Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer death in the United States, accounting for approximately 30,000 deaths each year (Michaud DS 2004). Worldwide, more than 200,000 people die from this cancer each year.

Little is known about the causes of pancreatic cancer. The disease is difficult to diagnose in its early stages, as it presents few symptoms and there are few tests to screen for it. As a result, most patients have incurable disease by the time they are diagnosed. Fewer than 5 percent of pancreatic cancer patients survive five years beyond diagnosis of the disease. Surgery is the only hope for cure; however, due to the aggressive nature of pancreatic tumors, only 5 percent to 20 percent of patients are candidates for surgery (Cleary SP et al. 2004). Chemotherapy and radiation therapy produce only minor increases in survival rates. Conventional medicine's inability to treat pancreatic cancer effectively is illustrated by the fact that more than 90 percent of patients die within 12 months of diagnosis. Along with lifestyle changes and nutritional approaches, novel therapeutic strategies are needed for the treatment of pancreatic cancer.

About the Pancreas

The pancreas is a pear-shaped gland located across the back of the belly, behind the stomach. It comprises the exocrine pancreas, which produces pancreatic enzymes that help break down carbohydrates, fats, and proteins, and the endocrine pancreas, which produces hormones such as insulin and glucagon that regulate how the body stores and uses food.

About 95 percent of pancreatic cancers begin in the exocrine pancreas, where enzymes are produced. The remaining 5 percent are cancers of the endocrine pancreas, where hormones are produced; these are also called islet cell cancers. Typically, pancreatic cancer spreads first to nearby lymph nodes, then to the liver and, less commonly, the lungs. It can also directly invade surrounding organs such as the upper region of the small intestine, stomach, and colon.

Alterations of Function in Pancreatic Cancer

Pancreatic cancer can alter the normal function of the pancreas by:

• Creating a deficiency of pancreatic enzymes, bicarbonate, and bile salt.
• Causing poor absorption of nutrients from food.
• Impairing the use of pancreatic enzymes.

The activity of pancreatic enzymes is impaired by an acidic environment, which is partly determined by dietary intake. Each day, the exocrine tissue secretes about 2 liters of bicarbonate (a buffer) to neutralize stomach acid in the small intestine. Reduced bicarbonate levels create an acidic microenvironment that weakens the activity of pancreatic enzymes. Some evidence suggests that antacids, alkaline diet, and essential fatty acids may be beneficial in treating pancreatic cancer (Nakamura T et al 1995; Ohta T et al 1996; Ravichandran D et al 1998).

Causes of and Risk Factors for Pancreatic Cancer

While the exact cause of pancreatic cancer is not known with certainty, several factors—including smoking, nutrition, glucose levels, hormones, and genetics—are thought to be involved in its initiation and development.

Smoking. Smoking is a major risk factor, accounting for 25-30 percent of all cases. Heavy smokers are two to three times more at risk for cancer than are nonsmokers (Lowenfels AB et al 2002). Several studies have observed a reduction in pancreatic cancer risk within a decade after smoking cessation (Michaud DS 2004).

Nutritional influences on pancreatic cancer. DNA damage caused by exposure to free radicals has been found in human pancreatic tissues (Uden S et al 1992). In pancreatic cancer cells, antioxidant levels are much lower compared to those in non-cancerous pancreatic cells. Nutritional supplements such as alpha-tocopherol (Ferreira PR et al 2004; Hernaandez J et al 2005; Rautalahti MT et al 1999), ascorbic acid (Zullo A et al 2000), zinc (Ertekin MV et al 2004; Prasad AS et al 2004; Uden S et al 1992), and selenium may be beneficial in elevating antioxidant levels (Zhan CD et al 2004).

Glucose levels and pancreatic cancer. Abnormal sugar metabolism, diabetes (DeMeo MT 2001 Gapstur SM et al 2000), and foods that elevate after-meal blood sugar levels are associated with increased pancreatic cancer risk in individuals with insulin resistance (Michaud DS et al 2002). Increasing soluble fiber intake has been shown to improve after-meal glucose levels and insulin response in healthy subjects (Aller R et al 2004; Lu ZX et al 2000). Thus, supplemental fiber may help to stabilize glucose levels (Rayes N et al 2002; Tsai AC et al 1987).

Phytoestrogens. Evidence suggests that the increased incidence of pancreatic cancer in Western nations may be related to the relatively low dietary content and qualities of naturally occurring plant hormones (phytoestrogens) (Stephens FO 1999). Daidzein, a phytoestrogen found in soybeans, chickpeas, and dietary supplements, has been shown to slow the growth of pancreatic cell lines (Guo JM et al 2004).

Folate. Maintaining adequate blood folate levels or increasing folate intake from dietary or vitamin sources may reduce pancreatic cancer risk significantly (Kim YI 1999). In a study of 27,101 healthy male smokers, 157 developed pancreatic cancer during 13 years of follow-up. Those with the lowest folate intake showed a 48 percent increased risk of pancreatic cancer (Stolzenberg-Solomon RZ et al 2001).

Lycopene. Data support an association between reduced lycopene levels and pancreatic cancer (Comstock GW et al 1991). In a clinical study, low levels of lycopene, retinol, and beta-carotene were strongly associated with pancreatic cancer (Abiaka CD et al 2001). Tomatoes are a rich dietary source of lycopene, which is also available as a dietary supplement (Ansari MS et al 2004).

Olive Oil. Olive oil contains several antioxidants and a protective fat called oleic acid that diminish the risk of cell damage (Owen RW et al 2004) by scavenging free radicals (Alarcon de la Lastra C et al 2001). In a study of 362 pancreatic cancer cases and 1502 controls in Italy, olive oil had a comparatively more favorable impact on pancreatic cancer risk than did other types of fats (La Vecchia C et al 1997).

Are Hormones Involved?

Testosterone: A low serum testosterone/dihydrotestosterone (DHT) ratio has been observed in some patients with pancreatic carcinoma (Corbishley TP et al 1986; Robles-Diaz G et al 2001). Based on findings that hormone receptors are contained in human pancreatic adenocarcinomas (Andren-Sandberg A et al 1990) and on experimental studies showing that pancreatic cancer development is influenced by sex hormones (Robles-Diaz G et al 2001), it is possible that hormonal manipulation might be of value in treating pancreatic cancer (Ganepola GA et al 1999). In one study, an anti-androgen was shown to prolong life significantly in patients with inoperable pancreatic carcinoma (Andren-Sandberg A et al 1990).

Parathyroid hormone-related protein (PTHrP): PTHrP regulates the growth and division of experimental pancreatic cancer (Grzesiak JJ et al 2004; Grzesiak JJ et al 2005). PTHrP is produced in pancreatic adenocarcinoma tumor specimens, suggesting that it may be a useful marker in monitoring the growth of pancreatic cancer in the body (Bouvet M et al 2002).

Genetic and Protein Changes

Genetic damage is highly associated with pancreatic cancer (Shiraishi K et al 2001). People with immediate family members affected by the disease are at increased risk for pancreatic cancer (Rulyak SJ et al 2003) and should consider pancreatic cancer screening if it becomes available.

At least 222 genes are overproduced and active in pancreatic cancer, and may be valuable in discovering novel ways to stop tumor growth (Grutzmann R et al 2003). Readers with neuroendocrine tumors are referred to Genzyme Genetics (www.genzymegenetics.com) for more information on how to obtain an analysis of genes found in their tumors, which may be beneficial in determining an optimal, individualized treatment plan.

Activation of cancer-associated genes (oncogenes)

K-ras and HER2/neu are cancer-associated genes (oncogenes) that acquire mutations resulting in the inactivation of genes that typically prevent tumor formation. These include p16, p53, DPC4, BRCA2, and FHIT (Moore PS et al 2003).

Ras genes. Ras proteins play a central role in regulating cell growth, multiplication, and life cycle. Mutations in the ras genes can transform normal cells into cancerous cells that grow rapidly and form tumors. Ras oncogene mutations have been identified in up to 95 percent of pancreatic cancers (Brasiuniene B et al 2003). Smoking and alcohol and coffee consumption have been linked with the occurrence of ras mutations in pancreatic tumors (Li D et al 2003).

Detection of K-ras mutations. The detection of K-ras mutations may help to predict treatment outcome. K-ras mutations are relatively easy to detect in different human tissues, including blood, intestinal fluid (Wilentz RE et al 1998), pancreatic fluid (Boadas J et al 2001), stool (Caldas C et al 1994), regional lymph nodes and other bodily fluids, and the tumor itself (Brasiuniene B et al 2003).

Ras gene activity can be slowed by:

• Fish oil containing the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Singh J et al 1997).
• Garlic’s natural component, diallyl disulfide (Gail MH et al 1998; Singh SV 2001).
• d-Limonene and perillyl alcohol, natural monoterpenes (Chen X et al 1999) from citrus fruits and essential oils.
• Green tea extract containing epigallocatechin gallate (EGCG) (Lyn-Cook BD et al 1999a).
• Black tea extract containing black tea polyphenol (BTP) (Lyn-Cook BD et al 1999a).

Tumor cells with a mutant ras are more difficult to kill with radiation than are cells with normal ras (McKenna WG et al 2003). However, laboratory experiments have shown that the FTI (farnesyl transferase inhibitor) drug L-744,832 makes pancreatic cancer cells with a K-ras mutation more sensitive to the killing effects of radiation (Alcock RA et al 2002). Therefore, the combination of an FTI and radiation may offer therapeutic advantages for those undergoing radiotherapy (Shi Y et al 2005).

HER2. HER2 is found in many pancreatic cancers and is associated with poor patient survival rates. In one study, patients with HER2 lived for only 7 months, whereas those without it lived at least 19 months (Lei S et al 1995).

• A flavonoid called apigenin reduces the growth of cancer cells containing HER2 significantly (Way TD et al 2004).
• HER2 can be targeted specifically by the neutralizing antibody drug Herceptin®.

EGF-R (epidermal growth factor receptor). In pancreatic cancer cells, EGF-R is turned on and levels are 4-fold higher than in normal healthy pancreatic cells (Friess H et al 1999).

• The green tea polyphenol EGCG has been shown to block EGF-R activity (Liang YC et al 1997), as have luteolin and quercetin (Baker CH et al 2002a).
• Curcumin prevents activation of EGF-R (Korutla L et al 1995).
• Genistein from soy is powerful in reducing levels of EGF-R (McIntyre BS et al 1998) and may disable the EGF-R signaling pathway (Bai J et al 2004).

Important genes turned off in pancreatic cancer

Compared to other major types of cancer, pancreatic cancer evinces a loss of activity of genes known to suppress tumor development, such as p16, DPC4, BRCA2, and p53.

p16 is turned off in virtually all pancreatic ductal cancers (Bartsch DK et al 2002; Cowgill SM et al 2003) and in 40 percent to 75 percent of all pancreatic cancers.

DPC4 is absent from approximately 50 percent of pancreatic cancers and is associated with more-invasive cancer growth (Cowgill SM et al 2003).

BRCA2 mutations have been clearly associated with pancreatic cancer development (Naderi A et al 2002).

p53: Because p53 is involved in repairing damaged DNA, when this gene is inactive (turned off) or malfunctions, damaged DNA is able to proliferate and form cancerous cells (Berrozpe G et al 1994). Nutritional supplements known to change levels or restore function of the p53 gene include:

• Red grape seed proanthocyanidins (Joshi SS et al 2001).
• Folate (Kim YI et al 2001).
• Phytochemicals such as genistein from soy (Lian F et al 1999), indole-3-carbinol (I3C) from cruciferous vegetables, and the green tea polyphenol EGCG (Katdare M et al 1998).

Regulation of Transcription Factors. A transcription factor controls whether a particular gene is turned on (active) or turned off (inactive). Transcription factors can be activated or deactivated selectively by other proteins, often as a final step in the process of transmitting their signals. The presence and activity of these factors can differ in normal and cancerous tissues.

STAT3 is a dormant transcription factor activated in pancreatic cancer but not in normal pancreatic tissue.

• Nutritional agents such as I3C and genistein inhibit STAT3 from functioning (Lian JP et al 2004).

NF-kappa B is another transcription factor activated in human pancreatic cancer but not in normal pancreatic tissue. Blocking NF-kappa B activity prevents cancer invasion and spread (metastasis) in animals with tumors. Furthermore, preventing NF-kappa B activity reduces levels of molecules involved in tumor blood-vessel development, thereby retarding tumor growth and slowing cancer spread (Fujioka S et al 2003).

• Genistein and curcumin both reduce NF-kappa B activation (Li L et al 2004; Li Y et al 2004).

Possible Signs and Symptoms of Pancreatic Cancer

• Jaundice (yellowing of the skin and whites of the eyes) due to blockage of the bile duct or liver malfunction.
• A gnawing pain from the stomach to the back.
• Unexplained weight loss from malabsorption of nutrients or loss of appetite.
• Fatigue or chronic tiredness.

Laboratory Testing

Early diagnosis of pancreatic cancer is difficult, even with recent advances in diagnostic methods. Symptoms develop gradually and steadily, and are often present for many months before diagnosis. Physicians typically use a range of imaging studies to confirm the diagnosis (see sidebar on “Diagnostic Imaging”). The development of improved early-detection methods is essential (Brand R 2001). No standard for pancreatic cancer screening exists, but strategies employing endoscopic, radiologic, and molecular methods to screen high-risk individuals are under investigation (Konner J et al 2002). Tumor markers (substances in the body that indicate the presence of tumors) do not permit early diagnosis of pancreatic cancer, but on follow-up are used to indicate the presence of tumors. Endoscopic ultrasound has been used to detect abnormal pancreatic cells in family members of pancreatic cancer patients; in high-risk patients, it has revealed cystic masses that were not detected by spiral CT scan (McBride 2004; Pezzilli 2004; Rulyak SJ et al 2004).

Blood Tests

CA 19-9 (carbohydrate antigen 19-9) is the mainstay tumor marker and is ordered when pancreatic cancer is suspected, particularly if the patient shows signs of jaundice (yellowing of the skin). CA 19-9 levels match the course of the disease following surgery, chemotherapy, or radiotherapy, normalizing or decreasing soon after treatment (Lamerz R 1999). Additional diagnostic methods are required because this test is only 70 percent sensitive and 87 percent specific for pancreatic cancer.

• Among the serum tumor markers that may be measured by a blood test and can be used in conjunction with other tests for the diagnosis and follow-up of surgically treated pancreatic cancer are CA19-9, CA-50, CA72-4, and CA242 (Jiang XT THZSC 2004).
• High platelet counts may be associated with a poor outcome and a shortening of the disease-free survival interval (Suzuki K et al 2004).

Assessment of pancreatic function. In pancreatic cancer, abnormal digestion associated with inadequate pancreatic enzymes and function (insufficiency) can occur (Bruno MJ et al 1995a; Grant AG et al 1978). When pancreatic enzyme levels fall below 1 percent to 2 percent of normal, poor nutrient digestion and incorporation occur. Poor digestion can cause significant weight loss, nutritional deficiencies, and foul-smelling or greasy bowel movements. It is also associated with changes in gastrointestinal function, such as changes in acid-base balance, bile acid metabolism, stomach emptying, and motility of the intestine.

Tests for pancreatic enzyme function. These tests are sensitive for moderate-to-severe pancreatic insufficiency, but are of limited value in mild pancreatic impairment.

• Bicarbonate secretion is probably the single most useful measure of pancreatic enzyme function (Ochi K et al 1997). Indirect estimation can be done via the 72-hour fat balance test, which determines fat losses as a percentage of daily fat intake.
• Measuring the activity of pancreatic chymotrypsin (a pancreatic enzyme).
• A test in which oral fluorescein dilaurate is broken down by esterase, a pancreatic enzyme.
• Fecal elastase-1 is a simple, non-invasive, and robust test (Sonwalkar SA et al 2003) of fat balance in the body.
• Cholesteryl-[14C]octanoate breath test (Bruno MJ et al 1995b).

With enzyme supplementation (for example, with pancrelipase, enteric-coated microspheres), body weight loss and biochemical indices of malnutrition can be greatly improved (Braga M et al 1988).