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Prognostic effects of statins in patients with non-small cell lung cancer: a systematic review and meta-analysis protocol

Journal:

BMJ Open

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Manuscript ID Article Type:

bmjopen-2018-022161 Protocol

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Date Submitted by the Author:

Complete List of Authors:

05-Feb-2018

Keywords:

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Li, Feng; Charite Universitatsmedizin Berlin, 1. Department of General, Visceral, Vascular and Thoracic Surgery; The First Affiliated Hospital of Zhengzhou University, Thoracic Surgery Department Liu, Guangyu; Peking University First Hospital, Roudi, Raheleh; Iran University of Medical Sciences, Huang, Qi; Peking University People's Hospital Swierzy, Marc; Charite Universitatsmedizin Berlin, 1. Department of General, Visceral, Vascular and Thoracic Surgery Ismail, Mahmoud; Charite Universitatsmedizin Berlin, 1. Department of General, Visceral, Vascular and Thoracic Surgery Zhao, Song; The First Affiliated Hospital of Zhengzhou University, Thoracic Surgery Department Rueckert, Jens; Charite Universitatsmedizin Berlin , statins, non-small-cell lung cancer, prognostic effects

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Prognostic effects of statins in patients with non-small cell lung cancer: a

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systematic review and meta-analysis protocol

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Feng Li,1,5 Guangyu Liu,2 Raheleh Roudi,3 Qi Huang,4 Marc Swierzy,1 Mahmoud

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Ismail,1 Song Zhao,5 Jens-Carsten Rückert1

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1. Department of General, Visceral, Vascular and Thoracic Surgery, Charité -

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China.

5. Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University

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4. Department of Thoracic Surgery, Peking University People's Hospital, Beijing,

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Iran.

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3. Oncopathology Research Center, Iran University of Medical Sciences, Tehran,

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China.

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2. Department of Anesthesiology, Peking University First Hospital, Beijing, 100035,

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Universitätsmedizin Berlin, Berlin Germany.

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FL, GL and RR are co-first authors and contributed to this work equally.

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Corresponding author: Jens-Carsten Rückert, PhD, MD

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Charitéplatz 1, 10117 Berlin, Germany

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Tel: +49 160 97389944

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Email:

[email protected]

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[email protected]

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[email protected] 1

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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[email protected]

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[email protected]

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[email protected]

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[email protected]

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[email protected]

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Abstract:

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Introduction: Lung cancer is the most common neoplasm and leading cause of

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cancer-related death worldwide. Non-small cell lung cancer (NSCLC), 85 % of all lung

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cancer cases, is mainly diagnosed at advanced and metastatic stage. Unfortunately,

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the survival of NSCLC did not improve significantly during the last decades. Statins

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are used as a cholesterol-lowering agent, but preclinical and clinical studies showed

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their anti-cancer effects. Thus, this systematic review and meta-analysis aims to

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clarify the prognostic effects of statins in patients with NSCLC.

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Methods and Analysis: We will search MEDLINE (PubMed), EMBASE, Web of

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Science and the Cochrane Central Register of Controlled Trials (CENTRAL) with no

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restriction of language. Both randomized controlled trials (RCTs) and observational

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studies evaluating the prognostic role of statins in patients with NSCLC will be

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included. Cancer specific survival is primary outcome and the secondary outcomes

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will include the overall survival, disease free survival and NSCLC recurrence. Two

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assessors will assess the randomized controlled trials using the Cochrane

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Collaboration’s risk of bias tool and observational studies according to the

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Newcastle-Ottawa Scale. Publication bias will be assessed by funnel plot or Egger’s

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test using STATA software (STATA Corp, College Station, TX).

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Ethics and dissemination: No ethical issues are predicted. This systematic review

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and meta-analysis will describe the prognostic effects of statins in NSCLC patients,

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which would help clinicians to optimize the treatment for patients with NSCLC. These

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findings will be published in a peer reviewed journal and presented at national and

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international conferences.

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Registration number: This systematic review protocol is registered in the

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PROSPERO

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(CRD42016047524).

International

Prospective

Register

of

Systematic

Reviews

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Strengths and limitations of this study

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This may be the first systematic review to evaluate prognostic effects of statins in

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patients with NSCLC.

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This systematic review may provide evidence for clinicians in optimizing the treatment

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for patients with NSCLC.

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This systematic review will include both randomized controlled trials (RCTs) and

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observational studies, and analyze them together.

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Introduction

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Lung cancer is the most common malignant tumor as well as the leading of

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cancer-related death all over the world.1 The incidence rate of lung cancer shows an

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alarming trend; and it is predicted that there will be about 733,300 newly diagnosed

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lung cancer cases in 2015 in China.2 Clinically, lung cancer is divided into two main

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categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)

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which accounts for 85% of all lung cancer and consists of squamous cell carcinoma,

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adenocarcinoma, and large cell carcinoma.1 3 4 In recent years, although studies have

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shown that the survival benefits of low dose computed tomography (CT) screening

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and EGFR TKI are quite clear,5-11 the five-year lung cancer specific survival is

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currently only 18%.1 This is partly because most patients are diagnosed at an

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advanced stage of disease, and a large proportion of advanced NSCLC patients

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shows drug resistance to radiotherapy and chemotherapy as well as targeted

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therapy.1

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optimize current treatment to improve the survival of NSCLC.

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Therefore, there is urgent requirement to explore new therapies and

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Statins are inhibitors of 3-hydroxy 3-methylglutaryl-CoA (HMG-CoA) reductase that

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are rate-controlling enzyme at production of mevalonate, the precursor of cholesterol

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synthesis.12 Statins reduce plasma cholesterol level and are used as the most

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common drugs for preventing cardiovascular diseases and decreasing mortality and

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morbidity.13 14 Mounting evidence indicated that statins are involved in the function of

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EGFR-related signaling pathways and c-Jun-N-terminal kinase (JNK) pathway.15

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Furthermore, statins have anti-cancer effects by induction of apoptosis, and inhibition

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of tumor cell growth and angiogenesis.16-18 Although it is controversial, many previous

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clinical publications suggest that statins use is associated with an increased survival

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time in patients with NSCLC.19-21 This meta-analysis will focus on the prognostic role

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of statins in NSCLC patients.

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Objectives

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The systematic review and meta-analysis will be conducted to summarize existing

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evidence and illustrate the profile of statins prognostic effects in NSCLC patients. The

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primary objective is to describe the profile of non-small cell lung cancer specific

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survival associated with statins using in NSCLC patients. The secondary objectives

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are to assess whether the profiles of non-small cell lung cancer recurrence, overall

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survival

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non-statins-using NSCLC patients.

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Methods

and

disease-free

survival

differ

between

the

statins-using

and

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This systematic review has been developed in accordance with the guidelines

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detailed on the Preferred Reporting Items for Systematic review and Meta-Analyses

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(PRISMA) checklist22 and the protocol is prepared according to its extension for

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protocols 2015 (PRISMA-P 2015)23 24. In addition, the flow (figure 1) chart will be

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employed to describe the study identification and selection process. The protocol of

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this systematic review has been registered in PROSPERO (registration number:

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CRD42016047524).

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Inclusion criteria

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Type of studies

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We will include both randomized controlled trials (RCTs) and observational studies.

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Studies assessing cell lines and animal models only, review articles, proceedings,

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conferences and case series on NSCLC patients will be excluded.

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Type of participants

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We will include all patients of both genders who are diagnosed with NSCLC. Tumor

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classification will be diagnosed according to 2011 WHO classification25.

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Type of intervention

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The intervention of studies will be included is statins treatment, which means patients

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who have taken statins prior to diagnosis or have started statins after diagnosis or in

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the perioperative period will be included and identified as the treatment group.

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Type of control

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Control group of studies will be included is patients who have never received a statins

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treatment.

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Type of outcomes

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The primary outcomes will be cancer specific survival of patients with NSCLC. The

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secondary outcomes will include the NSCLC recurrence, overall survival and disease

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free survival.

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Search strategy

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Two independent authors will search the following databases: MEDLINE (PubMed),

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EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials

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(CENTRAL), till 31 December 2017. If there are any disagreements, an independent

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third author will be consulted.

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PubMed search strategy

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The details of the PubMed database search strategy and syntax are sequentially

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provided in online supplementary appendix 1.

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Other resources

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Reference lists of relevant original studies will be searched for additional studies, as

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well as reviews and key journals.

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There will be no language or publication year restrictions. Studies written in

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languages other than English will be translated with the help of the international

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scientists in our institutes. 6


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Data collection and analysis

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Selection of studies

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Two reviewers will independently screen the titles and abstracts of all studies

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identified from the databases according to the inclusion criteria. Subsequently, the full

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texts of identified studies will be reassessed independently by the two reviewers with

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verifying the reasons for inclusion and exclusion. Disagreements will be resolved by

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consulting a third reviewer.

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Data extraction

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A data extraction form will be developed, and study data will be independently

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assessed and extracted by two reviewers. The following data will be extracted from all

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the included studies:

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1. Study characteristics (author, year of publication, study design, setting, locations

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and patient enrolment strategies).

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2. Participants’ characteristics (age, gender, smoking status, alcohol consumption,

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histopathological

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comorbidities and time of administration of statins).

TNM

stages,

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diagnosis,

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history

of

treatment,

associated

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If the reported data are not sufficient, we will contact the authors for further

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information.

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Assessment of methodically quality

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Two assessors will assess the methodological quality of randomized controlled trials

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using the Cochrane Collaboration’s risk of bias tool26 and observational studies

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according to the Newcastle-Ottawa Scale (NOS)27. The NOS uses a star system to 7


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evaluate a study in 3 domains which contain 8 items. For items in the Selection and

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Exposure categories, each study will be awarded 1 or 0 star; for items in the

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Comparability category, a maximum of 2 stars can be awarded for each study. Studies

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that score the maximum of 9 stars have a low risk of bias, studies that score 7 or 8

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stars have a moderate risk of bias, and those scoring 6 or fewer have a high risk of

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bias. The defined questions will be answered and the score of each article will be

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calculated by two reviewers independently. Disagreements will be resolved by

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consulting an independent third reviewer.

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Measurements of treating effect

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Hazard ratio (HR) and risk ratio (RR) will be used to summarize survival data and

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dichotomous data respectively along with 95% confidence interval (CI).

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Addressing missing data

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Missing relevant data will be excluded from analysis only after contacting with the

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author but failing to acquire it. Besides, sensitivity analysis will be conducted to

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explore if these missing data will influence on the results of the meta-analysis.

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Assessment of heterogeneity

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Heterogeneity among studies will be measured using the Cochran Q test

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(Chi-squared) and I2 test. We will interpret it using the following guide: I2 0%-25%

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suggesting

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heterogeneity.

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Assessment of reporting bias

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The publication bias will be assessed by Funnel plot if included studies are no less

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low

heterogeneity,

25%-50%

moderate,

and

75%-100%

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than 10, or Egger’s tests.

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Strategy for data synthesis

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Extracted data will be entered into Review Manager 5.3 software for aggregating risk

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estimates (hazard ratio and 95% confidence interval) by the first researcher

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independently, and checked by the second one. We will use fixed-effect or

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random-effects methods as appropriate for analysis. If heterogeneity among the

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studies is identified as considerable, we will apply the random-effects method for

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analysis.

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Subgroup analyses

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Subgroup analyses are planned as follows:

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1. Associated comorbidity such as hyperlipidaemia, coronary heart disease and so on.

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2. Disease stage. 3. Cancer subtype. 4. Treatment type: surgery, chemotherapy,

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radiotherapy. 5. The time points at which patients start to take statins: prediagnosis or

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postdiagnosis.

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Sensitivity analysis

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A sensitivity analysis will be conducted to test the impact of the results with respect to

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the methodological quality items rated by the NOS and the Cochrane tool. We will

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also implement sensitivity analyses to explore the impacts of methodological quality

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and sample size on the robustness of review conclusions. Meta-analyses will be

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repeated after excluding studies with lower methodological quality and studies with

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sample sizes much larger than those of other studies. Sensitivity analyses will be

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reported with a summary table, and reviewed conclusions will be interpreted by

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making comparisons between the two meta-analyses.

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Confidence in cumulative evidence

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The quality of the evidence will be assessed by the scoring system of the Grading of

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Recommendations Assessment, Development and Evaluation (GRADE) Working

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Group. According to the final score which will be acquired by summarizing the score

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of each item in the scoring system, the quality of evidence is categorized to four levels:

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high (≥4 points), moderate (three points), low (two points), very low (≤1 point)28.

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Discussion

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Lung cancer, especially non-small cell lung cancer, is among the most common

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cancers for both men and women. Although many NSCLC patients using EGFR-TKIs

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have achieved encouraging results, there are still a large proportion of patients cannot

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benefit from them. Statins, considered as safe, cheap and effective drugs, are usually

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used in the primary and secondary prevention of cardiovascular diseases; however,

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some preclinical and clinical studies indicated their anti-cancer effects and to

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repurpose them as promising anti-cancer agents.

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Our systematic review will clarify the prognostic effect of statins in patients with

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NSCLC, which would help patients and clinicians to determine the treatment for

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patients with NSCLC, especially patients coexisting cardiovascular disease. This

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systematic review may also help guideline developers in the management of patients

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with NSCLC.

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Authors’ contributions FL and GL came up with the original idea of this work, QH

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assisted in protocol design, MS, MI, SZ and JR provided valuable advice for the

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research protocol. RR, FL and GL drafted the protocol which was revised by all

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authors. GL and FL will search for studies, extracted and analyze data, and QH will be

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consulted if they do not reach an agreement. All authors approved the publication.

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Funding statement This research received no specific grant from any funding

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agency in the public, commercial or not-for-profit sectors

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Competing interests None declared.

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Data sharing statement The findings of this systematic review will be disseminated

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via peer-reviewed publications and conference presentations. Please contact the

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corresponding author for further information if the unpublished data from this study

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are available.

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26. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for

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assessing risk of bias in randomised trials. BMJ 2011;343:d5928 doi:

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10.1136/bmj.d5928.

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27. Wells GA, Shea B, Higgins JP, et al. Checklists of methodological issues for

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review authors to consider when including non-randomized studies in systematic

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reviews. Res Synth Methods 2013;4(1):63-77 doi: 10.1002/jrsm.1077.

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28. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE profiles

and

summary

of

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evidence

findings

tables.

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2011;64(4):383-94 doi: 10.1016/j.jclinepi.2010.04.026.

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Clin

Epidemiol

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Figure 1. Flow chart showing identification and screening of eligible studies from MEDLINE, Embase, CENTRAL, Web of Science for inclusion in this systematic review.

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Figure 1. Flow chart showing identification and screening of eligible studies from MEDLINE, Embase, CENTRAL, Web of Science for inclusion in this systematic review. 204x201mm (300 x 300 DPI)

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Appendix 1 PubMed search strategy: #1 "Lung Neoplasms"[Mesh] OR "Neoplasms, Lung"[Title/Abstract] OR "Lung Neoplasm"[Title/Abstract] OR "Neoplasm, Lung"[Title/Abstract] OR "Neoplasms, Pulmonary"[Title/Abstract] OR "Pulmonary Neoplasms"[Title/Abstract] OR "Neoplasm, Pulmonary"[Title/Abstract] OR "Pulmonary Neoplasm"[Title/Abstract] OR "Lung Cancer"[Title/Abstract]

OR

Cancers"[Title/Abstract]

OR

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"Cancer,

"Cancers,

Lung"[Title/Abstract] Lung"[Title/Abstract]

OR OR

"Lung

"Pulmonary

Cancer"[Title/Abstract] OR "Cancer, Pulmonary"[Title/Abstract] OR "Pulmonary

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Cancers"[Title/Abstract] OR "Cancers, Pulmonary"[Title/Abstract] OR "Cancer of the Lung"[Title/Abstract]

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OR

"Cancer

of

Lung"[Title/Abstract]

OR

"Carcinoma,

Non-Small-Cell Lung"[Mesh] OR "Carcinoma, Non-Small-Cell Lung"[Title/Abstract] "Carcinoma,

Non-Small-Cell

Non

Small

Cell


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OR

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OR

OR

"Lung

"Carcinomas, Carcinoma,

Non-Small-Cell"[Title/Abstract] OR "Lung Carcinomas, Non-Small-Cell"[Title/Abstract]

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OR "Non-Small-Cell Lung Carcinomas"[Title/Abstract] OR "Nonsmall Cell Lung

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Cancer"[Title/Abstract] OR "Non-Small-Cell Lung Carcinoma"[Title/Abstract] OR "Non Small Cell Lung Carcinoma"[Title/Abstract] OR "Carcinoma, Non-Small Cell Lung"[Title/Abstract] OR "Non-Small Cell Lung Cancer"[Title/Abstract]

#2

"Hydroxymethylglutaryl-CoA


Reductase

Reductase

Inhibitors"[Mesh]

OR

Inhibitors"[Title/Abstract]

OR

"Hydroxymethylglutaryl CoA Reductase Inhibitors"[Title/Abstract] OR "Inhibitors,


Page 19 of 22

Hydroxymethylglutaryl-CoA Reductase"[Title/Abstract] OR "Reductase Inhibitors, Hydroxymethylglutaryl-CoA"[Title/Abstract]

OR

"Inhibitors,

HMG-CoA

Reductase"[Title/Abstract] OR "Inhibitors, HMG CoA Reductase"[Title/Abstract] OR "Inhibitors,

Hydroxymethylglutaryl-Coenzyme

"Hydroxymethylglutaryl-Coenzyme Hydroxymethylglutaryl

A

A"[Title/Abstract]


Coenzyme

A"[Title/Abstract]

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OR

OR

"Inhibitors,

OR

"Statins,

HMG-CoA"[Title/Abstract] OR "HMG-CoA Statins"[Title/Abstract] OR "Statins, HMG CoA"[Title/Abstract] OR "HMG-CoA Reductase Inhibitors"[Title/Abstract] OR "HMG CoA

Reductase


OR

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"Reductase

Inhibitors,

HMG-CoA"[Title/Abstract] OR "Inhibitors, Hydroxymethylglutaryl-CoA"[Title/Abstract] OR

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Hydroxymethylglutaryl


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CoA"[Title/Abstract]

OR

OR

"Inhibitors,

"statin"[Title/Abstract]

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OR

"statins"[Title/Abstract] OR "Simvastatin"[Title/Abstract] OR "Lovastatin"[Title/Abstract] OR

"Pravastatin"[Title/Abstract]

OR

"Fluvastatin"[Title/Abstract]

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OR

"Atorvastatin"[Title/Abstract]

OR

"Rosuvastatin"[Title/Abstract]

OR

"Pitavastatin"[Title/Abstract]

OR

"Cerivastatin"[Title/Abstract]

OR

"Dalvastatin"[Title/Abstract]

OR

"Fluindostatin"[Title/Abstract]

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"Lipid-Lowering"[Title/Abstract]

#3 (animals [mh] NOT humans [mh])

#4 (#1 AND #2 NOT #3)


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PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to address in a systematic review protocol* Section and topic

Item No

Checklist item

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ADMINISTRATIVE INFORMATION Title:

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Page No.

Identification

1a

Identify the report as a protocol of a systematic review

Page 1, Line 2

Update

1b

If the protocol is for an update of a previous systematic review, identify as such

NA

Registration

2

If registered, provide the name of the registry (such as PROSPERO) and registration number

Page 3, Line 5355

Contact

3a

Provide name, institutional affiliation, e-mail address of all protocol authors; provide physical mailing address of corresponding author

Page1-2, Line 327

Contributions

3b

Describe contributions of protocol authors and identify the guarantor of the review

Page 11, Line 228-232

4

If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes; otherwise, state plan for documenting important protocol amendments

NA

5a

Indicate sources of financial or other support for the review

5b

Provide name for the review funder and/or sponsor

5c

Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol

NA

INTRODUCTION Rationale

6

Describe the rationale for the review in the context of what is already known

Objectives

7

Provide an explicit statement of the question(s) the review will address with reference to participants, interventions, comparators, and outcomes (PICO)

Page 3- 4, Line 65 - 90 Page 4, Line 91 98

METHODS Eligibility criteria

8

Specify the study characteristics (such as PICO, study design, setting, time frame) and report characteristics (such as years

Page 5 – 6, Line

Authors:

Amendments

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Support: Sources Sponsor Role of sponsor or funder

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Information sources

9

Search strategy

10

Study records:

considered, language, publication status) to be used as criteria for eligibility for the review Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other grey literature sources) with planned dates of coverage Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be repeated

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107 - 125 Page 6, Line 126 - 139 Page 6, Line 131 - 139

Data management

11a

Selection process

11b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the review Page 7, Line 141 (that is, screening, eligibility and inclusion in meta-analysis) - 146

Data collection process Data items

11c

Outcomes and prioritization Risk of bias in individual studies Data synthesis

13

12

14 15a

Describe the mechanism(s) that will be used to manage records and data throughout the review

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Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any processes for obtaining and confirming data from investigators List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data assumptions and simplifications List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the outcome or study level, or both; state how this information will be used in data synthesis Describe criteria under which study data will be quantitatively synthesised

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Page 7, Line 147 - 157 Page 7, Line 159 - 163 Page 6, Line 122 - 125 Page 7-8, Line 158 - 169 Page 9, Line 185191

15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and methods Page 8, Line170of combining data from studies, including any planned exploration of consistency (such as I2, Kendall’s τ) 173, 177-181 15c

15d If quantitative synthesis is not appropriate, describe the type of summary planned Meta-bias(es)

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Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression)

Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies)

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Confidence in Page 10, Line 17 Describe how the strength of the body of evidence will be assessed (such as GRADE) cumulative evidence 208-212 * It is strongly recommended that this checklist be read in conjunction with the PRISMA-P Explanation and Elaboration (cite when available) for important clarification on the items. Amendments to a review protocol should be tracked and dated. The copyright for PRISMA-P (including checklist) is held by the PRISMA-P Group and is distributed under a Creative Commons Attribution Licence 4.0.


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From: Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart L, PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 Jan 2;349(jan02 1):g7647.

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Do statins improve outcomes for patients with non-small cell lung cancer? A systematic review and meta-analysis protocol

Journal:

BMJ Open

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bmjopen-2018-022161.R1 Protocol

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26-May-2018

Primary Subject Heading: Secondary Subject Heading:

Respiratory medicine, Medical management, Evidence based practice, Cardiovascular medicine

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Keywords:

Oncology

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Li, Feng; Charite Universitatsmedizin Berlin, 1. Department of General, Visceral, Vascular and Thoracic Surgery; The First Affiliated Hospital of Zhengzhou University, Thoracic Surgery Department Liu, Guangyu; Peking University First Hospital, Roudi, Raheleh; Iran University of Medical Sciences, Huang, Qi; Peking University People's Hospital Swierzy, Marc; Charite Universitatsmedizin Berlin, 1. Department of General, Visceral, Vascular and Thoracic Surgery Ismail, Mahmoud; Charite Universitatsmedizin Berlin, 1. Department of General, Visceral, Vascular and Thoracic Surgery Zhao, Song; The First Affiliated Hospital of Zhengzhou University, Thoracic Surgery Department Rueckert, Jens; Charite Universitatsmedizin Berlin ,

statins, non-small-cell lung cancer, prognostic effects

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Do statins improve outcomes for patients with non-small cell lung cancer? A

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3


4

Ismail,1 Song Zhao,5 Jens-Carsten Rückert1

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China.


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Iran.

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China.

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Corresponding author: Jens-Carsten Rückert, PhD, MD

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Tel: +49 160 97389944

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Email:

[email protected]

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[email protected]

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[email protected] 1


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[email protected]

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[email protected]

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[email protected]

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[email protected]

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[email protected]

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Abstract:

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Introduction: Lung cancer is the most common neoplasm and the leading cause of

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cancer-related death worldwide. Non-small cell lung cancer (NSCLC), accounting for

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85 % of all lung cancer cases, is mainly diagnosed at an advanced and metastatic

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stage. Unfortunately, the survival of NSCLC has not improved significantly over recent

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decades. Statins are used as a cholesterol-lowering agent, but recently preclinical

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and clinical studies suggested anti-cancer effects. Thus, this systematic review and

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meta-analysis aims to clarify whether statins improve the prognosis of patients with

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NSCLC.

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Science, the Cochrane Central Register of Controlled Trials (CENTRAL) and

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ClinicalTrials.gov with no restriction of language. Both randomized controlled trials

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(RCTs) and observational cohort studies evaluating the prognostic role of statins in

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patients with NSCLC will be included. Overall survival will be the primary outcome and

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the secondary outcomes will include cancer specific survival, disease free survival

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and cancer recurrence. Two assessors will assess the randomized controlled trials

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using the Cochrane Collaboration’s risk of bias tool and observational cohort studies

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according to the ROBINS-I. Publication bias will be assessed by funnel plot using

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STATA software (STATA Corp, College Station, TX).

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and meta-analysis aims to describe the prognostic effects of statins in NSCLC

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patients, which would help clinicians to optimize the treatment for patients with

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NSCLC. These findings will be published in a peer-reviewed journal and presented at

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national and international conferences.

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Registration number: This systematic review protocol has been registered in the

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PROSPERO

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(CRD42016047524).

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International

Prospective

Register

of

Systematic

Reviews

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This is the first systematic review aiming to summarize the evidence regarding

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whether statins improve the prognosis of patients with NSCLC.

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Other strengths include detailed search strategy of published evidence from both

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randomized studies and observational studies, and duplicate independent screening

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and data extraction.

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This systematic review will be limited to excluding unpublished studies and including

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studies with the timing of intervention being both before and after the diagnosis of

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NSCLC.

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Introduction

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Lung cancer is the most common malignant tumor and the leading cause of

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cancer-related death all over the world.1 The incidence rate of lung cancer shows an

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alarming trend; and it is predicted that there will be about 733,300 newly diagnosed

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lung cancer cases in 2015 in China.2 Clinically, lung cancer is divided into two main

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histologic categories: small cell lung cancer (SCLC) and non-small cell lung cancer 3


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(NSCLC). NSCLC accounts for 85% of all lung cancer cases and consists of

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squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.1 3 4 In recent

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years, although studies have shown that the survival benefits from low dose

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computed tomography (CT) screening and tyrosine kinase inhibitors (TKI) specific for

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Epidermal Growth Factor Receptor (EGFR) are quite clear,5-11 the five-year lung cancer

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specific survival is only 18%.1 This is partly because most patients are diagnosed at

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an advanced stage of disease, and a large proportion of advanced NSCLC patients

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show resistance to radiotherapy and chemotherapy as well as targeted therapy.1 4

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Therefore, there is an urgent requirement to explore new therapies and optimize

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current treatment to improve the survival of patients with NSCLC.

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Statins are inhibitors of 3-hydroxy 3-methylglutaryl-CoA (HMG-CoA) reductase

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which is the rate-controlling enzyme in the production of mevalonate, the precursor of

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cholesterol synthesis.12 Statins can reduce the plasma cholesterol level, and are the

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most commonly used drugs for preventing cardiovascular diseases and decreasing

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mortality and morbidity.13 14 Mounting evidence indicates that statins are involved in

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the function of EGFR-related signaling pathways and c-Jun-N-terminal kinase (JNK)

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pathway.15 Furthermore, previous studies indicate that statins have anti-cancer effects

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by induction of apoptosis, and inhibition of tumor cell growth and angiogenesis.16-18

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Although it is controversial, many previous clinical publications suggest that statin use

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is associated with increased survival time in patients with NSCLC.19-21 This systematic

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review and meta-analysis will explore the effects of statins in patients with NSCLC .

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Objectives

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The systematic review and meta-analysis aims to summarize the existing evidence to

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determine whether statins change the prognosis of patients with NSCLC. The primary

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objective is to demonstrate whether statins improve the overall survival of patients

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with NSCLC. The secondary objectives are to assess whether cancer recurrence,

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cancer specific survival and disease-free survival differ between statins-using and

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102

Methods

103


104


105

(PRISMA) checklist22 and the protocol is prepared according to its extension for

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protocols 2015 (PRISMA-P 2015)23

107

employed in describing the study identification and selection process. The protocol of

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109

CRD42016047524).

110

Inclusion criteria

111

Type of studies

112

We will include both randomized controlled trials (RCTs) and observational cohort

113

studies. We will pay extra attention to the confounding factors in the retrospective

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observational cohort studies. Studies assessing cell lines and animal models only,

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review articles, proceedings, conferences and case-control studies will be excluded.

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. In addition, the flowchart (figure 1) will be

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classification will be made according to 2011 WHO classification25.

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The intervention will be the use of statins, which means patients who have taken

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statins at any type or dose before or after the diagnosis will be included in the

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treatment group.

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Type of control

124

Control group will be the patients who have been allocated to the control group during

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the study, which means the comparators given can be either placebos or no treatment

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of statins.

127

Type of outcomes

128

The primary outcome will be overall survival of patients with NSCLC. The secondary

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outcomes will include cancer recurrence, cancer specific survival and the disease free

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survival.

131

Search strategy

132

We will search the following databases: MEDLINE (PubMed), EMBASE, Web of

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Science, the Cochrane Central Register of Controlled Trials (CENTRAL) and the

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ClinicalTrials.gov, till 31 Jul. 2018.

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137

provided in the online supplementary appendix 1.

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Other resources

139

Reference lists of the relevant original studies will be searched for additional studies,

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as well as reviews and key journals, such as “Lung Cancer”, “Clinical Lung Cancer”,

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“Clinical Cancer Research” and “Journal of Clinical Oncology”.

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scientists in our institutes. Besides, we will exclude unpublished studies.

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149

texts of the identified studies will be re-assessed independently by the two reviewers,

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Data extraction

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and patient enrolment strategies, sample size).

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2. Participants’ characteristics (age, gender, ethnicity, smoking status, alcohol

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consumption, histopathological diagnosis, TNM stage, history of treatment,

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associated comorbidities, the timing of administration of the statins, the type of the

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statins, the dose of the statins, the comparator given and the follow-up period).

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information.

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according to the ROBINS-I27. ROBINS-I is a new tool to assess risk of bias in

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non-randomized studies of interventions. ROBINS-I has seven domains of bias

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including bias due to confounding, selection of participants, interventions themselves,

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deviations from intended interventions, missing data, measurement of outcomes and

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selection of the reported result. We have identified the following confounders: the

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Tumor, Node, Metastasis classification (TNM) stage, history of treatment (including

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chemotherapy, radiotherapy, targeted therapy and surgical therapy), that are

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important for the survival of NSCLC. The reviewers should response the signaling

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questions to judge the risk of bias in each domain, finally acquiring an overall risk of

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bias judgement for the outcome being assessed. Disagreements will be resolved by

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consulting a third independent reviewer.

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Measures of treatment effect

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The hazard ratio (HR) will be used to summarize survival data and dichotomous data

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respectively along with 95% confidence interval (CI). If a HR is not presented in an

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eligible study, for example only an odds ratio (OR) or relative risk (RR) is available, we

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will estimate the HR using the information available in the study according to the

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methods reported in the previous studies28,29. Because if there is sufficient data to

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estimate an OR or RR, then there is usually sufficient data to estimate a HR. Besides,

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if multiple effect estimates are presented in a paper we will extract the result adjusted

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for the greatest number of our pre-specified confounders 30.

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Missing relevant data will be excluded from analysis only after contacting the author

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but failing to acquire it. Sensitivity analysis will be conducted to explore if this missing

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data will influence the results of the meta-analysis.

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suggesting

195

heterogeneity.

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Since detecting and overcoming the publication bias is problematic and firm guidance

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is not yet offered, we will use Funnel plot to assess the reporting bias with results

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being interpreted cautiously.

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201


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estimates (hazard ratio and 95% confidence interval) by the first researcher, and

203

independently checked by the second one. We will use fixed-effect or random-effects

204

methods as appropriate for analysis. If heterogeneity among the studies is identified

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as considerable, we will apply the random-effects method for analysis.

low

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heterogeneity,

25%-50%

moderate,

and

75%-100%

high

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Subgroup analyses

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1. Associated comorbidity such as hyperlipidemia, coronary heart disease and so on.

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postdiagnosis. 6.study type: randomized controlled trial and retrospective studies. 7.

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Comparator given: placebo or no treatment.

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the methodological quality items rated by the ROBINS-I and the Cochrane tool. We

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will also implement sensitivity analyses to explore the impacts of methodological

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quality and sample size on the robustness of review conclusions. Meta-analyses will

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be repeated after excluding studies with lower methodological quality and studies with

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high or unclear risk of bias. To evaluate the stability of the results, we will also conduct

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the leave-one-out sensitivity analysis. Sensitivity analyses will be reported with a

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summary table, and reviewed conclusions will be interpreted by making comparisons

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between the two meta-analyses.

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Group. According to the final score, which will be acquired by summarizing the score

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229 230

Patient and public involvement

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Patients and public were not involved in this study.

232 233

Discussion

234

Lung cancer, especially NSCLC, is among the most common cancers for both men

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and women. Although many NSCLC patients using EGFR-TKIs have achieved

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encouraging results, there are still a large proportion of patients cannot benefit from

237

them. Statins, considered as safe, cheap and effective drugs, are commonly used in

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the primary and secondary prevention of cardiovascular diseases; however, some

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preclinical and clinical studies have shed light on their anti-cancer effects and

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repurposed them as promising anti-cancer agents.

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NSCLC, which would help patients and clinicians to optimize the treatment for

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patients with NSCLC, especially patients with coexisting cardiovascular disease. This

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systematic review may also help guideline developers in the management of patients

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with NSCLC.

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findings will be published in a peer reviewed journal and presented at national and 11


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are available.

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adenocarcinoma.

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Engl

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mutated

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EGFR.

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Engl

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trial.

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non-small

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cell

lung

cancer.

Clin

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on Res

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10.1136/bmj.b2535.

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2015;4:1 doi: 10.1186/2046-4053-4-1.

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classification

of

lung

tumours.

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Eur

Respir

J

2001;18(6):1059-68

doi:

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27. Sterne JA, Hernan MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of

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bias in non-randomised studies of interventions. BMJ 2016;355:i4919. doi:

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10.1136/bmj.i4919 .

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28. Tierney JF, Stewart LA, Ghersi D, et al. Practical methods for incorporating

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summary

time-to-event

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10.1186/1745-6215-8-16.

data

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into

meta-analysis.

Trials

2007;8:16

doi:

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29. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform

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meta-analyses of the published literature for survival endpoints. Stat Med

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1998;17(24):2815-34.

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30. Hunink MG, Wong JB. Meta-analysis of failure-time data with adjustment for

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covariates. Medical decision making : an international journal of the Society for

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Medical Decision Making 1994;14(1):59-70 doi: 10.1177/0272989X9401400108. 16


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31. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE

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evidence

profiles

and

summary

of

findings

tables.

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2011;64(4):383-94 doi: 10.1016/j.jclinepi.2010.04.026.

J

Clin

Epidemiol

360

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361 362 363

Figure 1. Flowchart showing identification and screening of eligible studies from MEDLINE, Embase, CENTRAL, Web of Science and the ClinicalTrials.gov for inclusion in this systematic review.

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Figure 1. Flowchart showing identification and screening of eligible studies from MEDLINE, Embase, CENTRAL, Web of Science and the ClinicalTrials.gov for inclusion in this systematic review. 204x201mm (300 x 300 DPI)

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Appendix 1 PubMed search strategy: #1 "Lung Neoplasms"[Mesh] OR "Neoplasms, Lung"[Title/Abstract] OR "Lung Neoplasm"[Title/Abstract] OR "Neoplasm, Lung"[Title/Abstract] OR "Neoplasms, Pulmonary"[Title/Abstract] OR "Pulmonary Neoplasms"[Title/Abstract] OR "Neoplasm, Pulmonary"[Title/Abstract] OR "Pulmonary Neoplasm"[Title/Abstract] OR "Lung Cancer"[Title/Abstract]

OR


OR

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"Cancer,

"Cancers,

Lung"[Title/Abstract] Lung"[Title/Abstract]

OR OR

"Lung

"Pulmonary

Cancer"[Title/Abstract] OR "Cancer, Pulmonary"[Title/Abstract] OR "Pulmonary

ee

Cancers"[Title/Abstract] OR "Cancers, Pulmonary"[Title/Abstract] OR "Cancer of the Lung"[Title/Abstract]

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OR

"Cancer

of


OR

"Carcinoma,

Non-Small-Cell Lung"[Mesh] OR "Carcinoma, Non-Small-Cell Lung"[Title/Abstract] "Carcinoma,

Non-Small-Cell

Non

Small

Cell


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OR

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OR

OR

"Lung

"Carcinomas, Carcinoma,

Non-Small-Cell"[Title/Abstract] OR "Lung Carcinomas, Non-Small-Cell"[Title/Abstract]

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OR "Non-Small-Cell Lung Carcinomas"[Title/Abstract] OR "Nonsmall Cell Lung

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Cancer"[Title/Abstract] OR "Non-Small-Cell Lung Carcinoma"[Title/Abstract] OR "Non Small Cell Lung Carcinoma"[Title/Abstract] OR "Carcinoma, Non-Small Cell Lung"[Title/Abstract] OR "Non-Small Cell Lung Cancer"[Title/Abstract]

#2



Reductase

Reductase

Inhibitors"[Mesh]

OR


OR

"Hydroxymethylglutaryl CoA Reductase Inhibitors"[Title/Abstract] OR "Inhibitors,


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Hydroxymethylglutaryl-CoA Reductase"[Title/Abstract] OR "Reductase Inhibitors, Hydroxymethylglutaryl-CoA"[Title/Abstract]

OR

"Inhibitors,

HMG-CoA

Reductase"[Title/Abstract] OR "Inhibitors, HMG CoA Reductase"[Title/Abstract] OR "Inhibitors,

Hydroxymethylglutaryl-Coenzyme

"Hydroxymethylglutaryl-Coenzyme Hydroxymethylglutaryl

A

A"[Title/Abstract]


Coenzyme

A"[Title/Abstract]

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OR

OR

"Inhibitors,

OR

"Statins,

HMG-CoA"[Title/Abstract] OR "HMG-CoA Statins"[Title/Abstract] OR "Statins, HMG CoA"[Title/Abstract] OR "HMG-CoA Reductase Inhibitors"[Title/Abstract] OR "HMG CoA

Reductase


OR

ee

"Reductase

Inhibitors,

HMG-CoA"[Title/Abstract] OR "Inhibitors, Hydroxymethylglutaryl-CoA"[Title/Abstract] OR

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OR

OR

"Inhibitors,

"statin"[Title/Abstract]

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OR

"statins"[Title/Abstract] OR "Simvastatin"[Title/Abstract] OR "Lovastatin"[Title/Abstract] OR

"Pravastatin"[Title/Abstract]

OR

"Fluvastatin"[Title/Abstract]

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OR

"Atorvastatin"[Title/Abstract]

OR

"Rosuvastatin"[Title/Abstract]

OR

"Pitavastatin"[Title/Abstract]

OR


OR

"Dalvastatin"[Title/Abstract]

OR

"Fluindostatin"[Title/Abstract]

OR

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"Lipid-Lowering"[Title/Abstract]

#3 (animals [mh] NOT humans [mh])

#4 (#1 AND #2 NOT #3)


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Item No

Checklist item

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Page No.

Identification

1a


Page 1, Line 2

Update

1b


NA

Registration

2


Page 3, Line 5254

Contact

3a


Page1-2, Line 326

Contributions

3b


Page 11, Line 246-250

4


NA

5a


Authors:

Amendments

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5b


5c


NA


6


Objectives

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Page 3- 4, Line 67 - 92 Page 4, Line 114 - 127


8


Page 5 – 6, Line


NA

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Information sources

9

Search strategy

10

Study records:


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Data management

11a

Selection process



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13

12

14 15a


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Page 7, Line 149 - 160 Page 7, Line 153 - 158 Page 6, Line 124 - 127 Page 7-8, Line 1561- 174 Page 9, Line 196201



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BMJ Open

Do statins improve outcomes for patients with non-small cell lung cancer? A systematic review and meta-analysis protocol

Journal:

BMJ Open

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bmjopen-2018-022161.R2 Protocol

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20-Jul-2018

Primary Subject Heading: Secondary Subject Heading:

Respiratory medicine, Medical management, Evidence based practice, Cardiovascular medicine

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Keywords:

Oncology

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Li, Feng; Charite Universitatsmedizin Berlin, 1. Department of General, Visceral, Vascular and Thoracic Surgery; The First Affiliated Hospital of Zhengzhou University, Thoracic Surgery Department Liu, Guangyu; Peking University First Hospital, Roudi, Raheleh; Iran University of Medical Sciences, Huang, Qi; Peking University People's Hospital Swierzy, Marc; Charite Universitatsmedizin Berlin, 1. Department of General, Visceral, Vascular and Thoracic Surgery Ismail, Mahmoud; Charite Universitatsmedizin Berlin, 1. Department of General, Visceral, Vascular and Thoracic Surgery Zhao, Song; The First Affiliated Hospital of Zhengzhou University, Thoracic Surgery Department Rueckert, Jens; Charite Universitatsmedizin Berlin ,

statins, non-small-cell lung cancer, prognostic effects

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Do statins improve outcomes for patients with non-small cell lung cancer? A

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3


4

Ismail,1 Song Zhao,5 Jens-Carsten Rueckert1

5


6 7

10

14

China.


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Iran.

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China.

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Corresponding author: Jens-Carsten Rueckert, PhD, MD

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Tel: +49 160 97389944

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Email:

[email protected]

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[email protected]

22

[email protected] 1


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[email protected]

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[email protected]

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[email protected]

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[email protected]

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[email protected]

28 29

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Abstract:

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Introduction: Lung cancer is the most common neoplasm and the leading cause of

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cancer-related death worldwide. Non-small cell lung cancer (NSCLC), accounting for

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85 % of all lung cancer cases, is frequently diagnosed at an advanced and metastatic

34

stage. Besides, the survival of NSCLC has not improved significantly over recent

35

decades. Statins are used as a cholesterol-lowering agent, but recently preclinical

36

and clinical studies have unrevealed their anti-cancer effects. Thus, this systematic

37

review and meta-analysis aims to clarify whether statins improve the prognosis of

38

patients with NSCLC.

39


40

Science, the Cochrane Central Register of Controlled Trials (CENTRAL) and

41

ClinicalTrials.gov with no restriction of language. Both randomized controlled trials

42

(RCTs) and observational cohort studies evaluating the prognostic role of statins in

43

patients with NSCLC will be included. Overall survival will be the primary outcome and

44

the secondary outcomes will include cancer specific survival, disease free survival

45

and cancer recurrence. Two assessors will assess the randomized controlled trials

46

using the Cochrane Collaboration’s risk of bias tool and observational cohort studies

47

according to the ROBINS-I. Publication bias will be assessed by funnel plot using

48

STATA software (STATA Corp, College Station, TX).

49


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and meta-analysis aims to describe the prognostic effects of statins in NSCLC

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patients, which would help clinicians to optimize the treatment for patients with

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NSCLC. These findings will be published in a peer-reviewed journal and presented at

53

national and international conferences.

54

Registration number: This systematic review protocol has been registered in the

55

PROSPERO

56

(CRD42016047524).

57

International

Prospective

Register

of

Systematic

Reviews

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59

This is the first systematic review aiming to summarize the evidence regarding

60

whether statins improve the prognosis of patients with NSCLC.

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Another strength could be the inclusion of both randomized studies and observational

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studies.

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This systematic review will be limited to excluding unpublished studies and including

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studies with the timing of intervention being both before and after the diagnosis of

65

NSCLC.

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Introduction

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Lung cancer is the most common malignant tumor and the leading cause of

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cancer-related death all over the world.1 The incidence rate of lung cancer still shows

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an alarming trend.2 Clinically, small cell lung cancer (SCLC) and non-small cell lung

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cancer (NSCLC) are two main subtypes of lung cancer, of which NSCLC accounts for

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approaximately 85% of the cases.1 3 4 In recent years, although studies have shown

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survival benefits from low dose computed tomography (CT) screening and tyrosine

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kinase inhibitors (TKI) specific for Epidermal Growth Factor Receptor (EGFR),5-11 the

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five-year lung cancer specific survival is only 18%.1 This is partly because most

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patients are diagnosed at an advanced stage of disease, and a large proportion of

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advanced NSCLC patients are resistant to radiotherapy and chemotherapy as well as

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targeted therapy.1

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therapies and optimize current treatment to improve the survival of patients with

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NSCLC.

4

Therefore, there is an urgent requirement to explore new

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Statins are inhibitors of 3-hydroxy 3-methylglutaryl-CoA (HMG-CoA) reductase

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which is the rate-controlling enzyme in the production of mevalonate.12 Statins can

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reduce the plasma cholesterol level, and are the most commonly used drugs for

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preventing cardiovascular diseases and decreasing mortality and morbidity.13

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Mounting evidence have demonstrated that statins are involved in the function of

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EGFR-related signaling pathways and c-Jun-N-terminal kinase (JNK) pathway.15

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Furthermore, previous studies have indicated that statins exert anti-cancer effects by

88

inducing apoptosis, and inhibiting tumor cell growth and angiogenesis.16-18 Although it

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is controversial, many previous clinical publications suggest that statin use is

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associated with improved survival in patients with NSCLC.19-21 This systematic review

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and meta-analysis will explore the effects of statins in patients with NSCLC .

92

Objectives

93

The systematic review and meta-analysis aims to summarize the existing evidence to

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determine whether statins change the prognosis of patients with NSCLC. The primary

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objective is to demonstrate whether statins improve the overall survival of patients

14

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with NSCLC. The secondary objectives are to assess whether cancer recurrence,

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cancer specific survival and disease-free survival differ between statins-using and

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99

Methods

100


101


102

(PRISMA) checklist22 and the protocol is reported according to its extension for

103

protocols 2015 (PRISMA-P 2015)23

104

employed in describing the study identification and selection process. The protocol of

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106

CRD42016047524).

107

Inclusion criteria

108

Type of studies

109

We will include both randomized controlled trials (RCTs) and observational cohort

110

studies. Studies assessing cell lines and animal models only, review articles,

111

proceedings, conferences and case-control studies will be excluded.

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113


114

classification will be made according to 2011 WHO classification25.

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116

The intervention will be the use of statins, which means patients who have taken

117

statins at any type or dose before or after the diagnosis will be included in the

24

. In addition, the flowchart (figure 1) will be

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treatment group.

119

Type of control

120

Control group will be the patients who have been allocated to the control group during

121

the study, which means the comparators given can be either placebos or no treatment

122

of statins.

123

Type of outcomes

124

The primary outcome will be overall survival of patients with NSCLC. The secondary

125

outcomes will include cancer recurrence, cancer specific survival and the disease free

126

survival.

127

Search strategy

128

We will search the following databases: MEDLINE (PubMed), EMBASE, Web of

129

Science, the Cochrane Central Register of Controlled Trials (CENTRAL) and the

130

ClinicalTrials.gov, till 31 Jul. 2018.

131


132


133

provided in the online supplementary appendix 1.

134

Other resources

135

Reference lists of the relevant original studies will be searched for additional studies,

136

as well as reviews and key journals, such as “Lung Cancer” (until 31.07.2018),

137

“Clinical Lung Cancer” (until 31.07.2018), “Clinical Cancer Research” (until

138

31.07.2018), “Journal of Clinical Oncology” (until 31.07.2018), “JAMA” (until

139

31.07.2018), “Lancet” (until 31.07.2018) and “the New England Journal of Medicine”

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(until 31.07.2018). The hand-searching approach will be a manual page-by-page

141

examination of all the issues.

142


143


144

scientists in our institutes. Besides, we will exclude unpublished studies.

145


146


147


148


149

texts of the identified studies will be re-assessed independently by the two reviewers,

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151


152

Data extraction

153


154


155


156


157

and patient enrolment strategies, sample size).

158

2. Participants’ characteristics (age, gender, ethnicity, smoking status, alcohol

159

consumption, histopathological diagnosis, TNM stage, history of treatment,

160

associated comorbidities, the timing of administration of the statins, the type of the

161

statins, the dose of the statins, the comparator given and the follow-up period).

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information. Besides, we will pay extra attention to the confounding factors in the

164

retrospective observational cohort studies.

165


166


167


168

according to the ROBINS-I27. ROBINS-I is a new tool to assess risk of bias in

169

non-randomized studies of interventions. ROBINS-I has seven domains of bias

170

including bias due to confounding, selection of participants, interventions themselves,

171

deviations from intended interventions, missing data, measurement of outcomes and

172

selection of the reported result. We have identified the following confounders: the

173

Tumor, Node, Metastasis classification (TNM) stage, history of treatment (including

174

chemotherapy, radiotherapy, targeted therapy and surgical therapy), that are

175

important for the survival of NSCLC. The reviewers should response the signaling

176

questions to judge the risk of bias in each domain, finally acquiring an overall risk of

177

bias judgement for the outcome being assessed. Disagreements will be resolved by

178

consulting a third independent reviewer.

179

Measures of treatment effect

180

The hazard ratio (HR) will be used to summarize survival data and dichotomous data

181

respectively along with 95% confidence interval (CI). If a HR is not presented in an

182

eligible study, for example only an odds ratio (OR) or relative risk (RR) is available, we

183

will estimate the HR using the information available in the study according to the

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methods reported in the previous studies28,29. Because if there is sufficient data to

185

estimate an OR or RR, then there is usually sufficient data to estimate a HR. Besides,

186

if multiple effect estimates are presented in a paper we will extract the result adjusted

187

for the greatest number of our pre-specified confounders 30.

188


189

Missing relevant data will be excluded from analysis only after contacting the author

190

but failing to acquire it. Sensitivity analysis will be conducted to explore if this missing

191

data will influence the results of the meta-analysis.

192


193


194


195

suggesting

196

heterogeneity.

197


198

Since detecting and overcoming the publication bias is problematic and firm guidance

199

is not yet offered, we will use Funnel plot to assess the reporting bias with results

200

being interpreted cautiously.

201


202


203

estimates (hazard ratio and 95% confidence interval) by the first researcher, and

204

independently checked by the second one. We will use fixed-effect or random-effects

205

methods as appropriate for analysis. If heterogeneity among the studies is identified

low

heterogeneity,

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25%-50%

moderate,

and

75%-100%

high

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as considerable, we will apply the random-effects method for analysis.

207

Subgroup analyses

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209

1. Associated comorbidity such as hyperlipidemia, coronary heart disease and so on.

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212

postdiagnosis. 6.study type: randomized controlled trial and retrospective studies. 7.

213

Comparator given: placebo or no treatment.

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the methodological quality items rated by the ROBINS-I and the Cochrane tool.

217

Meta-analyses will be repeated after excluding studies with lower methodological

218

quality and studies with high or unclear risk of bias. To evaluate the stability of the

219

results, we will also conduct the leave-one-out sensitivity analysis. Sensitivity

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analyses will be reported with a summary table, and reviewed conclusions will be

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interpreted by making comparisons between the two meta-analyses.

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Group. According to the final score, which will be acquired by summarizing the score

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Patient and public involvement

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Patients and public were not involved in this study.

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Discussion

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Lung cancer, especially NSCLC, is among the most common cancers for both men

234

and women. Although many NSCLC patients using EGFR-TKIs have achieved

235

encouraging results, there are still a large proportion of patients cannot benefit from

236

them. Statins, considered as safe, cheap and effective drugs, are commonly used in

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the primary and secondary prevention of cardiovascular diseases; however, some

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preclinical and clinical studies have shed light on their anti-cancer effects and

239

repurposed them as promising anti-cancer agents.

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NSCLC, which would help patients and clinicians to optimize the treatment of NSCLC,

242

especially patients with coexisting cardiovascular disease. This systematic review

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may also help guideline developers in the management of patients with NSCLC.

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findings will be published in a peer reviewed journal and presented at national and

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are available.

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30. Hunink MG, Wong JB. Meta-analysis of failure-time data with adjustment for

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covariates. Medical decision making : an international journal of the Society for

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359 360 361

Figure 1. Flowchart showing identification and screening of eligible studies from MEDLINE, Embase, CENTRAL, Web of Science and the ClinicalTrials.gov for inclusion in this systematic review.

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Figure 1. Flowchart showing identification and screening of eligible studies from MEDLINE, Embase, CENTRAL, Web of Science and the ClinicalTrials.gov for inclusion in this systematic review. 204x201mm (300 x 300 DPI)

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BMJ Open

Appendix 1 PubMed search strategy: #1 "Lung Neoplasms"[Mesh] OR "Neoplasms, Lung"[Title/Abstract] OR "Lung Neoplasm"[Title/Abstract] OR "Neoplasm,


Neoplasms"[Title/Abstract]

OR

OR

"Neoplasms,

"Neoplasm,

Pulmonary"[Title/Abstract]


OR OR

"Pulmonary "Pulmonary

Neoplasm"[Title/Abstract] OR "Lung Cancer"[Title/Abstract] OR "Cancer, Lung"[Title/Abstract] OR "Lung Cancers"[Title/Abstract] OR "Cancers, Lung"[Title/Abstract] OR "Pulmonary Cancer"[Title/Abstract] OR "Cancer,


OR

"Pulmonary


OR

"Cancers,

Pulmonary"[Title/Abstract] OR "Cancer of the Lung"[Title/Abstract] OR "Cancer of Lung"[Title/Abstract] OR "Carcinoma, Non-Small-Cell Lung"[Mesh] OR "Carcinoma, Non-Small-Cell Lung"[Title/Abstract] OR

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"Carcinoma, Non Small Cell Lung"[Title/Abstract] OR "Carcinomas, Non-Small-Cell Lung"[Title/Abstract] OR "Lung Carcinoma, Non-Small-Cell"[Title/Abstract] OR "Lung Carcinomas, Non-Small-Cell"[Title/Abstract] OR "Non-Small-Cell Lung Carcinomas"[Title/Abstract] OR "Nonsmall Cell Lung Cancer"[Title/Abstract] OR "Non-Small-Cell Lung Carcinoma"[Title/Abstract] OR "Non Small Cell Lung Carcinoma"[Title/Abstract] OR

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"Carcinoma, Non-Small Cell Lung"[Title/Abstract] OR "Non-Small Cell Lung Cancer"[Title/Abstract]

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#2 "Hydroxymethylglutaryl-CoA Reductase Inhibitors"[Mesh] OR "Hydroxymethylglutaryl-CoA Reductase

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Inhibitors"[Title/Abstract] OR "Hydroxymethylglutaryl CoA Reductase Inhibitors"[Title/Abstract] OR "Inhibitors, Hydroxymethylglutaryl-CoA

Reductase"[Title/Abstract]

Hydroxymethylglutaryl-CoA"[Title/Abstract] OR "Inhibitors, "Inhibitors,

HMG

OR

"Reductase

Inhibitors,

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HMG-CoA Reductase"[Title/Abstract]

OR

CoA Reductase"[Title/Abstract] OR "Inhibitors, Hydroxymethylglutaryl-Coenzyme

A"[Title/Abstract] OR "Hydroxymethylglutaryl-Coenzyme A Inhibitors"[Title/Abstract] OR "Inhibitors,

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Hydroxymethylglutaryl Coenzyme A"[Title/Abstract] OR "Statins, HMG-CoA"[Title/Abstract] OR "HMG-CoA Statins"[Title/Abstract]

OR

"Statins,

HMG


OR

"HMG-CoA

Reductase

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Inhibitors"[Title/Abstract] OR "HMG CoA Reductase Inhibitors"[Title/Abstract] OR "Reductase Inhibitors, HMG-CoA"[Title/Abstract]

OR


"Inhibitors,

Hydroxymethylglutaryl-CoA"[Title/Abstract]


OR

"Inhibitors,

OR


CoA"[Title/Abstract] OR "statin"[Title/Abstract] OR "statins"[Title/Abstract] OR "Simvastatin"[Mesh] OR "Simvastatin"[Title/Abstract] OR "Lovastatin"[Mesh] OR "Lovastatin"[Title/Abstract] OR "Pravastatin"[Mesh] OR "Pravastatin"[Title/Abstract] OR "Fluvastatin"[Supplementary Concept] OR "Fluvastatin"[Title/Abstract] OR "Atorvastatin Calcium"[Mesh] OR "Atorvastatin Calcium"[Title/Abstract] OR "Atorvastatin"[Title/Abstract] OR

"Rosuvastatin

Calcium"[Mesh]

OR

"Rosuvastatin

Calcium"[Title/Abstract]

OR

"Rosuvastatin"[Title/Abstract] OR "Pitavastatin"[Supplementary Concept] OR "Pitavastatin"[Title/Abstract] OR

"Cerivastatin"[Supplementary

Concept]

OR


OR

"Dalvastatin"[Supplementary Concept] OR "Dalvastatin"[Title/Abstract] OR "Fluindostatin"[Supplementary For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 21 of 24

Concept] OR "Fluindostatin"[Title/Abstract] OR "Lipid-Lowering"[Title/Abstract] #3 (animals [Mesh] NOT humans [Mesh]) #4 (#1 AND #2 NOT #3)

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Item No

Checklist item

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Identification

1a


Page 1, Line 2

Update

1b


NA

Registration

2


Page 3, Line 5254

Contact

3a


Page1-2, Line 326

Contributions

3b


Page 11, Line 246-250

4


NA

5a


5b


5c


NA


6


Objectives

7


Page 3- 4, Line 67 - 92 Page 4, Line 114 - 127


8


Page 5 – 6, Line

Authors:

Amendments

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Information sources

9

Search strategy

10

Study records:


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Data management

11a

Selection process



11c


13

12

14 15a


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Page 7, Line 149 - 160 Page 7, Line 153 - 158 Page 6, Line 124 - 127 Page 7-8, Line 1561- 174 Page 9, Line 196201



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