Adjuvant Chemotherapy in the Treatment of Intraductal Papillary Mucinous Neoplasms of the Pancreas: Systematic Review and Meta-Analysis

World J Surg https://doi.org/10.1007/s00268-021-06309-8 SCIENTIFIC REVIEW Adjuvant Chemotherapy in the Treatment of Intraductal Papillary Mucinous Neoplasms of the Pancreas: Systematic Review and Meta-Analysis Eric Chong1 • Bathiya Ratnayake1 • Bobby V. M. Dasari2 • Benjamin P. T. Loveday3,4 • Ajith K. Siriwardena5 • Sanjay Pandanaboyana6,7 Accepted: 13 August 2021 Ó The Author(s) 2021 Abstract Background The present systematic review aimed to compare survival outcomes of invasive intraductal papillary mucinous neoplasms (IIPMNs) treated with adjuvant chemotherapy versus surgery alone and to identify pathologic features that may predict survival benefit from adjuvant chemotherapy. Method A systematic search of MEDLINE, PubMed, Scopus, and EMBASE was performed using the PRISMA framework. Studies comparing adjuvant chemotherapy and surgery alone for patients with IIPMNs were included. Primary endpoint was overall survival (OS). A narrative synthesis was performed to identify pathologic features that predicted survival benefits from adjuvant chemotherapy. Results Eleven studies and 3393 patients with IIPMNs were included in the meta-analysis. Adjuvant chemotherapy significantly reduced the risk of death in the overall cohort (HR 0.57, 95% CI 0.38–0.87, p = 0.009) and nodepositive patients (HR 0.29, 95% CI 0.13–0.64, p = 0.002). Weighted median survival difference between adjuvant chemotherapy and surgery alone in node-positive patients was 11.6 months (95% CI 3.83–19.38, p = 0.003) favouring chemotherapy. Adjuvant chemotherapy had no impact on OS in node-negative patients (HR 0.53, 95% CI 0.20–1.43, p = 0.209). High heterogeneity (I2 [ 75%) was observed in pooled estimates of hazard ratios. Improved OS following adjuvant chemotherapy was reported for patients with stage III/IV disease, tumour size [ 2 cm, nodepositive status, grade 3 tumour differentiation, positive margin status, tubular carcinoma subtype, and presence of perineural or lymphovascular invasion. Conclusion Adjuvant chemotherapy was associated with improved OS in node-positive IIPMNs. However, the findings were limited by marked heterogeneity. Future large multicentre prospective studies are needed to confirm these findings and explore additional predictors of improved OS to guide patient selection for adjuvant chemotherapy. & Sanjay Pandanaboyana 1 Faculty of Medical and Health Sciences, Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand 2 Hepatobiliary and Transplant Unit, Queen Elizabeth Hospital, Birmingham, UK 3 Hepatobiliary and Upper Gastrointestinal Unit, Royal Melbourne Hospital, Victoria, Australia 4 Department of Surgical Oncology, Peter MacCallum Cancer Centre, Victoria, Australia 5 Hepatobiliary and Pancreatic Unit, Manchester Royal Infirmary, Manchester, UK 6 Pancreatic and Transplant Surgery, HPB and Transplant Unit, Department of Hepatobiliary, Freeman Hospital, Newcastle upon Tyne, UK 7 Population Health Sciences, Newcastle University, Newcastle upon Tyne, UK 123 World J Surg Abbreviations IPMN Intraductal papillary mucinous neoplasm IIPMN Invasive intraductal papillary mucinous neoplasm HR Hazard ratio OS Overall survival Introduction Intraductal papillary mucinous neoplasms (IPMNs) are mucin-producing epithelial neoplasms of the pancreas originating from the main pancreatic duct and/or one or more of its tributaries.Theworldwideprevalenceofincidentallydetected IPMNs is rising secondary to the widespread utilisation of cross-sectional abdominal imaging [1]. Historical concerns regarding the likely overestimated malignant potential of IPMNs meant indiscriminate resection. However, through experience and an improved understanding of the pathophysiology, IPMNs are now understood to be a spectrum of disease whereby low-risk selected patients perform well when a conservative surveillance approach is employed [2]. Indeed, IPMNsaredistributedintolow-gradedysplasia,intermediategradedysplasia,high-gradedysplasia,andinvasivecarcinoma [3]. High-risk clinical and radiological stigmata considered as predictors of high-grade dysplasia or invasive carcinoma include obstructive jaundice, enhancing mural nodule C5 mm, and main pancreatic duct (MPD) C 10 mm, while worrisome features include cyst C3 cm, enhancing mural nodule \5 mm, MPD 5–9 mm, abrupt change in MPD diameter with distal pancreas atrophy, lymphadenopathy, elevated CA 19–9, and cyst growth of [ 5 mm/2 year [2, 4]. Patients deemed to be at high risk would undergo pancreatic resection; however, the role of adjuvant chemotherapy is not standardised in patients with invasive IPMNs (IIPMNs) on post-operative histology. While the European Study Group on Pancreatic Cystic Neoplasms recommended adjuvant chemotherapy for IIPMNs with or without lymph node involvement [5], the revised Fukuoka consensus guidelines made no recommendations on adjuvant chemotherapy [2]. Currently, there remain no quantitative data to guide the use of adjuvant chemotherapy and prior systematic review is limited to narrative synthesis of historic literature [6]. The current systematic review and meta-analysis aimed to review the survival outcome of adjuvant chemotherapy compared to surgery alone for the treatment of patients with IIPMNs who underwent pancreatic resection and to identify pathologic features that may predict survival benefit from adjuvant chemotherapy. 123 Method Study selection The study was performed according to the Preferred Reporting for Systematic Reviews and Meta-analysis (PRISMA) guidelines [7]. A systematic search was performed on 5 February 2021 using four databases: PubMed, MEDLINE, Embase, and Scopus. A detailed analysis of the search strategy including the database specific syntax is reported in the Appendix. Reference lists of studies included in the full-text review were reviewed to identify additional articles not captured in the original search strategy. Eligibility criteria Two authors (EC and BR) independently screened the title and abstract of studies to identify relevant studies. Articles were included if they compared pancreatic resection followed by adjuvant chemotherapy versus pancreatic resection alone for IIPMNs in adults. Exclusion criteria were case reports, editorials, review articles, and non-English articles, and studies with less than five participants were excluded. Studies including IPMNs with concomitant pancreatic ductal adenocarcinoma (PDAC) were also excluded. Any enduring disagreement in study selection was adjudicated by the senior author (SP). Critical appraisal Two authors (EC and BR) independently performed the quality assessment using the ROBINS-1 tool [8]. Each study was assessed in seven different domains for biases that could occur in non-randomised studies. The domains were categorised as pre-intervention, during intervention, or post-intervention and graded as low, moderate, high, or critical risk of bias. An overall risk of bias was decided based on (...truncated)