Wenjun Luo1,2†
Chunyu Liu3†Luyin Han4†
Haidong Zhang1,2Chaoyong Shen1,2
Xiaonan Yin1,2
Zhou Zhao5Mingchun Mu1,2
Tianxiang Jiang1,2
Zhaolun Cai1,2*
Bo Zhang1,2*- 1Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- 2Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- 3Department of Pharmacy, Evidence-based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- 4Intensive Care Unit, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- 5Department of Gastrointestinal Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
Background: To date, several studies have compared the surgical and oncological outcomes of local excision (LE) and radical excision (RE) for rectal gastrointestinal stromal tumors (GISTs), but some have limited numbers of small series. This protocol outlines the planned scope and methods for a systematic review and meta-analysis that will compare the surgical and oncological outcomes of LE and RE in patients with rectal GISTs.
Methods: This protocol is presented in accordance with the PRISMA-P guideline. PubMed, Embase, Web of Science, Cochrane Library and Wanfang database will be systematically searched. Furthermore, reference lists of all included articles will be screened manually to add other eligible studies. We will include randomized controlled trials (RCTs) and non-randomized studies (NRS) in this study. The primary outcomes evaluated will be R0 resection rate and disease-free survival, while the secondary outcomes will contain overall survival, length of stay, tumor rupture rate and complications. Two reviewers will independently screen and select studies, extract data from the included studies, and assess the risk of bias of the included studies. Preplanned subgroup analyses and sensitivity analyses are detailed within this protocol. The strength of the body of evidence will be assessed using GRADE
Discussion: This review and meta-analysis will provide a comprehensive evaluation of the current evidence concerning the application of LE and RE in patients with rectal GISTs. The findings from this review will serve as a foundation for future research and emphasize the implications for clinical practice.
Systematic review registration: PROSPERO (CRD42017078338), https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=387409, PROSPERO CRD42017078338.
Introduction
Gastrointestinal stromal tumors (GISTs) arise from the Cajal stromal cells of the gastrointestinal tract (GI) and are the most common type of mesenchymal stromal tumors in the digestive tract (1). GISTs can occur anywhere from the esophagus to the anus but are predominantly found in the stomach (60-70%), followed by the small bowel (20-30%), and approximately 5% in the rectum (2). Although rectal GISTs are less frequent, their malignancy risk is higher than at other sites, making the rectum a worse prognostic factor for GISTs (3).
Surgical resection is the only curative treatment for primary localized GISTs (4, 5). As GISTs seldom have lymph node metastasis, complete resection with negative margins is sufficient, and routine lymphadenectomy is not necessary (6). However, the optimal surgical modality for rectal GISTs remains controversial due to the critical anatomical area, anus preservation, and postoperative urogenital nerve function (7).
Two types of surgical methods are used for rectal GIST resection: local excision (LE) and radical excision (RE). LE has the advantages of less trauma and quicker recovery but poses a higher risk of incomplete resection and disrupting the tumor capsule, potentially increasing the probability of local recurrence (8). RE can achieve complete resection with clear margins but often results in significant early and/or long-term morbidity and a worse quality of life (9). The standard treatment for rectal GISTs has not been developed, and the choice between local and radical excision for localized rectal GISTs is largely influenced by clinician preference and experience (10).
To date, several studies have compared the surgical and oncological outcomes of LE and RE for rectal GISTs (11–14), but some have limited numbers of small series. This study aims to systematically review available literature to compare the impact of LE and RE in localized rectal GIST patients on R0 resection, operation duration, length of stay, recurrence, and survival.
Methods
Protocol and registration
This present protocol has been registered at PROSPERO (ID: CRD42017078338). The protocol follows the reporting guidance provided in the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement (see PRISMA-P checklist in Additional file 1 (15)) and will be conducted according to the PRISMA 2020 statement and the standard methodology recommended by the Cochrane Collaboration (16–18).
Inclusion criteria
The inclusion criteria follow the PICOS (population, intervention, comparators, outcomes, and study design) framework (19). All studies meeting the inclusion criteria will be included without restrictions on language and publication year.
• Population: Patients with primary rectal GISTs who underwent surgical resection and had GISTs confirmed by pathological results (Immunohistochemical assay for SDHB, CD117, DOG1, and CD34 and molecular genetic testing for KIT and PDGFRA mutations, as well as other potential drivers (e.g., BRAF, NF1, NTRK, and FGFR fusions) will be included without restrictions on country, race, ethnic origin, age, sex, or occupation (20).
• Intervention: Local excision includes transanal excision, transanal minimally invasive surgery, transanal endoscopic microsurgery, trans-sacral resection, and transperineal resection.
• Comparators: Radical excision includes abdominal-perineal resection, low anterior resection, and Hartmann operation.
• Outcomes and measurement:
Primary outcome: 1.R0 resection rate; 2. disease-free survival.
Secondary outcome: 1.overall survival; 2. length of stay; 3. tumor rupture rate; 4. complications.
• Study designs: The study will also include non-randomized studies (NRS) (case–control studies, and cohort studies) and randomized controlled trials (RCTs). The included studies must report at least one of the prescriptive outcomes in rectal GIST patients who undergo any form of surgery.
Exclusion criteria
– The presence of metastatic, recurrent or other secondary rectal GISTs.
– Duplicate texts and articles.
– Articles with incomplete clinical data after a reasonable attempt at contacting corresponding authors.
– Any letters, conference abstracts, editorials, case reports, reviews or nonclinical studies without available data will be excluded.
– Full-text articles cannot be obtained after exhaustive searches.
Information sources and search strategy
A systematic literature search will be performed in PubMed, Embase, Cochrane Central Registry of Controlled Trials to identify all relevant studies from their inception to Sep 10th, 2023. The details of PubMed database search strategy are presented in Additional File 2. Reference lists of all included articles will be screened manually to add additional studies if they meet the eligibility criteria and full text will be retrieved.
Study selection and data extraction
All study records obtained by literature search will be imported in EndNote software. After removing duplicates, two reviewers (L.W and L.C) will conduct articles selection independently based on the eligibility criteria outlined above. First of all, titles and abstracts will be screened for relevance. Next, the two independent reviewers (L.W and L.C) will reassess all potentially relevant full-text articles. The articles screening process will be summarized in a PRISMA flow diagram (21).
Two reviewers (L.W and L.C) will independently complete data extraction for the included studies using a standardized data extraction form. The collected data will include baseline, disease and perioperative characteristics of patients, as well as data relevant to our primary and secondary outcomes. A third reviewer (Z.B) will make the final decision if any conflicts occur in the process of study selection and data extraction which couldn’t be resolved by the two reviewers.
Dealing with missing data
When some required data is missing, we will contact the corresponding author of the article via email. If no response is received in 14 days after the initial contact, we will no longer communicate with the study researcher, and the selected studies will be excluded from the present systematic review and meta-analysis.
Risk of bias assessment
Two independent reviewers (L.W and L.C) will also assess methodological quality/risk of bias of the included studies at the individual study level, and disagreements will be resolved through discussion or by a third reviewer (Z.B) (22). NRS will be assessed using Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool (23), while RCTs will be assessed risk of bias with the RoB 2 (24).
Data synthesis
Two reviewers (L.W and L.C) will independently extract data from the included studies, including publication year, primary author name, journal of publication, study type, number of patients, tumor size, type of surgery, surgical approach, margin status, length of stay, and survival. Additional data, such as tumor rupture rate, will also be recorded. Conflicts will be resolved through discussion or by involving a third reviewer (Z.B). If sufficient data is available for a quantitative synthesis, a meta-analysis will be conducted using STATA version 15.0 statistical software (STATA, College Station, TX). Binary data will be reported as odds ratios (OR) with 95% confidence intervals (95% CI) estimated using the Mantel-Haenszel method. For continuous data, mean differences and 95% CI will be estimated using inverse variance weighting. Outcome measures (mean + standard deviation and median + interquartile range) will be recorded. Results with a P-value less than 0.05 will be considered statistically significant.
Heterogeneity will be assessed using the chi-square-based Q test, and the I2 test will quantify the potential impact of heterogeneity on the meta-analysis. For chi-square values with P-value < 0.1, heterogeneity across the included studies will be considered statistically significant. An I² value of 0% to 40% represents “not important”; 30% to 60% represents “moderate heterogeneity”; 50% to 90% represents “substantial heterogeneity” (25). If the I2>50% and P ≤ 0.1, the random effects model will be used for meta-analysis. Any high heterogeneity will be explored through subgroup analysis or sensitivity analysis. Additionally, the study design and characteristics in the included studies will be analyzed.
A priori subgroup analyses
If multiple studies reported homogenous outcomes in the following subgroups, planned subgroup analysis of the primary outcomes include the following:
1. Administration of neoadjuvant Tyrosine Kinase Inhibitors (TKIs) Prior to surgery: We will compare cases where TKIs were utilized before surgery to those where they were not. The application of neoadjuvant TKIs can effectively decrease tumor volume, subsequently downstage the clinical condition, and therefore limit the need for extensive surgical intervention, thus preventing unnecessary organ resection.
2. Use of adjuvant TKIs post-operation: The analysis will contrast outcomes from instances where TKIs were employed following the surgical procedure to those where they were not. The application of adjuvant therapy has demonstrated a substantial improvement in recurrence-free survival duration, indicating its suitability for patients with an intermediate to high risk of recurrence.
3. Propensity score analyses in non-randomized studies (NRS): The comparison will be between scenarios where propensity score analyses were undertaken versus where they were not. The implementation of propensity score analyses potentially leads to a relative balance in baseline characteristics, mitigating inherent biases.
Sensitivity analysis
To exclude the situation that the results of the meta-analysis are substantially influenced by the presence of any individual study, we will conduct a sensitivity analysis by removing studies with a high risk of bias.
Meta-biases and quality of evidence
When over ten studies are available, funnel plot will be used to examine publication bias (25). We will use the GRADE approach to assess the quality of findings systematically, which is considered an effective method to provide detailed information on assessments (26, 27). The quality of findings will be classified as high, moderate, low, and very low according to four dimensions: risk of bias, inconsistency, indirectness, and imprecision. High-quality findings will indicate a high grade of confidence in efficacy and quality of intervention. The GRADE assessments will be presented in a summary table.
Discussion
Over the past decade, numerous studies have been published on the topic of local excision versus radical excision for rectal GISTs. However, the optimal choice between these surgical approaches remains a subject of debate. This review and meta-analysis aims to provide a comprehensive evaluation of the current evidence concerning the application of local excision and radical excision in patients with rectal GISTs. The findings from this review will serve as a foundation for future research and emphasize the implications for clinical practice.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.
Author contributions
WL, CL, and LH provided equal contributions and shared co-first authorship. The original idea of this research was conceived by BZ, ZC, and LH. HZ, WL, and CS designed the protocol and drafted the manuscript. XY, MM, ZZ, CS, and TJ participated in developing the eligibility criteria, search strategy, and data extraction methods. WL registered the protocol in the International Prospective Register for Systematic Reviews and Meta-analysis. BZ and LH reviewed the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This study was supported by the Key Research and Development Project of Sichuan Science and Technology Department (project number 2020YFS0234).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2023.1224725/full#supplementary-material
Abbreviations
GISTs, gastrointestinal stromal tumors; GI, gastrointestinal tract; LE, local excision; RE, radical excision; PRISMA-P, Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols; PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analysis; RCTs, randomized controlled trials; NRS, non-randomized studies; TKIs, tyrosine kinase inhibitors; ROBINS-I, Risk of Bias in Non-randomized Studies of Interventions; RoB 2, Revised Cochrane risk-of-bias tool for randomized trials; CI, confidence interval; OR, odd ratios; GRADE, Grading of Recommendations Assessment Development and Evaluations.
References
1. Mantese G. Gastrointestinal stromal tumor: epidemiology, diagnosis, and treatment. Curr Opin Gastroenterol (2019) 35(6):555–9. doi: 10.1097/MOG.0000000000000584
2. Parab TM, DeRogatis MJ, Boaz AM, Grasso SA, Issack PS, Duarte DA, et al. Gastrointestinal stromal tumors: a comprehensive review. J Gastrointest Oncol (2019) 10(1):144–54. doi: 10.21037/jgo.2018.08.20
3. Theodoropoulos DG. Gastrointestinal tumors of the colon and rectum. Clin Colon Rectal Surg (2011) 24(3):161–70. doi: 10.1055/s-0031-1286000
4. Cai Z, Yin Y, Shen C, Tang S, Yin X, Chen Z, et al. Role of surgical resection for patients with recurrent or metastatic gastrointestinal stromal tumors: A systematic review and meta-analysis. Int J Surg (2018) 56:108–14. doi: 10.1016/j.ijsu.2018.06.016
5. Cai Z, Xin C, Jiang Z, Liu C, Shen C, Zhao G, et al. Surgical resection for patients with recurrent or metastatic gastrointestinal stromal tumors: a protocol for a systematic review and meta-analysis update. Syst Rev (2021) 10(1):306. doi: 10.1186/s13643-021-01863-7
6. Pierie JP, Choudry U, Muzikansky A, Yeap BY, Souba WW, Ott MJ. The effect of surgery and grade on outcome of gastrointestinal stromal tumors. Arch Surg (2001) 136(4):383–9. doi: 10.1001/archsurg.136.4.383
7. Kameyama H, Kanda T, Tajima Y, Shimada Y, Ichikawa H, Hanyu T, et al. Management of rectal gastrointestinal stromal tumor. Transl Gastroenterol Hepatol (2018) 3:8. doi: 10.21037/tgh.2018.01.08
8. Guo W, Yang Z, Wei Y, Qin X, Li C, Huang R, et al. Radical excision versus local resection for primary rectal gastrointestinal stromal tumors. Cohort Study Int J Surg (2020) 77:190–7. doi: 10.1016/j.ijsu.2020.03.068
9. Farid M, Lee MJ, Chew MH, Ong WS, Sairi AN, Foo KF, et al. Localized gastrointestinal stromal tumor of the rectum: An uncommon primary site with prominent disease and treatment-related morbidities. Mol Clin Oncol (2013) 1(1):190–4. doi: 10.3892/mco.2012.25
10. Sista F, De Leonardis M, Carandina S, Pessia B, Clementi M, Vicentini R. Surgical management of rectal GIST. A case report and a review of literature. Ann Ital Chir (2021) 10:S2239253X2103485X.
11. Yang Z, Guo W, Huang R, Hu M, Wang H, Wang H. Transanal versus nontransanal surgery for the treatment of primary rectal gastrointestinal stromal tumors: a 10-year experience in a high-volume center. Ann Transl Med (2020) 8(5):201. doi: 10.21037/atm.2020.01.55
12. Romain B, Delhorme JB, Manceau G, Lefevre JH, Tresallet C, Mariani P, et al. Is nonanatomic rectal resection a valid therapeutic option for rectal gastrointestinal stromal tumors? A proposed decision algorithm. J Surg Oncol (2020) 122(8):1639–46. doi: 10.1002/jso.26215
13. Zhu R, Liu F, Grisotti G, Pérez-Irizarry J, Cha CH, Johnson CH, et al. Distinctive features of gastrointestinal stromal tumors arising from the colon and rectum. J Gastrointest Oncol (2018) 9(2):231–40. doi: 10.21037/jgo.2017.11.12
14. Hawkins AT, Wells KO, Krishnamurty DM, Hunt SR, Mutch MG, Glasgow SC, et al. Preoperative chemotherapy and survival for large anorectal gastrointestinal stromal tumors: A national analysis of 333 cases. Ann Surg Oncol (2017) 24(5):1195–201. doi: 10.1245/s10434-016-5706-1
15. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. Bmj (2016) 354:i4086. doi: 10.1136/bmj.g7647
16. Salandra R, Criscuolo P, Salter A. The power of weak signals: how systematic reviews direct researchers away from potentially biased primary studies. Cochrane Database Sys Rev (2022) 11(11):ED000160. doi: 10.1002/14651858.ED000160
17. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev (2021) 10(1):89. doi: 10.1186/s13643-021-01626-4
18. Cumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev (2019) 10:Ed000142. doi: 10.1002/14651858.ED000142
19. Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol (2011) 64(4):395–400. doi: 10.1016/j.jclinepi.2010.09.012
20. Casali PG, Blay JY, Abecassis N, Bajpai J, Bauer S, Biagini R, et al. Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol (2022) 33(1):20–33. doi: 10.1016/j.annonc.2021.09.005
21. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PloS Med (2009) 6(7):e1000097. doi: 10.1371/journal.pmed.1000100
22. Jiang Z, Cai Z, Yin Y, Shen C, Huang J, Yin Y, et al. Impact of surgical margin status on the survival outcome after surgical resection of gastric cancer: a protocol for systematic review and meta-analysis. BMJ Open (2020) 10(11):e040282. doi: 10.37766/inplasy2020.5.0028
23. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. Bmj (2016) 355:i4919. doi: 10.1136/bmj.i4919
24. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. Bmj (2011) 343:d5928. doi: 10.1136/bmj.d5928
25. Nasser M. Cochrane handbook for systematic reviews of interventions. Am J Public Health (2020) 110(6):753–4. doi: 10.2105/AJPH.2020.305609
26. Guyatt GH, Oxman AD, Schünemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol (2011) 64(4):380–2. doi: 10.1016/j.jclinepi.2010.09.011
27. Schunemann H BJ, Guyatt G, Oxman A. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach: The Cochrane Collaboration GRADE Working Group. (2013). gdt.gradepro.org/app/handbook/handbook.html.
Keywords: gastrointestinal stromal tumors, GIST, rectal, local excision, radical excision
Citation: Luo W, Liu C, Han L, Zhang H, Shen C, Yin X, Zhao Z, Mu M, Jiang T, Cai Z and Zhang B (2023) Local excision and radical excision for rectal gastrointestinal stromal tumors: a meta-analysis protocol. Front. Oncol. 13:1224725. doi: 10.3389/fonc.2023.1224725
Received: 18 May 2023; Accepted: 24 August 2023;
Published: 07 September 2023.
Edited by:
Stephen J. Pandol, Cedars Sinai Medical Center, United StatesReviewed by:
Francesca Pecchini, Baggiovara Civil Hospital, ItalyMarco Massani, ULSS2 Marca Trevigiana, Italy
Copyright © 2023 Luo, Liu, Han, Zhang, Shen, Yin, Zhao, Mu, Jiang, Cai and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Bo Zhang, zhangbo_scu@scu.edu.cn; Zhaolun Cai, caizhaolun@foxmail.com
†These authors have contributed equally to this work