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Introduction Pancreatic cancer is the second most common gastrointestinal cancer and the fourth leading cause of cancer

death in united states. Pancreatic cancer will be diagnosed in approximately 43,140 patients and account for 36,800 deaths in 2010.(1) Infiltrating ductal carcinomas account for the vast majority of cases and arise most frequently in the head of pancreas. Patients with pancreatic cancer have a poor prognosis. At the time of diagnosis 85-90% of patients have inoperable or metastatic disease, which is reflected in the 5-year survival rate of only 5% for all stage combined.(2) An improved 5-year survival of up to 20% may be achieved when the tumor is detected at an early stage and when complete surgical resection is accomplished.

Pancreatic Cancer A. Epidemiology The lifetime risk of being diagnosed with pancreatic cancer in United States is 1.27%. In the United States, it was estimated that 43,140 people would be diagnosed with pancreatic cancer in 2010.(1) Consistent with its associated poor prognosis, 36,800 were expected to die from this disease in the same year, making it the fourth leading cause of cancer-related death. The median age of diagnosis of pancreatic canceris 72 years, with the peak incidence of diagnosis between the ages of 65 and 84. It is rarely diagnosed in those <50 years of age. (2)The incidence is slightly higher in men than women, and it is also higher in African Americens then in whites. B. Etiology and risk factors The cause of pancreatic cancer (adenocarcinoma) remains unknown, but several factors show a modest association with its occurrence 1. Smoking Of the several risk factor that are known to be linked with pancreatic cancer, smoking has been the most extensively studied. Research on smoking and lung cancer published in 1960s led to an early publication on smoking as a risk factor for pancreatic cancer.(3) Of several of these research found that : Smokers have a twofold increased risk of pancreatic cancer compared to nonsmokers. About 25%-30% of all pancreatic caner is caused by this single factor. Cigarettes are more harmful than the other type of smoking exposure, but other factor delivery agents such as smokeless tobacco can cause pancreatic cancer. The risk of smoking increases with increasing duration and amount of cigarette smoking. The excess risk levels off to 10 to 15 years after cessation of smoking. 2. Drinking Heavy consumption of alcohol is the most common known risk factor for 2

chronic pancreatitis, so it is reasonable ro assum that alcohol might be a risk factor for pancreatic cancer.(3) However, numerous studies od moderate drinkers have failed to find any link between consuming alcohol and pancreatic cancer. The best explanation is that the pancreas must be less sensitive to the toxic effect of alcohol than, the liver, where an occasional moderate drinker develops alcohol-induced cirrhosis eventually leading to liver cancer. Because heavy drinkers are nearly always heavy smokers, it is likely that any putative association between heavy drinking and pancreatic cancer can be explained by tobacco exposure, rather than alcohol. 3. Diet A high intake of fat, meat, or both, is associated with increased risk, whereas the intake of fresh fruits and vegetables appears to have protective effect. As for many other type of cancer, the link between diet and pancreatic cancer remain elusive. However, rther than looking for a link between any individual dietary component and cancer, obesity resulting from either excessive caloric intake or reduced caloric expenditure may be the key factor. In a prospectice study of 900,000 persons conducted by the Ametican Canccer Society, obesity was strongly related to pancreatic cancer for both males and females.(3) 4. Diabetes Diabetes maybe an early manifestation of pancreatic cancer or a predisposing factor. It is found in 13% of patients with pancreatic cancer and in only 2% of controls.(3) Diabetes mellitus that occurs in patients with pancreatic cancer maybe characterized by marked insulin resistence, which moderates after tumor resection. Islet amyloid polypeptide, a hormonal factor secreted by pancreatic cells, reduce insulin sensitivity in vivo ang glycogen synthesis in vitro and may be present in elevated concentrations in patients with pancreatic cancer who have diabetes. 5. Pancreatitis The cumulative 20-year incidence of pancreatic cancer in patient with chronic pancreatitis is only about 5%.(3) In most studies, alcohol has not been suspected risk factor of pancreatic cancer, but heavy drinking is common cause for chronic pancreatitis. Thus, it is possible that alcohol, 3

especial when consumed in large amounts, can lead first to chronic pancreatitis, and then in small fraction of patients, to pancreatic cancer. The mechanism might be related to production of acetaldehyde, a degradation product of alcohol metabolism and a known carcinogen. Smoking is an important cofactor; most heavy drinkers are smokers, and smoking is a risk factor for both pancreatitis and pancreatic cancer. Althought alcoholic pancreatitis is the most common cause pancreatitis. Hereditary pancreatitis is a rare genetic cause of chronic pancreatitis with an onset in childhood or early adulthood. The risk pancreatic cancer is 40 to 50 times greater than in the background population. Similarly, tropical pancreatitis, which common in southern India and parts of Africa, also has a high risk of pancreatic cancer.(3) 6. Occupation Occupational exposure to 2-napthylamine, benzidine, and gasoline derivatives is associated with a fivefold increased risk for pancreatic cancer. Prolonged exposure to Dichloro-Diphenyl-Trichloroethane (DDT) and two DDT derivatives (ethylan and DichloroDiphenylDichloroethane/DDD) is associated with a fourfold to sevenfold increased risk for pancreatic cancer.(4) 7. Infectious Agents Infection agents are known to cause cancers of the liver, stomach, and cervix, three of the most common tumors throught the world. A viral or bacterial agent might cause pancreatic cancer either directly or indirectly by first causing pancreatits.(3) 8. Inherited disease and pancreatic cancer Inherited germline disorders are suspected to cause no more than 5% to 10% of all pancreatic cancer, although the frequency was considerably lower in one carefully studied European population. Breast Cancer 2 susceptibility protein (BRCA2), one of two inherited gene known to cause breast cancer, has also been associated with pancreatic cancer. In a study of European family with at least two first-degree member afflicted with pancreatic cancer, BRCA2 mutations were the most common detected germline mutations, afflicting 19% of the families. Many of the 4

families with this mutation had early onset pancreatic cancer. Then some study found that in patient with sporadic rather than familial pancreatic cancer, heavy smokers with deletion of the carcinogen metabolizing Glutathione S-transferase theta-1 (GSTT-1) polymorphic gene have an increased risk of pancreatic cancer.(3) 9. Partial gastrectomy Partial gastrectomy appears to correlate with a 2 to 5 times higher than expected incidence of pancreatic cancer 15 to 20 years later.(4) The increased formation of N-nitroso compounds by bacteria that produce nitrate reductase ang proliferate in hypoacidic stomach has been proposed to account for the increased occurrence of gastric and pancreatic cancer after partial gastrectomy. 10. Cholecystokinin Cholecystokinin is the primary hormone that causes growth of exocrine pancreatic cells; other include epidermal growth factor and insulinlike growth factor. Pancreatic cancer has been induced experimentally by long-term duodenogastric reflux, which is associated with increased cholecystokinin levels.(4) Some clinical evidence suggest that cholecystectomy, which also increases the circulating cholecystokinin, may increase the risk for pancreatic cancer 11. Tonsillectomy Tonsillectomy has been shown to be a protective factor against the development of pancreatic cancer, an observation that has been described for other cancers as well.(4) 12. Idiopathic deep-vein thrombosis Idiopathic deep-vein thrombosis is statistically correlated with subsequent development of mucinous carcinomas (including pancreatic cancer), especially among patients in whom venous thrombosis recurs during follow up.(4) C. Pathology Primary malignant tumors of the pancreas involve either the exocrine parenchyma or the endocrine islet cellss. Nonepithelial tumors (sarcomas and lymphomas) are rare. Ductal adenocarcinoma makes up 75-90% of malignant pancraetic neoplasm; 57% occur in the head of the pancreas, 9% in the body, 5

8% in the tail, 6% in ovelapping sites, and 20% in unknown anatomic subsutes. Uncommon but reasonably distinctive variants of pancraetic cancer include adenosquamous, oncocytic, clear cell, giany cell, signet ring, mucinous, and anaplastic carcinoma. Anaplastic carcinoma often involve the body and tail rather than the head of pancreas. Reported cases of pure epidermoid carcinoma ( a variant of adenosquamous carcinoma) probablu are associated with hypercalcemia. Cystadenocarcinomas have an indolent course and may remain localized from many years. Ampullary cancer (which carries as significantly better prognosis), duodenal cancer, and distal bile duct cancer may be difficult to distinguish from pancreatic adenocarcinoma.(4) Autopsy studies show that for every primary tumor of the pancreas, four metastatic tumors are found. The most common tumors or origin are breast, lung, cutaneous melanoma, and non-Hodgkin lymphoma. Mutant c-K-ras genes have been found in approximately 95% of all specimens of human pancreatic cercinoma and their metastase. D. Clinical features Common presenting features of pancreatic cancer include pain (present in >80% of patients with locally adcanced or metastatic disease), obstructive jaundice, weight loss, and anorexia.(2) Patients with jaundice may also have pruritus, pale stools, and dark urine; they often have tumors in the pancreatic head and tend to be diagnosed earlier and with earlier stage disease. Other symtopms tend to be more insidious, that in the absence of jaundice, the interval between onset and diagnosis can be prolonged. Pain, for example, is often more of a problem in patients with lesions in the body or tail of the pancreas where the primary tumor is more likely to become quite large or invade adjacent structures (such as the splachnic nerves) before becoming manifest; these patient frequently have in operable disease. When present, pain is often felt as a dullache in the upper abdomen and may radiate to the back, and characteristically may improve upon leaning forward. It may initially be intermittent and may worsen with meals. These patients may suffer from marked weight loss, which may result from a combination of anorexia, early satiety, malabsorption, or diarrhea/steatorrhea. Other less common presenting features include the diagnosis of glucose intolerance (particularly within 2 years of cancer diagnosis), previous pancreatitis, migratory superficial thrombophlebitis (Trousseaus syndrome), 6

gastrointestinal hemorrhage from varices, and splenomegaly. Patient with early disease may not have any significant abnormalities detectable on physical examination. Jaundice may be a presenting feature in some; in these patients a palpable, nontender gallbladder (Courvoisiers sign) may be palpated under the right costal margin. Patients with more advanced disease may have an abdominal mass, hepatomegaly, splenomegaly, or ascites. The left supraclavicular lymph node (Virchows node) may be involved with tumor, or widespread peritoneal disease may be palpable on rectal examination in the pouch of Douglas.(2) E. Diagnosis Imaging studies Ultrasound is often used as an initial investigation for patients with jaundice, or with less specific symptoms such as upper abdominal discomfort, and is able to assess the biliary tract, gallbladder, pancreas, and liver. Computed tomography (CT) scanning is preferable to ultrasound even though it is more costly, because it is less operator-dependent, more reproducible, and less susceptible to interference from intestinal gas. The sensitivity and specificity of CT is markedly improved by the use of pancreatic protocol scanning on modern multislice scaners. CT may show a pancreatic mass, dilatation of the biliary system or pancreatic duct, or distal spread to the liver, regional lymph nodes, or peritoneum (and/or associated ascites). When helical CT is combined with the use of intervenous contrast, it may also help determine resectability by providing information on the involvement of important vascular structures such as the celiac axis, superior mesenteric, or portal vessels. Endoscopic retrograde cholangiopancreatigraphy (ERCP) is also widely used in the diagnosis of pancreatic cancer, particularly when CT and ultrasound fail to show a mass lesion, and it may reveal either stricture or obstruction in either the pancreatic or common bile duct. ERCP can alsobe used to obtain brushing of strictur for cytology or for placing stents in order to relieve obstructive jaundice. Endoscopic UltraSound (EUS) may be useful in the diagnosis of small lesions (<2-3 cm in diameter) and, in some cases, for local staging as well as evaluating invasion of major vascilar structures. EUS-guided fine-needle aspiration may also be used to obtain cytology for confirming the diagnosis, particularly in patients with potentially operable disease. Although magnetic resonance 7

imaging (MRI) does not offer any advantages over CT in the routine evaluation of patients with possible pancreatic cancer, magnetic resonance cholangiopancreatography (MRCP) may be better than CT for finding the anatomy of the pancreatic duct and biliary tree, being able to image the ducts both above and below a stricture. The sensitivity of MRCP is comparable to ERCP but does not require contrast adminitration to the ductal system, so there is less associated morbidity. MRCP may be useful when cannulation of pancreatic duct by ERCP has been unsuccessful or may be difficult, such as when normal anatomy is changed by surgery. Positron emission tomography with 18F-flouro-2deoxyglucose (FDG-PET) may be useful for excluding occult distal metastasis in patients with localized disease who are being worked up for surgery or in patients with unresectable localized diseae being considerd for chemoradiotherapy.(2)

Tissues Diagnosis and Cytology Preoperative confirmation of malignancy is not always necessary in patients 8

with radiological appearances consistent with operable pancreatic cancer. However, EUS-guided fine-needle aspiration is the technique of choice when there is any doubt, and also for use in patients who require neoadjuvant treatment. It has an accuracy of approximately 90% and has a smaller risk of intraperitoneal dissemination compared with the percutaneous route. percutaneous biopsy of the pancreatic primary or liver metastasis only acceptable in patients with inoperable or metastatic disease. ERCP is a useful method to obtaining ductal brushing, but the diagnostic value of pancreatic juice sampling is only in the order of 25-30%.(1) Serum Markers Tumor-associated carbohydrate antigen 19-9 (CA19-9) is elevated in approximately 70-80% of patients with pancreatic carcinoma, but is not recommended as a routine diagnostic or screening test as its sensitivity and specificity are in adequate for accurate diagnosis. Preoperative CA 19-9 levels correlate with tumor stage, and postresection CA 19-9 levels has prognostic value. It is an indicator of asymptomatic recurrence in the patients with completely resected tumors and is used as biomarker of respond in patients with advanced disease undergoing chemotherapy. A number of studies have established a high pretreatment CA 19-9 level as an independent prognostic factor.(1) F. Staging The American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging of pancreatic cancer takes into account the location and the size of the tumor, the involvement of the lymph node, and distant metastasis. This information is the combined to assign a stage (fig. below). From a practical standpoint, patients are grouped according to whether the cancer is resectable, locally advanced (unresectable, but without distant spread), or metastatic.(1)

G.

Treatment Symptoms and the associated impaired performance status are significant issues in the management of patients with pancreatic cancer because they can have a marked negative impact on the ability to safely deliver chemotherapy od perform curative surgery. For example, patients with malabsorption secondary to pamcreatic insufficiency may be treated with pancreatic enzyme supplementation. Indeed effective symptom management is as important as therapeutic goal as survivak prolongation.

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Advanced Pancreatic Cancer These patients have metastatic or locally advanced inoperable disease and are the majority with newly diagnosed disease. Debulking surgery or partial resections have no role because these procedures are associated with the same risk as curative resection but unlikely to improve survival. Many patients may, However, benefit from endoscopic biliary or duodenal stenting, and some patients from nerve plexus blocks or ablation. Less frequently, intestinal bypass surgery is required. The deoxycytidine analogue gemcitabine, given as a single agent (gemcitabine, 1000 mg/m2, weekly for 7 weeks followed 1 week rest, then 3 weeks every 4 weeks thereafter), has been the preferred treatment for these patients because it was shown to yeild clinical benefit ( a composite parameter for evaluating symptomatic benefit od treatment used in some trials od this disease) and improved survival compared to 5-flouriuracil. The median survival observed with single-agent gamcitabine in randomized trials is 6 month, with a 12-moth survival of 18%. Futhermore, two randomized trials have shown improved survival from the addition of either oral flouropyrimidine, capecitabine (gemcitabine 1000 mg/m2, day 1, 8, and 15 plus capecitabine, 1660 mg/m2,day 1-21, repeated every 28 days), or the tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), erlotinib (standard gencitabine plus erlotinib, 100mg daily). The survival improvement observed with both these cpmbinations appears similar, and the addition of capecitabine to gemcitabine in this regimen does not appear to increase the toxicity above single-agent gemcitabine.(1) Either combination should, therefore, be considered as options for treating these patients. Second-line treatment options in pancreatic cancer are limited, although there may be an emerging role for oxaliplatin-based chemotherapy; fit patients who have failed first-line treatment should be offered entry into clinical trials. Ongoing clinical trials are evaluating the potential benefit of incorporating other novel targeted agents into the treatment of pancreatic cancer, usually together with gemcitabine. In patients with locally advanced unresectable disease, external beam chemotherapy may be useful, either as initial treatment or as consolidation after induction therapy.

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Operable Disease Complete surgical resection in patients with localized disease (stage I or II disease),with distal metastase exluded by prior CT scan of the abdomen and pelvis, and CT of the chest or chest x-ray is potentially curative. However, such surgery is only possible in 10-15% of patients, many of whom will suffer from recurrences of their disease. Indeed, the 5-year survival reported in randomized trials with surgery alone is 10%. Although modern series have improved on these results. Outcomes tend to be more favorable in patients with lymph nodenegative disease, smaller tumors (<3 cm), negative resection margins, and welldifferentiated tumors. Despite a dismal long-term outcome, these patients still have a better survival with surgery than with other palliative measures.(1) Surgery is usually preceded by lapatoscopy in order to exlude peritoneal metastasis not seen on other staging investigation. Pancreaticodudenectomy, also known as whipple procedure, is standard operation for cancer of the head or incinate process of the pancreas. The procedure involves resection of the pancreatic head, duodenum, first 15 cm of the jejunum, common bile duct, and gallbladder, and a partial gastrectomy, with teh pancreatic and biliary anastomosis placed 45-60 cm proximal to gastrojejunostomy. Perioperatif mortality rates have fallen to <5%, reflecting graeter experience with the syrgery and perioperative management of these patients. However, this type of surgery is highly specialized and should ideally only occur in dedicated centers with a high volume of these cases and specialized surgeons. Adjuvant treatment fro patients with curatively resected pancreatic cancer is controversial, with divergent treatment approaches preferred in the United States and in Europe, based on the result of different randomized trials conducted on both sides of the Atlantic. In United States, flouropyrimidinebased postoperative chemotherapy followed by adjuvant chemotherapy is preffered. In Europe, because a large rabdomized trial (the European Study Group for Pancreatic Cancer 1, or ESPAC1 trial) showed survival benefit for adjuvant chemotherapy with 5-flourouracil (5FU), this approach more common practice.

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H.

Prognosis Carcinoma of the pancreas, especially in the body or tail, has a poor prognosis. Reported 5-year survival rates range from 2% to 5%. Lesions of ampula hace better prognosis, with reported 5-year survival rates of 20% - 40% after resection; jaundice and lymph node involvement are adverse prognostic factors. (5) In carefully selected patients, resection of cancer of the pancreatic head is feasible and results in reasonable survival. In persons with a family history of pancreatic cancer, screening with helical CT and endoscopic ultrasonography should be considerd beginning 10 years before the age at which pancreatic cancer was diagnosed in a family member. For those patients whose disease progresses despite treatment, meticulous efforts at palliative care are essential.

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Conclusion From the description above we can conclude that pancraetic cancer is the second most common gastrointestinal cancer and the fourth leading cause of cancer death in United States. there are many risk factors of pancreatic cancer that is smoking, drinking, diabetes, pancreatitis, etc. The most common risk factor is smoking. Then, the symptoms of pancreatic cancer is not spesific like pain, jaundice, weight lose and anorexia. For diagnose, we have to use imaging like USG, CT scan, MRCP, ERCP, cytology or tumor markers. After that, the treatment of pancreatic cancer consist of surgery and chemotherapy. The last, prognosis of pancreatic cancer has poor, reported 5-year survival rates range from 2% to 5%.

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References 1. Harrisson's Contributors. Pancreas Cancer. In Harrison's Principle of Internal Medicine. 18th ed. Edt: Longo, Fauci, Kasper, Hauser, Jameson, Loscalzo. McGrawHill: United States; 2012. 2. Chua YJ, Cunningham. Pancreatic Cancer. In Harrison's Hematology and Oncology. Edt: Fauci AS, Kasper DL, Longo DL, Braunwald E, Hauser SL, Jameson JL, et al. McGrawHill: Unites States; 2010. p. 499-503. 3. Lowenfels AB, Maisonneuve P. Pancreas Cancer : Epidemiology and Risk Factor. In Principle an Practice of Gatrointestinal Oncology. Second edition. Edt: Kelsen DP, Daly JM, Kern SE, Levin B, Tepper JE, Cutsem EV. Wolters Kluwer: USA; 2008. 319-27. 4. Albert SR, Goldberg RM. Pancreatic Cancer.In Manual Of Clinical Oncology. 6th ed. Edt: Casciato DA, Territo MC. Wolters Kluwer: Phladelphia; 2009. 21722. 5. Freidman LS. Carcinoma of The Pancreas & The Periampullary Area. In Current Medical Diagnosis & Treatment. 48th ed. Edt: McPhee SJ, Papadakis MA. McGrawHill: 2009. p.1439-41.

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