DOI: 10.5061/dryad.k98sf7m4w
title: Impact of the surgical approach to thymectomy upon complete stable remission rates in myasthenia gravis: a meta-analysis

description: Objectives: To determine whether any of the available operative techniques
 confer variable chances for complete stable remission (CSR) in myasthenia
 gravis (MG), we performed a meta-analysis of all comparative studies of
 surgical approaches. Methods: Meta-analysis of all studies providing
 comparative data on thymectomy approaches, with CSR reported and minimum 3
 years mean follow-up. Results: 12 cohort studies and one randomized
 clinical trial, containing 1598 patients, met entry criteria. At 3 years,
 CSR from MG was similar following VATS extended vs. both basic (RR 1.00,
 p=1.00, 95% CI 0.39-2.58) and extended (RR 0.96, p=0.74, CI: 0.72-1.27)
 transsternal approaches. CSR at 3 years was also similar following
 extended transsternal vs. combined transcervical-subxiphoid (RR 1.08,
 p=0.62, CI: 0.8-1.44) approaches. VATS extended approaches remained
 statistically equivalent to extended transsternal approaches through 9
 years of follow-up (RR 1.51, p=0.05, CI: 0.99-2.30).  The only
 significant difference in CSR rate between a traditionally open and a
 minimally invasive approach was seen at 10 years when comparing the
 now-abandoned basic (non-sternum-lifting) transcervical approach and the
 extended transsternal approach (RR 0.4, p=0.01, CI: 0.2-0.8). Conclusions:
 A significant difference in the rate of CSR among various surgical
 approaches for thymectomy in MG was identified only at long-term
 follow-up, and only between what might be considered the most aggressive
 approach (extended transsternal thymectomy) and the least aggressive
 approach (basic transcervical thymectomy).  Extended minimally
 invasive approaches appear to have equivalent CSR rates to extended
 transsternal approaches and are therefore appropriate in the hands of
 experienced surgeons.
description: The protocol for this study is registered at PROSPERO
 (CRD42020166827)21. The manuscript is written using the Preferred
 Reporting Items for Systematic Reviews and Meta-analysis (PRISMA)
 guidelines22. <strong>Eligibility
 criteria</strong> We included studies comparing
 at least two thymectomy techniques in patients older than 18 years with
 MG.  Since the data is unclear whether the presence of a thymoma impacts
 MG outcomes following thymectomy23, we included studies of patients both
 with or without thymoma. The primary outcome measure for our study was
 Complete Stable Remission (CSR). We included in our definition of CSR
 patients who are asymptomatic with no medications for at least 6 months;
 or asymptomatic and taking only single drug immunosuppression for at least
 6 months (slightly broader than the strict MGFA definition, in order to
 include more studies in the analysis).  Because remissions following
 thymectomy in all studies accumulate progressively with time, and the
 steepest upward slope of this curve is in the first several years, we only
 included studies with a minimum of 3 years of follow-up. We classified the
 method of thymectomy according to the published, MGFA modified
 classification for thymectomy approaches24.
 <strong>Data sources and searches</strong>
 A comprehensive search of studies, in any language, from several
 databases, beginning on May 6th, 2019 was conducted. The databases
 included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process &
 Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central
 Register of Controlled Trials, Ovid Cochrane Database of Systematic
 Reviews, and Scopus. The search strategy was designed and conducted by an
 experienced librarian with input from the study's principle
 investigator. Controlled vocabulary supplemented with keywords was used to
 search for thymectomy performed in adults with myasthenia gravis25–27.
 Conference abstracts, literature reviews, case reports and editorials were
 excluded. The list of all search terms and combinations is available in
 tables e-1 and e-2. <strong>Study
 selection</strong> Search records were uploaded
 into a systematic review software program (DistillerSR, Ottawa, ON,
 Canada)28. Screening was performed by four reviewers (P.S-P., E.L-N.,
 W.T., I.B.) separately and in duplicate, using standardized instructions.
 Prior to the abstract screening phase, a pilot was performed with 20
 articles to assess for understanding and accuracy of the eligibility
 criteria. Articles included by at one reviewer during abstract screening
 were included into the next phase: screening of full-text reports. A pilot
 before full text screening was also performed. At this level,
 disagreements were resolved through consensus by three reviewers (P.S-P.,
 E.L-N., O.J.P.). Screening agreement was assessed using Cohen’s kappa
 (k=0.42).  <strong>Data collection and
 variables</strong> Two reviewers (P.S-P., E.L-N),
 working independently and in duplicate, extracted study data into a
 standardized form, and a third reviewer (O.J.P) randomly audited 30% of
 this data for accuracy and completeness. The variables of interest were:
 1) general characteristics (first author, date of publication, country,
 study design, data collection period); 2) setting (single center,
 multicenter); 3) patient characteristics before surgery (age at diagnosis
 of MG, sex, signs and symptoms, antibody titers, treatments before
 surgery); 4) thymectomy techniques; 5) patient characteristics after
 surgery (histology, complications, operative time, and hospital length of
 stay [LOS]); 6) outcomes of interest (CSR ).
 <strong>Data management</strong>
 Extracted data was later classified in several ways. Clinical MG
 findings were grouped according to the MGFA classification29. Table e-3
 describes the five classes and corresponding subclasses. Surgical
 techniques were classified according to the primary approach (e.g.,
 transcervical, videoscopic, transsternal, or any combination),30 and
 further subdivisions were made according to the MGFA thymectomy
 classification24, as follows:  T-1: transcervical thymectomy (basic,
 extended, extended with partial sternal split, extended with videoscopic
 technology); T-2: videoscopic thymectomy (classic unilateral VATS,
 bilateral VATS with neck dissection, unilateral videoscopic with robotic
 technology, bilateral videoscopic with robotic technology); T-3:
 transsternal thymectomy (basic, extended); T-4: transcervical and
 transsternal thymectomy; T-5: infra-sternal thymectomy (combined
 transcervical/subxiphoid, videoscopic subxiphoid, videoscopic with robotic
 technology subxiphoid, infrasternal mediastinoscopy) (Table
 e-4). The most common groups of surgeries in the
 publications that met our selection criteria were the transsternal and the
 various minimally invasive approaches to thymectomy (video-assisted
 extended thymectomy, robotic approaches, basic transcervical, subxiphoid,
 combined transcervical/subxiphoid). Classically, and in the MGFA
 classification, “extended” thymectomy refers to removing not only the
 intracapsular thymus, but also all of the anterior mediastinal fat between
 the phrenic nerves and from the thoracic inlet to the diaphragm31.  If
 authors used the term “extended” in their procedure descriptor, we
 classified it as such. For all approaches, if the authors did not use the
 term “extended”, but describes an operation that matches the above
 classical description of an “extended” thymectomy, then it was classified
 as “extended”.  All other operations were classified as “basic”
 thymectomies. There is no standard accepted histological classification
 for excised, non-neoplastic thymic tissue29. We therefore described
 histology using the most common histologic types reported by the studies
 (hyperplastic, normal, involuted).  
 <strong>Author contact</strong> We
 emailed corresponding authors of included studies asking them to share
 data about the association of different treatment approaches with CSR when
 this was unclear in the manuscript, or to otherwise clarify reported
 information. If authors failed to respond in a 2-week period, we contacted
 them with a second e-mail. If authors did not reply after 1 additional
 week, a final e-mail was sent. Those who still did not respond in another
 1-week period were contacted by telephone.  Four authors replied. Two
 helped to clarify reported data, and two shared hazard ratio
 information32,33. The data shared by one of the authors did not match what
 was reported in the publication and that publication was therefore
 excluded from this study34. <strong>Risk of bias
 in individual studies</strong> Risk of bias was
 assessed by two reviewers (P.S-P., E.L-N.). Disagreements were resolved by
 including a third reviewer (O.J.P.). To assess the risk of bias of
 cohort-studies, we used the CLARITY tool35. The domains for cohort studies
 were: 1) whether the selection of exposed and non-exposed cohorts were
 chosen from the same population; 2) confidence in the assessment of
 exposure; 3) whether the outcome of interest was absent at the start of
 the study; 4) if the study matched exposed and unexposed for all variables
 that are associated with the outcome of interest or if the statistical
 analyses adjusted for the specified prognostic variables; 5) confidence in
 the assessment regarding the presence or the absence of prognostic
 factors; 6) confidence in the assessment of the outcome; 7) if the follow
 up of cohort was adequate; and 8) if co-interventions between groups were
 similar. In this tool, there were four possible responses for each domain:
 “definitively yes”, “probably yes”, “probably no”, and “definitively no”.
  For a better understanding, we modified these responses to low, high, or
 unclear risk of bias. “Definitively yes” was interpreted as low; “probably
 yes” and “probably no” – unclear; and “definitively no” – high risk of
 bias. The risk of bias of clinical trials was assessed using the Cochrane
 Collaboration risk assessment tool, which included the following domains:
 1) randomization sequence generation; 2) allocation concealment; 3)
 blinding of participants and personnel; 4) blinding of outcome assessment;
 5) incomplete outcome data; 6) selective reporting; and 7) other bias.
 Each of these domains had three possible responses: low, unclear, and high
 risk of bias36. Studies with at least one domain
 considered as “high risk of bias” were judged  have a high overall risk of
 bias; studies with at least two domains at “unclear risk of bias” and
 without domains assessed as “high risk of bias” were considered to be at
 overall unclear risk of bias; and those studies with domains classified as
 “low risk of bias” without any “unclear” or “high risk of bias” domain
 were considered at overall low risk of bias.
 <strong>Certainty in the body of
 evidence</strong> The quality or certainty in the
 evidence was assessed with the “Grading of Recommendations Assessment,
 Development and Evaluation” (GRADE) approach37. This assessment reflects
 the level of confidence that the effect sizes or estimates from this
 systematic review are correct37. We evaluated each
 treatment-comparison-outcome triad (e.g. extended transsternal thymectomy
 - basic transsternal thymectomy - complete stable remission). To ease
 interpretation, only the longest follow-up of each triad was evaluated and
 reported. Two reviewers (P.S-P., E.L-N), working individually, assessed
 the quality of evidence, and consensus was used to resolve disagreements
 by involving a third reviewer (O.J.P). Overall, the
 quality of the evidence of each treatment-comparison-outcome triad can be
 graded as very low, low, moderate, and high. To assign these, we began by
 rating randomized trials as high quality of evidence and observational
 studies as low quality of evidence. Then, based on different factors, we
 either downgraded (risk of bias, inconsistency, indirectness, imprecision,
 and publication bias) or upgraded (large magnitude of effect, plausible
 confounding, and dose-response gradient) the initial rating. A detailed
 description of this methodology is found online37.
 <strong>Statistical analyses</strong>
 We had hoped to analyze time-to-event outcomes; however, none of
 included studies reported the necessary data. Although we contacted the
 authors asking to share this information, the low response rate rendered
 us unable to perform a meta-analysis of time-to-event data. As a second
 approach, we extracted data and analyzed it as relative risk
 (RR). We calculated the RR for each
 outcome-intervention-outcome triad and their 95% confidence intervals
 (CIs) using random-effects model with the restricted maximum-likelihood
 estimator. To observe how the effect changed over time, we calculated
 these effect sizes for different follow-up times.
 Heterogeneity across studies was assessed with the I2 statistic
 and visually38. We considered that I2&lt; 25% reflected low
 inconsistency and I2&gt; 75% reflected high inconsistency. Although we
 planned to perform subgroups analyses by age, sex, MGFA score, Osserman
 score, and anti-acetylcholine-receptor antibodies, not enough data was
 available. To perform this analysis and create the forest plots, we used
 the statistical program R Studio, an integrated development environment
 for R39. To ease interpretation and comparability of
 patient characteristics before and after surgery, we converted medians to
 means and ranges or interquartile ranges to standard deviations.