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Pancreatic cancer
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Pancreatic cancer
survival of 2e6 months for stage IV disease and 6e11 months for stage III disease.2 Even among patients who undergo surgery with curative intent, more than 90% develop disease progression within 12e18 months.2
Nilanjana Tewari Dileep N Lobo
Aetiology Although the causes of pancreatic cancer are unknown, several risk factors have been identified.3 A family history of pancreatic cancer is present in 7e10% of patients. First-degree relatives of individuals with familial pancreatic cancer have a ninefold increased risk over the general population. The strongest causative association exists with tobacco smoking. In a large caseecontrol study, ‘ever-smokers’ had a 60% increased risk of pancreatic cancer compared to ‘never-smokers’ and the risk was more pronounced among heavy smokers (20 pack years) compared to mild or moderate smokers. Risk factors are listed in Box 1.
Abstract Pancreatic cancer accounts for 3% of all cancers in the UK; 7000 new cases are diagnosed annually and a similar number die from the disease each year. It has an insidious onset and, as a result, presentation is usually late, with only about 10e20% of patients having disease amenable to surgical resection. Following resection, the median survival is 11e20 months and the 5-year survival is 7e25%. Patients with unresectable locally advanced disease have a median survival of 6e11 months, and those with metastatic disease have a median survival of 2e6 months. Accurate staging has a vital role in the management of pancreatic tumours now that non-surgical palliative options are available. Computed tomography is currently the imaging modality of choice for diagnosis and staging of pancreatic cancer. With recent advances in magnetic resonance imaging and endoscopic ultrasonography, it is now possible to improve the accuracy of preoperative staging, particularly with respect to local invasion and regional node involvement. Resection is the only treatment that offers the potential of cure; ideally, an R0 resection should be aimed for. Chemotherapy renders a survival advantage in the adjuvant setting, even in patients undergoing R1 resections. Palliative chemotherapy can improve survival by 10e15% and other palliative therapies are aimed at relieving jaundice, controlling pain, treating malabsorption and reversing cancer cachexia.
Pathology Pancreatic neoplasms (Table 1) may be epithelial, mesenchymal or secondary (metastatic). Epithelial neoplasms can be divided into solid tumours (ductal adenocarcinoma and acinar cell carcinoma) and cystic neoplasms (serous, mucinous, intraductal papillary and solid pseudopapillary types). Mesenchymal tumours and primary lymphoma are uncommon. Metastases may be found in the pancreas, usually from renal cell carcinoma and malignant melanoma. Intraductal papillary mucinous neoplasms (IPMNs) are mucin-producing neoplasms that arise in the main pancreatic duct or its branches. Some IPMN subtypes have a risk of associated high-grade dysplasia or invasive carcinoma, but many are benign with indolent biological behaviour.4 Most pancreatic cancers develop from microscopic precursors called pancreatic intraepithelial neoplasia (PanIN). Models of tumour evolution have been proposed whereby normal pancreatic epithelial cells accumulate genetic aberrations leading to various grades of PanIN and finally invasive adenocarcinoma. Although such evidence is not definitive, PanIN and invasive
Keywords Diagnosis; ductal adenocarcinoma; palliative care; pancreas; pancreatic cancer; periampullary cancer; treatment
Introduction Pancreatic cancer leads to an estimated 8.8 deaths per 100,000 population per year in the UK, with the number of new diagnoses per year being the same as the number of deaths from the disease (approximately 7000). Internationally, the 5-year survival is 5e7%; in the UK it is 3% and the majority of patients will survive less than 1e2 years. Only 10e20% cases would be considered resectable at new diagnosis.1 This is related to the fact that over 70% of patients have advanced disease (stage IIIeIV) at initial presentation. Advanced pancreatic cancer has a very poor prognosis with median
Risk factors for pancreatic cancer C C C C C C
Nilanjana Tewari MBChB MRCS MSc is a Research Fellow at the Division of Gastrointestinal Surgery, Nottingham Digestive Diseases Centre NIHR Biomedical Research Unit, Nottingham University Hospitals, Queen’s Medical Centre, Nottingham, UK. Conflict of interest: none.
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Dileep N Lobo DM FRCS FACS is Professor of Gastrointestinal Surgery at the Nottingham Digestive Diseases Centre NIHR Biomedical Research Unit, Nottingham University Hospitals, Queen’s Medical Centre, Nottingham, UK. Conflict of interest: none.
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C
Tobacco smoking Male sex AfricaneAmerican ethnic origin Family history of chronic pancreatitis Non-O blood group Obesity Diabetes mellitus Diets high in fat and meat, low in vegetables and folate Occupational exposure, e.g. chlorinated hydrocarbon solvents and nickel Possible association with Helicobacter pylori infection Possible association with periodontal disease
Box 1
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dependent clotting factors results in a prolonged prothrombin time. Patients with pancreatic cancer may also have diabetes or impaired glucose tolerance.
Types of malignant tumours of the exocrine pancreas in adults Type of tumour
Frequency
Ductal adenocarcinoma Anaplastic carcinoma Others C Mucinous cystadenocarcinoma C Mucinous non-cystic adenocarcinoma C Acinar cell carcinoma C Adenosquamous carcinoma C Small cell carcinoma C Squamous cell carcinoma C Intraductal papillary mucinous neoplasms (IPMN)
80e90% 5% 5e10%
Tumour markers: these are neither tumour-specific nor pancreatic cancer-specific. The glycoprotein carbohydrate antigen 19-9 (CA 19-9) has high sensitivity and specificity and is the most widely used tumour marker in pancreatic cancer. However, the poor predictive value of CA 19-9 serum levels and low prevalence of pancreatic cancer in the general population means that routine serum CA 19-9 level testing has no utility as a screening tool in asymptomatic patients. Even among patients with symptoms suspicious for malignancy, elevated CA 19-9 serum levels are a poor predictor of pancreatic cancer. ADAM9 has been identified recently as one of the genes overexpressed in pancreatic ductal adenocarcinoma. Cytoplasmic ADAM9 overexpression is significantly associated with survival in patients curatively resected for pancreatic ductal adenocarcinoma. Therefore, ADAM9 may be a useful prognostic marker. The SMAD4 (DPC4/MADH4) tumour suppressor gene is genetically inactivated in 55% of pancreatic cancers and those showing loss of SMAD4 protein expression have a poorer prognosis. SMAD4 expression can facilitate the interpretation of diagnostically difficult cytological specimens. However, these tumour markers are not in routine clinical use at present. Because of the high frequency of mutations in pancreatic cancer, K-ras has been investigated as a potential marker for pancreatic cancer. However, based on available evidence, K-ras is not recommended at present for routinely determining prognosis in patients with pancreatic cancer.5 Mucins are large membrane or extracellular proteins that are heavily glycosylated with complex oligosaccharides. The potential value of specific mucins in differentiating pancreatic cancer from benign pancreatic tissue has been studied. Compared with cytology alone, the measurement of mucins yielded higher sensitivity and specificity for mucinous tumours. Other markers such as carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), tissue polypeptide-specific antigen (TPS), macrophage inhibitory cytokine (Mic) and insulin-like growth factor binding protein-1 (IGFBP-1) have been proposed for pancreatic cancer but none are in routine clinical use.6
Table 1
disease are frequently both found in resected tissue and both display similar genetic mutations. There is inactivation of the tumour suppressor gene CDKN2A in over 90% of pancreatic ductal adenocarcinomas and some lesions are associated with inactivation of p53 and BRCA2. One of the earliest and most universal genetic alterations observed in pancreatic cancer is activating mutations in the oncogene K-ras. Up to 85% of pancreatic cancers have inactivation of the signalling molecule SMAD4.
Clinical features The early symptoms of pancreatic cancer are non-specific (epigastric and diffuse abdominal pain, bloating, flatulence, general malaise, diarrhoea, vomiting, constipation) and easily missed. Late symptoms include localized abdominal pain, radiation to the back in cases of retroperitoneal infiltration, weight loss and jaundice. Acute and chronic pancreatitis, acute cholecystitis, upper gastrointestinal haemorrhage, neuropsychiatric disturbances, polyarthritis, painful skin nodules, thrombophlebitis and pyrexia of unknown origin are also possible presentations. Physical signs usually indicate advanced disease. Important signs include an upper abdominal mass, icterus, hepatomegaly, splenomegaly, palpable gallbladder (Courvoisier’s sign), periumbilical nodules (Sister Mary Joseph’s node), ascites, and peripheral oedema. Migratory thrombophlebitis (Trousseau’s sign) is reported in about 10% of pancreatic cancers and may be the only presenting feature. Recent-onset diabetes mellitus is present in 5% of older patients and should serve as a warning sign. Tumours of the body and tail are often asymptomatic, present at an advanced stage, and have a worse prognosis than those in the head of the gland.
Imaging and staging Ultrasound: transabdominal ultrasound is the initial screening investigation in patients with jaundice. It is non-invasive and can provide information about the site and size of pancreatic masses, biliary and pancreatic duct dilation, proximity of the tumour to major vessels, ascites, lymph node involvement, and hepatic metastases. However, it is operator-dependent and may be inaccurate in more than one-third of cases due to obesity, ascites or bowel gas.7 Ultrasound coupled with Doppler gives a reasonably reliable measure of vascular patency and can improve accuracy in assessing vascular invasion. Power Doppler ultrasound is based on the total integrated power of the Doppler spectrum and has proved to be more sensitive than colour Doppler for demonstrating blood flow. Contrast-enhanced ultrasound has been used for the evaluation of pancreatic tumours, using carbon dioxide microbubbles and other echo-enhancing agents and demonstrates good correlation with
Diagnosis and investigations Haematological and biochemical tests: these tests are usually non-specific. Anaemia, hypoalbuminaemia, and obstructive jaundice on liver function tests are usually present. A disproportionate rise in the concentration of transaminases in serum is usually associated with extensive liver metastases. Malabsorption of vitamin K and decreased hepatic production of vitamin K-
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findings on dynamic CT. Pulse inversion harmonic imaging is another technique which can be used to visualize the vascularity of pancreatic masses and is useful for the differential diagnosis of pancreatic tumours.
accurate in the diagnosis of biliary stones and strictures. MRCP is especially useful when a mass is not seen with other imaging modalities but ductal stricture is suspected or known. As a sole technique for diagnosing pancreatic malignancy, MRCP has 84% sensitivity and 94% specificity.8 Diffusion-weighted MRI (DWI) has been studied as an additional technique to help differentiate benign from malignant disease. DWI had reported sensitivity and specificity of 96.2% and 98.6% in the detection of pancreatic carcinoma.
Contrast-enhanced multidetector CT (MDCT): contrastenhanced CT (Figure 1) is the primary imaging modality for the diagnosis and staging of pancreatic carcinoma. Scans are performed in three phases: non-contrast, pancreatic parenchymal and portal vein phases. Metastatic disease to the liver, peritoneum (ascites) and lung, and involvement of the peripancreatic vessels may be detected and usually indicates inoperability. Invasion into adjacent organs (e.g. stomach, colon) and lymph node involvement may also be detected, but these features do not preclude resection. Increased spatial resolution and optimal pancreatic parenchymal and peripancreatic vascular enhancement with MDCT have made a significant impact on accurate staging of pancreatic carcinoma and have improved detection of resectable tumours. MDCT has a negative predictive value of 87% for resectability and 100% for vascular invasion. Clear visualization of the pancreatic parenchyma during various phases of contrast enhancement allows the detection of small pancreatic lesions.
Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC): ERCP (Figure 2) can be used to demonstrate pancreatic and bile-duct anatomy. It is useful in cases of biliary obstruction to confirm the exact site of obstruction and it can be used to guide ductal brushing and lavage, which provides tissue for diagnosis. A combined PTC-ERCP approach may be necessary if access is difficult. ERCP can also be used in patients with jaundice in whom an endoscopic stent is required to relieve obstruction.9 Stenting can provide palliation for patients with jaundice who have unresectable or metastatic disease or are not fit for resection (Figure 3). Self-expandable metal stents (SEMSs) are generally preferred if survival is expected to be 6 months or more and plastic stents are favoured in patients with resectable disease. Previously the use of metallic stents was limited to unresectable cancers because they could not be removed. However, the covered metallic stent, which is coated with a membrane to
MRI: magnetic resonance imaging (MRI) is an accepted modality for imaging of patients with suspected pancreatic cancer, and magnetic resonance cholangiopancreatography (MRCP) is
Figure 1 CT images of pancreatic cancer. (a) Axial image of arterial phase CT scan with soft tissue surrounding the common HA. Aerobilia is in keeping with recent ERCP. (b) Axial image of portovenous phase CT scan demonstrating an 11-mm enlarged portal lymph node and tumour encasing the main portal vein. (c) Arterial phase axial CT image, demonstrating a cystic mass in the neck of the pancreas, with no invasion of the surrounding mesenteric fat. (d) Portal venous phase axial CT image demonstrating a low-density lesion in the neck of the pancreas with loss of the fat plane behind the main portal vein. There is also pancreatic duct dilatation. ERCP, endoscopic retrograde cholangiopancreatography; HA, hepatic artery; PV, portal vein; SMA, superior mesenteric vein.
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been re-evaluated and although it may miss metastatic disease in some, it can effectively reduce surgical morbidity by avoiding a laparotomy in 10e36% of patients. Laparoscopy can be enhanced by intraoperative ultrasound and high-resolution fluorescence to define pancreatic lesions. Currently, laparoscopy is used in some centres in combination with other staging modalities in the work-up of patients with pancreatic cancer. Pancreatic cancers are staged using the tumour/node/metastasis (TNM) classification (Table 2). Accurate staging has a vital role in the management of pancreatic tumours now that nonsurgical palliative options are available. An algorithm for the diagnosis and treatment of pancreatic cancer is shown in Figure 5.
Curative treatment Surgery: resection is the only treatment that offers the potential of cure.13 Discussion with the multidisciplinary team is held at all stages of the diagnostic and treatment process. Ideally, an R0 resection (clearance of all macroscopic and microscopic tumours) should be aimed for: the long-term survival of patients having R1 and R2 resections is significantly less than that of those having R0 resections. A standardized histopathological protocol should be used in assessing resection margins. Preoperative staging should help select patients with resectable disease and patients should be assessed for medical fitness for surgery. Contraindications to resection include: liver, lung and peritoneal metastases distant lymph node metastases major venous thrombosis of the portal vein or superior mesenteric vein extending for several centimetres major encasement (>2 cm in length, >50% circumference) of the portal or superior mesenteric veins encasement of the superior mesenteric, coeliac or hepatic arteries cirrhosis with portal hypertension medical co-morbidities precluding major surgery. Recently, guidelines on tumours deemed ‘borderline-resectable’, for example those with encasement of the gastroduodenal artery or minimal invasion of the superior mesenteric or portal vein, have been published.14 Whether these resections would result in a higher-than-expected rate of margin-positive resections and whether such resections would affect survival is yet to be determined. Resection should be undertaken in high-volume, specialized centres to increase resection rates and reduce hospital morbidity and mortality. Fluid and electrolyte deficits and clotting abnormalities should be corrected before surgery. The operation consists of three stages: assessment of resectability resection reconstruction. Most pancreatic cancers arise in the head of the gland and resection of these tumours can be achieved by the classical KauscheWhipple procedure or a pylorus-preserving pancreaticoduodenectomy (Figure 6). The advantages of pylorus preservation may include better postoperative gastric function and improved postoperative
Figure 2 An endoscopic retrograde cholangiopancreatography image from a patient with pancreatic cancer. A tight stricture is visible in the distal common bile duct (arrow).
prevent tissue ingrowth through the stent mesh, has recently been developed and can be used to treat resectable malignant biliary obstruction. Endoscopic ultrasound: it produces high-resolution images of the pancreas using a high-frequency ultrasound probe at the end of an endoscope placed in the stomach and duodenum in close proximity to the pancreas. It has a higher sensitivity and specificity, particularly in evaluating tumours less than 3 cm in diameter, when compared to CT. Endoscopic ultrasound (EUS) gives the ability to collect samples for cytopathological analysis by using EUS-guided fine-needle aspiration (FNA) and core biopsies, but it is an invasive procedure and there is an associated complication rate of less than 2%. A recent meta-analysis demonstrated that EUS-FNA had a sensitivity of 85% and specificity of 98% as a diagnostic test for solid pancreatic neoplasms.10 However, the results are operator-dependent and it is unlikely to detect distant metastatic disease. Therefore EUS should be considered complementary to other staging modalities. Positron emission tomography (PET): it is a non-invasive imaging tool that provides metabolic (rather than morphological) information on tumours (Figure 4). An analysis of early studies showed that management was changed in around one-third of cases when PET was used for initial staging. Contrast-enhanced PET/CT is superior to PET alone for the preoperative assessment of cancer resectability.11 The prospective diagnostic accuracy and clinical value of PET/CT in suspected pancreatic malignancy is currently being evaluated in the multicentre PETPANC study. Laparoscopy: staging laparoscopy may improve the detection of peritoneal and liver metastases, but high false-negative rates have previously been reported.12 More recently, laparoscopy has
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Figure 3 Percutaneous transhepatic cholangiogram showing a distal common bile duct stricture with deployment of an expandable metal stent.
reduce perioperative mortality.15 The reoperation rate following pancreatectomy is around 10% and the mortality rate for reoperations can be up to 60%.
nutritional status and weight gain compared to Whipple’s procedure. Total pancreatectomy has no advantage in survival compared with Whipple resection and may be justified only if there is diffuse involvement of the whole pancreas without evidence of spread. It may also be justified when pancreatic adenocarcinoma arises on a background of IPMN. There is no evidence that an extended lymphadenectomy and portal vein resection is superior to a standard lymphadenectomy. A distal (left) pancreatectomy with splenectomy and en bloc lymph node dissection (Figure 7) is indicated for cancers in the body and tail of the gland. Surgical mortality of less than 5% has been achieved in most specialized centres, but resection for pancreatic cancer has a morbidity rate of up to 30%. In addition to the medical complications that accompany complex surgery, major surgical complications include pancreatic fistulae, delayed gastric emptying, haemorrhage, wound infection, intra-abdominal sepsis, acute pancreatitis, portal vein thrombosis, chylous ascites and bile leaks. Postoperative octreotide (somatostatin analogue) therapy may help reduce the incidence of pancreatic fistulae but does not
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Prognosis and adjuvant therapy: the most important prognostic markers for survival after pancreatic resection are lymph node status, tumour size, tumour grade and resection margin status. Median survival after pancreatic resection is 11e20 months and 5-year survival ranges from 7 to 25%. A number of clinical trials have demonstrated benefit from adjuvant therapy in pancreatic cancer. The ESPAC-1 trial compared 5-fluorouracil (5-FU) based chemotherapy, chemoradiotherapy, a combination of the two, and no treatment in the adjuvant setting. It demonstrated a survival benefit with chemotherapy but not with chemoradiotherapy.16 Adjuvant chemoradiotherapy has not been demonstrated to provide a survival advantage in subsequent trials and its use is therefore not currently recommended. Interestingly, quality of life improved after adjuvant therapy irrespective of the modality.
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Obstructive jaundice Suspected pancreatic cancer
FBC, LFTs, clotting studies, blood glucose, CA 19-9
Transabdominal ultrasound + CT/MRI
Endoscopic ultrasound ± fine-needle aspiration/Trucut biopsy
Resectable
Unresectable
Surgical exploration
ERCP + biliary stent
Pancreaticoduodenectomy if resectable
Chemotherapy Pancreatic enzyme supplements Novel therapies Pain relief
Figure 4 Coronal image of a positron emission tomography/computed tomography scan demonstrating a bright spot in the uncinate process of the pancreas, in keeping with the primary tumour and two bright spots in the right lobe of the liver in keeping with metastatic deposits.
Figure 5 A suggested algorithm for diagnosis and treatment of cancer of the head of the pancreas.
receiving gemcitabine alone or combination 5-FU/folinic acid, but gemcitabine has a better safety profile. The ESPAC-4 trial is now comparing combination chemotherapy with gemcitabine plus capecitabine with gemcitabine alone.
Primary tumour not assessed Carcinoma in situ Tumour in pancreas only, 2 cm in size Tumour in pancreas only, >2 cm in size Tumour extends beyond pancreas, but does not involve coeliac axis or superior mesenteric artery (SMA) Primary tumour involves either coeliac axis or SMA Regional lymph nodes not assessed No involvement of regional lymph nodes Involvement of regional lymph nodes Distant metastasis cannot be assessed No distant metastasis Distant metastasis
Neoadjuvant chemotherapy and radiotherapy: to date, no randomized control trials comparing neoadjuvant therapy with immediate surgery have been published. However, there are a number of phase I/II studies and retrospective series. The reported median survival in patients undergoing preoperative therapy with chemoradiation, chemotherapy or both, is in the range of 2e3 years from the time of diagnosis. Although tumour downstaging may occur in a number of patients, rendering previously unresectable disease resectable, a significant number of patients experience tumour progression during treatment and a few may not eventually undergo surgery because of decline in performance status.
Table 2
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Consider duodenal stent/ gastric bypass if obstruction of gastric outlet is present
FBC: Full blood count; LFTs: Liver function tests; CA 19-9: carbohydrate antigen 19-9; ERCP: Endoscopic retrograde cholangiopancreatography; PTC: Percutaneous transhepatic cholangiography.
Tumour/node/metastasis 7 staging of pancreatic cancer
T4 Nx N0 N1 Mx M0 M1
PTC/combined PTC–ERCP + biliary stent if ERCP fails
Discussion with the multidisciplinary team is held at all stages of the diagnostic and treatment process.
A survival advantage has been demonstrated for adjuvant 5FU, doxorubicin and mitomycin C in combination, for single agent gemcitabine and for 5-FU and cisplatin, 5-FU/folinic acid and gemcitabine combination chemotherapy. The ESPAC-3 trial demonstrated no significant difference in overall survival, progression-free survival or quality of life between patients
Tx Tis T1 T2 T3
Biliary and gastric bypass if unresectable
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Figure 6
Palliative therapy
Stents and surgery: controlled trials of palliation of obstructive jaundice by stenting or surgical bypass do not favour one method for use in all cases. The median life of a plastic biliary stent is 6e10 weeks and expandable metal stents provide more prolonged palliation of obstructive jaundice. It is reasonable to place a stent in patients with advanced tumours who are unlikely to survive longer than the usual patency time of the stent. Endoscopically placed duodenal stents can also be used safely to treat gastric outlet obstruction, which may be a feature of advanced pancreatic carcinoma.
Chemotherapy: more than 80% of patients with pancreatic cancer have unresectable tumours because of locally advanced disease or metastatic disease. Pancreatic ductal adenocarcinoma cells are resistant to conventional cytotoxic agents. 5-fluorouracil and gemcitabine (the agent of choice) have been used as chemotherapeutic agents in patients with advanced disease, but the survival benefit has been 10e15% at best. Trials of combination chemoradiotherapy versus chemotherapy alone have shown variable results.
Figure 7
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Palliative bypass surgery is associated with a higher procedure-related complication rate than stenting but has the advantage that gastric outlet obstruction can also be addressed. As approximately 17% of patients treated by biliary bypass alone subsequently require a gastroenterostomy and addition of a duodenal bypass does not increase operative risk, duodenal bypass is recommended during palliative surgery.
complications associated with the procedure, including the development of pancreatitis, pancreatic fistulae and damage to surrounding structures.
Neuroendocrine tumours Pancreatic neuroendocrine tumours (PNETs) are uncommon, accounting for less than 5% of all pancreatic neoplasms. Their incidence increases with age, peak age ranges from 50 to 70 years.17 PNETs originate from well-differentiated endocrine cells or multipotent stem cells within the pancreas. They are classified on the basis of their malignant potential and functional (hormone secreting) activity. Insulinoma is the most common PNET type; other common types are gastrinoma, glucagonoma and somato statinoma. Functioning PNETs present with a range of symptoms including Whipple’s triad, carcinoid syndrome and watery diarrhoea/hypokalaemia/achlorhydria syndrome. Non-functioning PNETs are more likely to present with symptoms of local compression such as obstructive jaundice and waist pain and metastatic lesions.17 Surgery is the treatment of choice and the only curative option for PNETs. Unfortunately, a large number of PNETs are not amenable to curative resection. Debulking surgery may be undertaken with the aims of controlling tumour growth and reducing excessive hormone production. Traditional medical treatment of PNET includes streptozocin-based or platinumbased chemotherapy. Radioactive elements, somatostatin analogues, interferon-a, and molecular-targeted therapies such as sunitinib and everolimus are also used.17 The prognosis of PNETs is far superior to that of pancreatic ductal adenocar cinoma.
Pain management: analgesics are recommended according to the World Health Organization analgesic ladder. Pain may be intolerable in advanced disease and endoscopic pancreatic duct decompression, ablation (percutaneous, endoscopic ultrasoundguided, laparoscopic, or open) of the coeliac ganglia using 5% phenol or 50% ethanol and thoracoscopic division of the splanchnic nerves relieves pain. Pancreatic pain may also be palliated by external beam radiotherapy. Palliative and supportive care: there is good evidence that dying patients and their families benefit from the specialist care provided by palliative care units and hospices. Macmillan nurses liaise between health professionals in the hospital and the community; they provide emotional and psychological support for the patient and carer throughout the illness. Other measures: about 90% of patients with pancreatic cancer have significant weight loss at the time of diagnosis and all of them develop progressive cachexia due to neoplastic metabolic derangements. Secondary events such as pancreatic exocrine insufficiency due to pancreatic duct obstruction, fat malabsorption due to biliary obstruction and poor oral caloric intake caused by nausea or gastric outlet obstruction are also responsible for the progressive weight loss. Pancreatic enzyme supplements are useful if patients have features of malabsorption. u-3 fatty acids (fish oil) and thalidomide may help reverse the cachexia associated with advanced pancreatic cancer.
Conclusion Pancreatic cancer remains one of the most lethal malignancies of the gastrointestinal tract. Advances in imaging and the development of molecular and genetic markers are required to facilitate early diagnosis, which is the key to improved survival. Evidence to support the role of adjuvant and neoadjuvant therapies is increasing. However, symptom control and palliative care remain key to the management of this devastating disease. A
New therapies While traditional cytotoxic drugs target specific cellular process, the newer generation of agents target pathways or molecules which drive the growth, speed, survival, or maintenance of tumour cells. The development of new treatment modalities, including specific immunotherapy, is of great importance in the treatment of pancreatic cancer. Currently, the field of cancer immunotherapy using peptide- or cell-based approaches is in an active state of preclinical and clinical investigations. Vaccination with synthetic peptides has been performed in pancreatic cancer, gene therapy has been explored (replacement of tumour suppressor genes, suicide gene therapy, oncolytic-virus therapy, targeting apoptotic pathways and immunomodulatory gene therapy) and anti-angiogenic therapy is also under investigation. These should be used only in randomized clinical trials.
REFERENCES 1 Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet 2003; 378: 607e20. 2 Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an update. Dig Dis 2010; 28: 645e56. 3 Hidalgo M. Pancreatic cancer. N Engl J Med 2010; 362: 1605e17. 4 Shi C, Hruban RH. Intraductal papillary mucinous neoplasm. Hum Pathol 2012; 43: 1e16. 5 Garcea G, Neal CP, Pattenden CJ, Steward WP, Berry DP. Molecular prognostic markers in pancreatic cancer: a systematic review. Eur J Cancer 2005; 41: 2213e36. 6 Duffy MJ, Sturgeon C, Lamerz R, et al. Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report. Ann Oncol 2009; 21: 441e7.
Radiofrequency ablation (RFA): it utilizes high-frequency alternating current to heat surrounding tissues leading to thermal coagulation. RFA for the treatment of pancreatic cancer is in a very early stage of development. A number of case reports and small series suggest encouraging results in patients with locally advanced, unresectable disease. However, there are significant
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7 Takhar AS, Palaniappan P, Dhingsa R, Lobo DN. Recent developments in diagnosis of pancreatic cancer. Br Med J 2004; 329: 668e73. 8 Romagnuolo J, Bardou M, Rahme E, Joseph L, Reinhold C, Barkun AN. Magnetic resonance cholangiopancreatography: a meta-analysis of test performance in suspected biliary disease. Ann Intern Med 2003; 139: 547e57. 9 Dumonceau JM, Vonlaufen A. Pancreatic endoscopic retrograde cholangiopancreatography (ERCP). Endoscopy 2007; 39: 124e30. 10 Hewitt MJ, McPhail MJ, Possamai L, Dhar A, Vlavianos P, Monahan KJ. EUS-guided FNA for diagnosis of solid pancreatic neoplasms: a meta-analysis. Gastrointest Endosc 2012; 75: 319e31. 11 Strobel K, Heinrich S, Bhure U, et al. Contrast-enhanced 18F-FDG PET/CT: 1-stop-shop imaging for assessing the resectability of pancreatic cancer. J Nucl Med 2008; 49: 1408e13.
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12 Stefanidis D, Grove KD, Schwesinger WH, Thomas Jr CR. The current role of staging laparoscopy for adenocarcinoma of the pancreas: a review. Ann Oncol 2006; 17: 189e99. 13 Kim CB, Ahmed S, Hsueh EC. Current surgical management of pancreatic cancer. J Gastrointest Oncol 2011; 2: 126e35. 14 Callery MP, Chang KJ, Fishman EK, Talamonti MS, William Traverso L, Linehan DC. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol 2009; 16: 1727e33. 15 Gurusamy KS, Koti R, Fusai G, Davidson BR. Somatostatin analogues for pancreatic surgery. Cochrane Database Syst Rev 2012; 6: CD008370. 16 Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350: 1200e10. 17 Zhou C, Zhang J, Zheng Y, Zhu Z. Pancreatic neuroendocrine tumors: a comprehensive review. Int J Cancer 2012; 131: 1013e22.
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survival of 2e6 months for stage IV disease and 6e11 months for stage III disease.2 Even among patients who undergo surgery with curative intent, more than 90% develop disease progression within 12e18 months.2
Nilanjana Tewari Dileep N Lobo
Aetiology Although the causes of pancreatic cancer are unknown, several risk factors have been identified.3 A family history of pancreatic cancer is present in 7e10% of patients. First-degree relatives of individuals with familial pancreatic cancer have a ninefold increased risk over the general population. The strongest causative association exists with tobacco smoking. In a large caseecontrol study, ‘ever-smokers’ had a 60% increased risk of pancreatic cancer compared to ‘never-smokers’ and the risk was more pronounced among heavy smokers (20 pack years) compared to mild or moderate smokers. Risk factors are listed in Box 1.
Abstract Pancreatic cancer accounts for 3% of all cancers in the UK; 7000 new cases are diagnosed annually and a similar number die from the disease each year. It has an insidious onset and, as a result, presentation is usually late, with only about 10e20% of patients having disease amenable to surgical resection. Following resection, the median survival is 11e20 months and the 5-year survival is 7e25%. Patients with unresectable locally advanced disease have a median survival of 6e11 months, and those with metastatic disease have a median survival of 2e6 months. Accurate staging has a vital role in the management of pancreatic tumours now that non-surgical palliative options are available. Computed tomography is currently the imaging modality of choice for diagnosis and staging of pancreatic cancer. With recent advances in magnetic resonance imaging and endoscopic ultrasonography, it is now possible to improve the accuracy of preoperative staging, particularly with respect to local invasion and regional node involvement. Resection is the only treatment that offers the potential of cure; ideally, an R0 resection should be aimed for. Chemotherapy renders a survival advantage in the adjuvant setting, even in patients undergoing R1 resections. Palliative chemotherapy can improve survival by 10e15% and other palliative therapies are aimed at relieving jaundice, controlling pain, treating malabsorption and reversing cancer cachexia.
Pathology Pancreatic neoplasms (Table 1) may be epithelial, mesenchymal or secondary (metastatic). Epithelial neoplasms can be divided into solid tumours (ductal adenocarcinoma and acinar cell carcinoma) and cystic neoplasms (serous, mucinous, intraductal papillary and solid pseudopapillary types). Mesenchymal tumours and primary lymphoma are uncommon. Metastases may be found in the pancreas, usually from renal cell carcinoma and malignant melanoma. Intraductal papillary mucinous neoplasms (IPMNs) are mucin-producing neoplasms that arise in the main pancreatic duct or its branches. Some IPMN subtypes have a risk of associated high-grade dysplasia or invasive carcinoma, but many are benign with indolent biological behaviour.4 Most pancreatic cancers develop from microscopic precursors called pancreatic intraepithelial neoplasia (PanIN). Models of tumour evolution have been proposed whereby normal pancreatic epithelial cells accumulate genetic aberrations leading to various grades of PanIN and finally invasive adenocarcinoma. Although such evidence is not definitive, PanIN and invasive
Keywords Diagnosis; ductal adenocarcinoma; palliative care; pancreas; pancreatic cancer; periampullary cancer; treatment
Introduction Pancreatic cancer leads to an estimated 8.8 deaths per 100,000 population per year in the UK, with the number of new diagnoses per year being the same as the number of deaths from the disease (approximately 7000). Internationally, the 5-year survival is 5e7%; in the UK it is 3% and the majority of patients will survive less than 1e2 years. Only 10e20% cases would be considered resectable at new diagnosis.1 This is related to the fact that over 70% of patients have advanced disease (stage IIIeIV) at initial presentation. Advanced pancreatic cancer has a very poor prognosis with median
Risk factors for pancreatic cancer C C C C C C
Nilanjana Tewari MBChB MRCS MSc is a Research Fellow at the Division of Gastrointestinal Surgery, Nottingham Digestive Diseases Centre NIHR Biomedical Research Unit, Nottingham University Hospitals, Queen’s Medical Centre, Nottingham, UK. Conflict of interest: none.
C C C
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Dileep N Lobo DM FRCS FACS is Professor of Gastrointestinal Surgery at the Nottingham Digestive Diseases Centre NIHR Biomedical Research Unit, Nottingham University Hospitals, Queen’s Medical Centre, Nottingham, UK. Conflict of interest: none.
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C
Tobacco smoking Male sex AfricaneAmerican ethnic origin Family history of chronic pancreatitis Non-O blood group Obesity Diabetes mellitus Diets high in fat and meat, low in vegetables and folate Occupational exposure, e.g. chlorinated hydrocarbon solvents and nickel Possible association with Helicobacter pylori infection Possible association with periodontal disease
Box 1
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dependent clotting factors results in a prolonged prothrombin time. Patients with pancreatic cancer may also have diabetes or impaired glucose tolerance.
Types of malignant tumours of the exocrine pancreas in adults Type of tumour
Frequency
Ductal adenocarcinoma Anaplastic carcinoma Others C Mucinous cystadenocarcinoma C Mucinous non-cystic adenocarcinoma C Acinar cell carcinoma C Adenosquamous carcinoma C Small cell carcinoma C Squamous cell carcinoma C Intraductal papillary mucinous neoplasms (IPMN)
80e90% 5% 5e10%
Tumour markers: these are neither tumour-specific nor pancreatic cancer-specific. The glycoprotein carbohydrate antigen 19-9 (CA 19-9) has high sensitivity and specificity and is the most widely used tumour marker in pancreatic cancer. However, the poor predictive value of CA 19-9 serum levels and low prevalence of pancreatic cancer in the general population means that routine serum CA 19-9 level testing has no utility as a screening tool in asymptomatic patients. Even among patients with symptoms suspicious for malignancy, elevated CA 19-9 serum levels are a poor predictor of pancreatic cancer. ADAM9 has been identified recently as one of the genes overexpressed in pancreatic ductal adenocarcinoma. Cytoplasmic ADAM9 overexpression is significantly associated with survival in patients curatively resected for pancreatic ductal adenocarcinoma. Therefore, ADAM9 may be a useful prognostic marker. The SMAD4 (DPC4/MADH4) tumour suppressor gene is genetically inactivated in 55% of pancreatic cancers and those showing loss of SMAD4 protein expression have a poorer prognosis. SMAD4 expression can facilitate the interpretation of diagnostically difficult cytological specimens. However, these tumour markers are not in routine clinical use at present. Because of the high frequency of mutations in pancreatic cancer, K-ras has been investigated as a potential marker for pancreatic cancer. However, based on available evidence, K-ras is not recommended at present for routinely determining prognosis in patients with pancreatic cancer.5 Mucins are large membrane or extracellular proteins that are heavily glycosylated with complex oligosaccharides. The potential value of specific mucins in differentiating pancreatic cancer from benign pancreatic tissue has been studied. Compared with cytology alone, the measurement of mucins yielded higher sensitivity and specificity for mucinous tumours. Other markers such as carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), tissue polypeptide-specific antigen (TPS), macrophage inhibitory cytokine (Mic) and insulin-like growth factor binding protein-1 (IGFBP-1) have been proposed for pancreatic cancer but none are in routine clinical use.6
Table 1
disease are frequently both found in resected tissue and both display similar genetic mutations. There is inactivation of the tumour suppressor gene CDKN2A in over 90% of pancreatic ductal adenocarcinomas and some lesions are associated with inactivation of p53 and BRCA2. One of the earliest and most universal genetic alterations observed in pancreatic cancer is activating mutations in the oncogene K-ras. Up to 85% of pancreatic cancers have inactivation of the signalling molecule SMAD4.
Clinical features The early symptoms of pancreatic cancer are non-specific (epigastric and diffuse abdominal pain, bloating, flatulence, general malaise, diarrhoea, vomiting, constipation) and easily missed. Late symptoms include localized abdominal pain, radiation to the back in cases of retroperitoneal infiltration, weight loss and jaundice. Acute and chronic pancreatitis, acute cholecystitis, upper gastrointestinal haemorrhage, neuropsychiatric disturbances, polyarthritis, painful skin nodules, thrombophlebitis and pyrexia of unknown origin are also possible presentations. Physical signs usually indicate advanced disease. Important signs include an upper abdominal mass, icterus, hepatomegaly, splenomegaly, palpable gallbladder (Courvoisier’s sign), periumbilical nodules (Sister Mary Joseph’s node), ascites, and peripheral oedema. Migratory thrombophlebitis (Trousseau’s sign) is reported in about 10% of pancreatic cancers and may be the only presenting feature. Recent-onset diabetes mellitus is present in 5% of older patients and should serve as a warning sign. Tumours of the body and tail are often asymptomatic, present at an advanced stage, and have a worse prognosis than those in the head of the gland.
Imaging and staging Ultrasound: transabdominal ultrasound is the initial screening investigation in patients with jaundice. It is non-invasive and can provide information about the site and size of pancreatic masses, biliary and pancreatic duct dilation, proximity of the tumour to major vessels, ascites, lymph node involvement, and hepatic metastases. However, it is operator-dependent and may be inaccurate in more than one-third of cases due to obesity, ascites or bowel gas.7 Ultrasound coupled with Doppler gives a reasonably reliable measure of vascular patency and can improve accuracy in assessing vascular invasion. Power Doppler ultrasound is based on the total integrated power of the Doppler spectrum and has proved to be more sensitive than colour Doppler for demonstrating blood flow. Contrast-enhanced ultrasound has been used for the evaluation of pancreatic tumours, using carbon dioxide microbubbles and other echo-enhancing agents and demonstrates good correlation with
Diagnosis and investigations Haematological and biochemical tests: these tests are usually non-specific. Anaemia, hypoalbuminaemia, and obstructive jaundice on liver function tests are usually present. A disproportionate rise in the concentration of transaminases in serum is usually associated with extensive liver metastases. Malabsorption of vitamin K and decreased hepatic production of vitamin K-
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findings on dynamic CT. Pulse inversion harmonic imaging is another technique which can be used to visualize the vascularity of pancreatic masses and is useful for the differential diagnosis of pancreatic tumours.
accurate in the diagnosis of biliary stones and strictures. MRCP is especially useful when a mass is not seen with other imaging modalities but ductal stricture is suspected or known. As a sole technique for diagnosing pancreatic malignancy, MRCP has 84% sensitivity and 94% specificity.8 Diffusion-weighted MRI (DWI) has been studied as an additional technique to help differentiate benign from malignant disease. DWI had reported sensitivity and specificity of 96.2% and 98.6% in the detection of pancreatic carcinoma.
Contrast-enhanced multidetector CT (MDCT): contrastenhanced CT (Figure 1) is the primary imaging modality for the diagnosis and staging of pancreatic carcinoma. Scans are performed in three phases: non-contrast, pancreatic parenchymal and portal vein phases. Metastatic disease to the liver, peritoneum (ascites) and lung, and involvement of the peripancreatic vessels may be detected and usually indicates inoperability. Invasion into adjacent organs (e.g. stomach, colon) and lymph node involvement may also be detected, but these features do not preclude resection. Increased spatial resolution and optimal pancreatic parenchymal and peripancreatic vascular enhancement with MDCT have made a significant impact on accurate staging of pancreatic carcinoma and have improved detection of resectable tumours. MDCT has a negative predictive value of 87% for resectability and 100% for vascular invasion. Clear visualization of the pancreatic parenchyma during various phases of contrast enhancement allows the detection of small pancreatic lesions.
Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC): ERCP (Figure 2) can be used to demonstrate pancreatic and bile-duct anatomy. It is useful in cases of biliary obstruction to confirm the exact site of obstruction and it can be used to guide ductal brushing and lavage, which provides tissue for diagnosis. A combined PTC-ERCP approach may be necessary if access is difficult. ERCP can also be used in patients with jaundice in whom an endoscopic stent is required to relieve obstruction.9 Stenting can provide palliation for patients with jaundice who have unresectable or metastatic disease or are not fit for resection (Figure 3). Self-expandable metal stents (SEMSs) are generally preferred if survival is expected to be 6 months or more and plastic stents are favoured in patients with resectable disease. Previously the use of metallic stents was limited to unresectable cancers because they could not be removed. However, the covered metallic stent, which is coated with a membrane to
MRI: magnetic resonance imaging (MRI) is an accepted modality for imaging of patients with suspected pancreatic cancer, and magnetic resonance cholangiopancreatography (MRCP) is
Figure 1 CT images of pancreatic cancer. (a) Axial image of arterial phase CT scan with soft tissue surrounding the common HA. Aerobilia is in keeping with recent ERCP. (b) Axial image of portovenous phase CT scan demonstrating an 11-mm enlarged portal lymph node and tumour encasing the main portal vein. (c) Arterial phase axial CT image, demonstrating a cystic mass in the neck of the pancreas, with no invasion of the surrounding mesenteric fat. (d) Portal venous phase axial CT image demonstrating a low-density lesion in the neck of the pancreas with loss of the fat plane behind the main portal vein. There is also pancreatic duct dilatation. ERCP, endoscopic retrograde cholangiopancreatography; HA, hepatic artery; PV, portal vein; SMA, superior mesenteric vein.
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been re-evaluated and although it may miss metastatic disease in some, it can effectively reduce surgical morbidity by avoiding a laparotomy in 10e36% of patients. Laparoscopy can be enhanced by intraoperative ultrasound and high-resolution fluorescence to define pancreatic lesions. Currently, laparoscopy is used in some centres in combination with other staging modalities in the work-up of patients with pancreatic cancer. Pancreatic cancers are staged using the tumour/node/metastasis (TNM) classification (Table 2). Accurate staging has a vital role in the management of pancreatic tumours now that nonsurgical palliative options are available. An algorithm for the diagnosis and treatment of pancreatic cancer is shown in Figure 5.
Curative treatment Surgery: resection is the only treatment that offers the potential of cure.13 Discussion with the multidisciplinary team is held at all stages of the diagnostic and treatment process. Ideally, an R0 resection (clearance of all macroscopic and microscopic tumours) should be aimed for: the long-term survival of patients having R1 and R2 resections is significantly less than that of those having R0 resections. A standardized histopathological protocol should be used in assessing resection margins. Preoperative staging should help select patients with resectable disease and patients should be assessed for medical fitness for surgery. Contraindications to resection include: liver, lung and peritoneal metastases distant lymph node metastases major venous thrombosis of the portal vein or superior mesenteric vein extending for several centimetres major encasement (>2 cm in length, >50% circumference) of the portal or superior mesenteric veins encasement of the superior mesenteric, coeliac or hepatic arteries cirrhosis with portal hypertension medical co-morbidities precluding major surgery. Recently, guidelines on tumours deemed ‘borderline-resectable’, for example those with encasement of the gastroduodenal artery or minimal invasion of the superior mesenteric or portal vein, have been published.14 Whether these resections would result in a higher-than-expected rate of margin-positive resections and whether such resections would affect survival is yet to be determined. Resection should be undertaken in high-volume, specialized centres to increase resection rates and reduce hospital morbidity and mortality. Fluid and electrolyte deficits and clotting abnormalities should be corrected before surgery. The operation consists of three stages: assessment of resectability resection reconstruction. Most pancreatic cancers arise in the head of the gland and resection of these tumours can be achieved by the classical KauscheWhipple procedure or a pylorus-preserving pancreaticoduodenectomy (Figure 6). The advantages of pylorus preservation may include better postoperative gastric function and improved postoperative
Figure 2 An endoscopic retrograde cholangiopancreatography image from a patient with pancreatic cancer. A tight stricture is visible in the distal common bile duct (arrow).
prevent tissue ingrowth through the stent mesh, has recently been developed and can be used to treat resectable malignant biliary obstruction. Endoscopic ultrasound: it produces high-resolution images of the pancreas using a high-frequency ultrasound probe at the end of an endoscope placed in the stomach and duodenum in close proximity to the pancreas. It has a higher sensitivity and specificity, particularly in evaluating tumours less than 3 cm in diameter, when compared to CT. Endoscopic ultrasound (EUS) gives the ability to collect samples for cytopathological analysis by using EUS-guided fine-needle aspiration (FNA) and core biopsies, but it is an invasive procedure and there is an associated complication rate of less than 2%. A recent meta-analysis demonstrated that EUS-FNA had a sensitivity of 85% and specificity of 98% as a diagnostic test for solid pancreatic neoplasms.10 However, the results are operator-dependent and it is unlikely to detect distant metastatic disease. Therefore EUS should be considered complementary to other staging modalities. Positron emission tomography (PET): it is a non-invasive imaging tool that provides metabolic (rather than morphological) information on tumours (Figure 4). An analysis of early studies showed that management was changed in around one-third of cases when PET was used for initial staging. Contrast-enhanced PET/CT is superior to PET alone for the preoperative assessment of cancer resectability.11 The prospective diagnostic accuracy and clinical value of PET/CT in suspected pancreatic malignancy is currently being evaluated in the multicentre PETPANC study. Laparoscopy: staging laparoscopy may improve the detection of peritoneal and liver metastases, but high false-negative rates have previously been reported.12 More recently, laparoscopy has
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Figure 3 Percutaneous transhepatic cholangiogram showing a distal common bile duct stricture with deployment of an expandable metal stent.
reduce perioperative mortality.15 The reoperation rate following pancreatectomy is around 10% and the mortality rate for reoperations can be up to 60%.
nutritional status and weight gain compared to Whipple’s procedure. Total pancreatectomy has no advantage in survival compared with Whipple resection and may be justified only if there is diffuse involvement of the whole pancreas without evidence of spread. It may also be justified when pancreatic adenocarcinoma arises on a background of IPMN. There is no evidence that an extended lymphadenectomy and portal vein resection is superior to a standard lymphadenectomy. A distal (left) pancreatectomy with splenectomy and en bloc lymph node dissection (Figure 7) is indicated for cancers in the body and tail of the gland. Surgical mortality of less than 5% has been achieved in most specialized centres, but resection for pancreatic cancer has a morbidity rate of up to 30%. In addition to the medical complications that accompany complex surgery, major surgical complications include pancreatic fistulae, delayed gastric emptying, haemorrhage, wound infection, intra-abdominal sepsis, acute pancreatitis, portal vein thrombosis, chylous ascites and bile leaks. Postoperative octreotide (somatostatin analogue) therapy may help reduce the incidence of pancreatic fistulae but does not
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Prognosis and adjuvant therapy: the most important prognostic markers for survival after pancreatic resection are lymph node status, tumour size, tumour grade and resection margin status. Median survival after pancreatic resection is 11e20 months and 5-year survival ranges from 7 to 25%. A number of clinical trials have demonstrated benefit from adjuvant therapy in pancreatic cancer. The ESPAC-1 trial compared 5-fluorouracil (5-FU) based chemotherapy, chemoradiotherapy, a combination of the two, and no treatment in the adjuvant setting. It demonstrated a survival benefit with chemotherapy but not with chemoradiotherapy.16 Adjuvant chemoradiotherapy has not been demonstrated to provide a survival advantage in subsequent trials and its use is therefore not currently recommended. Interestingly, quality of life improved after adjuvant therapy irrespective of the modality.
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Obstructive jaundice Suspected pancreatic cancer
FBC, LFTs, clotting studies, blood glucose, CA 19-9
Transabdominal ultrasound + CT/MRI
Endoscopic ultrasound ± fine-needle aspiration/Trucut biopsy
Resectable
Unresectable
Surgical exploration
ERCP + biliary stent
Pancreaticoduodenectomy if resectable
Chemotherapy Pancreatic enzyme supplements Novel therapies Pain relief
Figure 4 Coronal image of a positron emission tomography/computed tomography scan demonstrating a bright spot in the uncinate process of the pancreas, in keeping with the primary tumour and two bright spots in the right lobe of the liver in keeping with metastatic deposits.
Figure 5 A suggested algorithm for diagnosis and treatment of cancer of the head of the pancreas.
receiving gemcitabine alone or combination 5-FU/folinic acid, but gemcitabine has a better safety profile. The ESPAC-4 trial is now comparing combination chemotherapy with gemcitabine plus capecitabine with gemcitabine alone.
Primary tumour not assessed Carcinoma in situ Tumour in pancreas only, 2 cm in size Tumour in pancreas only, >2 cm in size Tumour extends beyond pancreas, but does not involve coeliac axis or superior mesenteric artery (SMA) Primary tumour involves either coeliac axis or SMA Regional lymph nodes not assessed No involvement of regional lymph nodes Involvement of regional lymph nodes Distant metastasis cannot be assessed No distant metastasis Distant metastasis
Neoadjuvant chemotherapy and radiotherapy: to date, no randomized control trials comparing neoadjuvant therapy with immediate surgery have been published. However, there are a number of phase I/II studies and retrospective series. The reported median survival in patients undergoing preoperative therapy with chemoradiation, chemotherapy or both, is in the range of 2e3 years from the time of diagnosis. Although tumour downstaging may occur in a number of patients, rendering previously unresectable disease resectable, a significant number of patients experience tumour progression during treatment and a few may not eventually undergo surgery because of decline in performance status.
Table 2
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Consider duodenal stent/ gastric bypass if obstruction of gastric outlet is present
FBC: Full blood count; LFTs: Liver function tests; CA 19-9: carbohydrate antigen 19-9; ERCP: Endoscopic retrograde cholangiopancreatography; PTC: Percutaneous transhepatic cholangiography.
Tumour/node/metastasis 7 staging of pancreatic cancer
T4 Nx N0 N1 Mx M0 M1
PTC/combined PTC–ERCP + biliary stent if ERCP fails
Discussion with the multidisciplinary team is held at all stages of the diagnostic and treatment process.
A survival advantage has been demonstrated for adjuvant 5FU, doxorubicin and mitomycin C in combination, for single agent gemcitabine and for 5-FU and cisplatin, 5-FU/folinic acid and gemcitabine combination chemotherapy. The ESPAC-3 trial demonstrated no significant difference in overall survival, progression-free survival or quality of life between patients
Tx Tis T1 T2 T3
Biliary and gastric bypass if unresectable
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Figure 6
Palliative therapy
Stents and surgery: controlled trials of palliation of obstructive jaundice by stenting or surgical bypass do not favour one method for use in all cases. The median life of a plastic biliary stent is 6e10 weeks and expandable metal stents provide more prolonged palliation of obstructive jaundice. It is reasonable to place a stent in patients with advanced tumours who are unlikely to survive longer than the usual patency time of the stent. Endoscopically placed duodenal stents can also be used safely to treat gastric outlet obstruction, which may be a feature of advanced pancreatic carcinoma.
Chemotherapy: more than 80% of patients with pancreatic cancer have unresectable tumours because of locally advanced disease or metastatic disease. Pancreatic ductal adenocarcinoma cells are resistant to conventional cytotoxic agents. 5-fluorouracil and gemcitabine (the agent of choice) have been used as chemotherapeutic agents in patients with advanced disease, but the survival benefit has been 10e15% at best. Trials of combination chemoradiotherapy versus chemotherapy alone have shown variable results.
Figure 7
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Palliative bypass surgery is associated with a higher procedure-related complication rate than stenting but has the advantage that gastric outlet obstruction can also be addressed. As approximately 17% of patients treated by biliary bypass alone subsequently require a gastroenterostomy and addition of a duodenal bypass does not increase operative risk, duodenal bypass is recommended during palliative surgery.
complications associated with the procedure, including the development of pancreatitis, pancreatic fistulae and damage to surrounding structures.
Neuroendocrine tumours Pancreatic neuroendocrine tumours (PNETs) are uncommon, accounting for less than 5% of all pancreatic neoplasms. Their incidence increases with age, peak age ranges from 50 to 70 years.17 PNETs originate from well-differentiated endocrine cells or multipotent stem cells within the pancreas. They are classified on the basis of their malignant potential and functional (hormone secreting) activity. Insulinoma is the most common PNET type; other common types are gastrinoma, glucagonoma and somato statinoma. Functioning PNETs present with a range of symptoms including Whipple’s triad, carcinoid syndrome and watery diarrhoea/hypokalaemia/achlorhydria syndrome. Non-functioning PNETs are more likely to present with symptoms of local compression such as obstructive jaundice and waist pain and metastatic lesions.17 Surgery is the treatment of choice and the only curative option for PNETs. Unfortunately, a large number of PNETs are not amenable to curative resection. Debulking surgery may be undertaken with the aims of controlling tumour growth and reducing excessive hormone production. Traditional medical treatment of PNET includes streptozocin-based or platinumbased chemotherapy. Radioactive elements, somatostatin analogues, interferon-a, and molecular-targeted therapies such as sunitinib and everolimus are also used.17 The prognosis of PNETs is far superior to that of pancreatic ductal adenocar cinoma.
Pain management: analgesics are recommended according to the World Health Organization analgesic ladder. Pain may be intolerable in advanced disease and endoscopic pancreatic duct decompression, ablation (percutaneous, endoscopic ultrasoundguided, laparoscopic, or open) of the coeliac ganglia using 5% phenol or 50% ethanol and thoracoscopic division of the splanchnic nerves relieves pain. Pancreatic pain may also be palliated by external beam radiotherapy. Palliative and supportive care: there is good evidence that dying patients and their families benefit from the specialist care provided by palliative care units and hospices. Macmillan nurses liaise between health professionals in the hospital and the community; they provide emotional and psychological support for the patient and carer throughout the illness. Other measures: about 90% of patients with pancreatic cancer have significant weight loss at the time of diagnosis and all of them develop progressive cachexia due to neoplastic metabolic derangements. Secondary events such as pancreatic exocrine insufficiency due to pancreatic duct obstruction, fat malabsorption due to biliary obstruction and poor oral caloric intake caused by nausea or gastric outlet obstruction are also responsible for the progressive weight loss. Pancreatic enzyme supplements are useful if patients have features of malabsorption. u-3 fatty acids (fish oil) and thalidomide may help reverse the cachexia associated with advanced pancreatic cancer.
Conclusion Pancreatic cancer remains one of the most lethal malignancies of the gastrointestinal tract. Advances in imaging and the development of molecular and genetic markers are required to facilitate early diagnosis, which is the key to improved survival. Evidence to support the role of adjuvant and neoadjuvant therapies is increasing. However, symptom control and palliative care remain key to the management of this devastating disease. A
New therapies While traditional cytotoxic drugs target specific cellular process, the newer generation of agents target pathways or molecules which drive the growth, speed, survival, or maintenance of tumour cells. The development of new treatment modalities, including specific immunotherapy, is of great importance in the treatment of pancreatic cancer. Currently, the field of cancer immunotherapy using peptide- or cell-based approaches is in an active state of preclinical and clinical investigations. Vaccination with synthetic peptides has been performed in pancreatic cancer, gene therapy has been explored (replacement of tumour suppressor genes, suicide gene therapy, oncolytic-virus therapy, targeting apoptotic pathways and immunomodulatory gene therapy) and anti-angiogenic therapy is also under investigation. These should be used only in randomized clinical trials.
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Radiofrequency ablation (RFA): it utilizes high-frequency alternating current to heat surrounding tissues leading to thermal coagulation. RFA for the treatment of pancreatic cancer is in a very early stage of development. A number of case reports and small series suggest encouraging results in patients with locally advanced, unresectable disease. However, there are significant
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7 Takhar AS, Palaniappan P, Dhingsa R, Lobo DN. Recent developments in diagnosis of pancreatic cancer. Br Med J 2004; 329: 668e73. 8 Romagnuolo J, Bardou M, Rahme E, Joseph L, Reinhold C, Barkun AN. Magnetic resonance cholangiopancreatography: a meta-analysis of test performance in suspected biliary disease. Ann Intern Med 2003; 139: 547e57. 9 Dumonceau JM, Vonlaufen A. Pancreatic endoscopic retrograde cholangiopancreatography (ERCP). Endoscopy 2007; 39: 124e30. 10 Hewitt MJ, McPhail MJ, Possamai L, Dhar A, Vlavianos P, Monahan KJ. EUS-guided FNA for diagnosis of solid pancreatic neoplasms: a meta-analysis. Gastrointest Endosc 2012; 75: 319e31. 11 Strobel K, Heinrich S, Bhure U, et al. Contrast-enhanced 18F-FDG PET/CT: 1-stop-shop imaging for assessing the resectability of pancreatic cancer. J Nucl Med 2008; 49: 1408e13.
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12 Stefanidis D, Grove KD, Schwesinger WH, Thomas Jr CR. The current role of staging laparoscopy for adenocarcinoma of the pancreas: a review. Ann Oncol 2006; 17: 189e99. 13 Kim CB, Ahmed S, Hsueh EC. Current surgical management of pancreatic cancer. J Gastrointest Oncol 2011; 2: 126e35. 14 Callery MP, Chang KJ, Fishman EK, Talamonti MS, William Traverso L, Linehan DC. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol 2009; 16: 1727e33. 15 Gurusamy KS, Koti R, Fusai G, Davidson BR. Somatostatin analogues for pancreatic surgery. Cochrane Database Syst Rev 2012; 6: CD008370. 16 Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350: 1200e10. 17 Zhou C, Zhang J, Zheng Y, Zhu Z. Pancreatic neuroendocrine tumors: a comprehensive review. Int J Cancer 2012; 131: 1013e22.
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