Moekotte, A.L.

English

Ampullary adenocarcinoma is a rare tumor that arises from the ampulla of Vater; the confluence of the common bile duct and the pancreatic duct. It represent a heterogeneous group with considerable morphological heterogeneity and therefore, a broad range of survival rates. The only potential curative treatment is surgical resection through a pancreatoduodenectomy, a major procedure with high morbidity- and mortality rates. The role of adjuvant chemotherapy in ampullary adenocarcinoma is unclear. Given the rarity of ampullary adenocarcinomas, no single randomized clinical trial in adjuvant treatment has focused specifically on ampullary adenocarcinoma. The research in this thesis aims to improve the surgical aspect of the treatment, through minimally invasive pancreas surgery, with the focus on implementation and safety. Another pillar of this thesis is improving the prediction of survival after resection of ampullary adenocarcinomas by defining predictors of survival and recurrence as well as developing a prediction model to anticipate 3- and 5-year survival of individual patients. Lastly, the role of adjuvant chemotherapy in ampullary adenocarcinoma is investigated

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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)UvA-DARE (Digital Academic Repository)Improving outcomes of minimally invasive pancreas surgery and ampullarycancerMoekotte, A.L.Publication date2020Document VersionOther versionLicenseOtherLink to publicationCitation for published version (APA):Moekotte, A. L. (2020). Improving outcomes of minimally invasive pancreas surgery andampullary cancer. [Thesis, fully internal, Universiteit van Amsterdam].General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an opencontent license (like Creative Commons).Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, pleaselet the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the materialinaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letterto: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as possible.Download date:10 Mar 2023Chapter 1General introduction  and thesis outlineChapter 18EPIDEMIOLOGY AND PRESENTATIONAmpullary adenocarcinoma (AAC) is a rare malignancy, accounting for only 0.2%–0.5% of gastro-intestinal cancers1,2 and about 7% of all periampullary- and pancreatic head can-cers.3 The incidence is around 0.5 case per 100.000 people per year.4 Compared with other periampullary cancers, AAC generally presents at an early stage of the disease as a result of the biliary obstruction with jaundice it causes.5 Therefore, at initial presentation, AAC is more amenable to resection as compared to other periampullary cancers (50% versus 20%).6,7 In addition, patients with AAC have a more favorable prognosis with 5-year survi-val rates of 30-70% after curative resection.1,7–11 This wide survival range might be related to the extensive morphological heterogeneity of AAC.Anatomy and histologyThe ampullary region is complex since three anatomically distinct structures adjoin in this region. The confluence of the distal common bile duct and the pancreatic duct represents the ampulla of Vater, this common duct protrudes into the duodenum, which is referred to as the papilla of Vater.12,13 The ampulla of Vater is named after Abraham Vater, a German anatomist who was the first to describe this anatomical structure in 1720.14As a result of the convergence of these anatomically distinct structures, tumors arising in the ampullary region represent a heterogeneous group with considerable morphological heterogeneity. Different histopathologic subtypes have been described, depending on the epithelium they arise from.15,16 According to the 4th edition of the WHO classification of tumors, adenocarcinomas of the ampullary region are divided into two main subty-pes: intestinal- and pancreaticobiliary subtype.17 The intestinal subtype arises from the adjacent duodenal mucosa and is characterized by cribriform tubular glands with central necrosis, histologically resembling colonic adenocarcinoma. The pancreaticobiliary subty-pe derives from the terminal pancreatic or biliary ducts and is characterized by simple or branching glands within a desmoplastic stroma. In addition, a mixed subtype, with over-lapping features has been frequently described. Less common subtypes, categorized as ‘other’ by the WHO, include mucinous carcinoma, poorly cohesive signet ring cell carcino-ma, adenosquamous carcinoma, clear cell carcinoma, micropapillary carcinoma, hepatoid adenocarcinoma, squamous cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, and neuroendocrine carcinomas.17SurvivalThe 5-year overall survival rate after resection of AAC varies from 30% to 70%.1,7–11 This survival is far more favorable as compared to the 5-year survival rate of patients with pancreatic ductal adenocarcinoma, which is about 20-25%.18 Of the two main subtypes, the intestinal subtype is associated with a more favorable prognosis compared with the pancreaticobiliary subtype.15,19–24 Histopathologic characteristics associated with survival, General introduction and thesis outline 19after adjusting for other risk factors, are lymph node involvement,22,25–27 pancreaticobiliary subtype,20–22,28,29 perineural invasion,21,30,31 lymphovascular invasion21 and tumor differen-tiation.20TreatmentThe treatment of loco-regional disease consists primarily of surgical resection, a pancrea-toduodenectomy (either ‘classic Whipple’: pylorus-resecting pancreatoduodenectomy, or pylorus-preserving pancreatoduodenectomy).5 Traditionally, pancreatoduodenectomy, a procedure with high morbidity and mortality rates, is performed through an open ap-proach.32–34 Recently, minimally-invasive pancreatoduodenectomy (MIPD) has been pro-posed as an alternative to the open pancreatoduodenectomy (OPD). However, the adop-tion of minimally invasive techniques (robotic and laparoscopic) in pancreatic surgery have been slow. Presumably, due to the complexity of the procedures, the corresponding high morbidity, and the lack of training possibilities and practical guidance for the imple-mentation of minimally invasive pancreatic surgery. Recently, the first two monocenter randomized controlled trials showed beneficial outcomes in MIPD in terms of a reduced intraoperative blood loss and length of hospital stay, while maintaining oncological resec-tion standards when compared with OPD.35,36 These favorable findings are supported by several meta-analyses of retrospective studies comparing MIPD with OPD.37–39 However, a pan-European propensity score matched study comparing MIPD and OPD showed an increased rate of postoperative pancreatic fistula (POPF) after MIPD compared with OPD.40 Furthermore, the first multicenter randomized controlled trial comparing MIPD with OPD was stopped due to safety concerns.41 Therefore, it is currently unclear whether MIPD is a valid and safe alternative for OPD.At present, it is uncertain whether patients with resected AAC gain a survival benefit from adjuvant chemotherapy. Randomized controlled trials focusing specifically on AAC are lacking. The most recent high-level evidence regarding adjuvant chemotherapy in AAC derives from the ESPAC-3 trial, which was conducted in patients with pancreatic head- and periampullary cancer. A subgroup analysis including patients with AAC did not show a survival benefit from adjuvant chemotherapy.42 On the contrary, several retrospective studies have described an association between adjuvant chemotherapy and an improved survival.27,43–46THESIS OUTLINEThe aim of this thesis is to improve curative-intent treatment and prognosis of patients with ampullary adenocarcinoma. To that end, the studies described in this thesis focus on I) minimally invasive pancreas surgery and II) long-term outcomes of ampullary aden-ocarcinoma.Chapter 110Part I: Minimally invasive pancreas surgeryIn chapter 2, the development and validation of the first evidence-based guidelines for minimally invasive pancreas surgery are described. The recommendations provide gui-dance for clinical practice of minimally invasive pancreas surgery. Chapter 3 defines pre-requisites needed prior to start performing minimally invasive pancreas surgery, with the objective to guide safe implementation. Chapter 4 describes the implementation and learning curve of laparoscopic distal pancreatectomy during the first 11 years in the UK. In chapter 5, clinical short-term outcomes of laparoscopic distal pancreatectomy with- and without splenectomy are compared. Chapter 6 describes the study protocol of a rando-mized controlled trial comparing splenectomy with autogenic splenic implantation ver-sus standard splenectomy in patients undergoing laparoscopic distal pancreatectomy for benign or low-grade malignant lesions of the left pancreas. The aim is to investigate the immune capacity of autogenic splenic implantation. In chapter 7, a comparison of surgi-cal outcomes is performed in patients who underwent minimally invasive- or open pan-creatoduodenectomy for ampullary adenocarcinoma specifically. The primary outcome in this chapter is major morbidity.Part II: Long-term outcomes of ampullary adenocarcinomaIn chapter 8, histopathologic predictors of overall- and disease free survival in patients with resected ampullary adenocarcinoma are identified using multivariable Cox proporti-onal hazards models. In chapter 9, the benefit of gemcitabine-based adjuvant chemothe-rapy in the different histopathologic subtypes of ampullary adenocarcinoma is investiga-ted, by using propensity scores to match patients who received adjuvant chemotherapy to those who did not. Chapter 10 describes the development and external validation of a prediction model for survival after resection of ampullary adenocarcinoma. In addition, four different risk-groups are created and the impact of adjuvant chemotherapy in these risk-groups is investigated.General introduction and thesis outline 111Research questions addressed in this thesis Chapter2 Based on the current evidence, what are recommendations for performing mi-nimally invasive pancreas surgery?3 Which prerequisites are required prior to embarking on minimally invasive pancreas surgery, to optimize patient safety?4 Did the use of the laparoscopic approach in distal pancreatectomy increase du-ring the first 11 years of its use in the UK? Did clinical outcomes change during the study period?5 Are surgical outcomes after laparoscopic spleen-preserving distal pancreatec-tomy comparable to outcomes after laparoscopic distal pancreatectomy with splenectomy?6 Is the Salmonella specific antibody response after vaccination with the Typhim Vi™ polysaccharide vaccine comparable between patients who underwent autogenic splenic implantation during laparoscopic distal pancreatectomy to those who underwent spleen-preserving distal pancreatectomy?7 Are surgical outcomes comparable after minimally invasive- and open pancre-atoduodenectomy when performed for ampullary adenocarcinoma?8 Which histopathologic characteristics predict overall- and disease free survival after resection of ampullary adenocarcinoma?9 Do patients with ampullary adenocarcinoma benefit from adjuvant chemothe-rapy after curative intent resection?10 Can we create a prediction model to predict individual survival after resection of ampullary adenocarcinoma? Does the impact of adjuvant treatment differ between different risk-groups?Chapter 112REFERENCES1. Albores-Saavedra, J., Schwartz, A. M., Batich, K. & Henson, D. E. Cancers of the ampulla of vater: Demographics, morphology, and survival based on 5,625 cases from the SEER Program. J. Surg. Oncol. 100, 598–605 (2009).2. Jemal, A. et al. Cancer Statistics, 2008. CA. Cancer J. Clin. 58, 71–96 (2008).3. Howe, J. R., Klimstra, D. S., Moccia, R. D., Conlon, K. C. & Brennan, M. F. Factors predictive of survival in ampullary carcinoma. Ann. Surg. 228, 87–94 (1998).4. Henson, D. E., Schwartz, A. M., Nsouli, H. & Albores-Saavedra, J. Carcinomas of the pancreas, gallbladder, extrahepatic bile ducts, and ampulla of vater share a field for carcinogenesis a population-based study. Arch. Pathol. Lab. Med. 133, 67–71 (2009).5. Ahn, D. H. & Bekaii-Saab, T. Ampullary Cancer: An Overview. Am. Soc. Clin. Oncol. Educ. B. 34, 112–115 (2014).6. Riall, T. S. et al. Resected periampullary adenocarcinoma: 5-year survivors and their 6- to 10-year follow-up. Surgery 140, 764–772 (2006).7. Rostain, F. et al. Trends in incidence and management of cancer of the ampulla of Vater. World J. Gastroenterol. 20, 10144–10150 (2014).8. Kim, K. et al. Role of Adjuvant Chemoradiotherapy for Ampulla of Vater Cancer. Int. J. Radiat. Oncol. Biol. Phys. 75, 436–441 (2009).9. Narang, A. K. et al. Eluation of adjuvant chemoradiation therapy for ampullary adenocarcino-ma: the Johns Hopkins Hospital–Mayo Clinic collaborative study. Radiat. Oncol. 6, 1–11 (2011).10. Brown, K. M. et al. Pancreaticoduodenectomy is curative in the majority of patients with no-de-negative ampullary cancer. Arch. Surg. 140, 529–533 (2005).11. Song, J. et al. Long-term prognosis of surgical treatment for early ampullary cancers and impli-cations for local ampullectomy Hepato-biliary-pancreatic surgery. BMC Surg. 15, 1–7 (2015).12. Klimstra, D., Hruban, R. & Martha, B. Vaterian System and Minor Papilla. in Histology for Patholo-gists (Lippinscott Williams & Wilkins, 2007).13. Adsay, V. et al. Ampullary Region Carcinomas. Am. J. Surg. Pathol. 36, 1592–1608 (2012).14. Lerch, M. M. & Domschke, W. Abraham Vater of the Ampulla (Papilla) of Vater. Gastroenterology 118, 379 (2000).15. Kimura, W. et al. Different Clinicopathologic Findings in Two Histologic Types of Carcinoma of Papilla of Vater. Jpn J Cancer Res 85, 161–166 (1994).16. Albores-Saveedra, J., Henson, D. & Klimstra, D. Tumors of the Gallbladder, Extrahepatic Bile Ducts and Ampulla of Vater. in Atlas of Tumor Pathology 259–316 (2000).17. Bosman, F., Carneiro, F., Hruban, R. & Theise, N. WHO Classification of Tumors of the Digestive System (4th edition). (WHO press, 2010).18. Vincent, A., Herman, J., Schulick, R., Hruban, R. & Goggins, M. Pancreatic Cancer. Lancet 378, 1605–1617 (2011).19. Okano, K. et al. 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L. et al. Carcinoma of the ampulla of vater: Factors influencing long-term survival of 127 patients with resection. World J. Surg. 31, 137–143 (2007).26. de Paiva Haddad, L. B. et al. Lymph node involvement and not the histophatologic subtype is correlated with outcome after resection of adenocarcinoma of the ampulla of vater. J. Gastrointest. Surg. 14, 719–728 (2010).27. Jin, Z. et al. Prognostic factors and benefits of adjuvant therapy after pancreatoduodenectomy for ampullary adenocarcinoma: Mayo Clinic experience. Eur. J. Surg. Oncol. 44, 677–683 (2018).28. Robert, P. et al. Predictors of long-term survival following resection for ampullary carcinoma: a large retrospective French multicentric study. Pancreas 43, 692–697 (2014).29. Schueneman, A. et al. Validation of histomolecular classification utilizing histological subtype , MUC1 , and CDX2 for prognostication of resected ampullary adenocarcinoma. 113, 64–68 (2015).30. Duffy, J. P. et al. 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Improving outcomes of minimally invasive pancreas surgery and ampullary cancer

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Improving outcomes of minimally invasive pancreas surgery and ampullary cancer

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