Chandrasegaram MD, Gill AJ, Samra J, Price T, Chen J, Fawcett J, Merrett ND. Ampullary cancer of intestinal origin and duodenal cancer - A logical clinical and therapeutic subgroup in periampullary cancer. World J Gastrointest Oncol 2017; 9(10): 407-415
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Dr. Manju D Chandrasegaram, the Prince Charles Hospital, Rode Road, Chermside, Brisbane, Queensland 4032, Australia. email@example.com
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World J Gastrointest Oncol. Oct 15, 2017; 9(10): 407-415 Published online Oct 15, 2017. doi: 10.4251/wjgo.v9.i10.407
Ampullary cancer of intestinal origin and duodenal cancer - A logical clinical and therapeutic subgroup in periampullary cancer
Manju D Chandrasegaram, Anthony J Gill, Jas Samra, Tim Price, John Chen, Jonathan Fawcett, Neil D Merrett
Manju D Chandrasegaram, the Prince Charles Hospital, Brisbane, Queensland 4032, Australia
Manju D Chandrasegaram, Jonathan Fawcett, School of Medicine, University of Queensland, Queensland 4006, Australia
Anthony J Gill, Jas Samra, Sydney Medical School, University of Sydney, New South Wales 2006, Australia
Anthony J Gill, Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia
Jas Samra, Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia
Tim Price, Queen Elizabeth Hospital, Adelaide, South Australia 5011, Australia
Tim Price, University of Adelaide, South Australia 5005, Australia
John Chen, Flinders Medical Centre, Adelaide, South Australia 5042, Australia
John Chen, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia
Jonathan Fawcett, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia
Neil D Merrett, Department of Upper GI Surgery, Bankstown Hospital, Sydney, New South Wales 2200, Australia
Neil D Merrett, Discipline of Surgery, Western Sydney University, Sydney, New South Wales 2560, Australia
ORCID number: $[AuthorORCIDs]
Author contributions: All the authors made substantial contributions to (1) conception, design, analysis and interpretation of data; (2) making critical revisions related to important intellectual content of the manuscript; and (3) final approval of the version of the article to be published.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Manju D Chandrasegaram, the Prince Charles Hospital, Rode Road, Chermside, Brisbane, Queensland 4032, Australia. firstname.lastname@example.org
Telephone: +61-7-31930800 Fax: +61-7-33196761
Received: January 31, 2017 Peer-review started: February 8, 2017 First decision: May 8, 2017 Revised: June 26, 2017 Accepted: August 16, 2017 Article in press: August 17, 2017 Published online: October 15, 2017
Periampullary cancers include pancreatic, ampullary, biliary and duodenal cancers. At presentation, the majority of periampullary tumours have grown to involve the pancreas, bile duct, ampulla and duodenum. This can result in difficulty in defining the primary site of origin in all but the smallest tumors due to anatomical proximity and architectural distortion. This has led to variation in the reported proportions of resected periampullary cancers. Pancreatic cancer is the most common cancer resected with a pancreaticoduodenectomy followed by ampullary (16%-50%), bile duct (5%-39%), and duodenal cancer (3%-17%). Patients with resected duodenal and ampullary cancers have a better reported median survival (29-47 mo and 22-54 mo) compared to pancreatic cancer (13-19 mo). The poorer survival with pancreatic cancer relates to differences in tumour characteristics such as a higher incidence of nodal, neural and vascular invasion. While small ampullary cancers can present early with biliary obstruction, pancreatic cancers need to reach a certain size before biliary obstruction ensues. This larger size at presentation contributes to a higher incidence of resection margin involvement in pancreatic cancer. Ampullary cancers can be subdivided into intestinal or pancreatobiliary subtype cancers with histomolecular staining. This avoids relying on histomorphology alone, as even some poorly differentiated cancers preserve the histomolecular profile of their mucosa of origin. Histomolecular profiling is superior to anatomic location in prognosticating survival. Ampullary cancers of intestinal subtype and duodenal cancers are similar in their intestinal origin and form a logical clinical and therapeutic subgroup of periampullary cancers. They respond to 5-FU based chemotherapeutic regimens such as capecitabine-oxaliplatin. Unlike pancreatic cancers, KRAS mutation occurs in only approximately a third of ampullary and duodenal cancers. Future clinical trials should group ampullary cancers of intestinal origin and duodenal cancers together given their similarities and their response to fluoropyrimidine therapy in combination with oxaliplatin. The addition of anti-epidermal growth factor receptor therapy in this group warrants study.
Core tip: Periampullary cancers include pancreatic, ampullary, bile duct and duodenal cancers. Pancreatic cancer is the most common cancer resected with a pancreaticoduodenectomy followed by ampullary, bile duct and duodenal cancer. Patients with resected duodenal and ampullary cancers have better prognosis compared to pancreatic cancer. Ampullary cancers can be subdivided into intestinal or pancreatobiliary subtype cancers with histomolecular staining. Histomolecular profiling is superior to anatomic location in prognosticating survival. Ampullary cancers of intestinal subtype and duodenal cancers are similar in their intestinal origin and form a logical clinical and therapeutic subgroup. They respond to 5-FU based chemotherapeutic regimens such as capecitabine-oxaliplatin.
Citation: Chandrasegaram MD, Gill AJ, Samra J, Price T, Chen J, Fawcett J, Merrett ND. Ampullary cancer of intestinal origin and duodenal cancer - A logical clinical and therapeutic subgroup in periampullary cancer. World J Gastrointest Oncol 2017; 9(10): 407-415
Periampullary cancers are defined as cancers arising within 2 cm of the papilla of Vater and include pancreatic, ampullary, biliary and duodenal cancers. The region of the ampulla is anatomically complex because it is the area of convergence of the bile duct, pancreatic duct and the duodenum. Conceptually the distinction between pancreatic, biliary, ampullary and duodenal carcinoma is straightforward. The 7th edition 2009 AJCC staging manual states that this distinction is based solely on the presumed anatomical primary site of origin. However, in practice by the time of presentation, the majority of periampullary tumours have grown to involve the pancreas, bile duct, ampulla and duodenum. Therefore it may be difficult to define the primary site of origin in all but the smallest tumors. As a result the distinction between many non-pancreatic periampullary cancers arising in this region from pancreatic cancer is inherently difficult and subjective. This has led to variation in the reported proportions of pancreatic, ampullary, biliary and duodenal cancers resected with a pancreaticoduodenectomy (PD). Pancreatic cancers represent the majority of cancers resected with a PD in most series. There are fundamental genomic and molecular differences in the four cancer subtypes. There is a need to categorise these cancer subtypes in order to treat them in a way that respects their histological, molecular and behavioural differences.
PROPORTION OF PERIAMPULLARY CANCER SUBTYPES RESECTED WITH A PD
Pancreatic cancer accounts for the majority of periampullary cancers resected with a PD in most series, followed by ampullary 16%-50%, biliary 5%-39%, and duodenal cancer 3%-17%[6-8] (Table 1). The wide variation in the reported incidence and proportion of resected periampullary cancers relates partly to difficulties in accurate determination of the primary tissue origin. This is due to close anatomical proximity of the cancer subtypes and architectural distortion at time of presentation.
Table 1 Proportion of periampullary cancer subtypes resected in pancreaticoduodenectomy series.
Academic Medical Centre, The Netherlands Tol et al, 2015
Taipei Veterans General Hospital, Taiwan Chen et al, 2013
Ohio State University, United States Hatzaras et al, 2010
Oslo University Hospital, Norway Pomianowska et al, 2013
South Australian Pathology Database, Adelaide, Australia Chandrasegaram et al, 2015
University Medical Center Groningen, The Netherlands Van Roest et al, 2008
Leeds Teaching Hospitals NHS Trust, United Kingdom Menon et al, 2009
Queen Elizabeth Hospital, Birmingham, United Kingdom Jarufe et al, 2004
University of California San Diego, United States Katz et al, 2004
N/I: May not have been included.
Review of pathology slides results in reassignment of cancer origin in a significant number of cases and highlights the importance of central pathology review in clinical trials[9-12]. The Pomianowska et al study of 207 resected periampullary cancers, demonstrated that slide review changed the diagnosis in 27% of cases. Inaccurate subtyping of periampullary cancers or the addition of non-pancreatic cancers to pancreatic cancer studies can distort and may inflate survival data and skew tumour size and stage. Indeed, Verbeke et al proposed that the failure to accurately distinguish the cancer subtypes represented the most important factor in the variation in clinicopathological and survival data in periampullary cancer studies.
DIFFERENCES IN SURVIVAL IN PERIAMPULLARY CANCERS
Pancreatic cancer has the poorest survival amongst periampullary cancers. Reported median survival for each cancer subgroup is outlined in Table 2. He et al study of 2564 patients with resected periampullary cancers from Johns Hopkins, reported that patients with duodenal cancer had the highest estimated 5-year survival (49%), followed by ampullary cancer (45%), distal bile duct cancer (27%), and pancreatic cancer (18%). The recent Dutch study by Tol et al of 760 cancer resections reported that duodenal cancer patients had the most favourable survival. In the Taiwanese study of 501 patients with periampullary cancer, Chen et al reported that patients with ampullary cancer formed the majority (76%) of long-term (≥ 5 years) survivors.
Table 2 Median survival of patients following resection of periampullary cancers.
Academic Medical Centre, The Netherlands Tol et al, 2015
Taipei Veterans General Hospital, Taiwan Chen et al, 2013
Ohio State University, United States Hatzaras et al, 2010
Queen Elizabeth Hospital, Birmingham, United Kingdom Jarufe et al, 2004
N/I: Subtype not included or reported.
DIFFERENCES IN NODAL, NEUROVASCULAR AND MARGIN STATUS IN PERIAMPULLARY CANCERS
The poorer survival seen with pancreatic cancer has been attributed to differences in tumour behavior and invasiveness[6,16-18]. Pancreatic cancers have a higher incidence of nodal, neural and vascular invasion compared to non-pancreatic periampullary cancers[19-25]. Pancreatic cancers also tend to have a much higher incidence of margin positivity[14,22,26,27]. Multiple studies have demonstrated that resection margin status, neurovascular invasion, lymph node involvement and lymph node ratio > 0.2 are important prognostic factors for survival with periampullary adenocarcinomas[8,28,29].
Zenali et al, showed that patients with duodenal and ampullary cancer had lower frequencies of nodal metastasis, margin involvement and had improved survival compared to patients with pancreatic cancer. Interestingly such differences were not demonstrated between patients with ampullary and duodenal cancers.
Historically periampullary tumours have been treated as a single group. There is strong evidence that non-pancreatic periampullary cancers require further stratification in future clinical trials[7,31].
AMPULLARY CANCER SUBTYPES: INTESTINAL AND PANCREATOBILIARY SUBTYPES
The ampulla of Vater is made up of the union of 2 distinct mucosal tissue types, by virtue of its location at the opening of the bile duct into the duodenum. The ampullo-duodenal part of the papilla is lined by intestinal mucosa and the deeper part of the ampulla is lined by pancreatobiliary ductal mucosa. In 1994 Kimura et al classified ampullary cancers into two histological subtypes of either intestinal or pancreatobiliary subtype. Differentiating ampullary cancers into these subtypes is aided by the use of histomolecular staining. This method of subtyping ampullary cancers can overcome difficulties in distinguishing these cancers on the basis of histomorphology alone, as even poorly differentiated cancers preserve the histological marker profile of their mucosa of origin.
Transcription factor CDX2 is expressed in the nucleus of intestinal epithelium[34,35]. Mucin (MUC) 1 is expressed at the apical border of cells of pancreatobiliary ductal origin. In addition to CDX2 and MUC 1, other markers have been used to subtype ampullary cancers. CDX2, CK 20 and MUC 2 are expressed in intestinal subtype cancers, whereas CK 7, CK 17, MUC 1 and MUC 4 are expressed in pancreatobiliary subtype cancers.
The markers have varying sensitivity and specificity in tissue subtyping and often their reported performance depends more on the gold standard to which they are compared to than the clinical utility of the markers. For example, if a very rigid definition is applied so that the term ampullary carcinoma only applies to tumours in which there is absolute certainty of origin from the ampullary epithelium (usually very small tumours centred exquisitely on the ampulla of Vater), then ampullary carcinomas can be expected to be essentially uniformly CDX2 positive and MUC 1 negative. That is, the CDX2 positive, MUC 1 negative profile would be highly sensitive for ampullary carcinoma in this subgroup which, are not difficult to classify as ampullary by a conventional anatomic approach. However, if a more liberal interpretation is applied so that larger tumours which probably, possibly or potentially originally arose from the ampullary epithelium are considered ampullary, then the CDX2 positive, MUC 1 negative profile becomes much less specific for ampullary carcinoma both because larger tumours may lose differentiation and because this expanded subgroup must include at least some tumours which originally arose from the pancreas and merely mimic ampullary carcinoma. This is problematic because it is exactly these anatomically difficult to classify tumours in which ancillary markers would be most useful clinically. Therefore a more sensible approach to the investigation of ancillary markers of ampullary status is to not compare their expression to the older anatomical classification (which is known to be flawed) but to compare their expression to outcome or response to therapy.
For example, Chang et al subdivided anatomical periampullary cancers based on protein expression and immunohistochemistry to distinct cancer subtypes. In their study of 208 ampullary cancers, 74% were intestinal subtype (CDX2 +ve, MUC1-ve), and 22% were pancreatobiliary subtype (CDX2 -ve, MUC 1 +ve).
The Chang study demonstrated that patients with pancreatobiliary subtype cancers have poorer survival compared with those with intestinal subtype cancers consistent with historical studies[39-41]. The Schueneman et al study of 163 ampullary cancers validated the prognostic role of the histomolecular results of Chang et al, using MUC 1 and CDX2. In their study, 25% of their patients had pancreatobiliary subtype tumours. These patients had significantly poorer median overall survival of 21.1 mo compared to patients with intestinal subtype tumours, 108.3 mo (P < 0.0001).
In the Schiergens retrospective study of their prospective database, patients with pancreatobiliary subtype cancers receiving adjuvant gemcitabine had improved overall survival (32 mo vs 13 mo, P = 0.013) unlike patients with intestinal subtype cancers who tended to have poorer survival with gemcitabine (35 mo vs 112 mo, P = 0.193). This suggests patients with pancreatobiliary subtype cancers may benefit from gemcitabine.
Similarly Leo et al demonstrated significantly higher pathological stage and worse overall survival in pancreatic compared to intestinal phenotype ampullary carcinomas. In a more recent study of 510 patients undergoing PD, histopathologic phenotype was superior to tumour anatomic location in prognosticating survival. There was no difference in survival between pancreatobiliary subtype cancers and pancreatic cancer (33.3 mo vs 31.4 mo, P = 0.66).
Whilst these studies emphasize the clinical outcome differences between pancreatobiliary phenotype and intestinal phenotype ampullary carcinomas, at the genomic level these tumours show both similarities and differences. Yachida et al reported whole exome sequencing in a cohort of Japanese and American patients with ampullary cancers. While ampullary cancers were found to be similar to colorectal cancers, and pancreatobiliary subtype cancers similar to pancreatic cancer, the two subtypes also share similar mutational patterns and signatures differentiating them from colorectal and pancreatic cancers. The authors found tumour suppressor gene ELF3, to be a significant driver of ampullary cancers present in both histological subtypes.
Gingras et al evaluated 98 ampullary adenocarcinomas, comparing these to 44 distal bile duct and 18 duodenal adenocarcinomas. Mutations in the WNT signaling pathway occurred in approximately half and ELF3 approximately 10% of patients across all three tumour types.
A LOGICAL SUBGROUP: AMPULLARY CANCERS OF INTESTINAL SUBTYPE AND DUODENAL CANCERS
Ampullary cancers of intestinal subtype and duodenal cancers are similar in their intestinal origin and form a logical clinical and therapeutic subgroup of periampullary cancers. While KRAS mutation occurs in over 90% of pancreatic cancers, both these cancers have a much lower incidence of KRAS mutation[7,46].
Valsangkar et al reported the incidence of KRAS mutation in 75 patients with ampullary cancer was 33%. This was supported by the Kwon et al study of 62 ampullary cancers revealing a similar 31% incidence of KRAS mutation.
Mikhitarian et al analysed the incidence of KRAS mutation by ampullary cancer subtype. They reported that 52% of 25 intestinal subtype cancers and 42% of 24 pancreatobiliary subtype cancers had KRAS mutation. In the Hechtman et al study of 18 pancreatobiliary subtype cancers and 14 intestinal subtype cancer, there was an increased frequency of KRAS mutation in the pancreatobiliary subtype cancers (61% vs 29%).
While small bowel cancers are rare, the duodenum represents the most common site (56%) for adenocarcinoma of the small bowel, followed by the jejunum (16%) and ileum (13%)[50,51].
As with ampullary cancers, the incidence of KRAS mutation is much lower in duodenal cancers compared to pancreatic cancer. Fu et al reported the incidence of KRAS mutations to be 35% in 78 duodenal cancers.
Given ampullary and duodenal cancers have a much lower incidence of KRAS mutation compared to pancreatic cancer, the addition of anti-epidermal growth factor receptor (EGFR) treatment in the metastatic and advanced disease may well be a fruitful area of study on the basis of the morphological and biological similarity to KRAS wild type colorectal adrenocarcinoma where the benefits of this treatment are well proven[53,54].
ADJUVANT STUDIES IN PERIAMPULLARY CANCERS
Historically, non-pancreatic periampullary cancers have been included in trials of pancreatic cancer. In a summary of eleven of the most important randomized controlled trials of adjuvant trials in pancreatic cancer, 4 studies deliberately included non-pancreatic cancers. In most studies, shortcomings in pathological assessment and the lack of standardized pathology to determine the tissue of origin of these cancers may have led to the unintentional inclusion of non-pancreatic cancers.
In the ESPAC-3 periampullary cancer trial, 428 patients with periampullary cancer; 297 with ampullary cancers, 96 with bile duct cancers, and 35 with other cancers were randomized to either observation (n = 144) or 6 mo of 5-FU and Folinic acid (n = 143) or gemcitabine (n = 141). There was no survival benefit from adjuvant treatment. However, after adjusting for age, bile duct cancer, poor tumour differentiation and lymph node involvement, on multiple regression analysis there was a survival benefit for chemotherapy compared to observation with a HR of 0.75 (95%CI: 0.57-0.98, P = 0.03).
A recent meta-analysis of 1671 patients reported no survival benefit for adjuvant chemotherapy or chemoradiotherapy in the management of periampullary cancer. The median 5-year survival was 40.0% with adjuvant treatment vs 37.5% in the control group with a HR of 1.08 (95%CI: 0.91-1.28; P = 0.067).
Interestingly, the recent UK BILCAP study has shown a benefit for adjuvant capecitabine in bile duct cancers. Of the 447 patients in the study, 156 (35%) had extrahepatic bile duct cancers which would include distal bile duct cancers resected with a PD. In the per-protocol analysis, median survival with capecitabine was 53 mo (95%CI 40-not reached) compared to 36 mo with observation (95%CI: 30-44), HR = 0.75 (95%CI: 0.58-0.97, P = 0.028).
Duodenal cancer studies are often reported with other small bowel cancers, including those arising from the jejunum and ileum. Halfdanarson et al in a retrospective review of 491 small bowel adenocarcinomas (57% duodenum; 29% jejunum, 10% ileum) reported a median overall survival of 20.1 mo. Adjuvant therapy did not improve survival in their study. In the Khan et al study of 48 resected small bowel adenocarcinomas (63% duodenum, 21% jejunum, 15% ileum), 56% received adjuvant chemotherapy. Adjuvant therapy again did not improve survival in their study.
In the study by Overman et al of 54 resected small bowel adenocarcinomas (67% duodenum, 20% jejunum, ileum 13%) although there was no improvement in overall survival with adjuvant chemotherapy, on multivariate analysis, adjuvant therapy improved disease-free survival (HR = 0.27; 95%CI: 0.07-0.98, P = 0.05).
In a more recent National Cancer Database study (NCDB), patients with resected small bowel adenocarcinoma who received adjuvant chemotherapy (n = 1674) were compared to those undergoing surgery alone (n = 3072). This study found that adjuvant chemotherapy improved survival in patients with AJCC stage III disease (Median OS 42.4 mo vs 26.1 mo; P < 0.001). The addition of radiotherapy did not improve survival in another adjuvant NCDB study of duodenal adenocarcinoma patients.
The role of adjuvant chemotherapy in small bowel adenocarcinomas will be investigated in the international phase III study (the BALLAD study) promoted by the International Rare Cancer Initiative.
SYSTEMIC CHEMOTHERAPY IN ADVANCED AND METASTATIC AMPULLARY AND DUODENAL CANCER
Several studies have investigated the role of chemotherapy in the advanced or metastatic setting[66-68]. Response rates in ampullary and small intestinal cancers with chemotherapy alone vary between 10%-50%.
A retrospective study of 905 resected periampullary cancers, reported fluoropyrimidine-based chemotherapy was superior to gemcitabine-based chemotherapy in prolonging time to progression in metastatic ampullary cancer suggesting it is a more appropriate first-line approach for ampullary cancers.
Overman et al achieved an overall response rate (complete response and partial response) of 50% (95%CI: 31%-69%) in their phase II study of capecitabine and Oxaliplatin (CAPOX) for advanced or metastatic ampullary and small intestinal adenocarcinoma. Patients with intestinal adenocarcinoma (n = 18) had a response rate of 61% (95%CI: 36-83%) and those with ampullary adenocarcinoma (n = 12) a response rate of 33% (95%CI: 10%-65%). The poorer response rates in the ampullary compared to the intestinal cancers in this study was thought to be due to the inclusion of ampullary adenocarcinomas of pancreatobiliary origin which may be less responsive to CAPOX.
In the study by Khan et al, 46/59 (78%) patients received systemic chemotherapy for relapsed, unresectable or metastatic small bowel adenocarcinoma (68% duodenum, 19% jejunum, 14% ileum). Of these, 40 were evaluable for response with a response rate of 50% (1 Complete response, 19 Partial response). The overall 1 year survival was better with chemotherapy 60.9% (95%CI: 45.8-76.0) vs 27.3% (P = 0.042). Of the 23 patients who received triplet chemotherapy, 13 received EOX (Epirubicin, Oxaliplatin and Capecitabine) and 4 received ECF (Epirubicin, Cisplatin and 5-FU). Of the 18 patients on doublet chemotherapy, 6 received CAPOX, 4 received FOLFOX (5-FU and oxaliplatin), 3 received FOLFIRI (5-FU and irinotecan) and 3 received capecitabine with Mitomycin C.
In a large multicentre retrospective series of different chemotherapy regimens in small bowel cancers, 38 patients received FOLFOX with a tumour response rate of 34% and 11 patients received FOLFIRI with a response rate of 9%. The authors concluded that FOLFOX is the most effective platinum-based chemotherapy for small bowel cancers.
From these studies, the combination of a fluoropyrimidine-regimen and oxaliplatin such as FOLFOX or CAPOX appears to be an active regimen in both ampullary and small bowel cancer (i.e., duodenal cancer) suggesting this is a logical treatment regimen in this subgroup of periampullary cancers.
The lower incidence of KRAS mutation in both ampullary and duodenal cancer suggest a potential role for anti-EGFR therapy trials in this subgroup. In the phase II study of panitumumab in KRAS wild-type metastatic adenocarcinoma of the small bowel and ampulla, 9 patients (1 ampullary - pancreatobiliary subtype, 3 duodenal, 5 jejunal/ileal) received panitumumab with minimal clinical activity. This was thought to relate to these tumours being of foregut origin, given the recent findings of less benefit with anti-EGFR therapy in right sided colon cancers compared to left sided cancers.
Santini et al reported the use of anti-EGFR treatment with Cetuximab in advanced duodenal (n = 2) and jejunal (n = 2) cancers. Cetuximab was associated with CPT-11-based chemotherapy in first-line (2 patients) or second-line (2 patients) therapy for metastatic disease. The patients previously treated had progressed on Folfiri. One patient had a complete response, 2 patients had a partial response and one had stable disease.
While targeted therapy against anti-EGFR pathway is not established in advanced small intestinal cancers, studies are currently evaluating the safety and efficacy of these targeted therapies in this group[75,76].
Ampullary and duodenal cancer form a significant proportion of cancers resected with a PD. A strong argument can be made that future clinical trials should group ampullary cancers of intestinal origin and duodenal cancers together given their similarities and their response to fluoropyrimidine therapy in combination with oxaliplatin. Furthermore, treatment response should be compared to both established (CDX2 and MUC1) and more investigational biomarkers. The addition of anti-EGFR therapy in this group warrants further study.
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Sarmiento JM, Nagomey DM, Sarr MG, Farnell MB. Periampullary cancers: are there differences?Surg Clin North Am. 2001;81:543-555.
Edge SE, Byrd DR, Comptom CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual Seventh Edition.
New York: Springer; 2010;.
Leo JM, Kalloger SE, Peixoto RD, Gale NS, Webber DL, Owen DA, Renouf D, Schaeffer DF. Immunophenotyping of ampullary carcinomata allows for stratification of treatment specific subgroups.J Clin Pathol. 2016;69:431-439.
Bledsoe JR, Shinagare SA, Deshpande V. Difficult Diagnostic Problems in Pancreatobiliary Neoplasia.Arch Pathol Lab Med. 2015;139:848-857.
Verbeke CS, Gladhaug IP. Resection margin involvement and tumour origin in pancreatic head cancer.Br J Surg. 2012;99:1036-1049.
Chandrasegaram MD, Chiam SC, Chen JW, Khalid A, Mittinty ML, Neo EL, Tan CP, Dolan PM, Brooke-Smith ME, Kanhere H. Distribution and pathological features of pancreatic, ampullary, biliary and duodenal cancers resected with pancreaticoduodenectomy.World J Surg Oncol. 2015;13:85.
Chandrasegaram MD, Chen JW, Price TJ, Zalcberg J, Sjoquist K, Merrett ND. Advances in Molecular Pathology and Treatment of Periampullary Cancers.Pancreas. 2016;45:32-39.
Tol JA, Brosens LA, van Dieren S, van Gulik TM, Busch OR, Besselink MG, Gouma DJ. Impact of lymph node ratio on survival in patients with pancreatic and periampullary cancer.Br J Surg. 2015;102:237-245.
Nitecki SS, Sarr MG, Colby TV, van Heerden JA. Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving?Ann Surg. 1995;221:59-66.
Brown KM, Tompkins AJ, Yong S, Aranha GV, Shoup M. Pancreaticoduodenectomy is curative in the majority of patients with node-negative ampullary cancer.Arch Surg. 2005;140:529-532; discussion 532-533.
Valsangkar NP, Ingkakul T, Correa-Gallego C, Mino-Kenudson M, Masia R, Lillemoe KD, Fernández-del Castillo C, Warshaw AL, Liss AS, Thayer SP. Survival in ampullary cancer: potential role of different KRAS mutations.Surgery. 2015;157:260-268.
Chang DK, Jamieson NB, Johns AL, Scarlett CJ, Pajic M, Chou A, Pinese M, Humphris JL, Jones MD, Toon C. Histomolecular phenotypes and outcome in adenocarcinoma of the ampulla of vater.J Clin Oncol. 2013;31:1348-1356.
Pomianowska E, Grzyb K, Westgaard A, Clausen OP, Gladhaug IP. Reclassification of tumour origin in resected periampullary adenocarcinomas reveals underestimation of distal bile duct cancer.Eur J Surg Oncol. 2012;38:1043-1050.
He J, Ahuja N, Makary MA, Cameron JL, Eckhauser FE, Choti MA, Hruban RH, Pawlik TM, Wolfgang CL. 2564 resected periampullary adenocarcinomas at a single institution: trends over three decades.HPB (Oxford). 2014;16:83-90.
Chen SC, Shyr YM, Wang SE. Longterm survival after pancreaticoduodenectomy for periampullary adenocarcinomas.HPB (Oxford). 2013;15:951-957.
Pomianowska E, Westgaard A, Mathisen Ø, Clausen OP, Gladhaug IP. Prognostic relevance of number and ratio of metastatic lymph nodes in resected pancreatic, ampullary, and distal bile duct carcinomas.Ann Surg Oncol. 2013;20:233-241.
Katz MH, Bouvet M, Al-Refaie W, Gilpin EA, Moossa AR. Non-pancreatic periampullary adenocarcinomas: an explanation for favorable prognosis.Hepatogastroenterology. 2004;51:842-846.
Kim K, Chie EK, Jang JY, Kim SW, Han SW, Oh DY, Im SA, Kim TY, Bang YJ, Ha SW. Prognostic significance of tumour location after adjuvant chemoradiotherapy for periampullary adenocarcinoma.Clin Transl Oncol. 2012;14:391-395.
Morris-Stiff G, Alabraba E, Tan YM, Shapey I, Bhati C, Tanniere P, Mayer D, Buckels J, Bramhall S, Mirza DF. Assessment of survival advantage in ampullary carcinoma in relation to tumour biology and morphology.Eur J Surg Oncol. 2009;35:746-750.
Balachandran P, Sikora SS, Kapoor S, Krishnani N, Kumar A, Saxena R, Kapoor VK. Long-term survival and recurrence patterns in ampullary cancer.Pancreas. 2006;32:390-395.
Sommerville CA, Limongelli P, Pai M, Ahmad R, Stamp G, Habib NA, Williamson RC, Jiao LR. Survival analysis after pancreatic resection for ampullary and pancreatic head carcinoma: an analysis of clinicopathological factors.J Surg Oncol. 2009;100:651-656.
Winter JM, Cameron JL, Campbell KA, Arnold MA, Chang DC, Coleman J, Hodgin MB, Sauter PK, Hruban RH, Riall TS. 1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience.J Gastrointest Surg. 2006;10:1199-1210; discussion 1210-1211.
Mayo SC, Nathan H, Cameron JL, Olino K, Edil BH, Herman JM, Hirose K, Schulick RD, Choti MA, Wolfgang CL. Conditional survival in patients with pancreatic ductal adenocarcinoma resected with curative intent.Cancer. 2012;118:2674-2681.
Hatzaras I, George N, Muscarella P, Melvin WS, Ellison EC, Bloomston M. Predictors of survival in periampullary cancers following pancreaticoduodenectomy.Ann Surg Oncol. 2010;17:991-997.
van Roest MH, Gouw AS, Peeters PM, Porte RJ, Slooff MJ, Fidler V, de Jong KP. Results of pancreaticoduodenectomy in patients with periampullary adenocarcinoma: perineural growth more important prognostic factor than tumor localization.Ann Surg. 2008;248:97-103.
Verbeke CS, Leitch D, Menon KV, McMahon MJ, Guillou PJ, Anthoney A. Redefining the R1 resection in pancreatic cancer.Br J Surg. 2006;93:1232-1237.
Jarufe NP, Coldham C, Mayer AD, Mirza DF, Buckels JA, Bramhall SR. Favourable prognostic factors in a large UK experience of adenocarcinoma of the head of the pancreas and periampullary region.Dig Surg. 2004;21:202-209.
Farid SG, Falk GA, Joyce D, Chalikonda S, Walsh RM, Smith AM, Morris-Stiff G. Prognostic value of the lymph node ratio after resection of periampullary carcinomas.HPB (Oxford). 2014;16:582-591.
Zenali M, Overman MJ, Rashid A, Broaddus RB, Wang H, Katz MH, Fleming JB, Abbruzzese JL, Wang H. Clinicopathologic features and prognosis of duodenal adenocarcinoma and comparison with ampullary and pancreatic ductal adenocarcinoma.Hum Pathol. 2013;44:2792-2798.
Westgaard A, Pomianowska E, Clausen OP, Gladhaug IP. Intestinal-type and pancreatobiliary-type adenocarcinomas: how does ampullary carcinoma differ from other periampullary malignancies?Ann Surg Oncol. 2013;20:430-439.
Kimura W, Futakawa N, Yamagata S, Wada Y, Kuroda A, Muto T, Esaki Y. Different clinicopathologic findings in two histologic types of carcinoma of papilla of Vater.Jpn J Cancer Res. 1994;85:161-166.
Fischer HP, Zhou H. Pathogenesis of carcinoma of the papilla of Vater.J Hepatobiliary Pancreat Surg. 2004;11:301-309.
Werling RW, Yaziji H, Bacchi CE, Gown AM. CDX2, a highly sensitive and specific marker of adenocarcinomas of intestinal origin: an immunohistochemical survey of 476 primary and metastatic carcinomas.Am J Surg Pathol. 2003;27:303-310.
Moskaluk CA, Zhang H, Powell SM, Cerilli LA, Hampton GM, Frierson HF Jr. Cdx2 protein expression in normal and malignant human tissues: an immunohistochemical survey using tissue microarrays.Mod Pathol. 2003;16:913-919.
Lau SK, Weiss LM, Chu PG. Differential expression of MUC1, MUC2, and MUC5AC in carcinomas of various sites: an immunohistochemical study.Am J Clin Pathol. 2004;122:61-69.
Kawabata Y, Tanaka T, Nishisaka T, Inao T, Nishi T, Yano S. Cytokeratin 20 (CK20) and apomucin 1 (MUC1) expression in ampullary carcinoma: Correlation with tumor progression and prognosis.Diagn Pathol. 2010;5:75.
Kumari N, Prabha K, Singh RK, Baitha DK, Krishnani N. Intestinal and pancreatobiliary differentiation in periampullary carcinoma: the role of immunohistochemistry.Hum Pathol. 2013;44:2213-2219.
Schiergens TS, Reu S, Neumann J, Renz BW, Niess H, Boeck S, Heinemann V, Bruns CJ, Jauch KW, Kleespies A. Histomorphologic and molecular phenotypes predict gemcitabine response and overall survival in adenocarcinoma of the ampulla of Vater.Surgery. 2015;158:151-161.
Roh YH, Kim YH, Lee HW, Kim SJ, Roh MS, Jeong JS, Jung GJ. The clinicopathologic and immunohistochemical characteristics of ampulla of Vater carcinoma: the intestinal type is associated with a better prognosis.Hepatogastroenterology. 2007;54:1641-1644.
Westgaard A, Tafjord S, Farstad IN, Cvancarova M, Eide TJ, Mathisen O, Clausen OP, Gladhaug IP. Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma.BMC Cancer. 2008;8:170.
Schueneman A, Goggins M, Ensor J, Saka B, Neishaboori N, Lee S, Maitra A, Varadhachary G, Rezaee N, Wolfgang C. Validation of histomolecular classification utilizing histological subtype, MUC1, and CDX2 for prognostication of resected ampullary adenocarcinoma.Br J Cancer. 2015;113:64-68.
Williams JL, Chan CK, Toste PA, Elliott IA, Vasquez CR, Sunjaya DB, Swanson EA, Koo J, Hines OJ, Reber HA. Association of Histopathologic Phenotype of Periampullary Adenocarcinomas With Survival.JAMA Surg. 2017;152:82-88.
Yachida S, Wood LD, Suzuki M, Takai E, Totoki Y, Kato M, Luchini C, Arai Y, Nakamura H, Hama N. Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma.Cancer Cell. 2016;29:229-240.
Gingras MC, Covington KR, Chang DK, Donehower LA, Gill AJ, Ittmann MM, Creighton CJ, Johns AL, Shinbrot E, Dewal N. Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation.Cell Rep. 2016;14:907-919.
Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.Nature. 2012;491:399-405.
Kwon MJ, Kim JW, Jung JP, Cho JW, Nam ES, Cho SJ, Kim JS, Park HR, Min SK, Seo J. Low incidence of KRAS, BRAF, and PIK3CA mutations in adenocarcinomas of the ampulla of Vater and their prognostic value.Hum Pathol. 2016;50:90-100.
Mikhitarian K, Pollen M, Zhao Z, Shyr Y, Merchant NB, Parikh A, Revetta F, Washington MK, Vnencak-Jones C, Shi C. Epidermal growth factor receptor signaling pathway is frequently altered in ampullary carcinoma at protein and genetic levels.Mod Pathol. 2014;27:665-674.
Hechtman JF, Liu W, Sadowska J, Zhen L, Borsu L, Arcila ME, Won HH, Shah RH, Berger MF, Vakiani E. Sequencing of 279 cancer genes in ampullary carcinoma reveals trends relating to histologic subtypes and frequent amplification and overexpression of ERBB2 (HER2).Mod Pathol. 2015;28:1123-1129.
Bilimoria KY, Bentrem DJ, Wayne JD, Ko CY, Bennett CL, Talamonti MS. Small bowel cancer in the United States: changes in epidemiology, treatment, and survival over the last 20 years.Ann Surg. 2009;249:63-71.
Gleason D, Miller-Hammond KE, Gibbs JF. Small Bowel Cancer. In Surgical Oncology. New York: Springer.
Fu T, Guzzetta AA, Jeschke J, Vatapalli R, Dave P, Hooker CM, Morgan R, Iacobuzio-Donahue CA, Liu B, Ahuja N. KRAS G>A mutation favors poor tumor differentiation but may not be associated with prognosis in patients with curatively resected duodenal adenocarcinoma.Int J Cancer. 2013;132:2502-2509.
Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.Cancer Res. 2006;66:3992-3995.
Peeters M, Douillard JY, Van Cutsem E, Siena S, Zhang K, Williams R, Wiezorek J. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab.J Clin Oncol. 2013;31:759-765.
Kim SM, Eads JR. Adjuvant and Neoadjuvant Therapy for Resectable Pancreatic and Periampullary Cancer.Surg Clin North Am. 2016;96:1287-1300.
Erdmann JI, Eskens FA, Vollmer CM, Kok NF, Groot Koerkamp B, Biermann K, van Eijck CH. Histological and Molecular Subclassification of Pancreatic and Nonpancreatic Periampullary Cancers: Implications for (Neo) Adjuvant Systemic Treatment.Ann Surg Oncol. 2015;22:2401-2407.
Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, Carter R, Tebbutt NC, Dervenis C, Smith D. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial.JAMA. 2012;308:147-156.
Acharya A, Markar SR, Sodergren MH, Malietzis G, Darzi A, Athanasiou T, Khan AZ. Meta-analysis of adjuvant therapy following curative surgery for periampullary adenocarcinoma.Br J Surg. 2017;104:814-822.
Primrose JN, Fox R, Palmer DH, Prasad R, Mirza D, Anthoney DA, Corrie P, Falk S, Wasan HS, Ross PJ. Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study.J Clin Oncol. 2017;35:4006.
Halfdanarson TR, McWilliams RR, Donohue JH, Quevedo JF. A single-institution experience with 491 cases of small bowel adenocarcinoma.Am J Surg. 2010;199:797-803.
Khan K, Peckitt C, Sclafani F, Watkins D, Rao S, Starling N, Jain V, Trivedi S, Stanway S, Cunningham D. Prognostic factors and treatment outcomes in patients with Small Bowel Adenocarcinoma (SBA): the Royal Marsden Hospital (RMH) experience.BMC Cancer. 2015;15:15.
Overman MJ, Kopetz S, Lin E, Abbruzzese JL, Wolff RA. Is there a role for adjuvant therapy in resected adenocarcinoma of the small intestine.Acta Oncol. 2010;49:474-479.
Ecker BL, McMillan MT, Datta J, Mamtani R, Giantonio BJ, Dempsey DT, Fraker DL, Drebin JA, Karakousis GC, Roses RE. Efficacy of adjuvant chemotherapy for small bowel adenocarcinoma: A propensity score-matched analysis.Cancer. 2016;122:693-701.
Ecker BL, McMillan MT, Datta J, Lee MK, Karakousis GC, Vollmer CM Jr, Drebin JA, Fraker DL, Roses RE. Adjuvant chemotherapy versus chemoradiotherapy in the management of patients with surgically resected duodenal adenocarcinoma: A propensity score-matched analysis of a nationwide clinical oncology database.Cancer. 2017;123:967-976.
Keat N, Law K, Seymour M, Welch J, Trimble T, Lascombe D, Negrouk A. International rare cancers initiative.Lancet Oncol. 2013;14:109-110.
Tsushima T, Taguri M, Honma Y, Takahashi H, Ueda S, Nishina T, Kawai H, Kato S, Suenaga M, Tamura F. Multicenter retrospective study of 132 patients with unresectable small bowel adenocarcinoma treated with chemotherapy.Oncologist. 2012;17:1163-1170.
Zaanan A, Gauthier M, Malka D, Locher C, Gornet JM, Thirot-Bidault A, Tougeron D, Taïeb J, Bonnetain F, Aparicio T; Association des Gastro Entérologues Oncologues. Second-line chemotherapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) in patients with advanced small bowel adenocarcinoma after failure of first-line platinum-based chemotherapy: a multicenter AGEO study.Cancer. 2011;117:1422-1428.
Overman MJ, Kopetz S, Wen S, Hoff PM, Fogelman D, Morris J, Abbruzzese JL, Ajani JA, Wolff RA. Chemotherapy with 5-fluorouracil and a platinum compound improves outcomes in metastatic small bowel adenocarcinoma.Cancer. 2008;113:2038-2045.
Jiang ZQ, Varadhachary G, Wang X, Kopetz S, Lee JE, Wang H, Shroff R, Katz M, Wolff RA, Fleming J. A retrospective study of ampullary adenocarcinomas: overall survival and responsiveness to fluoropyrimidine-based chemotherapy.Ann Oncol. 2013;24:2349-2353.
Overman MJ, Varadhachary GR, Kopetz S, Adinin R, Lin E, Morris JS, Eng C, Abbruzzese JL, Wolff RA. Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater.J Clin Oncol. 2009;27:2598-2603.
Zaanan A, Costes L, Gauthier M, Malka D, Locher C, Mitry E, Tougeron D, Lecomte T, Gornet JM, Sobhani I. Chemotherapy of advanced small-bowel adenocarcinoma: a multicenter AGEO study.Ann Oncol. 2010;21:1786-1793.
Raghav K, Overman MJ. Small bowel adenocarcinomas--existing evidence and evolving paradigms.Nat Rev Clin Oncol. 2013;10:534-544.
Gulhati P, Raghav KP, Shroff RT, Varadhachary GR, Javle MM, Qiao W, Wang H, Morris J, Wolff RA, Overman MJ. Phase II study of panitumumab in KRAS wild-type metastatic adenocarcinoma of the small bowel or ampulla of vater.J Clin Oncol. 2017;35:published online before print.
Santini D, Fratto ME, Spoto C, Russo A, Galluzzo S, Zoccoli A, Vincenzi B, Tonini G. Cetuximab in small bowel adenocarcinoma: a new friend?Br J Cancer. 2010;103:1305; author reply 1306.
Zaaimi Y, Aparicio T, Laurent-Puig P, Taieb J, Zaanan A. Advanced small bowel adenocarcinoma: Molecular characteristics and therapeutic perspectives.Clin Res Hepatol Gastroenterol. 2016;40:154-160.
Menon KV, Gomez D, Smith AM, Anthoney A, Verbeke CS. Impact of margin status on survival following pancreatoduodenectomy for cancer: the Leeds Pathology Protocol (LEEPP).HPB (Oxford). 2009;11:18-24.