Pancreatic adenocarcinoma

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15

Pancreatic adenocarcinoma

Introduction

Adenocarcinoma of the pancreas accounts for 3% of new cancer cases per annum,1 yet it is the fourth leading cause of cancer-related death in Western countries. The insidious nature of the disease and its vagueness of presentation contribute to late diagnosis. Eighty per cent of patients have unresectable tumours at initial diagnosis. The overall survival at 5 years still remains at 6%, unchanged over the last four decades.1 However, in recent years improvements in preoperative imaging and staging modalities, coupled with advancements in adjuvant therapies with the use of immunomodulators and monoclonal antibodies, have resulted in some degrees of optimism. Progress has been made as the molecular basis of the disease is better understood. With such poor survival rates and recent high-profile media attention, a renewed interest in tackling this elusive cancer has arisen.

Around 95% of pancreatic tumours are adenocarcinoma, originating from the exocrine part of the pancreas. Nearly all of these are ductal adenocarcinomas, which is the focus of this chapter.

Epidemiology

An estimated 44  000 new cases of adenocarcinoma of the pancreas occurred in the USA in 2011, and almost 38  000 died in the same year.2 In the UK, 8085 people were diagnosed with pancreatic cancer and 8020 people died during 2009.3 The incidence of pancreatic cancer varies with age, sex and ethnicity. In 2008, the standardised incidence rate of pancreatic cancer was 3.9 per 100 000 population, while the standardised mortality rate was slightly lower at 3.7 per 100 000 population. Pancreatic cancer is the eleventh commonest cancer in males and eighth commonest cancer in females.4 The peak incidence for the disease occurs between the seventh and eighth decades of life, and is rare under the age of 30. In the American population, African and Hawaiian ethnicities confer a higher incidence than Caucasian, whereas Asian and Hispanic ethnic groups have a lower risk of developing the disease. The incidence of pancreatic cancer is rising, particularly in Europe, although this observation is subject to reporting bias related to improved diagnostics. However, pancreatic neoplasm must be detected at an early stage to enable the potential for curative treatment.

Risk factors (see Box 15.1)

Smoking

Tobacco smoking is by far the leading preventable cause of pancreatic cancer, with an estimated 2.5-fold increase in risk when compared to non-smokers.5 In 1986, the International Agency for Research on Cancer (IARC) classified smoking as a proven carcinogen with respect to cancer of the pancreas. Observational studies suggest that a dose-dependent relationship exists, necessitating long-term exposure.5 However, smokers who have quit for more than 10 years no longer experience an increased risk.5 While the chemical cause is unclear, it is hypothesised that N-nitroso compounds in tobacco are carried to the pancreas in the blood. The time in which cigarette smoking exerts its negative influence is also subject to debate; however, observational studies seem to point towards the latter stages of carcinogenesis, particularly in the 15 years preceding development.

Diet and alcohol

Excessive body weight appears to increase the risk of pancreatic cancer. It has been shown that obesity has a positive association, with a relative risk of 1.72.6 Diets high in saturated fat have a suggested contributing role in carcinogenesis,6 although data are limited. Caffeine and meat preservatives have been suggested to have a negative association, but in recent years this has become more debated due to the studies having methodological flaws, and more recent studies demonstrating the opposite. Vitamin C, vitamin D and high-fibre diets have suggested protective associations with pancreatic neoplasm.79

The role of heavy alcohol consumption in the development of pancreatic cancer still remains controversial.

Past medical history

Chronic pancreatitis is a progressive inflammatory process with associated irreversible histological changes. It is highly linked to excessive alcohol consumption, with up to an 18-fold increase in risk of pancreatic cancer compared to the general population. Quantifying the risk is still difficult due to confounding factors such as smoking, alcohol and diet.11

Diabetes has a positive association for pancreatic cancer. Meta-analysis has shown that type 2 diabetes increases the risk of pancreatic cancer by 82%.11 The high prevalence of diabetes in society excludes hyperglycaemia as a screening tool for pancreatic cancer.

Other conditions linked with pancreatic cancer include Gardner’s syndrome, cystic fibrosis and multiple endocrine neoplasia type 1 (neuroendocrine cancers).

Hereditary pancreatic cancer

The accurate incidence of familial pancreatic cancer remains elusive, despite various reports of pancreatic cancer families.

Pancreatic carcinogenesis has an established genetic predisposition. Familial conditions such as Peutz–Jeghers syndrome, germ-line mutation in the STK11/LKB11 gene,13 BRCA2 expression14 and familial atypical multiple mole melanoma (p16/CDKN2A germ-line mutation) may predispose to pancreatic cancer.14 Links with hereditary non-polyposis colorectal cancer (Lynch syndrome), BRCA1 and von Hippel–Lindau have been suggested but not confirmed, as conferring increased risk.15 With the speed of developing technology, matched with reduced genetic diagnostic expense, one can foresee the potential for the discovery of further genes relating to familial pancreatic cancer.

Precursor lesions

Histologically distinct precursor lesions have been attributed to pancreatic carcinogenesis. Preneoplastic lesions are usually asymptomatic and can be incidentally discovered at the time of resection. They appear to follow a multi-step progression to invasive carcinoma.15 These precursor lesions include pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN).16 Because of their small size (usually < 5 mm), they are difficult to detect, making them elusive to computerised tomography (CT) or magnetic resonance imaging (MRI).15

Pan-INs are the most frequent preneoplastic lesions, observed in approximately 82% of pancreas with neoplasm.17 They are subclassified into PanIN-1, PanIN-2 and PanIN-3 depending upon the degree of cytological and architectural atypia.17 Each of these precursor lesions harbours a unique repertoire of clinicopathological and genetic characteristics that has an impact on the natural history and prognosis of these lesions.

Workers in Johns Hopkins University proposed pancreatic intraepithelial neoplasms (PanIN; 1A → 1B → 2 → 3) as the precursor lesions to invasive carcinoma.18 The model is analogous to that of ductal carcinoma in situ (DCIS) of the breast or adenomatous polyps in colorectal cancer. The lesions display atypical mucinous epithelium replacing the physiological cuboidal epithelium. The evidence for PanIN being a true premalignant state is largely circumstantial. These lesions were first described adjacent to resected adenocarcinoma. The more atypical PanIN-2 and -3 were seen exclusively in neoplastic pancreas. These lesions also display similar genetic aberrations to the frankly invasive samples. In particular, the percentage of p16 and K-ras mutations increases with the more atypical PanIN. These data have heralded development of a tumour genesis model involving sequential progression from PanIN-1a to invasive adenocarcinoma.19

Classically, evolution from precursor lesions to pancreatic neoplasm (ductal adenocarcinoma) involves diverse molecular changes (Fig. 15.1). Recent studies indentified at least 119 independent loci that may potentially play a role in tumour progression, including K-ras, TP53, p16/CDKN2A, MYC and AKT2.20 The K-ras gene product mediates signal transduction in a number of growth factor receptors. K-ras single point mutation is observed in 90–95% of pancreatic ductal adenocarcinoma, representing the most common mutation in this disease.21 K-ras is currently the focus of multiple ongoing studies to see if it can be utilised as a diagnostic tool.13 Altered epidermal growth factor receptor expression (EGFR) causing overexpression is thought to be an early event in pancreatic carcinogenesis.22

Inactivation of numerous tumour suppressor genes, including p16/CDKN2A and TP53, plays a pivotal role in the development of pancreatic cancer. Loss of tumour suppression is noted in 70–95% of pancreatic neoplasm.17 Other targets including transforming growth factor-β (TGF-β) receptor genes, BRCA2, HER-2/NEU, DPC4, MKK4 and EBER-1 are currently under investigation. The discussion about these genes is outside the scope of this chapter. However, the best chance for cure in the treatment of pancreatic cancer lies with detecting these non-invasive lesions before progression to invasive carcinoma.

Presentation

The majority of patients present with vague and non-specific symptoms (Box 15.2). As a result, the disease is commonly widespread at diagnosis, and approximately 80% of patients present with unresectable disease.

Tumours in the body and tail of the pancreas usually present late. Pain is the most consistent symptom. Painless jaundice is seen in 13% of patients while 34% present with only pain and 46% present with both pain and jaundice. Weight loss and anorexia are observed in 7% of patients. Rarely, tumour invasion into stomach or duodenum can present as haematemesis and malaena. Patients may also present with late-onset diabetes mellitus and acute pancreatitis.23 Limited series have examined the screening of asymptomatic cohorts, with little evidence to support the introduction of population screening for pancreatic cancer.14 However, there may be a place for targeted screening of high-risk groups in the near future.

The classical Courvoisier sign (palpable gallbladder in the presence of painless jaundice) occurs in less than 25% of patients. Jaundice may represent either primary disease causing biliary obstruction or external compression of the biliary system by metastatic nodal disease. Pain is a more common symptom than physicians usually appreciate, occurring due to the involvement of the visceral afferent nerves or relating to an induced local pancreatitis. Pain on initial presentation is synonymous with a higher incidence of unresectability. Weight loss is common, often associated with early satiety, nausea or vomiting. The latter symptom may be due to gastric outlet obstruction.

Virchow’s node (left supraclavicular node associated with upper gastrointestinal (GI) malignancy), thrombophlebitis migrans (non-specific paraneoplastic sign named after Trousseau) and Sister Mary Joseph nodule (umbilical metastatic lesion via the falciform ligament) are well-described features of advanced disease. Hepatomegaly is seen in 65% of patients and may indicate liver metastases. Blumer’s shelf (rectally palpable rectovesical or rectovaginal mass) rarely occurs and is not usually sought as part of routine examination.

The most useful aid in disease diagnosis is a high index of suspicion. Vague epigastric symptoms and weight loss in the presence of normal endoscopy and preliminary radiology should initiate further detailed investigation.

Investigation

Markers

There still remains no ideal tumour marker for pancreatic carcinoma. Carbohydrate antigen 19-9 (CA 19-9; 0–37 U/mL) exists in tissue as an epitope of sialylated Lewis a-type blood group antigen, and is the most widely utilised tumour marker. It was based on a monoclonal antibody to colorectal cancer cell lines. CA 19-9 is elevated in only approximately 50% of cases.24 Among symptomatic patients, CA 19-9 has a sensitivity of 81–85% and specificity of 81–90%.24 However, the positive predictive value remains low among the asymptomatic population, making it a very poor screening test. Falsely elevated CA 19-9 is documented in other neoplasms including gastric, colorectal, cholangiocarcinoma and urothelial malignancies, as well as benign conditions such as pancreatitis, hepatitis, thyroiditis and biliary obstruction. In addition patients expressing Lewis blood group antigens (a and b) may have elevated levels.25 CA 19-9 may be used to assess recurrence of disease, with a level higher than 500 U/mL signifying advanced disease.25 A level exceeding 243 U/mL for patients undergoing primary chemoradiotherapy for locoregionally advanced disease also indicates poorer median survival (7.1 vs. 12.3 months).26

Several other tumour markers are currently being investigated including carcinoembryonic antigen (CEA), K-ras, p53, CA242, CA50, SPAN-1, DU-PAN2, CAM-17.1 and a number of mucins (MUC1, MUC3, MUC4 and MUC5AC). They are proposed as having application in pancreatic neoplasms, although none of these markers are sensitive enough to be recommended for clinical use. CA242 shows promise as an independent prognostic factor.27

Diagnosis

Imaging studies

Transabdominal (TA) ultrasound (US) is the initial investigation in the jaundiced patient. It is noted for its superior sensitivity for determining cholelithiasis over CT. Common bile duct dilatation (> 7 mm; > 10 mm in post-cholecystectomy patients) is an indirect sign, together with pancreatic duct dilatation (> 2 mm). The primary pancreatic lesion is often visible together with liver metastases and ascites if present. For lesions > 3 cm TAUS has approximately 95% sensitivity; however, this is considerably lower for smaller lesions.28 The main criticism of TAUS is machine quality difference and operator experience; thus it is user dependent.29 The role of colour Doppler US has been suggested to examine portal vein or superior mesenteric involvement. Ultrasound remains a useful imaging modality for the initial screening of the jaundiced patient, but further radiological modalities are necessary to examine the pancreas and assess resectability.

CT remains the most common staging modality. Conventional CT has been replaced by more sensitive dynamic CT with thinner slice/cuts (1–3 mm) with multidetector and 3D reconstruction. The sensitivity is approximately 90% for lesions greater than 2 cm, decreasing to approximately 60% for smaller lesions.30,31 CT allows for assessment of the primary lesion, its relationship to the remainder of the pancreas and peripancreatic vasculature, and determination of resectability (Figs 15.2 and 15.3). Direct evidence of a tumour is often seen as a hypodense mass, with other subtle signs such as pancreatic atrophy, deformity of the glandular contour or dilatation of the common bile and pancreatic ducts (Fig. 15.4). Metastatic lesions can be detected, and portal vein or superior mesenteric artery involvement can be determined.

MRI is mainly used as an adjuvant to other imaging modalities for planning treatment options. The combination of T1/T2-weighted imaging with magnetic resonance cholangiopancreatography (MRCP) is useful to visualise the primary tumour and its relationship to the biliary and pancreatic ducts, as well as peripancreatic vasculature. MRI/MRCP is considered to be equivalent to CT for assessing primary disease.33,34

Positron emission tomography (PET) shows accumulation of [18F]2-fluoro-2-deoxy-D-glucose (FDG) by tumour cells, and has the advantage of combining metabolic activity and imaging characteristics. PET-CT scanners are able to detect small pancreatic neoplasms up to 7 mm in diameter, and to diagnose metastatic disease in about 40%.35 PET is becoming a more common method of measuring tumour response to treatment and may help predict prognosis. However, FDG-PET is not accurate in pancreatic disease due to its reliance on normal glucose haemostasis. The combination of PET-CT has a sensitivity of 92%, and is superior to either modality alone.36,37

Endoscopic retrograde cholangiopancreatography (ERCP) is reserved mainly to assess obstructive intraductal lesions and to relieve biliary obstruction in selected cases. MRCP has replaced ERCP as a diagnostic modality of choice.

Endoscopic ultrasound (EUS) is becoming more commonly used in staging pancreatic cancer. It provides high-quality images and is noted to be more sensitive than CT for detecting small pancreatic lesions. EUS is also accurate in determining cancer involvement of the portal or splenic vein.38 It has similar efficacy to ERCP in defining small periampullary lesions. EUS may also help clarifying benign conditions mimicking cancer such as sclerosing pancreatitis or atypical choledocholithiasis. Fine-needle aspiration (FNA) of a lesion can be achieved with similar sensitivity and specificity to CT-guided FNA. However, the main drawbacks of EUS include cost, invasiveness and operator dependency.

Advanced staging techniques

Laparoscopy

Despite advances in non-invasive imaging, laparoscopic staging and ultrasound have a role in selected cases.38,39 Laparoscopy can be performed immediately before conversion to laparotomy40,41 or as an interval staging measure.42

The role of staging laparoscopy is dependent on institution protocol, and there still exists some considerable controversy regarding its use. Its aim is to identify radiographically occult metastatic disease via a minimally invasive approach to prevent non-therapeutic laparotomies. Laparoscopic examination allows for direct visualisation of intra-abdominal organs. It has been shown to be very sensitive in detecting small metastatic deposits < 3 mm on peritoneal and hepatic structures43 (Figs 15.5 and 15.6). The added value of laparoscopy over state-of-the-art dynamic multislice CT remains up to 20%.42

Those who oppose minimal access staging suggest that a significant proportion of patients require surgical bypass and therefore laparoscopic staging should only be used if this would not be contemplated at laparotomy.43 Single-centre studies suggest that the need for subsequent operative palliation is less than 5%.44

General laparoscopy is performed with an angled (usually 30°) lens looking for small-volume peritoneal and liver metastases. The liver is examined systematically and usually all but segment 7 can be viewed. Biopsy of hepatic or peritoneal deposits for frozen section histology is taken, and the procedure is terminated if positive. If metastases are not seen, the hepaticoduodenal ligament is inspected for nodal disease. The lesser sac is opened by incising the gastrocolic omentum to inspect for tumour, and biopsies of the primary may be performed. This is achievable in approximately 80%. In certain centres, mobilisation of the duodenum is performed, but in the majority of cases this is unnecessary. With more efficacious neoadjuvant therapies, it is important to use laparoscopic strategies to define patients who may be suitable for downstaging similar to advanced rectal lesions.

Peritoneal cytology taken at the time of laparoscopic staging may also improve the accuracy of laparoscopic staging. In a prospective study of 150 consecutive patients with pancreatic carcinoma, unexpected metastases were found in 5–10%.48 Positive cytology is associated with advanced disease; it predicts unresectability of pancreatic adenocarcinoma and a decreased survival. As both radiological and endoscopic imaging will continue to advance, staging laparoscopy and LUS will have a selective role, especially in cases of equivocal findings.

Treatment

Treatment options should be discussed at a multidisciplinary level, with emphasis on established guidelines. The American Joint Committee on Cancer TMN staging is outlined in Table 15.1. Figure 15.8 outlines our current treatment algorithm for patients with pancreatic cancer.

Table 15.1

American Joint Committee on Cancer TNM staging, 2010

Tumour (T) Node (N) Metastasis (M)
Tx: Primary tumour cannot be assessed Nx: Regional lymph nodes cannot be assesed
T0: No evidence of primary tumour N0: no regional nodes M0: no metastases
Tis: Carcinoma in situ
T1: < 2 cm within pancreas N1: Regional lymph node metastasis M1: spread to distant organs or non-regional nodes (e.g. aortocaval)
T2: > 2 cm within pancreas
T3: Tumour extends beyond the pancreas but without involvement of the coeliac axis or the SMA
T4: Tumour involves the coeliac axis or the SMA (unresectable primary tumour)
Stage 0: Tis, N0, M0
Stage IA: T1, N0, M0
Stage IB: T2, N0, M0
Stage IIA: T3, N0, M0
Stage IIB: T1, N1, M0/T2, N1, M0/T3, N1, M0
Stage III: T4, Any N, M0
Stage IV: Any T, Any N, M1

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springer.com

Resection

Surgical treatment remains the only potential cure for pancreatic cancer, yet patient selection remains key.

If jaundice is present, then the controversy is whether preoperative biliary decompression should be undertaken. Evidence suggests an increased risk of perioperative sepsis, pancreatic fistula and wound infection.49,50 However, a recent meta-analysis questioned these previous findings.51 The authors’ practice is not to decompress the bile duct preoperatively, unless symptoms and signs of cholangitis or secondary signs of hyperbilirubinaemia are present. If a neoadjuvant approach is being considered, biliary stenting is required prior to commencing chemo/radiotherapy. Coagulopathy, if present, is treated with vitamin K prior to resection.

Patient selection is paramount, including cardiovascular and respiratory evaluation. Surgery with curative intent is associated with a median survival of 11–23 months, with approximately 10–18% alive at 5 years.52 Previously, pancreatic resections were associated with significant mortality; however, with advances in perioperative supportive care, mortality rates have now been reduced to less than 5% in high-volume centres.53

Pancreatico-duodenectomy

Kausch first described pancreatico-duodenectomy in 1912, later popularised by Whipple in 1935. The classical Whipple procedure (two-stage) was an en-bloc resection of the pancreatic head, duodenum, common bile duct, with the distal stomach and surrounding lymph nodes. Later being preformed as a one-stage operation, it still remains the mainstay of surgical therapy for tumours of the pancreatic head and neck.

The right colon is mobilised, exposing the third and fourth parts of the duodenum, and an extended Kocherisation is performed. This allows a tumour in the head of the pancreas to be palpated and views of the left renal vein. The aortocaval and portal vein (PV) nodal packages are dissected and the respective vessels are skeletonised. Resectability is finally assessed as extensive involvement of the confluence of the PV/superior mesenteric vein (SMV) may herald termination of the procedure. It is important to remember that short segments of the PV can be resected if necessary, and therefore an involved PV does not necessarily denote unresectability.

The remaining porta hepatis is dissected, and nodes are cleared. Cholecystectomy facilitates higher ligation of the bile duct, which is transected just proximal to the insertion of the cystic duct. It is our practice to send a biliary aspirate for routine culture and sensitivity as postoperative infective complications tend to involve enteric organisms.54

The common bile duct is mobilised distally and the hepaticoduodenal ligament is dissected along its length, taking care to identify and preserve the common hepatic artery and PV. The gastroduodenal artery is ligated while care is taken not to damage an aberrant right hepatic artery.

In a conventional Whipple, the distal stomach is resected. This is the authors’ favoured approach as resection includes the nodes along the greater and lesser curves, reduces stomach-emptying dysfunction postoperatively, diminishes the density of parietal cells and theoretically reduces the risk of gastritis. The stomach is transected at the antrum along with the attached omentum. The proximal jejunum along with its mesentery is transected and the mobilised duodenum and jejunum is delivered back under the ligament of Treitz.

The pancreas is transected between four stay sutures (to facilitate haemostasis in the marginal arteries) after the uncinate process is dissected from the superior mesenteric vessels. Retroperitoneal dissection allows the tumour and nodal package to be delivered en bloc. If any doubt exists regarding the adequacy of tumour clearance, the pancreatic resection margin should be sent for frozen section histology.

Reconstruction is undertaken with the biliary anastomosis followed by the pancreatic and finally the gastric. The most significant cause of morbidity is the development of pancreatic fistula, observed in up to 10–20% of cases.56

Pancreatico-jejunostomy and pancreatico-gastrostomy are the most commonly employed techniques for pancreatico-enteric reconstruction. These suggest a marginal decrease in fistula rates with the former, although differences are not clinically significant and have not induced a change in operative strategy, with jejunal reconstruction still favoured.57

The nature of the pancreatic reconstruction is subject to individual variation. The authors favour a two-layered pancreatico-jejunal anastomosis with mucosa-to-mucosa reconstruction. Choledocho-jejunostomy is performed in a similar manner (end to side), leaving the gastro-jejunostomy until the end.

Morbidity following resection varies, with the majority of complications being minor; however, pancreatic fistula can occur in 10–20% of cases. Most complications can be dealt with either conservatively or using drains placed by interventional radiology. Less than 5% of cases require re-operation.

Pylorus-preserving pancreatico-duodenectomy (PPPDR)

Many centres recommend a PPPDR approach, first described by Watson in 1942. It is believed to retain a functioning pylorus with an intact neurovascular supply, thus ensuring good gastrointestinal function and diminishing nutritive, dumping and bile reflux sequelae.59 Both pancreatico-duodenectomy and PPPDR have similar perioperative adverse events; however, in overall analysis PPPDR has decreased operating times, fewer blood transfusions, lower mortality and improved long-term patient survival.59 Detractors of PPPDR point to delayed gastric emptying as a potential cause for concern with this procedure.60

The procedure dictates conventional mobilisation up to where the stomach requires transection. In PPPDR the right gastric artery is preserved and the duodenum is transected at least 2 cm distal to the pylorus. Reconstruction is usually accomplished by duodeno-jejunostomy or gastro-jejunostomy.

Extended lymph node and vascular dissection

It is the authors’ practice to perform extended dissection including aortocaval nodal clearance in the majority of cases. At presentation, most tumours have involvement of lymph nodes beyond the gland. Ishikawa et al. demonstrated increased median (but not long-term) survival following extended lymph node dissection.61 However, outside of Japan, findings of increased survival have not been validated. Studies have failed to demonstrate increased morbidity that one would expect with a radical operation, although in our experience there is invariably increased ascites in those who undergo extended lymphadenectomy. We believe that clearance of the left gastric and aortocaval nodes increases the specificity of staging and therefore predicted prognosis, and increases the likelihood of a negative surgical margin, although this remains controversial.

The role of extensive vascular resection has been proposed in certain cases. Pancreatico-duodenectomy with major vascular resection had been reported in recent years with acceptable outcomes, despite the increased challenging nature. Survival benefits are slight, and require further investigation.62

Laparoscopic pancreatectomy

Laparoscopic pancreatectomy remains one of the most challenging laparoscopic abdominal operations, and hence case series have low numbers. Two centres have shown total laparoscopic pancreatico-duodenectomy to be safe and feasible, with comparable results to the open approach.63,64 However, laparoscopic distal pancreatic resection is currently the most frequently performed laparoscopic pancreatic operation. It is associated with a higher likelihood of splenic preservation, increased operative time, decreased blood loss and decreased length of stay.63 With the further development of robot-assisted surgery, minimally invasive pancreatico-duodenectomy is likely to become more common.

Surgical palliation

Adjuvant therapies

Gemcitabine is becoming more favoured than 5- fluorouracil (5-FU) because its safety profile is better with similar efficacy.68

The role of adjuvant chemoradiation is less well defined, with conflicting outcomes from the trials. The Gastrointestinal Study Group (GITSG) showed a survival with 5-FU and radiotherapy, but the study size (n = 43) was criticised.69 The European Organization of Research and Treatment of Cancer (EORTC) trial showed no statistical survival benefit for those treated with adjuvant chemoradiation compared with an observation group.70 More recently, the Johns Hopkins–Mayo Clinic Collaborative study demonstrated that chemoradiation post pancreatico-duodenectomy was associated with improved survival.71

Despite the role of adjuvant therapy, survival remains poor, with the need to discover more efficacious treatment and further studies to elucidate the optimum therapy protocol, with consideration of timing and the need for more individualised treatment regimens.

Neoadjuvant therapy

In recent years, many centres support the role of neoadjuvant therapy in the treatment of pancreatic cancer. Theoretical advantages include the delivery of chemotherapy or radiotherapy to well-oxygenated tissue, and hence early treatment of micrometastatic disease. Neoadjuvant therapy may help to identify patients who have more aggressive disease, and therefore would not be ideal surgical candidates. There is speculation that neoadjuvant chemoradiation decreases the risk of pancreatic leaks and makes pancreatic reconstruction easier.72 Detractors of neoadjuvant therapy claim that the delay in surgery may allow local disease to progress; however, this is difficult to prove. It has been suggested recently that neoadjuvant treatment should be targeted at patients with borderline pancreatic cancer with the aim to downstage the disease, allowing for resection at later date, with evidence of improved survival rates.72,73

Future areas of interest

The last decade has seen considerable improvements in diagnosis, as well as advances in minimally invasive and endoscopic management of pancreatic cancer. Biological agents like erlotinib (epidermal growth factor receptor inhibitor), cetuximab, bevacizumab and axitinib are currently being investigated for their role in the treatment of pancreatic cancer. Unfortunately, so far none have shown a significant survival benefit.

Despite recent radiological developments, there remains a limited ability to detect pancreatic cancer at an early stage. Therefore, an emphasis on better understanding of cancer genetics, predisposing factors and the role of tumour markers in aiding the diagnosis is crucial. Further trials will help utilise neoadjuvant or adjuvant therapy in appropriate cases. Surgical techniques, especially oncological dissection methods, will need to be standardised to ensure stricter quality control and better data comparison.

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