Pancreatic Cancer

What is Pancreatic Cancer?

Pancreatic cancer is a malignant neoplasm of the pancreas. Each year in the United States, about 42,470 individuals are diagnosed with this condition and 35,240 die from the disease. The prognosis is relatively poor but has improved; the three-year survival rate is now about thirty percent (according to the Washington University School of Medicine), but less than 5 percent of those diagnosed are still alive five years after diagnosis. Complete remission is still rather rare.

About 95% of exocrine pancreatic cancers are adenocarcinomas. The remaining 5% include adenosquamous carcinomas, signet ring cell carcinomas, hepatoid carcinomas, colloid carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with osteoclast-like giant cells. Exocrine pancreatic cancers are far more common than endocrine pancreatic cancers (also known as islet cell carcinomas), which make up about 1% of total cases.

The pancreas is an organ located behind the stomach. It is shaped a little bit like a fish with a wide head, a tapering body, and a narrow, pointed tail. It is about 6 inches long but less than 2 inches wide and extends horizontally across the abdomen. The head of the pancreas is on the right side of the abdomen, behind the place where the stomach meets the duodenum (the first part of the small intestine). The body of the pancreas is located behind the stomach and the tail of the pancreas is on the left side of the abdomen next to the spleen.

The pancreas contains 2 different types of glands: exocrine and endocrine.

The exocrine glands make pancreatic "juice," which is released into the intestines. This juice contains enzymes that help you digest fats, proteins, and carbohydrates in the food you eat. Without these, some of the food you eat would just pass through your intestines without being absorbed. The enzymes are released into tiny tubes called ducts. These tiny ducts merge together to form larger ducts that empty into the pancreatic duct. The pancreatic duct merges with the common bile duct (the duct that carries bile from the liver), and empties the pancreatic juice into the duodenum (the first part of the small intestine). More than 95% of the cells in the pancreas are exocrine glands and ducts.

A small percentage of the cells in the pancreas are endocrine cells. These cells are arranged in small clusters called islets (or islets of Langerhans). The islets release important hormones, such as insulin and glucagon, directly into the blood. Insulin reduces the amount of sugar in the blood, while glucagon increases it. Diabetes results from a defect in insulin production.

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Pancreatic Cancer Causes

Risk factors for pancreatic cancer include:

  • Age (particularly over 60)
  • Smoking. Cigarette smoking has a risk ratio of 1.74 with regard to pancreatic cancer; a decade of non-smoking after heavy smoking is associated with a risk ratio of 1.2.
  • Diets low in vegetables and fruits
  • Diets high in red meat
  • Obesity
  • Diabetes mellitus is both risk factor for pancreatic cancer, and, as noted earlier, new onset diabetes can be an early sign of the disease.
  • Chronic pancreatitis has been linked, but is not known to be causal. The risk of pancreatic cancer in individuals with familial pancreatitis is particularly high.
  • ''Helicobacter pylori'' infection
  • Family history, 5–10% of pancreatic cancer patients have a family history of pancreatic cancer. The genes responsible for most of this clustering in families have yet to be identified. Pancreatic cancer has been associated with the following syndromes; autosomal recessive ataxia-telangiectasia and autosomal dominantly inherited mutations in the BRCA2 gene and PALB2 gene, Peutz-Jeghers syndrome due to mutations in the STK11 tumor suppressor gene, hereditary non-polyposis colon cancer (Lynch syndrome), familial adenomatous polyposis, and the familial atypical multiple mole melanoma-pancreatic cancer syndrome (FAMMM-PC) due to mutations in the ''CDKN2A'' tumor suppressor gene.
  • Gingivitis or periodontal disease

Alcohol

It is controversial whether alcohol consumption is a risk factor for pancreatic cancer. Drinking alcohol excessively is a major cause of chronic pancreatitis, which in turn predisposes to pancreatic cancer, but "chronic pancreatitis that is due to alcohol doesn't increase risk as

much as other types of chronic pancreatitis." Overall, the association is consistently weak and the majority of studies have found no association. with risk increasing with increasing amount of alcohol intake. Risk is greatest in heavy drinkers mostly on the order of four or more drinks per day. But there appears to be no increased risk for people consuming up to 30g of alcohol a day, so most of the U.S. consumes alcohol at a level that "is probably not a risk factor for pancreatic cancer." Even if a link exists, it "could be due to the contents of some alcoholic beverages" other than the alcohol itself. One Dutch study even found that drinkers of white wine had lower risk.

A pooled analysis concluded, "Our findings are consistent with a modest increase in risk of pancreatic cancer with consumption of 30 or more grams of alcohol per day."

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Pancreatic Cancer Diagnosis

Pancreatic cancer is sometimes called a "silent killer" because early pancreatic cancer often does not cause symptoms,

  • Clinical depression has been reported in association with pancreatic cancer, sometimes presenting before the cancer is diagnosed. However, the mechanism for this association is not known.

Most patients with pancreatic cancer experience pain, weight loss, or jaundice.

Pain is present in 80 to 85 percent of patients with locally advanced or advanced metastic disease. The pain is usually felt in the upper abdomen as a dull ache that radiates straight through to the back. It may be intermittent and made worse by eating. Weight loss can be profound; it can be associated with anorexia, early satiety, diarrhea, or steatorrhea. Jaundice is often accompanied by pruritus and dark urine. Painful jaundice is present in approximately one-half of patients with locally unresectable disease, while painless jaundice is present in approximately one-half of patients with a potentially resectable and curable lesion.

The initial presentation varies according to location of the cancer. Malignancies in the pancreatic body or tail usually present with pain and weight loss, while those in the head of the gland typically present with steatorrhea, weight loss, and jaundice. The recent onset of atypical diabetes mellitus, a history of recent but unexplained thrombophlebitis (Trousseau sign), or a previous attack of pancreatitis are sometimes noted.

Courvoisier sign defines the presence of jaundice and a painlessly distended gallbladder as strongly indicative of pancreatic cancer, and may be used to distinguish pancreatic cancer from gallstones.

Tiredness, irritability and difficulty eating due to pain also exist. Pancreatic cancer is usually discovered during the course of the evaluation of aforementioned symptoms.

Liver function tests can show a combination of results indicative of bile duct obstruction (raised conjugated bilirubin, γ-glutamyl transpeptidase and alkaline phosphatase levels). CA19-9 (carbohydrate antigen 19.9) is a tumor marker that is frequently elevated in pancreatic cancer. However, it lacks sensitivity and specificity. When a cutoff above 37 U/mL is used, this marker has a sensitivity of 77% and specificity of 87% in discerning benign from malignant disease. CA 19-9 might be normal early in the course, and could be elevated due to benign causes of biliary obstruction.

Imaging studies, such as computed tomography (CT scan) and Endoscopic ultrasound (EUS) can be used to identify the location and form of the cancer. However, percutaneous needle biopsy of the cancerous pancreatic tissue is necessary to establish a definitive diagnosis. Endoscopic ultrasound is often used to visually guide the needle biopsy procedure.

In the September 2009 issue of the journal Cancer Prevention Research, scientists from the University of Texas M.D. Anderson Cancer Center identified microRNAs associated with pancreatic cancer from blood samples of pancreatic cancer patients, leading to a new and minimally invasive approach to early detection. Expression of higher levels of miR-155 circulating in blood was identified as a potential early stage biomarker, and expression of miR196a was shown to increase during disease progression. Using a panel of 4 miRNA biomarkers, miR-21, miR-210, miR-155, and miR-196a, the study achieved 64% sensitivity and 89% specificity in a sample of 28 pancreatic cancer patients and 19 healthy controls.

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Pancreatic Cancer Prevention

According to the American Cancer Society, there are no established guidelines for preventing pancreatic cancer, although cigarette smoking has been reported as responsible for 20–30% of pancreatic cancers.

The ACS recommends keeping a healthy weight, and increasing consumption of fruits, vegetables, and whole grains while decreasing red meat intake, although there is no consistent evidence that this will prevent or reduce pancreatic cancer specifically.

In 2006 a large prospective cohort study of over 80,000 subjects failed to prove a definite association. The evidence in support of this lies mostly in small case-control studies.

Several studies, including one published on 1 June 2007, indicate that B vitamins such as B12, B6, and folate, can reduce the risk of pancreatic cancer when consumed in food, but not when ingested in vitamin tablet form.

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Pancreatic Cancer Treatments

Surgery

Treatment of pancreatic cancer depends on the stage of the cancer. The Whipple procedure is the most common surgical treatment for cancers involving the head of the pancreas. This procedure involves removing the pancreatic head and the curve of the duodenum together (pancreato-duodenectomy), making a bypass for food from stomach to jejunum (gasto-jejunostomy) and attaching a loop of jejunum to the cystic duct to drain bile (cholecysto-jejunostomy). It can only be performed if the patient is likely to survive major surgery and if the cancer is localized without invading local structures or metastasizing. It can therefore only be performed in the minority of cases.

Spleen-preserving distal pancreatectomy can also be used as a method to remove a cancer running through centre of pancreas; this is invasive surgery, resulting in loss of body and tail. Cancers of the tail of the pancreas can be resected using a procedure known as a distal pancreatectomy.

After surgery, ''adjuvant'' chemotherapy with gemcitabine has in several large randomized studies been shown to significantly increase the 5-year survival (from approximately 10 to 20%), and should be offered if the patient is fit after surgery (Oettler et al. JAMA 2007, Neoptolemos et al. NEJM 2004, Oettler et al. ASCO proc 2007) . There is a study being done currently by Washington University that is using interferon to treat the cancer, and it has boosted survival times somewhat further. Addition of radiation therapy is a hotly debated topic, with groups in the US often favoring the use of adjuvant radiation therapy, while groups in Europe do not, due to the lack of any large randomized studies to show any survival benefit of this strategy.

Surgery can be performed for palliation, if the malignancy is invading or compressing the duodenum or colon. In that case, bypass surgery might overcome the obstruction and improve quality of life, but it is not intended as a cure., a recently published study ECOG 6201 failed to show superiority of GEMOX over gemcitabine alone (Poplin et al, JCO 2009, Louvet et al. JCO 2005). Fluorouracil (5FU) may also be included, however no large randomized study has shown significant survival benefit from this addition (Berlin et al. JCO 2002). One sofar unpublished trial has shown a significant benefit from adding capecitabine to gemcitabine (Cunningham et al. ASCO proc 2005),

On the basis of a Canadian led Phase III Randomised Controlled trial involving 569 patients with advanced pancreatic cancer, the US FDA has licensed the use of erlotinib (Tarceva) in combination with gemcitabine as a palliative regimen for pancreatic cancer. This trial compared the action of gemcitabine/erlotinib vs gemcitabine/placebo and demonstrated improved survival rates, improved tumor response and improved progression-free survival rates(Moore et al. JCO 2005). The survival improvement with the combination is on the order of less than four weeks, leading some cancer experts to question the incremental value of adding erlotinib to gemcitabine treatment. New trials are now investigating the effect of the above combination in the adjuvant and neoadjuvant setting. A trial of anti-angiogenesis agent bevacizumab (Avastin) as an addition to chemotherapy has shown no improvement in survival of patients with advanced pancreatic cancer (Kindler et al.). It may cause higher rates of high blood pressure, bleeding in the stomach and intestine, and intestinal perforations.

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Pancreatic Cancer Prognosis

Patients diagnosed with pancreatic cancer typically have a poor prognosis partly because the cancer usually causes no symptoms early on, leading to locally advanced or metastatic disease at time of diagnosis. Median survival from diagnosis is around 3 to 6 months; 5-year survival is less than 5%.

With 37,170 cases diagnosed in the United States in 2007, and 33,700 deaths, pancreatic cancer has one of the highest fatality rates of all cancers and is the fourth highest cancer killer in the United States among both men and women. Although it accounts for only 2.5% of new cases, pancreatic cancer is responsible for 6% of cancer deaths each year.

Pancreatic cancer may occasionally result in diabetes. Insulin production is hampered and it has been suggested that the cancer can also prompt the onset of diabetes and vice versa. Thus diabetes is both a risk factor for the development of pancreatic cancer and diabetes can be an early sign of the disease in the elderly.

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