TITLE: Overall survival of non-small cell lung cancer with spinal metastasis: a protocol for systematic review
AUTHORS: Chung Liang  Chai, Fon-yih Tsuang, Jin  Pyeong Jeon

[DESCRIPTION]
<div class = "text-blocks"><div class = "text-block">Our study aimed at deriving a summary survival curve in the population of non-small cell lung cancer (NSCLC) with spine metastasis. The pooled survival probabilities could provide information for a neurosurgeon to consider the extent or surgical method when handling spine metastasis in NSCLC patients.  This data is currently still lacking.</div></div>

[STEPS]
?. Review TitleOverall survival of non-small cell lung cancer with spinal metastasis: a systematic review and meta-analysis
?. Anticipated or actual start date07 June 2021
?. Anticipated completion date31 August 2021
?. Stage of review at time of this submissionPreliminary searchesYesNoPiloting of the study selection processNoNoFormal screening of search results against eligibility criteriaNoNoData extractionNoNoRisk of bias (quality) assessmentNoNoData analysisNoNo
Preliminary searchesYesNoPiloting of the study selection processNoNoFormal screening of search results against eligibility criteriaNoNoData extractionNoNoRisk of bias (quality) assessmentNoNoData analysisNoNo
?. Funding source/sponsorspending
?. Conflicts of interestnone declared
?. Review question1. What are the survival (time to event of death) of patients of non-small cell lung cancer (NSCLC) presented with a spinal metastasi(e)s?2. What are the differences of the above between patients that underwent spinal surgery against those that did not? 3. What is the trend of the survival above over the recent years, i.e. the introduction of tyrosine kinase inhibitors?
?. SearchesDatabase to be searched 1. MEDLINE2. EMBASE3. Google Scholar (to complement grey literature)One local database of the author's institute National Taiwan University Hospital is included as "Identification of new studies via other methods" within PRISMA 2020 flowchart (Page, 2021).Reference:Page MJ, McKenzie JE, Bossuyt PM. et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71 doi:10.1136/bmj.n71
?. Participants/populationPopulations diagnosed with non-small cell lung cancer that presents with spinal metastasis(es).Definitions: 1. non-small cell lung cancer: pathologically proven of any pathologies fall under the category of non-small cell lung cancer,2. spine metastasisInclusion criteria1. Dataset must have both NSCLC and spine metastasis, regardless of treatment modalityExclusion criteria1. Dataset that could not be isolated from non-NSCLC pathologies2. Dataset that could not be isolated from unknown pathologies3. Dataset that could not be isolated from those with absence of spinal metastasis
?. Intervention(s), exposure(s)Definition: There is no designated intervention or exposure in this study because the aim of this review is obtain the survival curve.Inclusion criteria1. Extractable survival curve, Kaplan-Meier curve2. Raw data available for the survival dataExclusion criteria1. The above data not available/extractable2. Number of patients at risks or the total number of events is not available.3. Censored data not available or could not be re-estimated (data incomplete/unavailable).
?. Comparator(s)/controlno comparator is designated because this study is a single-arm data meta-analysis
?. Types of study to be includedNo restriction of the types of study.This is a single-arm study, hence all types of studies were analyzed as a whole. However, a separation check of randomized studies vs. non-randomized studies can allow us to identify the existence of survival differences between real-world data and those included in trials.  It is well known that populations included in trials can be 'perfect patients.'
?. ContextGive summary details of the setting or other relevant characteristics, which help define the inclusion or exclusion criteria.
?. Primary outcome(s)Survival curve of1. surgical patients, 2. non-surgical patients, and3. all/mixed: extracted patients, including those data inseparable into either group aboveDefinition of the outcomes1. surgical patients: underwent surgery such as palliative decompression, debulking, total vertebrectomy, separation surgery, and any forms of minimal invasive (access) surgeries.2. non-surgical patients: include any forms of non-surgical treatment such as radiotherapy, chemotherapy, or palliative care3. all/mixed: extracted patients, including those data inseparable into either group aboveMeasures of effectSummary survival curve for aggregated survival data (manage in R, package Survival)
?. Data extraction (selection and coding)A pre-piloted form will be designed by Chai CLJeon JP and Chai CL work independently on concluding the search strategy and study selection according to the aforementioned inclusion and exclusion criteria. Chai CL work independently on the extraction of data from included studies using a pre-piloted form. Jeon JP oversees the accuracy. WhereTsuang FY will resolve disagreements.Extraction of the survival data:1. Use individual patient data if available2. Extract the published figure (image) of survival curve with Webplotdigitizer, Rohatgi (2020)3. Convert to IPD via package IPDfromKM in R, Liu 20214. Obtain survival function or Kaplan-Meier curve data, with number of patients at risk (best effort to calculate if possible)All excluded and failure of extraction studies are reported with reasons documented (in data supplements).Coding: as per defined outcome.  Whereas data inseparable to surgical vs. non-surgical group, (and individual data not available despite contacting the corresponding author) will be placed in "3. all group"Survival data are converted accordingly under the framework proposed by Tierney et al (2007)Reference:1. Tierney JF, Stewart LA, Ghersi D. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:162. Ankit Rohatgi. WebPlotDigitizer. Available at https://automeris.io/WebPlotDigitizer, Version: 4.4Accessed 27 May 20213. Liu N, Zhou YH, Lee JJ. IPDfromKM: Reconstruct Individual Patient Data from Published Kaplan-Meier Survival Curves https://doi.org/10.21203/rs.3.rs-117525/v1 Accessed 28 May 2021
?. Secondary outcome(s)None designated
?. Strategy for qualitative synthesisGRADE for the certainty of evidenceRisk of bias (limitation) assessmentDr. Tsuang and Dr. Chai work independently on risk of bias (limitations) assessment for individual outcomes and body of evidence according to GRADE guidelines: 4 (see reference).Outcomes listed below is specified to be assessed using GRADE for quality of evidence and presented in the summary of findings (Guyatt, 2011).2. Median overall survival of all patients, surgical patients, and non-surgical patientsThe funnel plot will be performed to assess publication bias if feasible.All disagreement and accuracy will be resolved by discussion between Jeon and ChaiReferences:Gordon H. Guyatt et al. GRADE guidelines: 1. Introductiond GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 64 (2011) 383e394 doi: 10.1016/j.jclinepi.2010.04.026Gordon H. Guyatt et al. GRADE guidelines: 4. Rating the quality of evidencedstudy limitations (risk of bias). Journal of Clinical Epidemiology 64 (2011) 407e415 doi: 10.1016/j.jclinepi.2010.07.017
?. Strategy for quantitative synthesisDerive a summary survival curve for from individual survival data in R, package Survival. Log Rank's test to compare the curves for statistical reason.  Beware that both surgical and non-surgical populations are two different populations.1. Survival curve of all patients (represents all included studies)2. Surgical patients, and 3. Non-surgical patientsIf data is not suitable for pooling, a narrative synthesis will be performed.Meta-analysis of trials and observational studies are separately performed and not subject to pooling.A standard of 95% confidence interval will be used in the meta-analysis.P value We will assess heterogeneity using the χ² test and the I² statistic (I² less than 40%: unimportant; 30-60%: moderate; 50-90%: substantial, 75-100%: considerable (Higgins, 2008).Reference:1. Liu N, Zhou YH, Lee JJ. IPDfromKM: Reconstruct Individual Patient Data from Published Kaplan-Meier Survival Curves https://doi.org/10.21203/rs.3.rs-117525/v1 Accessed 28 May 2021
?. Analysis of subgroups or subsets or moderatorsA moderator analysis will be performed using a frailty model in R to explore study-level factors potentially associated with survival.  Each study is regarded as a cluster.Note that moderators are analyzed separately within the surgical and non-surgical patients respectively.  It is because the two groups are believed to have similar baseline that permits direct comparison.Predefined moderators:1. Last follow-up date of the study2. Mean age of the study3. Proportion of positivity of EGFR mutation4. Proportion of patients receiving tyrosine kinase inhibitors (TKIs) (cancer immunotherapy)5. Proportion of patients with synchronous spine metastasisDefinitionssynchronous metastasis: the metastasis is diagnosed within 6 months of the primary cancer.metachronous metastasis: the metastasis is diagnosed more than 6 months after the diagnosis of the first primary cancerArrange median survival time with catepillar plots to check the trend of survival over the years.
?. Type and method of reviewSingle-arm meta-analysis of survival studies, oncology, spinal metastasis, non-small cell lung cancer
?. Dissemination plansWe will publish the review on completion
?. Current review statusReview Started