without any restrictions. We will conduct a meta-analysis of randomised controlled trial if possible. The therapeutic effects according to the standard for treatment of solid tumours by the WHO and the quality of life as evaluated by Karnofsky score and weight will be applied as the primary outcomes. We will also evaluate the data synthesis and risk of bias using Review Manager 5.3 software.

Dissemination
The results of this review will offer implications for the use of Fei-Liu-Ping ointment as an adjunctive treatment for NSCLC. This knowledge will inform recommendations by surgeons and researchers who are interested in the treatment of NSCLC. The results of this systematic review will be disseminated through presentation at a conference and publication of the data in a peer-reviewed journal.

Trial registration number
PROSPERO CRD42016036911.

Full text

Chinese patent medicine Fei-Liu-Ping
ointment as an adjunctive treatment for
non-small cell lung cancer: protocol for
a systematic review
Honggang Zheng,
1
Shulin He,
1,2
Rui Liu,
1
Xinyao Xu,
1,2
Tao Xu,
1
Shuntai Chen,
1,2
Qiujun Guo,
1,2
Yebo Gao,
1,2
Baojin Hua
1
To cite: Zheng H, He S,
Liu R, et al. Chinese patent
medicine Fei-Liu-Ping
ointment as an adjunctive
treatment for non-small cell
lung cancer: protocol for a
systematic review. BMJ Open
2017;7:e015045.
doi:10.1136/bmjopen-2016-
015045
▸Prepublication history for
this paper is available online.
To view these files please
visit the journal online
(http://dx.doi.org/10.1136/
bmjopen-2016-015045).
HZ and SH are co-first
authors.
Received 8 November 2016
Accepted 19 December 2016
1
Department of Oncology,
Guang’anmen Hospital, China
Academy of Chinese Medical
Sciences, Beijing, China
2
Beijing University of Chinese
Medicine, Beijing, China
Correspondence to
Professor Honggang Zheng;
honggangzheng@126.com
ABSTRACT
Introduction: Fei-Liu-Ping ointment has been widely
applied as adjunctive drug in the treatment of non-
small cell lung cancer (NSCLC). However, there has
been no systematic review of research findings
regarding the efficacy of this treatment. Here, we
provide a protocol for assessing the effectiveness and
safety of Fei-Liu-Ping ointment in the treatment of
NSCLC.
Methods and analysis: The electronic databases to
be searched will include MEDLINE (PubMed),
Cochrane Central Register of Controlled Trials
(CENTRAL) in the Cochrane Library, Excerpt Medica
Database (EMBASE), China National Knowledge
Infrastructure (CNKI), China Scientific Journal Database
(VIP), Wanfang Database and Chinese Biomedical
Literature Database (CBM). Papers in English or
Chinese published from inception to 2016 will be
included without any restrictions. We will conduct a
meta-analysis of randomised controlled trial if possible.
The therapeutic effects according to the standard for
treatment of solid tumours by the WHO and the quality
of life as evaluated by Karnofsky score and weight will
be applied as the primary outcomes. We will also
evaluate the data synthesis and risk of bias using
Review Manager 5.3 software.
Dissemination: The results of this review will offer
implications for the use of Fei-Liu-Ping ointment as an
adjunctive treatment for NSCLC. This knowledge will
inform recommendations by surgeons and researchers
who are interested in the treatment of NSCLC. The
results of this systematic review will be disseminated
through presentation at a conference and publication of
the data in a peer-reviewed journal.
Trial registration number: PROSPERO
CRD42016036911.
DESCRIPTION OF THE CONDITION
Lung cancer is a lethal cancer and remains a
primary cause of cancer-related deaths in the
USA among both genders, with non-small
cell lung cancers (NSCLCs) accounting for
85% of lung cancer-related deaths.
1
It is esti-
mated that there will be 224 390 new diagno-
ses of lung cancer and nearly 158 080 deaths
in 2016.
2
The American Joint Committee on
Cancer (AJCC) has developed a staging
system to determine the development of
cancer in the body. A list of three variables,
that is, the initial tumour, spread to lymph
nodes, and metastasis, is normally applied as
the reference for staging.
3
Generally, the
staging system is beneficial for the doctor to
plan treatment and predict prognosis. For
example, staging in lung and bronchial
cancer cases reflects different 5-year survival
rates.
4
Lung cancer was first recorded in an
ancient Chinese medical text ‘The Yellow
Emperor’s Internal Classic’(Chinese name:
‘Huang Di Nei Jing’). Based on the theory of
traditional Chinese medicine (TCM), health
qi deficiency was proposed to be responsible
for lung cancer development. Qi is literally
translated into gas or breath, which is the
vital energy for human activity, similarly with
immunity and vitality. TCM theory insists that
the lung masters qi and breath. Abundant qi
will enable the body to fight against diseases,
while qi deficiency will cause pathogenic
Strengths and limitations of this study
▪We will objectively evaluate the efficacy and
safety of Fei-Liu-Ping ointment for the treatment
of non-small cell lung cancer (NSCLC) in this
systematic review.
▪Our review may provide evidence for researchers
and be helpful for clinical practitioners in treating
NSCLC.
▪The systematic review will also have obvious lim-
itations, especially the language bias. Medical
studies prepared in Japanese and Korean will not
be covered in this review.
Zheng H, et al.BMJ Open 2017;7:e015045. doi:10.1136/bmjopen-2016-015045 1
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factors such as ‘qi stagnation’,‘blood stasis’,‘phlegm’,
‘damp’, and ‘toxicity’, which may contribute to the
occurrence of lung cancer. Therefore, clinical practices
focus on dispelling these pathogenic factors and
strengthening qi at the same time.
DESCRIPTION OF THE INTERVENTION
Surgery is proposed as the best treatment for lung
cancer. However, only about 20–25% of tumours are suit-
able for resection.
5
Chemotherapy and radiotherapy
were also thought to be the main treatments but are
associated with serious side effects including toxicity to
normal cells and tissues.
6
Despite the discovery and
application of targeted therapies, the overall survival
remains poor, with an overall 5-year survival rate of
∼16.6%.
7
Therefore, an ideal treatment regime for lung
cancer is still required.
Traditional medicine (TM) is accepted worldwide as
an alternative or adjunctive treatment to the conven-
tional treatments.
8
As reported, at least 30% Americans
see TM practitioners annually. Interestingly, TM has
good efficacy in treating illnesses that are insensitive to
conventional treatment.
9
TCM is an important branch
of TM, which follows the theoretical concepts of
Yin-Yang and the five elements. Herbal medicine is
widely applied in disease treatment based on TCM
theory. There are several different ways to prepare
herbal medicines, including Chinese patent medicine
and herbal extract injection, doctor-prescribed decoc-
tion, classical decoctions described in ancient Chinese
texts, and hospital patent formula.
3
Fei-Liu-Ping (FLP)
ointment was developed by Guang’anmen Hospital,
China Academy of Chinese Medical Sciences and
patented as one of the hospital patent formulas.
Although FLP ointment is widely applied in China to
treat NSCLC, there have been no systematic reviews
evaluating its effectiveness and safety.
HOW THE INTERVENTION MIGHT WORK
FLP ointment is a Chinese patent medicine with a long
history of application in China. FLP ointment consists of
several medical herbs, with the main components being
Astragalus membranaceus, American ginseng, Adenophora
stricta, Radix Ophiopogonis, Oldenlandia diffusa, Bistort
root, Patrinia,semen persicae and pseudoginseng. The
action of As. membranaceus, American ginseng, Ad. stricta
Miq, and Radix Ophiopogonis is to influence the
immune system, suppress cancer cell migration, modu-
late various cancer signalling pathways, and interact with
specific transcription molecules during protection
against inflammation and cancers.
10 11
The action of per-
sicae and pseudoginseng is to activate blood, remove blood
stasis, change the whole blood viscosity, reduce metasta-
sis, and promote immune response.
12
The other herbs,
Oldenlandia diffusa, Bistort root and Patrinia, have the
function of removing toxicity and exert antitumour
effects.
13
FLP ointment has been shown to have many
anticancer activities,
14
which include stimulating den-
dritic cells,
15
inhibiting vascular endothelial growth
factor (VEGF) signalling,
16
modulating matrix metallo-
proteinase 9 (MMP9) and tissue inhibitor of metallopep-
tidase 1 (TIMP-1) expression,
15
and regulating
inflammation through interactions with the nuclear
factor κB (NF-κB) signalling pathway within the tumour
microenvironment.
16 17
According to TCM theory, FLP
ointment can be used for the treatment of symptoms
caused by a dual deficiency of qi, such as fatigue, excess
sweating, etc. Patients always suffer from general weak-
ness and fatigue after chemotherapy or radiotherapy.
18
The symptoms are consistent to the syndrome of qi defi-
ciency in TCM theory. In order to determine the safety
and efficacy of FLP ointment in patients with cancer
receiving chemotherapy, a systematic review will be
performed.
OBJECTIVES
We aimed to propose a protocol for a systematic review
to evaluate the effectiveness and safety of FLP ointment
for the treatment of NSCLC.
METHODS AND ANALYSIS
Criteria
Types of studies
Any available randomised controlled trials (RCTs) in
English and Chinese, both published and unpublished,
will be included in the review.
Types of participants
Patients diagnosed with NSCLC for the first time will be
included. The patients with stage III and IV tumours will
be included, regardless of their age, sex, and ethnicity.
NSCLC must be diagnosed based on the The National
Comprehensive Cancer Network (NCCN) guideline by
pathology and/or cytology methods.
Types of interventions
Studies reporting FLP ointment treatment will be
included. The control group will consist of patients
given no treatment, placebo ointment, or other conven-
tional treatment including chemotherapy, radiotherapy,
and targeted therapy. Trials that evaluate the effects of
FLP ointment used in combination with another therapy
will also be included in the review.
Outcomes
Primary outcomes
The primary outcomes will be the therapeutic effects of
treatment according to standards for the treatment of
solid tumours by the WHO and quality of life as evalu-
ated by Karnofsky score and weight.
Secondary outcomes
Secondary outcomes will include: (a) syndrome accord-
ing to standards for evaluating TCM; (b) safety based on
2Zheng H, et al.BMJ Open 2017;7:e015045. doi:10.1136/bmjopen-2016-015045
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adverse effects; (c) peripheral blood counts of immuno-
competent cells, specifically activity of natural killer cells
and the T lymphocyte subset and (d) survival time.
Search methods for identification of studies
Databases
The electronic databases to be searched will include
MEDLINE, the Cochrane Central Register of Controlled
Trials (CENTRAL) in the Cochrane Library, the Excerpt
Medica Database (EMBASE), the China National
Knowledge Infrastructure (CNKI), China Scientific
Journal Database (VIP), the Wanfang Database, and the
Chinese Biomedical Literature Database (CBM) from
inception to 2016 in English or Chinese.
Searching other resources
We will also search for other relevant systematic review
articles and trials. The cited manuscripts will be manu-
ally searched once one systematic review is included.
Data collection and analysis
Selection of studies
The manuscripts will be included without restrictions on
language or publication status from inception to 2016.
The search terms consist of: non-small cell lung cancer,
FLP ointment, chemotherapy, and RCTs (table 1).
Data extraction and management
Two authors (HZ and SH) will be responsible for the
data extraction independently following the criteria in
the Cochrane Handbook for Systematic Reviews of
Intervention (V.5.1.0).
Excluded studies and the reasons for exclusion will be
listed in a table. Discrepancies during the process of
selection will be resolved by discussion, and a consensus
will be reached by a third person (RL). New information
will be transferred into Review Manager 5.3.
Assessment of risk of bias
Two authors (HZ and SH) will independently assess the
methodological quality of included trials. The methodo-
logical quality of the included RCTs will be assessed
according to the guidance of the Cochrane Handbook
for Systematic Review of Interventions (V.5.1.0), which
includes the following criteria: selection bias caused by
random sequence generation and allocation conceal-
ment, performance bias caused by blinding of partici-
pants and personnel, detection bias caused by blinding
of outcome assessments, attrition bias caused by incom-
plete outcome data, and reporting bias caused by select-
ive outcome reporting. Consensus will be reached via
discussion with a third author (RL) in case of discrepan-
cies. If necessary, we will contact the authors for missing
data, methods of blinding, and randomisation.
Measurements of treatment effect
HRs will be used to summarise survival data. Risk ratios
will be calculated for dichotomous data, and weighted
mean differences will represent continuous outcomes.
For both types of data, 95% CIs will be calculated.
Addressing missing data
If relevant data are missing, we will contact the authors
to request the missing data. If those relevant data are
not acquired, those data will be excluded from the ana-
lysis. Sensitivity analyses will be explored to evaluate how
meta-analysis results change if these were excluded. In
addition, we will discuss the influence of missing data on
the findings of the review.
Assessment of heterogeneity
We will use χ
2
test and I
2
statistic test to assess the hetero-
geneity. If the I
2
value is <50% or p>0.10, we will pool
data using a fixed-effect model. Otherwise, a random
effects model will be used, or we will conduct a descrip-
tive analysis. If substantial heterogeneity is identified,
this point will be listed and potential reasons will be
assessed using subgroup analyses.
Assessment of reporting bias
If 10 or more studies are included in the meta-analysis,
funnel plots will be used to detect reporting bias and
poor methodological quality of small studies. The Egger
method
19
will be also used to explain the asymmetry.
Table 1 Search strategy used in Pubmed database
No Search items
1 Carcinoma, Non-Small Cell Lung
2 Carcinoma, Non Small Cell Lung
3 Carcinomas, Non-Small Cell Lung
4 Lung Carcinoma, Non-Small Cell Lung
5 Lung Carcinomas, Non-Small Cell Lung
6 Non-Small Cell Lung Carcinomas
7 Non-Small Cell Lung Cancer
8 Non-Small Cell Lung Carcinoma
9 Non-Small Cell Lung Carcinoma
10 Carcinoma, Non-Small Cell Lung
11 Non-Small Cell Lung Cancer
12 1 or 2-11
13 fei-liu-ping
14 FLP ointment
15 13 or 14
16 Medicine, Chinese Traditional
17 Traditional Chinese Medicine
18 Chinese Medicine, Traditional
19 Chung I Hsueh
20 Hsueh, Chung I
21 Zhong Yi Xue
22 Chinese Traditional Medicine
23 Traditional Medicine, Chinese
24 16 or 17-23
25 12 and 15 or 24
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Data synthesis
Statistical analyses will be performed using RevMan
manager 5.3 software (The Cochrane Collaboration). If
there is no substantial statistical heterogeneity (I²<50%),
afixed-effect model will be applied. Otherwise, we will
use the random-effect model to reach a conclusion. If
significant heterogeneity is detected, we will search for
the clinical and methodological causes and provide an
explanation. Otherwise, we will exclude the data and
conduct a systematic narrative synthesis to summarise
the findings of the included studies.
Subgroup analysis
If the data are available and sufficient, we will also
conduct subgroup analyses. Relevant subgroups might
include those treated with: FLP ointment versus placebo
ointment or no treatment; FLP ointment versus conven-
tional chemotherapy; FLP ointment plus conventional
chemotherapy versus conventional chemotherapy only;
FLP ointment versus chemoradiotherapy; FLP ointment
plus chemoradiotherapy versus chemoradiotherapy; FLP
ointment versus target therapy; and FLP ointment plus
target therapy versus target therapy. Data will be com-
pared between patients of different sexes and between
stages (diagnosed with III or IV stage).
Sensitivity analysis
We also conduct sensitivity analysis to verify the study
conclusions. The reliability of the conclusions will be
determined according to the methodological qualities,
the sample size, and the option of using missing data.
20
Ethics and dissemination
Ethical approval is not required for the proposed
meta-analysis, because the data used in this systematic
review will not concern the privacy of individual patient.
We will disseminate the results of this systematic review
by publishing the manuscript in a peer-reviewed journal
or presenting the findings at a relevant conference.
DISCUSSION
Chemotherapy causes significant adverse effects on
patients’activities and quality of life, and FLP ointment
is widely used in China to improve the relevant symp-
toms. However, there has been no systematic review of
the efficacy of treatment with FLP ointment. Therefore,
it is necessary to perform an objective systematic review
to assess the efficacy and safety of FLP ointment in the
treatment of NSCLC.
We provide a flow chart for this systematic review
(figure 1). Our review may provide evidence for
researchers and be helpful for clinical practitioners in
treating NSCLC. The systematic review will also have
obvious limitations, especially the language bias. Medical
studies prepared in Japanese and Korean will not be
covered in this review.
Contributors HZ and SH contributed to the conception of the study. HZ and
SH wrote the draft of manuscript, and was revised by XX, TX, SC, QG, YG
and BH. The search strategy was developed by all of the authors, HZ and SH
will search, extract data, assess the risk of bias, and complete the data
synthesis. RL will arbitrate in case of disagreement and ensure the absence of
errors. All authors approved the publication of the protocol.
Funding This work was supported by the National Natural Science
Foundation of China (grant numbers 81273718 and 81102719).
Disclaimer The funders had no influence on the study design, data collection
and analysis, as well as the right to publish.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The findings of this systematic review will be
disseminated via peer-reviewed publications and conference presentations.
Please contact the corresponding author for further information if the
unpublished data from this study are available.
Open Access This is an Open Access article distributed in accordance with
the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work non-
commercially, and license their derivative works on different terms, provided
the original work is properly cited and the use is non-commercial. See: http://
creativecommons.org/licenses/by-nc/4.0/
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systematic review
non-small cell lung cancer: protocol for a
ointment as an adjunctive treatment for
Chinese patent medicine Fei-Liu-Ping
Qiujun Guo, Yebo Gao and Baojin Hua
Honggang Zheng, Shulin He, Rui Liu, Xinyao Xu, Tao Xu, Shuntai Chen,
doi: 10.1136/bmjopen-2016-015045
2017 7: BMJ Open
http://bmjopen.bmj.com/content/7/1/e015045
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