Pancreatic cancer

PANCREAS AND SPLEEN

Pancreatic cancer

year, with a mortality rate of 9.1 per 100,000 and a 5-year survival rate of 3.3%.4 Without any substantive improvement in curative therapies, pancreatic cancer is anticipated to be second leading cause of deaths in 2030.1 Complete surgical resection remains the only treatment that can provide prolonged survival. However, the majority of patients have advanced disease at presentation. Recently, increased awareness, improved understanding of the pathogenesis of the disease, enhanced diagnostics and the development of more effective chemotherapeutic strategies have led to a sense that new therapeutic opportunities in pancreatic cancer may be soon available.5 This article reviews these developments.

Rebeca Sanabria Mateos Kevin C Conlon

Abstract It is anticipated that by 2030 pancreatic cancer will be the second leading cause of death from cancer. Surgery remains the only potentially curative therapy. However, less than a quarter of patients are suitable for surgical resection. The lack of early symptoms, the propensity for pancreatic cancer cells to metastasize early in disease development together with the marked resistance to chemotherapy and radiotherapy, are partly responsible for the poor survival rates. Recent improvements in diagnostic imaging, such as pancreas protocol computed tomography and the role of endoscopic ultrasound, allow for earlier detection and facilitate earlier management of pancreatic cancer. In recent years, the approved use of FOLFIRINOX and gemcitabine nab-paclitaxel regimens in patients with metastatic disease has seen an improvement in survival rates and there has been increasing interest in its use in neoadjuvant chemotherapy. Future perspectives include studying the carcinogenesis of pancreatic malignancy and tumour-related genetic mutations, which it is hoped will lead to new developments in the management of pancreatic cancer, and indeed in survival rates.

Aetiology Pancreatic ductal adenocarcinoma accounts for the majority of malignant pancreatic diseases. A number of aetiological variables have been identified. The major environmental factor appears to be smoking. Obesity has also been implicated. It is strongly associated with changes in the physiological function of adipose tissue, leading to insulin resistance, chronic inflammation and altered secretion of adipokines, all of which are involved in carcinogenesis and cancer progression.5 Long-standing type 2 diabetes mellitus also appears to be associated with increased pancreatic cancer risk. In contrast, diabetes mellitus of recent onset (<2e3 years) is rather considered as an early para-neoplastic manifestation, caused by paracrine cancer-induced b-cell dysfunction and peripheral insulin resistance and probably is not an aetiological factor. Patients with chronic pancreatitis have an increased risk of developing pancreatic cancer. Despite the elevated risk, screening in patients with non-hereditary chronic pancreatitis is not recommended because the absolute risk is limited (4% after 20 years of evolution) and tumour detection by imaging is challenging in a remodelled parenchyma. Others factors have been suggested to increase pancreatic cancer risk such as non-O blood group, Helicobacter pylori infection and chronic hepatitis B or C infection, but further studies are needed to confirm these associations. Finally, a familial history of pancreatic cancer is present in 7e10% of patients. Following the International Cancer of the Pancreas Screening Guidelines published in 2012, individuals with at least two blood relatives with pancreatic cancer, with at least one affected first-degree relative and absence of the criteria for other inherited tumour syndromes associated with increased risk of pancreatic cancer, should be considered for screening.

Keywords Chemotherapy; genetic mutation; neoadjuvant treatment; palliative care; pancreas cancer; pancreatic ductal adenocarcinoma; surgery

Introduction For the majority of patients diagnosed with pancreatic cancer it remains a lethal disease. Currently it is the fourth leading cause of cancer-related death in Europe and the United States.1 Pancreatic cancer accounts for 2.5% of all invasive cancers in Ireland and is the 11th most common cancer with 478 new cases diagnosed in 2012.2 It is the fifth most common cause of invasive cancer death, with 478 deaths per year. Pancreatic cancer is predominantly a disease of the elderly, occurring mainly between the seventh and eighth decade, with the risk increasing with age. It rarely affects individuals younger than 45 years of age. In common with other Western countries the majority of patients present with advanced disease. The annual incidence of pancreatic cancer is rising with approximately 48,960 new cases and nearly 40,560 deaths estimated in 2015 in the United States, with an overall 5-year survival rate of 7.2%.3 In the UK, the incidence of pancreatic cancer has been reported to be 15.7 per 100,000 population per

Pathology and pathogenesis Pancreatic ductal adenocarcinoma arises from a series of progressive genetic mutations and specific precursor lesions, such a mucinous cystic neoplasm, pancreatic intraepithelial neoplasm (PanIN) and intraductal papillary mucinous neoplasms (IPMN).

Rebeca Sanabria Mateos MD is a Specialty Trainee in the Department of HPB Surgery at St. Vincent’s University Hospital, Dublin, Ireland. Conflicts of interest: none declared.

Genetic Germ line and somatic mutations contribute to the development of pancreatic cancer. It is becoming clear that pancreatic cancer tumours are highly heterogeneous showing that tumours contain

Kevin C Conlon MA MCh MBA FRCSI FACS FRCS FTCD is Professor of Surgery in the Department of HPB Surgery at St. Vincent’s University Hospital, Dublin and at Trinity College Dublin, Ireland. Conflicts of interest: none declared.

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pancreatic ducts. The process preceding PanIN formation is also known as acinar-to-ductal metaplasia. Following pancreatic injury or k-ras activation, acinar cells gradually lose their acinar features and acquire ductal phenotype 17. These lesions are classified into four grades (PanIN-1A, -1B, -2 and -3) depending of increasing dysplasia in parallel with the accumulation of mutations (Figure 1). Intraductal papillary mucinous neoplasm (IPMN) is the second major pancreatic cancer precursor lesion after PanIN. IPMNs are a heterogeneous group of cystic macroscopic lesions that can arise from the main or branch pancreatic ducts. These tumours often produce large amounts of mucin leading to ductal dilatation and occasionally pancreatitis as the result of the obstruction of the pancreatic duct. The 5-year risk of pancreatic cancer has been estimated at 10e15% for branch duct IPMN and exceeds 50% in cases of main duct IPMN (Levy et al, 2006).6 Four histologic subtypes have been described (gastric, intestinal, pancreatobiliary, and oncocytic). Branch duct IPMNs are mainly of the gastric phenotype. The intestinal type is mostly seen in main duct IPMN progressing into invasive cancer of colloid or tubular type. International consensus guidelines for the management of IPMN are shown in Figure 2. Mucinous cystic neoplasms (MCN) are large mucin-producing pre-malignant lesions of the pancreas arising mostly in the body or tail of the gland. The median age at diagnosis is 40e50 years and almost exclusively in women. MCNs are not connected with the pancreatic duct, typically are unique, unilocular or paucilocular cysts with few septations. They usually display a thick wall (>2 mm) and are surrounded by a pathognomonic ovariantype stroma. The presence of mural nodules, a thick wall and a

an average of 63 genetic alterations. This heterogeneity may partially explain the resistance of pancreatic cancer to chemotherapy. Over 90% of patients with pancreatic cancer possess mutations in the k-ras oncogene which is mutated in 20e30% of all human malignancies. Mutations within this oncogene are most often located on exon 1 of codon 12 and sometimes on codons 61 and 13. k-ras seems to appear in early stages of pancreatic carcinogenesis, but accumulation of other cooperative genetic alterations is required for full oncogenic transformation.2 The most recognized tumour suppressor gene implicated in pancreatic cancer development (p53) is found in over 75% of specimens mutated. SMAD4 inactivation is a late event present in 50e60% of cases and may be associated with more aggressive disease.1 Others tumour suppressor genes include DPC4 (deleted in Pancreatic Cancer, locus 4), LKB1 (liver kinase B1), MAPK (mitogen activated protein kinase), BRCA2 and CDKN2A. Global genomic analyses have provided a new insight into pancreatic cancer genetic complexity. Recently, studies using whole-exome sequencing and copy number analysis have uncovered novel mutated genes including genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM), axon guidance (SLIT/ROBO) and other mechanisms.7 Further studies will determine whether these mutations affect oncological outcomes and if this tumour microenvironment could represent a therapeutic target. Pre-malignant lesions Pancreatic intraepithelial neoplasms (PanIN) are microscopic (<0.5 cm), non-invasive epithelial proliferations within the

Pancreatic intraepithelial neoplasms tumour progression (PanIN) K-ras Mutation

Her-2/neu

PanIN 1A

Normal Epithelium

PanIN 1B p53 Mutation DPC4 Mutation p16 Inactivation

Invasive Carcinoma

PanIN 3

PanIN 2

Figure 1

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Management of suspected branch duct IPMN Resection is recommended

Main Duct IPMN

High risk stigmata of malignancy present

Yes

Yes

Branch Duct IPMN Worrisome features present1 Yes

suspicious*2

No

No Size of the cyst

<1 cm: CT/MRI in 2 years

1–2 cm: CT/MRI yearly

2–3 cm: EUS in 3–6 months,then lengthen interval. Consider surgery in

>3 cm: close surveillance alternating EUS/MRI every 3–6 months. Strong surgery recommendation

*High risk stigmata of malignancy: obstructive jaundice, enhancing solid component. *1Cyst over 3 cm; thickness/enhancing cyst walls; main duct 5–9 mm; non-enhancing mural node; abrupt change in calibre of pancreatic duct *2 suspicious or positive for malignancy.

Figure 2

cyst size of over 4 cm has been proposed to predict the risk of malignant transformation, but their natural history remains illdefined.

with disseminated disease may have clinical signs of cachexia (temporal wasting, loss of muscle mass) and ascites. Haematological and biochemical analyses have limited benefit. Elevated liver function tests in the presence of obstructive jaundice are non-specific and require imaging to determine the aetiology. Carbohydrate antigen 19-9 (CA19.9), a sialylated Lewis blood group antigen, is often elevated. Its diagnostic sensitivity and specificity in symptomatic patients is 79%e81% and 82%e90%, respectively, but its positive predictive value remains insufficient to be used for screening and diagnosis. The absolute value is important with regards to the diagnostic utility. Published studies suggest that CA 19.9 levels below 100 U/mL are correlated with likely resectable disease (41e80%) whereas levels above 100 U/ mL suggest unresectable or metastatic disease (60e85%). Patients with a Lewis negative blood group (5e10% of the population) may be negative. In contrast, increased false positivity may occur in patients with obstructive jaundice, decompensated diabetes mellitus, and in smokers or in association with other adenocarcinoma.

Clinical presentation The type and timing of clinical manifestations depend largely on the primary tumour location. Peri-ampullary tumours may present relatively early with obstructive jaundice, whereas tumours located in the body and tail of the pancreas may be asymptomatic resulting in a late diagnosis at a more advanced stage.2 Non-specific symptoms such as nausea, early satiety, weight loss, abdominal bloating and steatorrhoea are common at presentation. Pain may be present in the epigastrium with radiation to the back and is a worrisome symptom as it may indicate neural invasion and poor prognosis. Weight loss is a common finding, being usually associated with malabsorption. Diabetes is present in at least 50% of patients; long-standing diabetes is associated with poor prognosis. Physical examination may be normal. Patients with jaundice may have a palpable gallbladder (Courvoisier’s sign). Patients

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Computed tomography and magnetic resonance imaging Currently, the diagnostic modality of choice for imaging the pancreas is a pancreas protocol computed tomography(CT)-with thin sections, using both non-enhanced and late arterial (at 40 e50 s) plus portal venous phases (at 65e70 s) after contrast injection and reconstructions. The primary tumour appearance, size and localization, relationship with surrounding visceral vessels (portal vein, superior mesenteric vein, splenic vein, superior mesenteric artery, and the branches of the celiac axis), and extra-pancreatic extension (lymph nodes and liver, peritoneal and lung metastasis) are precisely evaluated (Figure 4aed). These scans typically demonstrate both the tumour and metastases as hypoattenuating during the arterial phase, and best seen during the venous phase of contrast enhancement. A recent meta-analysis reported an overall diagnostic sensitivity of 91% for CT compared with 84% for magnetic resonance imaging (MRI) and diagnostic specificities of 85% and 82%, respectively.8 Regarding determination of resectability, and locoregional extension, MRI has been shown to be equally sensitive and specific as CT, and no advantage has been demonstrated by obtained both imaging for uncomplicated patients. MRI can be used in patients with renal impairment or in the characterization of poorly visible pancreatic lesions or indeterminate liver lesions seen on prior CT examinations.8 Magnetic resonance cholangiopancreatography (MRCP) is also valuable for diagnosis, and for assessing cystic lesions of the pancreas and main pancreatic duct stenosis (Figure 5).

Figure 3 Trans-abdominal ultrasound: pancreatic duct dilatation.

Imaging and staging There has been considerable improvement in the last decade with regards to diagnostic imaging modalities which have resulted in earlier diagnosis and improved staging. Trans-abdominal ultrasound Trans-abdominal ultrasound is usually the first approach in patients with jaundice. It is a non-invasive technique, which images the liver and biliary tree. Intra and extra-hepatic biliary dilation can be appreciated and the presence or absence of gallstones determined. In thin patients a reasonable assessment of the pancreas can be made (Figure 3). However, it is operator dependent and often fails to obtain adequate images of the pancreas due to body habitus or overlying visceral gas. Nonetheless, it should be the first investigation in patients presenting with obstructive jaundice.

Endoscopic ultrasonography (EUS) The role of EUS remains controversial. At tertiary referral centres EUS is widely used both for diagnostic and staging purposes. As ultrasound imaging is operator dependent, this factor may

Figure 4 Radiological appearances of pancreatic cancer. (a) Resectable head of pancreas cancer. (b) Borderline pancreas cancer. Replace right hepatic artery from superior mesenteric artery in contact with tumour. (c) Locally advanced/unresectable disease. Tumour in contact with coeliac trunk. (d) Metastatic disease. Liver metastasis in segment IV shows same echogenicity as pancreas tumour.

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considered for neo-adjuvant chemoradiotherapy. ERCP as a diagnostic modality is not recommended. 18

Fluorodeoxyglucose-positron emission tomography (FDG-PET) This imaging modality is based on the observation that neoplastic cells exhibit accelerated glucose uptake and metabolism, and is playing an increasing role in patients with gastrointestinal malignancies. However, recent prospective studies, including the PANDA study, concluded that FDG-PET has no obvious advantage compared to currently diagnostic tools.9 Laparoscopy The role of staging laparoscopy remains controversial. Laparoscopic staging is used by many centres to decrease the number of unnecessary open explorations in detection of liver and peritoneal metastasis. Patients with potentially resectable tumours have been found to have unsuspected metastasis 20e35% of the time despite preoperative imaging. However, improvements in cross-sectional imaging modalities have reduced the benefit for laparoscopic staging. Contemporary reports suggest that the added value of laparoscopic staging is 15e20%. A more selective approach is recommended with laparoscopic staging being used for all tumours of the head of the gland >3 cm, or with a CA 19-9 >150 IU/L. A recent Cochrane review suggested that patients with resectable disease following a combination of CT and laparoscopy would have a 17% risk of having unresectable disease at a subsequent laparotomy compared to 40% in those staged with CT alone. The authors concluded that laparoscopic staging prevented 23 unnecessary laparotomies in 100 patients who were considered resectable by imaging alone.10 The current consensus guidelines of the American HepatoPancreato-Biliary Association is that for patients with apparent resectable pancreatic cancer, staging laparoscopy should be used selectively on pancreatic head tumours >3 cm, tumours of the pancreas body and tail, in cases with equivocal findings on CT and in patients with high CA 19.9 serum levels (>100 U/mL) (Figure 7).

Figure 5 MRCP: Double duct sign.

account for the wide range of diagnostic sensitivities reported (69 e94%). However, some studies have found EUS to be superior to CT in lesion smaller than 2 cm, this fact together with the possibility of biopsy via fine-needle aspiration has led to EUS becoming more established in the diagnostic algorithm. EUS is mainly used in four clinical situations: (1) in negative cross-sectional evaluation with CT or MRI when the suspicion of pancreatic cancer is high; (2) to characterize ambiguous pancreatic lesions; (3) to obtain pathological information in locally-advanced cases; or (4) before neoadjuvant treatment of resectable/borderline tumours when obtaining histological confirmation is essential (Figure 6). Endoscopic retrograde cholangio-pancreatography (ERCP) ERCP is indicated in patients with obstructive jaundice who have unresectable or metastatic disease and in selected patients with resectable pancreatic tumours (i.e. bilirubin level > 150 mg/L or patients with cholangitis). It is also widely used in patients

Figure 6 EUS: Relation between tumour and vessels: gastroduodenal artery (GDA) and portal vein (PV), Size of the tumour on right side of image.

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Laparoscopic exploration. Minor epiplon opened.

Gastric vessels

Caudate lobe

Stomach Figure 7

indicator. EUS is recommended when further imaging tests are unclear in the diagnosis.

Laparoscopic staging should be also be considered in patients with locally advanced pancreatic cancer that are considered candidates for local radiation treatment or experimental protocols as these patients will have an incidence of sub-radiological occult disease in approximately 35% of cases.11

Management For management purposes tumours can be divided into four categories: (1) localized resectable; (2) localized borderline resectable; (3) localized advanced/unresectable; and (4) metastatic. The criteria for each is detailed in Table 1. Although these definitions are somewhat arbitrary e in conjunction with patient related factors e they are used to make decisions regarding the treatment strategy for individual patients (Figure 8). In general, it is recommended that patients with CT/ MRI resectable disease undergo primary resection with adjuvant therapy as standard. A number of centres have popularized the role of neo-adjuvant chemotherapy or chemoradiotherapy. Published single centre experience has demonstrated that this approach can be delivered safely without an increase in perioperative morbidity or mortality, avoids unnecessary surgery in a cohort of patients who progress early and therefore would have

Differential diagnosis The differential diagnosis of a solid pancreatic mass seen on a radiographic imaging study includes a primary exocrine pancreatic cancer; pancreatic neuroendocrine tumour (typically highly vascular with enhancement in the early arterial phase and washout in the early portal venous phase); lymphoma (suspected if large mass and surrounding lymphadenopathy); metastatic cancer; focal chronic pancreatitis and autoimmune pancreatitis (also known as lymphoplasmacytic sclerosing pancreatitis5). Autoimmune pancreatitis is suspected in younger patients e the finding of increased serum immunoglobulin (Ig) G levels is supportive of a diagnosis, although an elevated level of serum IgG4 specifically is the most sensitive and specific laboratory

Criteria for resectable head of pancreas tumour, based on the American Hepato-Pancreatico-Biliary Association consensus report

Resectable Borderline

Locally advanced

Arterial

Venous

SMA, CHA, CA clear from tumour SMA contact
180 CHA contact, CA clear Variant arterial anatomy in contact with tumour affecting resectability SMA contact >180 CA contact >180 SMA first jejunal branch affected

SMV clear, non or
180 PV tumour contact Tumour contacting inferior cava SMV or PV contact >180 Thrombosis or irregularity <180 of the vein (reconstruction possible) Unreconstructable SMV/PV occlusion Distal metastasis

SMA, superior mesenteric artery; CHA, common hepatic artery; CA, coeliac axis; SMV, superior mesenteric vein; PV, portal vein.

Table 1

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Therapeutic algorithm following NCCN Guidelines Clinical suspicion of pancreas cancer MSCT scan, EUS, MRCP CA 19-9 Localized disease

Metastastic disease Locally advanced disease Borderline resectable

Resectable Head >2 cm All body/tail CA 19-9 >150 ku/l

Head <2 cm CA 19-9 <150 ku/l Neo-Adjuvant Tx Laparotomy

Laparoscopy

Resectable

Unresectable

Resection

Laparoscopy

Symptomatic therapy Chemotherapy Best supportive care Combined modality therapy

Adjuvant Tx

Figure 8

had a non-therapeutic laparotomy and may result in a greater percentage of R0 resections. However, both median disease specific and overall survival do not appear to be improved. Two recently published prospective randomized control trials (RCTs) appear to support this contention. In the first published RCT, Golcher and co-workers randomized 66 patients of whom 29 received chemoradiation (Gemcitabine/Cisplatin plus RT). The treatment was well tolerated but the results were not significant with regards to resection status, nodal positivity or survival.12 Similarly, Casadei and colleagues randomized 38 patients to surgery alone (n ¼ 20) or neo-adjuvant chemoradiation (gemcitabine, gemcitabine/RT). The treatment was tolerated but resulted in no improvement in either R0 resections or survival.13 Both trials were hampered by poor recruitment. There is the need for further trials. Patients with borderline resectable disease should, if fit, receive neo-adjuvant chemotherapy or chemoradiotherapy. Such protocols have been shown to downstage patients with borderline resectable or locally advanced disease resulting in conversion to resectable disease in up to 67% of cases. Prior attempts to address borderline resectable disease have been limited by the limited efficacy of available chemotherapeutic options. In recent times, however, evidence of two significantly more active regimens have been presented, FOLFIRINOX and the combination of gemcitabine with nab-paclitaxel have been shown to be associated with higher response rates and better disease control. In the absence of a direct comparison it is not clear which regimen is more active, although the gemcitabine/nab-paclitaxel regimen may be more tolerable for patients. Current National Comprehensive Cancer Network guidelines recommend neoadjuvant therapy for borderline resectable

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disease. Histologic confirmation is mandatory before the administration of therapy. FOLFIRINOX is a combination therapy consisting of 5-FU/leucovorin plus oxaliplatin and irinotecan. Adverse effects such as thrombocytopenia, neutropenia, diarrhoea and sensorial neuropathy are commonly described, but appear to be tolerated by patients. Fatigue, neutropenia and neuropathy are the most common adverse events seen in patients treated with gemcitabine/nab-paclitaxel. FOLFIRINOX with or without radiotherapy has been shown in a recent meta-analysis to be associated with R0 resection rates of 64% in borderline resectable disease and 23% in locally advanced pancreatic cancer14 (Figure 9).

Surgery The standard approach for a tumour in the head of the gland is pancreaticoduodenectomy. The goal of the surgeon should be to achieve a complete macroscopic resection (R0). A pancreaticoduodenectomy, which includes resection of gallbladder, bile duct, duodenum, head of the pancreas as well peri-pancreatic lymphatics, can either be performed open or laparoscopically and may involve an antrectomy (classical Whipple procedure) or preservation of the pylorus (pylorus preserving). Meticulous perivascular dissection is performed with resection and/or reconstruction of the peri-pancreatic vessels in order to achieve an R0 resection (Figure 10). As differentiation between tumour infiltration of the peri-pancreatic vessels (SMV, PV, SMA) and tumour-related desmoplasia is difficult to determine during surgery, many surgeons advocate a liberal approach to vein resection as data suggests that outcomes are similar if an R0 resection is achieved irrespective of whether or not a vein resection is performed.

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Overall survival pivotal phase III trials in patients with advanced disease and management algorithm Trial

Gemcitabine (Burris H.A. et al. 1997)

Folfirinox (Convoy T. et al. 2011)

Nab-paclitaxel (Von Hoff D.D. et al. 2013)

Overall survival

<6 months

11 months

9 months

Locally advanced diagnosis

Neoadjuvant therapy

Metastatic diagnosis

Palliative chemotherapy

Chemotherapy + supportive care

Resection

Overall survival

Yes: 23%

No: 77%

20 months

10 months

Less than 6 months

Figure 9

Whipple procedure • Cholecystectomy

• Pancreatic neck and CHD margin FS

• Mobilization of right colon and wide kocherization of the duodenum

• Pancreas transection SMV/PV and SMA dissection

• Aorto-caval node dissection

• Gastric transection • CHD division Culture swab taken

• Separation of gastrocolic omentum from colon Pancreatic neck dissection

• Proximal jejenum division • Ligament of Trietz dissection • Dissection of SMV/PV • Superior pancreatic dissection HA/GDA/PV/Bile duct

Figure 10

additional gemcitabine, are listed as category 1 in the setting of adjuvant therapy. The ESPAC-1 trial suggested that 5-FU/leucovorin is superior to observation, but compared to gemcitabine in the adjuvant scenario there was no difference in overall survival. The ESPAC-

Adjuvant therapy The current National Comprehensive Cancer Network (NCCN) guidelines recommend the use of adjuvant chemoradiotherapy following resection, either 5-fluorouracil (5-FU)/leucovorin, gemcitabine- or fluoropyrimidine-based chemoradiation with

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3 trial found that completion of the full course of chemotherapy was an independent prognostic factor for survival, but time to treatment initiation was not, recommending initiation of adjuvant therapy within 12 weeks after surgery. Although the mechanism of radiosensitization is not entirely clear, it is postulated that gemcitabine and fluoropyrimidines decrease the number of tumour cells in the S phase of the cell cycle, a stage at which cells are resistant to radiation damage.

resectional surgery and the resultant convergence of expertise in these high-volume centres. It is of interest that in Scotland despite centralization the annual mortality attributed to pancreas cancer did not change.18

Metastatic disease Chemotherapy regimes such as FOLFIRINOX (5-flurouracil, oxaliplatin, irinotecan, and leucovorin) and nab-paclitaxel plus gemcitabine have shown significantly increased response rates and improved median survival benefit in patients with metastatic disease. Symptom management has also advanced with endoscopic placement of stents preferred for biliary and/or duodenal obstruction. Symptomatic biliary obstruction is seen in 65e75% of pancreatic cancer patients. For patients with unresectable disease endoscopic biliary stent achieves the best palliation. Covered metallic stents appear to offer improved palliation as they have a reduced incidence of cholangitis and rarely require replacement. When the endoscopic approach is not an option, percutaneous drainage is an alternative. Subsequent internalization is preferred and can provide adequate palliation. While our preference is to proceed non-operatively it must be stated that several meta-analyses have shown no survival benefit for biliary drainage by endoscopic or percutaneous routes stenting compared to surgical bypass. However, perioperative morbidity and length of hospital stay is increased in the surgical group. Symptomatic gastric outlet obstruction occurs in 10e25% of patients. In patients with widespread metastatic disease or with a poor performance status, an endoscopically placed enteral stent should be considered. Otherwise, in patients with a good performance status, limited disease burden or in whom technical difficulties preclude an endoscopic procedure, an open or laparoscopic gastric bypass procedure should be considered and may provide effective and durable palliation. End of life care, particularly nutrition support and pain control has also developed and is now recognized as an essential component in the management of patients with pancreatic cancer. Little or no data exists as to whether these elements of care have expanded with the drive to centralize resectional surgery. Patients with locally advanced or metastatic disease are often old with significant co-morbidities. Borgida and co-workers, identified patients in Ontario, Canada with a pathologic diagnosis of pancreas cancer between 2003 and 2006.19 Patients were mailed questionnaires addressing epidemiologic and treatment issues. The response rate was 26%. Non-responders were older and more commonly treated in non-academic centres. The rate of adjuvant and palliative chemotherapy was stage and treatment centre dependent and was low. This would suggest the diffusion of management protocols from the academic (i.e., centre of excellence) to the community is low. In part, this may relate to the increased travel distance required to access a high-volume centre. In an observational study utilizing administrative data, Stitzenberg and colleagues examined discharge data between 1996 and 2006 from New Jersey, New York and Pennsylvania in the United States.20 During this time period, 13,472 patients with pancreatic cancer were identified. Centralization was noted with a shift of procedural volume from low-volume hospitals to high-volume providers. Travel distance

Regionalization of care Recently many countries have regionalized the delivery of pancreatic surgery. The association between high hospital and surgeon volume and improved outcome following pancreatic resection has been generally accepted following the landmark work of Birkmeyer and colleagues. A multitude of recent publications have supported this concept and have led many countries to centralize pancreatic resectional surgery into a selected number of larger academic centres. Recent work has highlighted the benefits of such a move. In Japan, Yoshioka and colleagues reported a significant correlation between increased hospital volume and reductions in inhospital mortality, length of stay and costs for patients undergoing pancreaticoduodenectomy.15 This is similar to the situation pertaining in the Netherlands where centralization of pancreatic resectional surgery since 2006 has resulted in a reduction in the overall perioperative mortality from 9.8% to 5.1%16 with the reduction most apparent in high-volume centres. During a 6-year period between 2004 and 2009, mortality was noted to be 14.7%, 9.8%, 6.3% and 3.3% in very low-, low-, medium- and highvolume hospitals, respectively. This was also associated with an increased resectability rate and in high-volume hospitals, an improved overall survival.17 In contrast, Young and co-workers in Scotland did not demonstrate an increase in the proportion of patients undergoing resectional surgery despite 80% of procedures being performed in five major cancer hospitals.18 They did, however, comment that adverse events relating to direct procedural complications and decision-making errors appeared to have decreased over time. The reason for improved results is complex with the following institutional and personal factors implicated;  specialized surgeons and anaesthetists  multidisciplinary teams with comprehensive protocols for diagnosis and staging  more consistent processes for perioperative care  better staffed and equipped HDU/ICUs  greater resources for dealing with postoperative complications  adjuvant therapies (chemotherapy/radiotherapy) more likely to be available to the patient. While it is understandable that surgeons have concentrated on patients who present with potentially resectable disease, these only represent less than 20% of all patients with pancreatic cancer. The majority of patients continue to present with either locally advanced (approximately 30%) or metastatic disease (approximately 40%). It is unclear from the available literature as to whether these patients have actually benefited or have in fact been disadvantaged from centralization of pancreatic cancer

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increased particularly for patients living outside urban areas. The authors suggested that this may be a significant barrier to access quality cancer care.

7 Lennon AM, Wolfgang CL, Canto MI, et al. The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? Cancer Res 2014; 74: 3381e9. 8 Bipat S, Phoa SS, van Delden OM, et al. Ultrasonography, computed tomography and magnetic resonance imaging for diagnosis and determining resectability of pancreatic adenocarcinoma: a meta-analysis. J Comput Assist Tomogr 2005; 29: 438e45. 9 Rijkers AP, Valkema R, Duivenvoorden HJ, van Eijck CH. Usefulness of F-18-fluorodeoxyglucose positron emission tomography to confirm suspected pancreatic cancer: a meta-analysis. Eur J Surg Oncol 2014; 40: 794e804. 10 Allen VB, Gurusamy KS, Takwoingi Y, Kalia A, Davidson BR. Diagnostic accuracy of laparoscopy following computed tomography (CT) scanning for assessing the resectability with curative intent in pancreatic and periampullary cancer. Cochrane Database Syst Rev 2013 Nov 25. Issue 11. Art. No.: CD009323. 11 Shoup Margo, Winston Corinne, Brennan Murray F, Bassman Diane, Conlon Kevin C. Is there a role for staging laparoscopy in patients with locally advanced, unresectable pancreatic adenocarcinoma? J Gastrointest Surg 2004; 8: 1068e71. 12 Golcher H, Brunner TB, Witzigmann H, et al. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial. Strahlenther Onkol 2015; 191: 7e16. 13 Casadei R, Di Marco M, Ricci C, et al. Neoadjuvant chemoradiotherapy and surgery versus surgery alone in resectable pancreatic cancer: a single. Center prospective, randomized, controlled trial which failed to achieve accrual targets. J Gastrointest Surg 2015; 19: 1802e12. 14 Petrelli F, Coinu A, Borgonovo K, et al. FOLFIRINOX-based neoadjuvant therapy in borderline resectable or unresectable pancreatic cancer: a meta-analytical review of published studies. Pancreas 2015; 44: 515e21. 15 Yoshioka R, Yasunaga H, Hasegawa K, et al. Impact of Hospital volume on hospital mortality, length of stay and total costs after pancreaticoduodenectomy. Br J Surg 2014; 101: 523e9. 16 De Wilde RF, Besselink MGH, van der Tweel I, et al. Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality. Br J Surg 2012; 99: 404e10. 17 Gooiker GA, Lemmens VEPP, Besselink MG, et al. Impact of centralization of pancreatic cancer surgery on resection rates and mortality. Br J Surg 2014; 101: 1000e5. 18 Young J, Thompson A, Tait I, et al. Centralization of services and reduction of adverse events in pancreatic cancer surgery. World J Surg 2013; 37: 2229e33. 19 Borgida AE, Ashamalla S, Wigdan A-S, et al. Management of pancreatic adenocarcinoma in Ontario, Canada; a populationbased study using novel case ascertainment. Can J Surg 2011; 54: 54e60. 20 Stitzenberg KB, Sigurdson ER, Egleston BL, et al. Centralization of cancer surgery; Implications for patient access to optimal care. J Clin Oncol 2009; 27: 4671e8.

Follow-up Following resectional surgery with or without adjuvant therapy, patients require postoperative follow-up in order to detect disease recurrence and assess endocrine and exocrine functionality. NCCN guidelines recommend history and physical examination for symptom assessment every 3 to 6 months for 2 years, then annually. CA 19-9 determinations and follow-up CT of the chest, abdomen and pelvis are suggested 3 to 6 monthly for 2 years after surgical resection. In the case of recurrent disease, it is recommended that if adjuvant therapy was completed less than 6 months prior to development of metastatic disease, an alternative chemotherapy option be administered. When this period is greater than 6 months, systemic therapy as previously administered or an alternative systemic regimen is recommended. Recommended regimens for patients with previous adjuvant treatment and good performance status are gemcitabine/ albumin-bound paclitaxel and FOLFIRINOX. With regard to physiological functionality, it is now appreciated that 10e25% of patients will become diabetic after a pancreaticoduodenectomy and that 30e60% will have some degree of pancreatic enzyme insufficiency. It is also recognized that this increases over time.

Future directions Pancreatic cancer remains a difficult and frustrating disease to deal with. However, recent insights into the biology of the disease coupled with improvements in the diagnostic armamentarium, enhanced perioperative care and the development of more effective chemotherapeutic agents give optimism for the future. It is hoped that these developments will lead to an improvement in overall survival e an aspiration which heretofore has eluded clinicians treating patients with this disease. A REFERENCES 1 Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014; 74: 2913e21. 2 National Cancer Registry of Ireland. Cancer in Ireland 2013: annual report of the National Cancer Registry. Cork, Ireland: National Cancer Registry, 2013. 3 NCI-cancer.gov. SEER stat fact sheets: pancreatic cancer 2015. 4 Cancer Research, UK. Pancreatic cancer 2015. 5 Neuzillet Cindy, Tijeras-Raballand Annemilaï, Bourget Philippe, et al. State of the art and future directions of pancreatic ductal adenocarcinoma therapy. Pharmacol Ther 2015; 155: 80e104. 6 Levy P, Jouannaud V, O’Toole D, et al. Natural history of intraductal papillary mucinous tumors of the pancreas: actuarial risk of malignancy. Clin Gastroenterol Hepatol 2006; 4: 460e8. http://dx.doi.org/10.1016/j.cgh.2006.01.018.

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Please cite this article in press as: Sanabria Mateos R, Conlon KC, Pancreatic cancer, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2016.03.011