Pancreatic Cancer

Pancreatic Cancer

1 Introduction

Summary and Quick Facts

  • Pancreatic cancer is an aggressive form of cancer for which treatment options are limited. Surgery is generally the only potentially curative treatment, but promising new therapies such as immunotherapy are currently under investigation, in clinical trials.
  • This protocol will help you understand pancreatic cancer and the treatment options currently available. Also learn about the potential of some off-label drugs that complement conventional pancreatic cancer treatments under guidance of an oncologist.
  • Curcumin, which is derived from the spice turmeric, has been shown to promote healthy expression patterns of several genes involved in the development and progression of pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer death in the United States and is responsible for an estimated 270,000 deaths worldwide each year (Ferlay 2010).

Multiple factors, including a complex and poorly understood pathophysiology and difficulty in early detection and diagnosis make successful treatment of pancreatic cancer extremely challenging. Pancreatic cancer is typically not detected until it has already reached a locally advanced or metastatic stage due to the relative lack of symptoms in early disease. Current standard of care comprises surgery if the tumor is contained within the pancreas, followed by adjuvant chemotherapy and possibly radiation. However, if the cancer has spread, conventional treatment is limited, and long-term survival rates remain very low.

The rapidly accelerating use of specialized immunotherapies and innovative genetic analysis technology represent the next generation of novel medical treatments for pancreatic cancer. The ability to tailor treatment based upon the unique molecular biology of a patient’s cancer promises to considerably improve a currently bleak outlook.

Life Extension advocates a comprehensive pancreatic cancer management stratagey including intensive cancer cell biology testing to determine which specific conventional therapies are most likely to be effective. Off-label use of pharmaceutical agents such as metformin and chloroquine, an anti-malaria drug, hold promise in the treatment of pancreatic cancer as well. In addition, select nutritional ingredients can combat genetic abnormalities common in pancreatic cancer cells and offer an affordable means to pharmacogenomically target pancreatic cancer progression for all patients.

Life Extension Foundation® will be funding an aggressive, multidisciplinary pancreatic cancer clinical trial at the City of Hope Cancer Center. This groundbreaking trial will assess the effects of conventional chemotherapy in combination with various natural ingredients discussed in this protocol in patients with locally advanced unrescetable or metastatic pancreatic cancer.

2 About the Pancreas

The pancreas is located behind the stomach. It comprises the exocrine pancreas, which produces pancreatic enzymes that break down carbohydrates, fats, and proteins, and the endocrine pancreas, which produces the hormones insulin and glucagon that regulate how the body stores and uses food.

About 95 percent of pancreatic cancers begin in the exocrine pancreas, while the remaining 5 percent are of the endocrine pancreas. Typically, pancreatic cancer spreads first to nearby lymph nodes, then to the liver and, less commonly, the lungs.

Alterations of Function in Pancreatic Cancer

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

  • Creating a deficiency of pancreatic enzymes and bile salts, thus disrupting pH.
  • Causing poor absorption of nutrients from food.
  • Impairing the use of pancreatic enzymes.

The pancreas 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 and an alkaline diet may be beneficial for managing symptoms associated with pancreatic cancer and its treatment (Uwagawa 2010; Nakamura 1995; Ohta 1996).

3 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.

Genetic susceptibility is thought to account for 10% to 20% of cases, but ongoing research may reveal that the role of genetics exceeds these estimates (Brand 2000). About 40% of cases are associated with inflammatory conditions caused by poor nutrition, excessive alcohol consumption, chronic pancreatitis, obesity, and chemical exposure (Greer 2009).

Modifiable/Acquired Risk Factors

Smoking. Thirty percent of all pancreatic cancers are associated with smoking and tobacco use (Tranah 2011). Both active cigarette or cigar smoking, as well as exposure to tobacco smoke, increase pancreatic cancer risk. That risk, however, is reduced to levels of non-smokers within 5-10 years of quitting. Heavy cigarette smokers and cigar smokers have roughly a 50 – 60% increased risk compared to non-smokers (Bertuccio 2011). People who smoke and drink are diagnosed with pancreatic cancer at a younger age compared to never-smokers (Brand 2009).

Diabetes Mellitus. Long-standing diabetes (diabetes diagnosed at least 5 years prior to the diagnosis of pancreatic cancer) increases the risk of pancreatic cancer by 40-100%. Recent-onset diabetes (within 3 years) is associated with a 4- to 7-fold increase in risk, such that 1-2% of patients with recent-onset diabetes will develop pancreatic cancer within 3 years (Magruder 2011; Yang 2009).

Glucose levels. Over-consumption of sugar, sugar-sweetened soft drinks or foods, and foods that elevate after-meal blood sugar levels increase the risk of pancreatic cancer, particularly in individuals with insulin resistance (Larsson SC 2006; Bao Y 2008). A high glycemic load (glucose load in the blood) and fructose were associated with a greater risk of pancreatic cancer (Michaud 2002) and hyperglycemia (high blood sugar/glucose levels) promotes pancreatic cancer progression in cell-based studies (Liu 2011; Bao 2011).

Dietary factors. Dietary factors play a major role in the development of pancreatic cancer. High intake of dietary fat of animal origin, saturated fats and oils (Zhang 2009), cholesterol (Lin 2005), including omega-6 fatty acids (Funahashi 2008), fried foods, meat, and dairy products clearly increase the risk (Thiébaut 2009). Likewise, intake of excess calories, carbohydrates and processed meat (which are sources of dietary nitrates, nitrites and nitrosamines) increase the risk (Johnson 2011; Aschebrook-Kilfoy 2011).

Vitamin and Micronutrient Deficiency. Deficiency in folate, vitamin B6, B12 and methionine, as well as reduced intake of vitamins C, D, and E, calcium, potassium, and selenium increase the risk of pancreatic cancer development (Schernhammer 2007). Conversely, a high dietary intake of vitamins C, D and E, selenium, fruits, vegetables, and fiber lower the risk (Bidoli 2011; Bravi 2011). Higher vitamin D intake (greater than or equal to 600 IU per day) is associated with a 41% lower risk of pancreatic cancer compared to those with the lowest intake (<150 IU/day) (Skinner 2008; Bao 2010).

Folate. Folate deficiency increases risk of pancreatic cancer, due to hypomethylation of DNA (Friso 2002). Conversely, higher folate intake from food sources (or fortified foods with folic acid) and methionine, significantly decrease the risk of pancreatic cancer by 53% (Oaks 2010; Schernhammer 2007).

Periodontal Disease. Those with a history of periodontal disease have a 54% to 100% greater risk of pancreatic cancer. Tooth loss was positively associated with pancreatic cancer development (Michaud 2007; Michaud 2008). In addition, helicobacter pylori (H. Pylori) are found in dental plaque and are associated with periodontal disease and pancreatic cancer (Stolzenberg-Solomon 2003).

High Body Mass Index (BMI) and/or Obesity. Individuals who are overweight and have a high BMI have an increased risk of developing pancreatic cancer (Li 2009). A high BMI and hyperinsulinemia often occur together, and it is well-established that insulin promotes pancreatic cancer growth and development (Fisher 1996; Dandona 2011). Those who are overweight or obese from the ages of 20 to 49 years have an earlier onset of pancreatic cancer (Berrington de Gonzalez 2003). Obesity at an older age is associated with a lower overall survival in pancreatic cancer patients (Li 2009).

Alcohol. Heavy drinking (>9 alcoholic drinks per day) and binge drinking increase pancreatic cancer risk (Lucenteforte 2011; Gupta 2010). A significant increase in risk was seen among men consuming 45 or more grams of alcohol from liquor per day (Michaud 2010). Drinking >3 liquor drinks (but not beer or wine) was associated with death from pancreatic cancer (Gapstur 2011).

Chronic Pancreatitis. Chronic pancreatitis is associated with a 13- to 18-fold increase in the subsequent development of pancreatic cancer (Kudo 2011; Talamini 1999). Chronic pancreatitis is associated with heavy alcohol consumption; approximately 10% of heavy drinkers develop chronic pancreatitis (Nitsche 2011).

Chemical Exposure. Chemical exposure has been implicated in the cause of pancreatic cancer. Chemicals such as DDT (dichlorodiphenyltrichloroethane), formaldehyde, petroleum products, synthetic rubber, resins, polyesters, plastics, and styrene are involved in causing pancreatic cancer (National Toxicology Program 2012; Huff 2011).

Helicobacter Pylori (H.Pylori) Infection. Recently a population-based case control study, and a meta-analysis evaluating 2335 patients, demonstrated an association between the development of pancreatic cancer and H. pylori infection, particularly for individuals with non-O blood types (Risch 2010; Trikudanathan 2011).

Intrinsic/Unmodifiable Risk factors

Age, sex, race, and ethnicity. The disease is more common in the elderly, men, and among African-Americans (Ghadirian 2003).

Inherited pancreatic disease. Individuals with hereditary pancreatitis have a higher lifetime risk for developing pancreatic cancer (Langer 2009). Individuals with immediate family members affected by the disease are at increased risk (up to 57-fold with 3 or more family members affected) and should consider pancreatic cancer screening if it becomes available (Zubarik 2011; Stoita 2011).

Are Hormones Involved?

Clinical studies indicate that pancreatic cancer patients have sex steroid hormone imbalances and respond to various hormonal therapies. However, the treatment outcome may be dependent on individual patient and tumor characteristics, such as hormone receptor expression (Stolzenberg-Solomon 2009; Ganepola 1999).

Testosterone. A recent study indicates that hormone imbalances in pancreatic cancer patients are associated with shortened survival (Skipworth 2011).

Male pancreatic cancer patients often have lower levels of free testosterone and progesterone and higher levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol. Female pancreatic cancer patients often have higher levels of estradiol and lower levels of LH, FSH and progesterone (Fyssas 1997). In addition, pancreatic cancer patients have significantly lower testosterone / dihydrotestosterone (DHT) ratios (Jansa 1996; Robles-Diaz 2001).

A low serum testosterone in men and excess estrogen in women is associated with shortened survival in advanced pancreatic cancer, indicating a critical need for hormone manipulation and dietary intervention. Hypogonadal males have a 3 times greater risk of death compared with those with balanced hormones (Skipworth 2011).

Systemic inflammation (determined by C-reactive protein [CRP], and interleukin-6 [IL-6] levels) and opioid use are associated with decreased total testosterone and free testosterone and worsened survival (opioid use almost doubles the risk of death). Furthermore, women with high estrogen showed worsened survival (2.43 times greater risk of death) compared with those with balanced hormones (Skipworth 2011).

Hormone levels (total testosterone, free testosterone, FSH and LH and pro-inflammatory mediators (CRP, IL-6) can be measured by a simple blood test to determine hormone and inflammation status, both of which can be improved with nutritional supplementation. Studies indicate that poor nutritional status correlates with lower total testosterone levels in pancreatic cancer patients (Sperti 1992).

Genetics and Pancreatic Cancer

Several key genes are overproduced and/or activated in pancreatic cancer, and these can be specifically targeted to stop tumor growth (Xu 2011). Therefore, genetic analyses may be valuable in helping to determine an optimal individualized treatment plan, involving gene targeting, to prevent cancer progression (Grutzmann 2003). These tests can be performed by Genzyme Genetics (www.sanofigenzyme.com).

Activation of cancer-associated genes (oncogenes)

Four cancer-associated genes (oncogenes) are mutated in most cases of pancreatic cancer (K-ras, p16, p53, and MADH4 genes). Activation of the K-ras oncogene plus inactivation of tumor suppressor genes (p53, p16, DPC4, and BRCA2) are associated with the development of pancreatic cancer (Moore 2003). The transcription factors STAT3 and NFkB (nuclear factor kappa B) are aberrantly activated in pancreatic cancer. These mutated genes, transcription factors, and inactivated tumor suppressor genes can be specifically targeted by nutritional supplements and dietary-derived targeted therapies (see sections below).

Nearly 95% of all cases of pancreatic cancer have K-ras mutations, 90% have p16 mutations, (Bartsch 2002), 75% have p53 mutations, and 55% have DPC4 mutations (Cowgill 2003).

Ras genes. Ras proteins play a central role in regulating cell growth and multiplication. Mutations in the ras genes can transform normal cells into cancerous cells that grow rapidly and form tumors. Mutations in the ras oncogene is a molecular fingerprint of this disease (Brasiuniene 2003). Smoking, alcohol, milk, and dairy consumption have been linked with the occurrence of ras mutations in pancreatic tumors (Greer 2011).

Detection of K-ras mutations. The detection of K-ras mutations may help to predict treatment outcome (Bussom 2010). K-ras mutations are relatively easy to detect (Parker 2011) in different human tissues, including blood, intestinal fluid (Wilentz 1998), pancreatic fluid (Boadas 2001), stool (Caldas 1994; Kisiel 2011), regional lymph nodes and other bodily fluids, and the tumor itself (Brasiuniene 2003).

The cellular response to Ras gene activity can be inhibited in vitro by genistein, curcumin, green tea extract containing epigallocatechin gallate (EGCG) (Johnson 2011; Singh 2011; Lyn-Cook 1999) and fish oil containing the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Morales 2007).

Ras gene activity can be slowed by:

  • D-Limonene and perillyl alcohol, natural monoterpenes from citrus fruits (Johnson 2011; Stayrook 1998).
  • Black tea extract containing black tea polyphenols (Lyn-Cook BD 1999).
  • Garlic’s bioactive constituent, diallyl disulfide (Lai KC 2011; Singh SV 2001).

HER2 (human epidermal growth factor receptor-2) is found in many pancreatic cancers and is associated with poor patient survival rates. Patients with HER2 overexpression tumors had significantly shorter survival times than those with HER2 normal expression tumors (median survival time, 14.7 vs 20.7 months, respectively (Komoto 2009). Therefore, nutritional supplements that target HER2 are crucial to improve survival of many pancreatic cancer patients:

  • The tocotrienol form of vitamin E can cause pancreatic cancer cell death by downregulating HER2 and suppression of vital tumor cell survival pathways (Shin-Kang 2011).
  • HER2 can be targeted specifically by the anti-HER2 monoclonal antibody drug trastuzumab (Herceptin®) (Mihaljevic 2009).

EGFR (epidermal growth factor receptor). In pancreatic cancer cells, EGFR is activated and levels are up to 4-fold higher than in normal healthy pancreatic cells (Friess 1999).

  • Genistein is powerful in reducing levels of EGFR (McIntyre 1998) and disables the EGFR signaling pathway (Johnson 2011).
  • Curcumin and EGCG from Green Tea also block EGFR activity in pancreatic cancer cells (Vaccaro 2011; Shehzad 2010).
  • The pharmaceutical agent erlotinib inhibits signaling of EGFR, and is FDA approved for use in combination with gemcitibine for patients with locally advanced unresectable or metastatic pancreatic cancer (FDA 2005; Mountzios 2011). In clinical trials, erlotinib has performed well in combination with gemcitibine and other chemotherapeutic agents (Oh 2011), but survival is not significantly prolonged. Some preliminary evidence suggests that erlotinib may improve chemosensitivity in pancreatic cancer (Saif 2011).

Important genes turned off in pancreatic cancer

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

P16: Ninety percent of pancreatic carcinomas suffer a loss of p16 function. Moreover, carriers of p16 germline mutations have a 12- to 20-fold increased risk of developing pancreatic cancer (Schutte 1997).

DPC4: The absence of this gene is associated with more invasive cancer growth (Cowgill 2003). However, pancreatic cancer cells with a DPC4 homozygous (complete) deletion are sensitive to nontoxic doses of alpha-tocopherol succinate (Greco 2010).

BRCA2: This is the most common mutation in patients with hereditary pancreatic cancer. Carriers of BRCA2 mutations have a 3.5- to 10-fold increased risk of developing pancreatic cancer. A clinical case study suggests that patients with metastatic pancreatic carcinoma and BRCA2 mutations may have disease that is more sensitive to camptothecin-11 chemotherapy and consequently have prolonged survival (James 2009).

p53: Because the p53 gene is a tumor suppressor gene involved in repairing damaged DNA, when the gene is inactive (turned off) or malfunctions, damaged DNA is able to proliferate and form cancerous cells (Berrozpe 1994).

Nutritional supplements known to restore function of the p53 tumor suppressor gene include:

  • Curcumin and resveratrol both upregulate p53 in pancreatic cancer cells (Goel 2008; Zhou 2011).
  • Omega-3 fatty acids activate p53 (Wendel 2009).
  • Gamma-tocotrienol reduces cell survival proteins through the p53 pathway (Kannappan 2010).
  • Red grape seed proanthocyanidins (Roy 2005; Joshi 2001).
  • Phytochemicals such as genistein from soy (Lian 1999), indole-3-carbinol (I3C) from cruciferous vegetables, the green tea polyphenol EGCG (Shankar 2007; Katdare 1998), and resveratrol (Zhou 2011).

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. STAT3 is a dormant transcription factor activated in pancreatic cancer but not in normal pancreatic tissue; it plays an important role in the progression of pancreatic cancer. Silencing of the STAT3 gene using nutritional agents such as I3C and genistein (Lian 2004) may be a novel therapeutic option for treatment of pancreatic cancer (Huang C 2011). Omega-3 fatty acids inhibited the proliferation of pancreatic cancer cells by decreasing STAT3 phosphorylation (Hering 2007).

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

  • Gamma-tocotrienols inhibit human pancreatic tumor growth and sensitize them to gemcitabine by suppressing NFkB-mediated inflammatory pathways linked to the formation of tumors (Kunnumakkara 2010).
  • Genistein and curcumin both reduce NFkB activation (Jutooru 2010; Kim 2007; Li 2004).
  • The omega-3 fatty acid EPA inhibits NF-kB (Ross 2003)

4 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.
  • Fatigue, weakness, dark urine, light stools, and anorexia.

Screening and Early Detection

One of the main reasons that pancreatic cancer has a poor survival rate is the inability to screen for and prevent this disease. Pancreatic cancer needs to be detected early (precancerous lesions or small pancreatic cancers) in order to improve the chance of survival. Unfortunately, premalignant lesions and early pancreatic cancers are asymptomatic and current screening strategies are ineffective and inefficient (Kim 2011).

Currently, there are no approved screening tests for pancreatic cancer. CA 19-9 is elevated in 70-90% of patients but it is not accurate enough for early detection (poor sensitivity), nor is carcinoembryonic antigen (CEA) (Kim 2004). Efforts are underway to identify biomarkers with a high level of accuracy that detect pancreatic cancer at an early stage, e.g. early mutations in K-ras, p53, and p16, but none are yet in routine clinical use (Bussom 2010).

Future screening tests might incorporate biomarkers in addition to endoscopic ultrasound (EUS), possibly contrast-enhanced (Stoita 2011), or non-contrast MRI with ultrasound, which is now used in Japan (Kuroki-Suzuki 2011). In the future, proteomic analysis of pancreatic fluid aspirate will be a novel method of pancreatic cancer detection (Cuoghi 2011).

Laboratory Testing

Blood Tests: Serum tumor markers can be detected by a simple blood test and can be used in conjunction with diagnostic imaging tests for the diagnosis of pancreatic cancer and for monitoring progress after surgery. Tumor markers used include CA19-9, CEA, CA-50, CA72-4, and CA242 (Jiang 2004).

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. CA 19-9 levels match the course of the disease following treatment (Lamerz 1999). A high preoperative CA19-9 level (>500-1000 IU/mL) implies more advanced disease that is not amenable to resection (Fogelman 2008). Additional diagnostic methods are required because this test is only 70 percent sensitive and 87 percent specific for pancreatic cancer.

The EUROPAC study is currently evaluating fasting blood glucose as a marker for early pancreatic cancer in sporadic cases (Stolzenberg-Solomon 2005) and molecular analysis of pancreatic juice (K-ras and p53 mutations, and p16 promoter methylation). Screening for recent onset diabetes could possibly lead to early diagnosis or reduce pancreatic cancer deaths (Lowenfels 2006).

An alkaline phosphatase blood level that is four to five times the upper limits of normal (and disproportionate to the bilirubin level) may occur from tumor obstruction of the bile duct.

Assessment of pancreatic function. In pancreatic cancer, abnormal digestion associated with inadequate pancreatic enzymes and function (insufficiency) can occur (Bruno 1995a). When pancreatic enzyme levels fall below 1 - 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 intestines (Grant 1978).

Tests for pancreatic enzyme function include:

  • Lipase, amylase, chymotrypsin levels and bicarbonate secretion (Ochi 1997; Bruno 1995b).

With enzyme supplementation, weight loss and biochemical indices of malnutrition can be greatly improved (Braga 1988).

Tests for pancreatic hormone function include:

  • Insulin: Fasting blood sugar levels and an oral glucose tolerance test (OGTT) (Yamaguchi 2000).
  • Measurement of hormone levels (insulin, glucagon, somatostatin, and pancreatic polypeptide) after a meal (Schusdziarra 1984).

5 Diagnosis

Poor survival in pancreatic cancer is due not to early spread but to late diagnosis. Early diagnosis of this cancer is rare because symptoms develop gradually and cancer is often present for many months or even years before diagnosis. Physicians use a range of imaging techniques to confirm the diagnosis. Tumor markers do not yet enable early diagnosis of pancreatic cancer (Lowenfels 2006).

The use of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for fluid collection enables physicians to detect tumor markers and abnormal cells which supplement EUS imaging in pancreatic cancer diagnosis (Turner 2010), and with a minimal risk of tumor seeding (Paquin 2005). EUS-FNA can also reveal, in approximately 10% of patients, metastatic spread (Dumonceau 2011).

Future Methods of Diagnosis. Optical coherence tomography (OCT) imaging can reliably distinguish between low risk (benign) and high risk (potentially malignant) pancreatic cystic lesions with over 95% accuracy (specificity and sensitivity ex vivo). However, at the time of writing, this technique is not yet available to patients with pancreatic disease, as a minimally invasive probe for intra-cystic OCT imaging still needs to be developed (Iftimia 2011).

Prognosis

Prognostic biomarkers are indicators of the tumor’s aggressiveness (or growth potential) and the patients’ final outcome, regardless of the treatment used. A recent study showed that circulating tumor cells (CTCs) are an independent prognostic biomarker (De Albuquerque 2011). CTCs are cancer cells that detach from the primary tumor and travel in the blood, leading to cancer spread (Fidler 2003). CTCs were detected in 49.3% of blood samples from patients with advanced pancreatic adenocarcinoma and their detection correlated with poor prognosis. The median progression free survival was 60.7 days in patients with positive CTC detection vs. 163.6 days in those with negative CTC detection (X u 2011). As of the time of writing, CTC analysis is currently not commercially available for pancreatic cancer.

High platelet counts are associated with poor survival (Brown 2005; Suzuki 2004).

Patients with a neutrophil to lymphocyte ratio (NLR) value of < 5 have a significantly higher median survival duration compared to those with a NLR value of ≥ 5 (Aliustaoglu 2010).

6 Conventional Medical Treatments for Pancreatic Cancer

Pancreatic cancer is one of the most challenging cancers for oncologists. Typical conventional treatments for pancreatic cancer include chemotherapy, radiation therapy, immunotherapy, biologically-targeted therapies, and surgery. Chemotherapy and radiation therapy are typically not curative and provide only minor increases in survival rates in most cases. The median survival is only 10-12 months (Kim 2007). The 5-year survival of patients who undergo conventional treatment with surgery, chemotherapy, and radiation therapy is about 20%. However, the overall 5-year survival rate is 5%, as only 15% of patients are eligible for surgery (Fisher 2011). In those cases diagnosed with locally advanced unresectable or metastatic pancreatic cancer, palliative management is typically the goal (Gomez-Martin 2011).

Surgery

Only 15% of pancreatic cancer patients may be eligible for complete surgical removal of their tumors, a procedure known as a Whipple resection. This is a high-risk procedure with a mortality rate of 15% and a five-year survival rate of only 10% (Snady 2000). The median survival time for the inoperable 85-90% of cases is often only a few months. Management of these cases is based on relieving symptoms (referred to as palliative care).

Various chemotherapy drugs may be used before or after surgery to remove most of the tumor. Chemotherapy combined with radiotherapy is often used in the standard treatment of pancreatic cancer (Snady 2000).

Radiation

Radiation therapy, such as intensity modulated radiation therapy (IMRT) is used to provide symptom relief, improve pain and rarely prolongs survival (Gomez-Martin 2011). Refer to the Cancer Radiation protocol for information on supporting healthy tissues during radiation therapy.

Pancreatic tumor cells with mutant ras genes are more difficult to kill with radiation than are cells with normal ras genes (McKenna 2003). However, experiments showed that the FTI (farnesyl transferase inhibitor) tipifarnib (Zamestra™) made pancreatic cancer cells with a K-ras mutation more sensitive to the killing effects of radiation (Hussein 2009; Alcock 2002). Therefore, the combination of dietary-derived ras inhibitors and radiation may offer therapeutic advantages for those undergoing radiotherapy (Shi 2005).

Chemotherapy

Gemcitabine (Gemzar™) has been the standard chemotherapeutic agent for the past decade but it has not significantly improved the average survival rate. Furthermore, chemotherapy often causes intolerable levels of toxicity. Six months of chemotherapy with Gemzar™ after surgery improves 5-year survival from 9% to 21% (Neuhaus 2008). Even when Gemzar™ is combined with other chemotherapy drugs (Xeloda™ or cisplatin), or targeted-therapies such as EGFR inhibitors (Tarceva™ or Cetuximab™), there is minimal improvement in survival (Fisher 2011). Clinical trials with the favored, but aggressive FOLFIRINOX (chemotherapy cocktail) produced a median overall survival of 11.1 vs. 6.8 months (with Gemzar™) but with significantly worse side-effects (Conroy 2011).

Pancreatic cancer-gemcitabine chemoresistance is associated with enhanced NF-kB activation. The well-known capacity of omega-3 fatty acids to inhibit NF-kB (Ross 2003) and promote tumor cell death has the potential to restore or facilitate gemcitabine chemosensitivity (Hering 2007). Curcumin may also help circumvent chemoresistance via downregulation of NF-kB signaling (Yu 2011).

Anticoagulants in the Management of Pancreatic Cancer

Increased coagulation (blood clot formation or thrombosis) is common in pancreatic cancer patients and presents a life-threatening complication (Shah 2010). Moreover, advanced pancreatic cancer is associated with a high risk of patients developing venous thromboembolism (VTE); incidence range from 17% to 57% and is associated with a poor prognosis (Yates 2011; Pruemer 2005). Emerging clinical data strongly suggests that anticoagulant treatment may improve pancreatic cancer patient survival by decreasing thromboembolic complications as well as by separate anticancer activity (Mandalà 2011; Nakchbandi 2008).

Pancreatic cancer is usually associated with obstruction of the bile duct, which can elevate the level of fibrinogen. Elevated fibrinogen increases the risk of thrombosis and is also associated with increased invasiveness, metastasis, and poor clinical outcome. Increased fibrinogen levels result in increased platelet aggregation and therefore increased risk of blood clotting (Wang 2009).

Aspirin inhibits platelet aggregation (i.e. has antithrombotic effects) primarily by irreversibly inhibiting cyclooxygenase-1 (COX-1). Moreover, daily aspirin use (75 mg and up) for at least 5 years reduces deaths due to pancreatic cancers. The benefit increases with duration of use (Rothwell 2011).

Furthermore, recent data suggests that aspirin use greater than or equal to 1 day/month is associated with significantly decreased risk of developing pancreatic cancer. This association was also found for those who took low-dose aspirin for heart disease prevention (Tan 2011).

Preclinical studies confirm that aspirin significantly suppresses pancreatic cancer development by inhibiting the proliferation of pancreatic cancer cells, in vitro, through cell cycle arrest. In vivo studies show that aspirin delays the progression, and partially represses the invasion, of pancreatic cancer formation through inhibition of NF-kappaB activation (Fendrich 2010; Sclabas 2005).

Aspirin augments the anti-cancer effects of gemcitabine as well as its pro-apoptotic effect in pancreatic cancer cells. It also inhibits proliferation of gemcitabine-resistant human pancreatic cancer cells (Ou 2010).

Data indicate that the anticoagulants low molecular weight heparin (LMW heparin) and warfarin have a beneficial effect on the treatment of patients with pancreatic carcinoma (Conroy 2011; Sohail 2009). LMW heparin (added to gemcitabine plus cisplatinum) resulted in a significant improvement in survival over the use of chemotherapeutic agents alone (13.0 versus 5.5 months) (Icli 2007). However, another recent study did not show a survival benefit of LMW heparin (nadroparin) in patients with advanced pancreatic cancer (van Doormaal 2011). The addition of warfarin to chemotherapy increased mean survival from 2.3 to 5.0 months (Nakchbandi 2006).

Many dietary and botanical supplements have anticoagulant, antiplatelet and/or anti-thrombotic effects. These include omega 3-fatty acids from fish oil, vitamin E, ginger, and gingko (antiplatelet properties); dong quai and anise (anticoagulant effects); fucus (bladder wrack) (heparin-like activity); and high doses of vitamin E. However, caution should be exerted as the aforementioned can interact with standard anticoagulants and antiplatelet drugs such as aspirin, warfarin, and LMW heparin (Mousa 2010).

Determining thrombotic risk with biomarker tests (via blood tests) is crucial to identify those pancreatic cancer patients at highest risk of VTE in order to improve prognosis (Menapace 2010). Biomarkers associated with increased VTE risk in cancer include platelet and leukocyte counts, C-reactive protein, D-dimer, and PT time (Sohail 2009).

Biologically Targeted Therapies

It is well-known that specific gene mutations (e.g., K-ras, p53) are involved in pancreatic cancer development and progression, which is why drugs have been developed to specifically target these genes. However, even patients that have a known gene mutation (e.g., K-ras) respond differently to targeted treatments because the gene mutation itself can vary between patients (e.g., K-ras often mutates at codons 12, 13, or 64). Therefore, when the targeted treatment is tested in genetically dissimilar patients, it often fails (Fisher 2011). Clinical trials investigating therapies targeting K-ras, EGFR, vascular endothelial growth factor (VEGF), immunotherapy using tumor-associated antigens, and biologic therapy such as TNFerade (GenVec, Inc., Gaithersburg, MD) have all failed to substantially improve survival (Fisher 2011).

Example: K-ras. In pancreatic cancer, constitutively active K-ras is found in over 95% of tumors, making it a molecular fingerprint of this cancer (Kranenburg 2005). K-ras initiates pancreatic cancer development and is also involved in its progression. As K-ras plays such a critical role in pancreatic cancer, there has been extensive research to discover compounds that inhibit it and the pathways it affects. Researchers have tried using farnesyltransferase inhibitor (FTI) drugs to suppress the K-ras gene, but with no success: A phase III clinical trial with Tipifarnib (Zamestra™), which targets Ras farnesylation, plus gemcitabine, did not improve survival (Fisher 2011).

For targeted therapy to work, the target must be present in the tumor cells, even if the percentage of tumor cells harboring that mutation is small. Therefore, tumor cell gene mutation analyses would need to be performed for each patient prior to any proposed targeted treatment strategy. These molecular analyses (which are not FDA-approved or widely available to pancreatic cancer patients) for the expression of drug targets (e.g., K-ras, p53, etc.) and chemoresistance markers, in tumor cells can be performed by independent laboratories, such as Sanofi Genzyme.

The Pharmacogenomics Approach

In the personalized genomic approach a patient’s tumor(s) would be biopsied and undergo rapid sequencing analysis or biotyping and then compared to the patient’s genetic mutations, so that a personalized treatment strategy could be developed. This method would quickly decipher all targets and differences among patients and their tumors thus identifying which patients should respond to particular combinations of targeted therapies. Instead of taking a one-size-fits-all approach to pancreatic cancer, shared mutations would be matched to a particular drug. For example, Her2 amplification, which occurs in 2% – 3% of pancreatic cancers, might allow some pancreatic cancer patients to be candidates for anti-Her2 drugs, such as trastuzumab or lapatinib.

With a personalized genomic approach, a combination of multiple targeted therapies is most likely to be effective for patients whose tumors have been analyzed and shown to have specific markers (e.g., Kras, p53, Her2 etc.) that can actually be targeted. Repeat sequencing analysis could be performed at frequent intervals during treatment, or if new metastases or recurrent disease occurred, and treatment could be changed accordingly to take into consideration any genetic differences between the original tumor and metastatic cancer cells.

Certain genetic tests are already commercially available by direct consumer marketing to patients, even though their efficacy has not been proven in large scale clinical trials. For example, European laboratories perform molecular analyses of tumor cells for the expression of drug targets and chemoresistance markers, from a blood sample, tumor tissues, ascites or bone marrow. In the future, the genome of individual patients and their tumors will be available at an affordable cost.

To learn more about advanced molecular testing, refer to the Life Extension Magazine article "Designing an Individually Tailored Cancer Treatment Utilizing Advanced CTC Molecular Analysis".

7 Innovative Drug Strategies

Several innovative drug strategies are being explored for the treatment of pancreatic cancer, including FDA approved drugs that were not originally developed for pancreatic cancer treatment but have incidentally been shown to hinder its growth and progression; these include the “Off-label Use” of the anti-diabetic drug metformin and the anti-malarial drug chloroquine. It has been proposed that chloroquine and metformin could eliminate pancreatic cancer cell traits in pre-invasive pre-malignant lesions by inhibiting the genesis and self-renewal of cancer cells (Vazquez-Martin 2011).

  • Chloroquine, Antimalarial: Off-label Use

Chloroquine (Aralen®), which is used to prevent and treat malaria worldwide, selectively stops the growth of pancreatic tumors by inhibiting ‘autophagy’ (Zeilhofer HU 1989). Autophagy is the process whereby cancer cells ‘self-eat,’ or cannibalize, part of their self to survive. Pancreatic cancers have a unique dependence on autophagy and require autophagy for tumor growth (Yang 2011). In pancreatic cancers, K-ras drives autophagy. Chloroquine inactivates this process of autophagy and this causes tumor regression and prolonged survival in pancreatic cancer mouse experiments (Mirzoeva 2011).

These results are immediately translatable to the clinical treatment of pancreatic cancer patients, and provide an urgently needed novel therapeutic strategy. Currently, Hopkins researchers are pushing chloroquine into clinical trials of pancreatic cancer treatment.

Furthermore, chloroquine specifically sensitizes cancer cells to radiation therapy and chemotherapy and could possibly increase the efficacy of conventional cancer therapies (Solomon 2009).

Caution should be exerted by pancreatic cancer patients with hepatic impairment and/or alcoholics.

  • Metformin: Anti-Diabetic Drug, Off-label Use

Metformin has emerged as a novel treatment strategy for pancreatic cancer patients. Metformin is a drug of the biguanide class, approved for the treatment of type 2 diabetes mellitus (i.e., non-insulin dependent diabetes mellitus) worldwide because of its primary anti-hyperglycemic effects (Nathan 2009).

Many studies suggest that diabetes mellitus can cause pancreatic cancer with possible mechanisms involving insulin resistance and high levels of insulin in the blood. Moreover, successful treatment of type 2 diabetes and/or obesity reduces the risk of pancreatic cancer by reducing high insulin levels; insulin is known to stimulate cancer growth and pancreatic cancers overexpress insulin/IGF-1 receptors (Gallagher 2010).

Metformin reduces the risk of pancreatic cancer through antidiabetic and antitumor actions (Magruder 2011). Several studies found that metformin users (including diabetics) had a significantly lower relative risk for developing pancreatic cancer (Lee 2011). Noteworthy, a 62% reduction in the risk of pancreatic cancer in diabetic patients having taken metformin for more than 5 yeas was reported. By contrast, long-term insulin use in patients with long standing diabetes mellitus was associated with an increased risk of pancreatic cancer (Li 2009).

Clinical studies show that metformin reduces insulin resistance and increases complete tumor response rates following neoadjuvant chemotherapy for breast cancer (Jiralerspong 2009). An Italian retrospective cohort study of 3685 type II diabetic patients without cancer found that each 5-year metformin exposure was associated with a significant reduction in cancer death compared to insulin and sulfonylureas (Bo 2011).

A study presented at the 2011 American Society of Clinical Oncology (ASCO) meeting shows that metformin prolongs survival and decreases risk of death in patients with pancreatic malignancy and diabetes (Hsu 2011). The median survival was 16.6 vs. 11.5 months for metformin ever-users vs. never-users, respectively.

Metformin users are cautioned to monitor their vitamin B-12 and homocysteine levels, as its use causes both folate and vitamin B12 deficiency (i.e., serum total B12 level ≤ 150 pmol/L) in up to 30% of diabetic patients (Ting 2006; Lee 2011).

Pancreatic Enzyme Therapy

Pancreatic cancer creates a deficiency of pancreatic enzymes (termed pancreatic insufficiency), bicarbonate, and bile salt, resulting in poor absorption of nutrients from food, profound weight loss, and severe malnutrition. Fortunately pancreatic enzyme supplementation can prevent this occurrence and greatly improve quality of life in these patients (Imrie 2010). To avoid malnutrition-related morbidity and mortality and to improve patients' weight and nutritional status, pancreatic enzyme replacement therapy with oral pancreatic enzymes (enteric-coated minimicrospheres) at meal-times, (aiming at providing the duodenal lumen with a sufficient amount of active lipase at the time of gastric emptying of nutrients) can greatly improve quality of life (Domínguez-Muñoz 2011; Imrie 2010).

Clinical Studies with Pancreatic Enzymes. In a randomized, double-blind trial of twenty-one patients with unresectable cancer of the pancreatic head region (with suspected pancreatic duct obstruction), eight weeks of high dose enteric coated pancreatic enzyme supplementation and dietary counseling prevented weight loss. Patients on pancreatic enzymes gained 1.2% (0.7 kg) body weight whereas patients on placebo lost 3.7% (2.2 kg). Fat absorption and daily total energy intake in patients on pancreatic enzymes improved whereas in placebo patients it worsened (Bruno 1995). Aggressive pancreatic enzyme replacement is important to optimize bowel function and prevent malnutrition in pancreatic cancer patients (Armstrong 2007).

COX-2 (Cyclooxygenase-2) Inhibitors

The COX-2 enzyme is a major angiogenic mediator found to be elevated in pancreatic cancer (Tucker 1999) and indirectly prevents cancer cells from dying (Chu 2003). Therefore, suppressing the COX-2 enzyme may inhibit pancreatic cancer cell propagation. The COX-2 inhibitor apricoxib is now being investigated for enhancing the efficacy of gemcitabine and erlotinib in pancreatic cancer treatment (Strimpakos 2011 Abstract #227).

Selective reduction of COX-2 levels improves response to both chemotherapy and radiotherapy without being toxic to normal healthy tissues (Ferrari 2005).

A well-known COX-2 inhibitor, celebrex has already been combined with gemcitabine and curcumin in an ongoing study in Tel Aviv (ClinicalTrials.gov NCT00486460). Its pre-clinical activity in pancreatic cell lines and other cancer cell lines have been well-documented, it is commercially available, and actively investigated in many cancer studies. In the CALGB 30203 study, celecoxib was shown to confer survival advantage to lung cancer patients who overexpressed COX-2 ( Ferrari 2006; Dragovich 2008).

In addition, the following nutritional supplements which have been shown to reduce COX-2 expression in vitro and in vivo could be employed (Gescher 2004):

  • Gamma-tocotrienol prevents the growth of human pancreatic tumors by reducing COX-2 expression (Kunnumakkara 2010).
  • Omega-3 fatty acids, in particular EPA and DHA, found principally in oily fish, inhibit production of COX-2 significantly. EPA treatment decreases intracellular levels of COX-2 protein in pancreatic tumors (Shirota 2005).
  • Curcumin down-regulates COX-2 expression in pancreatic cancer cells resulting in increased tumor cell death (Lev-Ari 2007).

For a detailed discussion of COX-2 inhibition in cancer treatment, please review the protocol Cancer Treatment: The Critical Factors.

5-LOX (5-Lipoxygenase) Inhibitors

The 5-LOX enzyme is produced in pancreatic cancer (but not in normal pancreatic ducts) and is critical for its growth (Hennig R 2002). Reducing levels of 5-LOX prevents human pancreatic cancer cell lines from multiplying and induces apoptosis (cell death) (Andersen 1998).

Zileuton , a powerful 5-LOX inhibitor, pre-clinical models suggest synergy with various agents in cancer cell lines. Its use in CALGB 30203, an eicosanoid modulation clinical trial in lung cancer was not promising in a factorial designed experiment, however, its role in pancreatic cancer has not been evaluated, and several pre-clinical hamster models suggest it may be active in pancreatic cancer, alone or in combination with Celebrex (Edelman 2008; Gregor 2005; Wenger 2002).

For a detailed discussion of 5-LOX inhibition in cancer treatment, review the protocol Cancer Treatment: The Critical Factors.

Immunotherapy/Vaccine Therapy for Pancreatic Cancer

Vaccines for pancreatic cancer are employed to prevent recurrence and/or metastasis after surgery and to boost immune responses and improve clinical outcome when used in combination with chemotherapy. Several early phase I/II clinical trials have shown that the vaccines studied in pancreatic cancer treatment appear to be safe and well-tolerated. However, their immunogenicity (ability to produce an immune response) has been variable. The survival data indicate that induction of an immune response is correlated with prolonged survival and most clinical trials show increased survival associated with immune responses (see Table 1). Whole tumor cells were initially used to produce vaccines because the proteins expressed by tumor cells that are recognized by the immune system were unknown. However, the identification of proteins expressed by pancreatic tumors enabled the production of specific peptide vaccines such as mutant K-ras, MUC-1, vascular endothelial growth factor receptor 2 (VEGFR2), and telomerase (Koido 2011; Jaffee 1999).

In phase I/II trials, vaccination of advanced pancreatic cancer patients using peptide vaccines of mutant K-ras (Abou-Alfa 2011; Weden 2011), MUC1 (Lepisto 2008; Yamamoto 2005; Ramanathan 2005), VEGFR2 (Miyazawa 2010), or telomerase (Bernhardt 2006) was significantly associated with immune responses and in most cases, prolonged survival.

In clinical trials, patients with advanced or non-resectable pancreatic cancer have been treated by combination therapy of chemotherapy (gemcitabine) with personalized peptide vaccines (Yanagimoto 2007; Yanagimoto 2010) or VEGFR2 (Miyazawa 2010). Combination therapy was shown to be safe and possibly effective in patients with advanced pancreatic cancer refractory to standard treatment (Kimura 2011).

Mutant K-ras Peptide Vaccines: In a recent phase I study using long synthetic mutant ras peptides, 23 patients were vaccinated after surgery for pancreatic cancer. Significantly, 10-year survival was 20% (four patients out of 20 evaluable) versus zero (0/87) in a group of non-vaccinated patients (Weden 2011).

In another recent study of 24 patients with resected pancreatic cancer that were vaccinated with K-ras peptide in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), the median overall survival was 20.3 months. However, although the vaccine was safe and well-tolerated, it did not stimulate an immunogenic response (Abou-Alfa 2011).

In a phase I/II study of 48 patients with pancreatic cancer (38 with advanced disease and 10 post-surgery), vaccination with mutant K-ras peptides in combination with GM-CSF resulted in immune responses and prolonged survival (Gjertsen 2001).

A phase II clinical trial of mutant ras peptide-based vaccine as adjuvant therapy in pancreatic and colorectal cancers was performed with 12 patients (with no evidence of disease). Five pancreatic and seven colorectal cancer patients were vaccinated with mutant ras peptide, corresponding to their tumor's ras mutation. Five out of eleven patients showed a positive immune response. Furthermore, the five patients that responded had a mean disease-free survival of 35.2+ months and a mean overall survival of 44.4+ months. The researchers noted that the vaccine is safe, can induce specific immune responses, and has a positive outcome in overall survival (Toubaji 2008).

MUC1 Peptide Vaccines: MUC1 is a glycoprotein highly overexpressed and mutated in pancreatic tumors, providing a tumor specific antigen and target.

A phase I/II clinical trial evaluated a vaccine consisting of liposomal MUC1 peptide-loaded dendritic cells (DC) (see below for more information on dendritic cell based vaccines). Twelve pancreatic and biliary cancer patients were vaccinated following surgical removal of their primary tumors. MUC1-specific immune responses were observed even in patients with pretreated and advanced disease. Vaccinated patients were followed for over four years and four of the twelve patients were alive at that point, all without evidence of recurrence (Lepisto 2008).

Vaccination of 16 patients with resected or locally advanced pancreatic cancer with MUC1 peptide and SB-AS2 adjuvant (which induces a more portent immune response) resulted in low MUC1-specific immune responses in some patients. Moreover, 2 of 15 vaccinated patients were alive and disease free during follow-up at 32 and 61 months (Ramanathan 2005).

hTERT mRNA Dendritic Cell (DC) Vaccine: hTERT (Human telomerase reverse transcriptase) is an ideal tumor-associated antigen with which to develop a dendritic cell (DC) vaccine (Cui 2011). Immunotherapy targeting the hTERT subunit of telomerase induces powerful immune responses in cancer patients after vaccination with single hTERT peptides. A complete remission was reported in a pancreatic cancer patient associated with the induction of hTERT-specific immune responses against several hTERT epitopes (pieces of the antigen that are recognized by the immune system) (Suso 2011):

A 62-year-old female patient underwent radical surgery for a pancreatic adenocarcinoma. After relapse, she attained stable disease with gemcitabine treatment. Due to severe neutropenia, the chemotherapy was discontinued. The patient was subsequently treated with autologous DCs loaded with hTERT mRNA for 3 years. Immune parameters were monitored regularly after vaccination and clinical outcome was assessed by CT and PET/CT scans. The patient developed an immune response against several hTERT-derived antigens. At the time of writing, she showed no evidence of active disease based on PET/CT scans and continues to receive regular booster injections (Suso 2011).

Telomerase Peptide Vaccines and GM-CSF: A phase I/II study demonstrated the safety, tolerability, and immunogenicity of telomerase peptide (GV1001) vaccination in 48 patients with non-resectable pancreatic cancer. Immune responses were observed in 24 of 38 evaluable patients. One-year survival was 25% for the evaluable patients in the intermediate dose group. Median survival for this group was 8.6 months (Bernhardt 2006).

GV-1001, an injectable telomerase (hTERT) MHC class II peptide vaccine (by GemVax AS), was reported to be undergoing phase III clinical trials for pancreatic cancer in 2007 (Nava-Parada 2007).

HSPPC-96 (gp96, Oncophage): A phase I pilot study of autologous heat shock protein vaccine HSPPC-96 (gp96, Oncophage) in patients with resected pancreatic adenocarcinoma was performed. Ten patients who received neither adjuvant chemotherapy nor radiation were vaccinated with HSPPC-96 weekly with 4 doses. Median overall survival was 2.2 years. Three of 10 treated patients were alive and without disease at 2.6, 2.7, and 5.0 years follow-up (Maki 2007). However, there have been no follow-up studies reported.

Poxvirus Vaccines Targeting CEA and MUC-1: A Phase 1 clinical study of poxviruses targeting carcinoembryonic antigen (CEA) and MUC-1 in 10 patients with advanced pancreatic cancer was conducted. Results showed the poxvirus vaccine to be safe, well tolerated, and capable of generating antigen-specific immune responses in patients with advanced pancreatic cancer. Median overall survival was 6.3 months and a significant increase in overall survival was noted in patients who generated anti CEA- and/or MUC-1-specific immune responses compared with those who did not (15.1 vs. 3.9 months, respectively) (Kaufman 2007).

Personalized Peptide Vaccines: A case of complete remission of liver metastasis of pancreatic cancer, refractory to gemcitabine chemotherapy, under vaccination with a HLA-A2 restricted peptide derived from survivin peptide was reported (Wobser 2006).

Immunotherapy combined with Chemotherapy. Emerging evidence suggests that immunotherapy used in combination with conventional chemotherapy may improve clinical outcome. Noteworthy, gemcitabine has direct antitumor (chemotherapeutic) activity but also mediates immunological effects beneficial for cancer immunotherapy. Gemcitabine treatment is not immunosuppressive and may enhance responses to specific vaccines or immunotherapy and therefore could be combined with vaccines or other immunotherapy (Plate 2005).

Vascular Endothelial Growth Factor Receptor 2 (VEGFR2). VEGFR2 is an essential factor in tumor angiogenesis and in the growth of pancreatic cancer. A phase I clinical trial using a peptide vaccine for VEGFR2 in combination with gemcitabine for patients with advanced pancreatic cancer (metastatic and/or unresectable) was conducted. The median overall survival time of all 18 patients who completed at least one course of treatment was 8.7 months and the disease control rate was 67% (Miyazawa 2010).

A phase II study of personalized peptide vaccination with gemcitabine as the first line therapy in patients with non-resectable pancreatic cancer was performed. The reactive personalized peptides (maximum of 4 types of peptides) were administered with gemcitabine to 21 patients with untreated and nonresectable pancreatic cancer. Median survival time of all 21 patients was 9.0 months with a one-year survival rate of 38%. Immune responses correlated well with overall survival (Yanagimoto 2010).

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF). GM-CSF is a myeloid growth factor and immune activating protein used clinically. The GM-CSF gene inserted into tumor cells has been used to immunize patients. These genetically modified tumor cells produce GM-CSF in the local environment of the tumor, specifically activating the patient's T cells.

A Phase II trial tested the safety and effectiveness of GM-CSF-based immunotherapy given to 60 patients with resected pancreatic adenocarcinoma. The immunotherapy treatment was given 8 to 10 weeks after surgery followed by 5-fluorouracil (5-FU) based chemoradiation and further immunotherapy. The median survival was 24.8 months and the immunotherapy was well tolerated (Lutz 2011).

Dendritic Cell (DC)-based Vaccines. Dendritic cells (DC) are potent antigen-presenting cells and play a pivotal role in T cell-mediated immunity and thus immunotherapy of cancer. DC-based vaccines are safe and efficient in inducing strong tumor-specific immune responses (i.e., cytotoxic T-cell (CTL) responses) against tumor antigens (in vitro and in vivo) (Dauer 2005). The long-term outcome of dendritic cell (DC) vaccination and immunotherapy for patients with refractory pancreatic cancer has been demonstrated (Nakamura 2009):

Seventeen pancreatic cancer patients underwent immunotherapy in the Kyushu University and the Yakuin CA Clinic. Six patients had postoperative recurrence, 11 were inoperable due to metastasis, 16 developed chemotherapy-resistant cancers, while 1 patient had no prior chemotherapy for recurrent cancer after surgical resection because of leukopenia. Immunotherapy was combined with chemotherapy in 11 patients and without chemotherapy in 6 patients. Immunotherapy was classified into two groups; combined dendritic cell (DC) vaccination and injection of activated lymphocytes (DC vaccine therapy), or injection of lymphokine-activated killer lymphocytes (LAK) alone (LAK therapy). This immunotherapy of refractory pancreatic cancer resulted in a median survival of 9 months. DC vaccine therapy gave a significantly better survival period than LAK therapy alone. Results suggest that immunotherapy utilizing DC vaccination may prolong the survival of patients with refractory pancreatic cancer (Nakamura 2009).

A recent study indicates that DC vaccine-based immunotherapies combined with gemcitabine/S-1 are effective in patients with advanced pancreatic cancer refractory to standard chemotherapy (Kimura 2011). In this report, 38 out of 49 patients had received vaccination with WT1 peptide-pulsed DCs with or without combination of other peptides such as MUC1, CEA, and CA125. Prior to this combination therapy, 46 out of 49 patients had been treated with chemotherapy, radiotherapy, or hyperthermia but without clinical effects. Of 49 patients, 2 patients had complete remission (CR), 5 had partial remission (PR), and 10 had stable disease (SD) and median survival time was 360 days. Survival of patients receiving DC vaccine and chemotherapy plus LAK cell therapy was longer than those receiving DC vaccine in combination with chemotherapy but no LAK cells. “Dendritic cell vaccine-based immunotherapy combined with chemotherapy was shown to be safe and possibly effective in patients with advanced pancreatic cancer refractory to standard treatment” (Kimura 2011).

Another recent pilot study showed that DC-based vaccination can stimulate an antitumor T cell response in patients with advanced or recurrent pancreatic carcinoma receiving concomitant gemcitabine treatment (Bauer 2011). In this study patients were eligible for DC vaccination after recurrence of pancreatic cancer or as palliative care. Twelve patients received DC vaccinations and simultaneous chemotherapy. One patient developed a partial remission, and two patients exhibited stable disease. Median survival was 10.5 months and no severe side effects occurred. DC vaccination increased the frequency of tumor-reactive cells in all patients tested; however, the degree of this increase varied. The patient with the longest overall survival of 56 months had a high frequency of tumor-reactive cells, indicating that the presence of a pre-vaccination antitumor T cell response might be associated with prolonged survival. Five patients survived 1 year or more (Bauer 2011).

Table 1. Vaccines for Pancreatic Cancer

Vaccine

Patients

Response

Reference

Dendritic cell-based with concomitant chemotherapy (gemcitabine)

12 advanced or recurrent pancreatic cancer

1 partial remission (PR), 2 stable disease (SD), median survival 10.5 months

Bauer 2011

GM-CSF post-surgery with 5-FU chemoradiation

60 resected pancreatic adenocarcinoma

Median survival was 24.8 months

Lutz 2011

Dendritic cell-based loaded with WT1, MUC1, CEA, and CA125

Gemcitabine/S-1

49 advanced pancreatic cancer patients refractory to standard chemotherapy

2 complete remissions (CR), 5 PR, and 10 with SD. Median survival 360 days.

Kimura 2011

hTERT mRNA dendritic cell vaccination

1 patient post- chemotherapy

Complete response (i.e., no evidence of active disease based on PET/CT scans).

Suso 2011

Mutant K-ras long peptide

23 resected pancreatic cancer

Ten-year survival was 20% (four patients out of 20 evaluable).

Wedén 2011

MUC1 peptide-loaded dendritic cell

12 pancreatic and biliary cancer patients with resected tumors

4 of the 12 patients followed for over four years were alive.

Lepisto 2008

13-mer mutant ras peptide

12 patients with no evidence of disease; 5 pancreatic and 7 colorectal

Mean DFS of 35.2+ months and a mean overall survival (OS) of 44.4+ months.

Toubaji 2008

Allogeneic GM-CSF-secreting pancreatic cancer cell, alone or in sequence with cyclophosphamide

30 advanced pancreatic cancer

Median survival in gemcitabine-resistant patients was similar to chemotherapy alone.

Laheru 2008

Telomerase peptide with adjuvant GM-CSF

48 advanced pancreatic cancer

One-year survival for the evaluable patients in the intermediate dose group was 25%.

Bernhardt 2006

HLA-A2 restricted peptide derived from Survivin antigen

1 metastatic (liver) pancreatic cancer patient refractory to gemcitabine

Complete remission of liver metastasis with a duration of 8 months.

Wobser 2006

Personalized peptide vaccine

11 advanced pancreatic cancer

The 6- and 12-month survival rates for 10 patients who received >3 vaccinations were 80% and 20%, respectively.

Yamamoto 2005

MUC1 peptide with SB-AS2 adjuvant

16 resected or locally advanced pancreatic cancer

2 of 15 resected pancreatic cancer patients were alive and disease free at follow-up of 32 and 61 months.

Ramanathan 2005

Dendritic cell transfected with MUC1 cDNA

10 patients with advanced pancreatic, breast, or papillary cancer

A vaccine-specific delayed-type hypersensitivity (DTH) reaction occurred in 3 out of 10 patients.

Pecher 2002

Allogeneic GM-CSF-secreting pancreatic cancer cell

14 resected pancreatic cancer

3 patients had DTH responses; 3 patients remained disease-free at least 25 months after diagnosis

Jaffee 2001

Mutant K-ras peptide with adjuvant GM-CSF

10 resected and 38 advanced pancreatic cancer

Prolonged survival of immune -responders compared to nonresponders.

Gjertsen 2001

DFS = Disease Free Survival

Preserving Postoperative Immune Function with Interleukin-2

Pancreatic cancer, more so than many other malignancies, has retained a relatively poor prognosis over recent decades despite dedication of considerable resources and research efforts aimed at improving patient outcomes (Caprotti 2008).

One reason pancreatic cancer remains such a feared disease is that carcinogenic pancreatic tissue appears to directly influence the milieu of cell-signaling molecules that govern immune response within the body, culminating in dramatic suppression of patients’ anti-tumor immunity and allowance of unimpeded growth of malignant cells (Caprotti 2008; Hansel 2003; Elliott 2005; Furukawa 2006).  Exacerbating this problem is that major invasive surgery, which is an important aspect of treatment for individuals with early-stage pancreatic cancer, further weakens the immune system (Caprotti 2008). This dualistic assault on the immune system often heralds poor post-surgery survival for pancreatic cancer patients.

The good news is that scientists at the forefront of cancer immunology research are elucidating strategies for countering immunosuppression associated with pancreatic cancer.

A most promising modality on this front involves administering an immune-boosting cytokine called interleukin-2 to pancreatic cancer patients prior to surgery. Interleukin-2 is naturally produced in the body and one of its chief physiological roles is to promote proliferation of immune cells involved in anti-cancer immunity, namely T-lymphocytes and natural killer (NK) cells (Caprotti 2008).

Evidence from animal and human studies shows that administering interleukin-2 prior to radical surgery for pancreatic cancer, even for just a few days preceding surgery, considerably mitigates the decline in immune function that often compromises outcomes (Wang 2013; Degrate 2009; Uggeri 2009; Caprotti 2008; Nobili 2008).

In a study involving 19 pancreatic cancer patients scheduled for radical surgery, researchers administered interleukin-2 (9 million IU) for 3 days preceding surgery in 9 subjects, and the other 10 underwent the surgery without receiving any preoperative interleukin-2. Both groups were well matched for age, sex, and disease stage. The 2-year survival rate in the group that did not receive interleukin-2 before surgery was 10%, whereas 33% of subjects that received interleukin-2 survived 2 years following surgery. Moreover, postoperative complications occurred more frequently in the group of patients that did not receive interleukin-2 (Angelini 2006).

In a similar but slightly larger study, 30 pancreatic cancer patients were allocated to radical surgery alone (control group) or 3 consecutive days of interleukin-2 (12 million IU) therapy preceding radical surgery. T-lymphocyte counts fell significantly in the control group following surgery (reflecting diminished anti-cancer immunity), whereas they rose significantly in the group that received interleukin-2. After a 3-year follow-up period, both progression-free survival (survival without evidence of disease progression) and overall survival were significantly higher in the interleukin-2 treated patients (Caprotti 2008).

It appears that 12 million IU of interleukin-2 for 3 consecutive days prior to surgery may deliver a more favorable result than 9 million IU. In a trial on 31 pancreatic cancer patients undergoing surgery, researchers allotted 3 treatment variations: surgery alone, 9 million IU of interleukin-2 for 3 days before surgery, or 12 million IU of interleukin-2 for 3 days before surgery. Following surgery, the group allocated to the 12 million IU interleukin-2 dose exhibited more favorable measures of immunological competence than those who received 9 million IU. The scientists concluded “This preliminary result suggests that preoperative subcutaneously IL-2 immunotherapy at 12 million IU for 3 consecutive days before surgery is able to abrogate the effects of the surgical trauma and recover a normal immunofunction in pancreatic cancer patients” (Uggeri 2009).

8 Nutritional Therapy and Supplements

Dietary-Derived Targeted Therapy

Biologically active extracts (from fruits, vegetables, and herbs) that specifically target cancer cell growth provide complementary therapy options to pancreatic cancer patients who do not have time to wait for large-scale clinical trials to validate the usefulness of these dietary agents, either alone or in combination with conventional treatments.

Dietary-derived extracts with proven specific bioactivity that have been used clinically to treat pancreatic cancer patients include curcumin, genistein, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), alpha-lipoic acid, perillyl alcohol (Belanger 1998), and antioxidants. These dietary agents contain several biologically active constituents, in addition to vitamins, minerals, and micronutrients that exert multiple anti-cancer effects on pancreatic cancer cells and tumors, and specifically target pathways at the molecular, cellular, and physiological level, resulting in suppression of cancer growth, invasion, and metastasis (Johnson 2011)

Other dietary-derived extracts that suppress pancreatic cancer cell/tumor growth, progression, and spread (in vivo and in vitro) include green tea (EGCG), resveratrol, pomegranate, pterostilbene, and limonene. These nutritional supplements prevent pancreatic progression and cause tumor cell death by affecting multiple intracellular signaling molecules in pancreatic cancer development such as p53, K-ras, NF-kB, EGFR, STATs, COX-2, and TNF-α (Shanmugan 2011).

Studies suggest that a diet containing multiple dietary-derived bioactive agents is preferable and much more effective over single agents for the prevention and/or treatment of pancreatic cancer. For example, curcumin combined with omega-3 fatty acids, and isoflavones together with curcumin, provided synergistic inhibitory activities against pancreatic cancer (Swamy 2008). Combinatorial treatment with multiple dietary-derived bioactive agents exerts superior anti-tumor effects than either agent alone, partly due to the specific inhibition of multiple signaling pathways (in this case Notch-1 and NF-kB) (Wang 2006).

Curcumin. Curcumin is extracted from the Indian spice turmeric (Curcuma longa L.). It is one of the most important bioactive anticancer compounds and has been extensively researched for preventing and treating pancreatic cancer.

Curcumin inhibits several signaling pathways in pancreatic cancer cells at multiple levels, such as transcription factors (NF-kB, Notch-1, STAT3, and AP-1) (Lev-Ari 2006; Wang 2006), enzymes (COX-2, MMPs, and 5-LOX), cell cycle growth factors (cyclin D1), proliferation (Ras, EGFR, HER2, and Akt), survival pathways (β-catenin and adhesion molecules), and TNF, prostaglandin E2, and interleukin-8 (Li 2004; Shehzad 2010), ultimately leading to increased pancreatic cancer cell death (Dhillon 2008). In pancreatic cancer studies, curcumin has been used as a bioactive agent in lab, animal, and phase I, II, and III human trials.

Clinical Trials with Curcumin. Phase II clinical trials of curcumin determined that curcumin can be safely taken by cancer patients at oral doses up to 8 grams (g) per day (Johnson 2011). However, results of the most recent clinical trial using curcumin to treat advanced pancreatic cancer patients revealed that the curcumin dose of 8g/d was difficult to tolerate (due to abdominal fullness/discomfort) and the researchers recommended that other formulations of curcumin (with improved systemic bioavailability and therapeutic efficacy) be evaluated for future trials (Epelbaum 2010).

A phase I/II study of 21 gemcitabine-resistant patients with pancreatic cancer receiving 8 g daily of oral curcumin in combination with gemcitabine-based chemotherapy found the combination therapy to be safe, well-tolerated, and feasible. Median survival time after initiation of curcumin was 161 days (109-223 days) and 1-year survival rate was 19% (4.4-41.4%) (Kanai 2011).

Curcumin continues to exhibit promise as an anti-cancer agent, as it is remarkably bioactive but also non-toxic even at high doses. Pilot phase I clinical trials have shown curcumin to be safe even when consumed at a daily dose of 12g for 3 months (Goel 2008). At the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, preclinical evidence was presented regarding the efficacy of curcumin (Strimpakos 2011 Abstract #222). Please note that the forms of curcumin used in these clinical studies were not the superior absorbing forms of curcumin that are now available over-the-counter. These newer curcumin formulas absorb about seven times better into the bloodstream, thus providing a way for patients to obtain levels of curcurmin that might offer therapeutic efficacy.

Genistein. Genistein, an isoflavone extracted from soybeans, has been widely studied in pancreatic cancer. Genistein inhibits pancreatic cancer progression at the genetic, cellular, and physiological level.

At the genetic level, genistein prevents pancreatic cancer growth via targeted inhibition of Ras (Berner 2010), NFkB (Jotooru 2010), EGFR (McIntyre 1998), HER2 (Wang 2010), STAT3 (Huang 2011) and activation of p53 (Lian 1999). At the cellular level, genistein regulates glucose metabolism (Boros 2001). At the physiological level, genistein exerts potent antiangiogenic and anti-metastatic activities by impairing the activation of hypoxia inducible factor-1 (HIF-1) and suppressing VEGF (in vivo) (Buchler 2004). Intratumoral hypoxia is known to lead to increased tumor aggressiveness and distant metastasis and genistein prevents this occurrence.

Clinical Trials with Genistein. A phase II clinical trial on the use of genistein in combination with gemcitabine and erlotinib to treat patients with advanced or metastatic pancreatic cancer was performed. Genistein in the form of soy isoflavones at a dose of 531 mg twice daily was taken by pancreatic cancer patients. The trial showed that the addition of soy isoflavones to gemcitabine and erlotinib did not increase the survival of advanced pancreatic cancer patients (El-Rayes 2011). The researchers speculate that the benefit of adding soy isoflavones may be limited to patients whose tumors overexpress NF-kB, thus emphasizing the urgent need for individualized treatment plans.

As of September 2011, there is a phase I/II clinical trial investigating the effect of a crystalline form of genistein (AXP107-11) alone, and in combination with gemcitabine, in patients with advanced or metastatic cancer of the pancreas (www.clinicaltrials.gov).

The suggested dose of genistein is approximately 500 mg daily, which requires the swallowing of about five soy isoflavone concentrated capsules (3,500 mg soy extract daily flavones). This should be taken in two daily doses, each consisting of about 1,750 mg of soy isoflavone extract (to provide a total daily intake of 3,500 mg) (Miltyk 2003; Takimoto 2003).

Fish Oil. Weight loss in advanced pancreatic cancer patients (catabolic wasting or cachexia) is refractory to conventional nutritional support. However, it is well-established that supplementation with fish oil, rich in omega-3 fatty acids (EPA and DHA), reverses tumor-related weight loss (cachexia). Eicosapentaenoic acid (EPA) modulates the inflammatory response that contributes to weight loss in cancer and thus reverses cancer cachexia (Arshad 2011).

Omega-3 fatty acids, EPA and DHA, prevent pancreatic cancer progression and cause pancreatic tumor cell death by activating p53 (Wendel 2009) and blocking the activity of Ras (Strouch 2011), EGFR (Rogers 2010), COX-2 and 5-LOX (Swamy 2008), STAT3 (Hering 2007), and NF-kB (Ross 2003).

In a phase I study of five pancreatic cancer cachexia patients, a mean dose of approximately 18 grams per day (doses ranged from 9 to 27 grams per day) of a high-purity preparation of EPA was tolerated (Barber 2001).

Fish oil supplements providing at least 2,400 mg of EPA and 1,800 mg of DHA daily have been recommended (Anderson 1998a). To reduce cachexia, an estimated 2 to 12 grams per day of EPA is needed (Persson 2005).

Clinical Studies with Fish Oil. Many clinical studies in pancreatic cancer patients show that fish oil, omega-3 fatty acids, and/or EPA supplementation reverses weight loss caused by cancer (cachexia).

In an international, multicenter, randomized trial, a nutrition prescription of a protein and energy dense, oral nutritional supplement +/- omega-3 fatty acids taken by 200 untreated patients with unresectable pancreatic cancer over an 8-week period significantly improved weight (1.7 kg), protein (25.4 g) and energy (501kcal) intake (Bauer 2005).

Consumption of a protein- and energy-dense nutritional supplement containing omega-3 fatty acids (EPA) improved body weight, lean body mass, and quality of life in patients undergoing chemotherapy (Chen da 2005).

In a prospective, randomized, double-blinded clinical trial on 44 cancer patients undergoing major abdominal tumor surgery, daily fish oil and soybean oil supplementation (0.2 and 0.8 g/kg body weight, respectively) prevented weight loss and enabled a faster recovery (Heller 2004).

In a study of 24 home-living cachectic patients with advanced pancreatic cancer, the administration of an energy and protein dense oral supplement enriched with EPA, over an 8-week period, was associated with an increase in physical activity and improved quality of life (Moses 2004).

EPA enriched protein supplements improved physical activity levels and increased total energy expenditure in advanced pancreatic cancer patients, thereby increasing their quality of life (Klek 2005).

Vitamin D. Pancreatic cancer patients have a high prevalence of vitamin D deficiency indicating the need for appropriate supplementation (Fisher 2009). Low serum vitamin D levels, as defined by serum vitamin D levels of <32 ng/mL using Labcorp testing method for 25-hydroxyvitamin D, in pancreatic cancer patients take longer to respond to oral vitamin D supplementation compared to healthy individuals (Vashi 2010), suggesting that more aggressive supplementation may be required to obtain Life Extension’s optimal level of 50 – 80 ng/mL.

Vitamin D3 has multiple protective effects against pancreatic cancer including anti-angiogenic, anti-metastatic, anti-inflammatory, and immunomodulatory effects (Hung Pham 2011; Bulathsinghala 2010).

Perillyl Alcohol. Perillyl alcohol is a naturally derived monoterpene with activity against pancreatic cancers that have a K-ras mutation. It prevents the mutated ras proteins from stimulating pancreatic cancer growth (Stayrook 1998). Perillyl alcohol treatment causes complete pancreatic tumor regression in animal experiments (Burke 2002). Clinically achievable concentrations of perillyl alcohol combined with a virally delivered therapeutic cytokine (adenovirus-mediated mda-7/IL-24 gene therapy (Ad.mda-7)) effectively eliminated human pancreatic cancer cells grown in mice and increased their survival (Lebedeva 2008).

Clinical Studies with Perillyl Alcohol. A pilot study of perillyl alcohol in 8 pancreatic cancer patients showed that perillyl alcohol was well tolerated. Survival time was longer in patients who received full perillyl alcohol treatment (288 +/- 32 days) compared to those who did not (204 +/- 96 days), but this result did not achieve statistical significance. There was a trend toward greater apoptosis in tumors versus normal pancreatic tissue of patients receiving perillyl alcohol (Matos 2008).

Twelve clinical trials have investigated the use of perillyl alcohol in various types of cancer treatments. A 2050-mg dose given four times daily was found to be easily tolerated (Morgan-Meadows 2003). The minimum required antitumor dose is 1.3 grams per day (Boik 2001).

Antioxidants. Individual variations in the capacity to defend against oxidative stress and to repair oxidative DNA damage influence pancreatic cancer risk, and some of these genetic effects are modified by dietary antioxidants (Zhang 2011). Moreover, antioxidant levels are reduced in pancreatic tumors compared to healthy pancreatic tissue, resulting in increases in reactive oxygen species (ROS) that are capable of stimulating cancer growth (Garcea 2005; Vaquero 2004).

Vitamins A, C, and E. An overview of 14 randomized trials (with a total of 170,525 patients) showed significant effects of supplementation with beta-carotene, vitamins A, C, E, and selenium (alone or in combination) versus placebo on pancreatic cancer incidence (Bjelakovic 2004).

Retinoic acid slows pancreatic tumor progression and reduces motility of pancreatic stellate cells (PSCs) (Froeling 2011). A study of 23 pancreatic cancer patients tested retinol palmitate (vitamin A) and beta-interferon with chemotherapy. Eight patients responded and eight patients had stable disease. For all patients, median time to disease progression and survival time were 6.1 months and 11 months, respectively. Toxicity was high, but patients who had responses and disease stabilization had prolonged symptom relief (Recchia 1998).

Vitamins A, C, and E, as well as selenium, increase antioxidants needed to reduce free-radical damage in the body (Woutersen 1999). A double-blind, placebo-controlled, randomized clinical trial involving 36 cancer patients undergoing surgery for pancreatic cancer evaluated the impact of an oral nutritional supplement (enriched with antioxidants, glutamine and green tea extract) on postoperative oxidative stress. Patients received the antioxidant-enriched supplement twice the day before surgery and once 3 hours before surgery. The nutritional supplement improved total antioxidant capacity (plasma levels of vitamin C, vitamin E, selenium, and zinc) shortly after surgery and increased plasma vitamin C levels (Braga 2011).

Recent data support the use of pharmacological doses of ascorbate in adjunctive treatment (e.g., with gemcitabine) for pancreatic cancer (Espey 2011). Ascorbate induces autophagy in pancreatic cancer cells (Cullen 2010).

Melatonin. Recently, it was discovered that melatonin reduces pancreatic tumor cell viability by altering mitochondrial physiology (Gonzalez 2011). Furthermore, advanced pancreatic cancer patients have abnormal circadian fluctuations in melatonin levels (Muc-Wierzgon 2003), which should be corrected by melatonin supplementation because even low (physiologically normal) concentrations of melatonin have a pro-apoptotic effect on pancreatic cancer cells resulting in tumor cell death (Leja-Szpak 2010).

Clinical Studies with Melatonin. A clinical-study of melatonin plus immunotherapy in the treatment of fifty advanced pancreatic adenocarcinoma patients resulted in a significantly higher 1 year survival rate in the melatonin treated group than other groups tested (3/12 vs 1/38), suggesting that melatonin immunotherapy is a promising treatment of advanced pancreatic cancer (Lissoni 1994).

A phase II study of melatonin plus tamoxifen in metastatic solid tumor patients was performed. Included in the study were five pancreatic cancer patients, for whom no other standard therapy was available. Melatonin (20 mg at night) and tamoxifen (20 mg at noon) were given orally every day. Results indicated that the combination of melatonin plus tamoxifen may have some benefit in untreatable metastatic solid tumor patients (Lissoni 1996).

In another clinical study in which melatonin plus low-dose interleukin-2 (IL-2) was used to treat pancreatic cancer patients with a life expectancy of less than 6 months, a complete response was achieved in one pancreatic cancer patient, and a partial response in three others. Immunotherapy with melatonin and IL-2 was a well-tolerated and effective therapy for almost all advanced cancer patients with solid tumors, including those who did not respond to IL-2 alone or to chemotherapy (Lissoni 1995).

Investigational Nutritional Supplements

Pancreatic cancer treatment advances, whether conventional or alternative, have to be proven first in the laboratory before applying them to patients. However, epidemiological or population-based studies also provide evidence of the benefits of specific dietary interventions.

Epidemiological studies as well as laboratory and animal experiments suggest the following nutritional components may have a role in pancreatic cancer treatment.

Limonene is extracted from citrus fruits. It has been shown to reduce growth of pancreatic cancer cells by 50% (Karlson 1996; Crowell 1996). Limonene is well tolerated in cancer patients at doses that may have clinical activity (Chow 2002). One partial response in a breast cancer patient at a dose of 8 g/m2/day (8 grams taken twice daily) was maintained for 11 months. Three patients with colorectal cancer showed disease stabilization for longer than 6 months on d-limonene at 0.5 or 1 gram twice daily (Vigushin 1998). The tentative dose recommendation for limonene is 7.3 to 14.4 grams per day (Boik 2001; Vigushin 1998). Daily consumption of d-limonene from food sources is estimated to be 16.2 mg/person/day (0.27 mg/kg body weight/day) (Sun 2007).

Selenium levels were found to be reduced in 57% of pancreatic cancer patients who underwent surgery to remove the upper portion of their intestines. Many long-term survivors (>6 months) of pancreatic surgery have frank selenium deficiencies. Thus, it is recommended that micronutrient status should be regularly checked in these patients and treated where necessary (Armstrong 2007).

High-selenium yeast was shown to reduce cancer risk in an intervention trial (Clark 1996). Patients with previous skin cancer were supplemented with 200 mcg of selenium or placebo daily for an average of 4.5 years. At a 6-year follow up, it was found that those in the selenium group had a significant reduction in total cancer mortality, total cancer incidence, and incidences of lung, colorectal, and prostate cancers. Additional studies utilizing selenium supplementation have shown benefit in prostate and lung cancer (Combs 1997; Meyer 2005).

Selenium and beta-carotene were found to restrain the growth of pancreatic tumors caused by carcinogen exposure in mice (Appel 1996). In another preclinical study, a diet high in selenium reduced the number of carcinogen-induced pancreatic cancers significantly (Kise 1990).

Vitamin K. Population studies as well as animal and laboratory data suggest a role for vitamin K in cancer prevention and treatment (Nimptsch 2008; Osada 2001). In one laboratory study, vitamin K combined with the drug sorafenib strongly inhibited growth and induced apoptosis in pancreatic cancer cells (Wei 2010)

Vitamin B6. Animal and epidemiological studies have linked anti-tumorigenic and anti-inflammatory effects to dietary vitamin B6 (Larsson 2010). In a pooled analysis of data from 4 cohorts including 208 pancreatic cancer cases and 623 controls, subjects in the highest quartile (one-fourth) for plasma vitamin B6 concentrations were 20% less likely to have pancreatic cancer than those in the lowest quartile (Schernhammer 2007). Among male smokers in another study, those in the lowest one-third distribution of concentrations of the active form of vitamin B6 – pyridoxal-5’-phosphate – were about twice as likely to develop pancreatic cancer compared to those in the highest one-third (Stolzenberg-Solomon 1999).

Green Tea. In a large population-based case-control study conducted in China it was found that drinking green tea lowers the risk of pancreatic cancer (Ji 1997).

Epigallocatechin gallate (EGCG) is the main bioactive polyphenolic constituent in green tea. Animal studies show that EGCG inhibits pancreatic tumor growth, angiogenesis, invasion, and metastasis (Shankar 2007). Furthermore, EGCG, suppressed the development of pancreatic tumors in Syrian hamsters (Majima 1998; Hiura 1997).

Increasing evidence suggests an association of chronic inflammation in cancer development in which IL-1 plays a crucial role. Recent experimental studies show that EGCG downregulates IL-1RI expression and suppresses IL-1-induced tumorigenic factors in human pancreatic cancer cells resulting in tumor cell death (Hoffmann 2011).

EGCG’s anticancer activities in human pancreatic carcinoma cells are partly via the inhibition of insulin-like growth factor-I receptor (IGF-1R) (Vu 2010). EGCG (and the buckwheat flavonoid rutin) decrease induced glucotoxicity in pancreatic beta cells, preserving insulin signaling (Cai 2009). Furthermore, EGCG improves pancreatic injury in animal models of acute pancreatitis (Babu 2009). Green tea polyphenols (GTPs) prevent pancreatic fibrosis by inhibiting activated pancreatic stellate cells (PSCs). PSCs play a central role in the pathogenesis of pancreatic fibrogenesis and inflammation. EGCG inhibits PSC activation through antioxidant mechanisms (Asaumi H 2006) and prevents migration of PSCs (Masamune 2005). EGCG also decreases the expression of the K-ras gene (Lyn-Cook 1999).

Clinical evidence shows that green tea supplementation is safe and protective against some types of cancer (Stingl 2011).

Zinc is a trace element essential for normal cell growth. Zinc deficiency may have role in cancer promotion (Prasad 2009).

L-carnitine has been shown to augment the cytotoxicity of cisplatin and is involved in the mitochondrial transport of acetyl groups (Peluso 2000; Pisano 2010).

Acetyl-L-carnitine may indirectly influencethe stability of the p53 tumor suppressor gene. The activity of this gene enhances the cytotoxicity of cisplatin chemotherapy drugs. Based on this information, researchers investigated the effects of acetyl-L- carnitine in combination with cisplatin on cancer cell lines. The results revealed a significant antimetastatic activity of acetyl-L-carnitine and enhancement of the antitumor potential of platinum chemotherapy (Pisano 2010).

L-carnitine deficiency is proposed to be a cause of cancer-related weight loss (cachexia). In a randomized controlled trial, advanced pancreatic cancer patients receiving 4 grams of L-carnitine daily for 12 weeks gained weight (BMI increased 3.4%), while the control group continued to lose weight (BMI decreased 1.5%). Patients supplemented with L-carnitine also experienced improved nutritional status, increased overall survival and reported better quality of life (Kraft 2012).

Complementary Alternative Therapies

PSK (Polysaccharide K). PSK is a protein-bound polysaccharide derived from the mycelium of the mushroom Coriolus versicolor (Tsukagoshi 1984). In Japan, PSK is used as a non-specific biological response modifier to enhance the immune system in cancer patients (Koda 2003).

Two patients who had unresectable pancreatic cancer were treated with combined chemotherapy using cisplatin, PSK, and UFT (uracil-tegafur). During therapy, a partial response was observed, with a remarkable decrease in tumor size and no significant side effects. From the results of these two cases, this combination chemotherapy was considered to be one of the most effective therapies available for pancreatic cancer (Sohma 1987). PSK has been used as adjuvant immunotherapy for cancer at a dose of 3 grams daily (Ito 2004).

Recent studies showed that PSK has strong antitumor effects via stimulation of both innate and adaptive immune pathways (Lu 2011a). Furthermore, PSK activates human natural killer (NK) cells and significantly potentiates the anti-tumor effect of anti-HER2 monoclonal antibody therapy (in mice). Therefore, concurrent treatment of PSK and trastuzumab may be a novel way to augment the anti-tumor effect of trastuzumab (Lu 2011b).

PSK suppresses tumor cell invasiveness by down-regulating several invasion-related factors (Zhang 2000). PSK enhances pancreatic cancer cell death induced by Taxotere® (docetaxel) by inhibiting docetaxel-induced NF-kB activation (Zhang 2003).

Ukrain (NSC-631570). Ukrain is a semisynthetic derivative of the Chelidonium majus L. alkaloid chelidonine shown to prolong survival of pancreatic cancer patients.

In a phase II trial of advanced pancreatic cancer patients, Ukrain either alone or together with Gemzar® (gemcitabine) doubled median survival times (Gansauge 2002).

In another clinical study, Ukrain with vitamin C treatment prolonged the survival and improved the quality of life of patients with advanced pancreatic cancer. In this study, patients were administered IV therapy consisting of either vitamin C (5.4 g every second day, repeated 10 times) and Ukrain (10 mg every second day, repeated 10 times) (21 patients), or vitamin C (5.4 g every second day x 10) and normal saline (10 ml) (control group, 21 patients). The one-year survival was 81% versus 14% and the 2-year survival was 43% versus 5% (Ukrain vs control group). Median survival was 17.17 versus 6.97 months in the Ukrain versus control group, respectively. The longest survival in the Ukrain group was 54 months (Zemskov 2000).

Ukrain’s proapoptotic activity is based on Chelidonium majus L. alkaloids and is mediated via a mitochondrial death pathway (Habermehl 2006). Ukrain is able to control the expression of some of the key mediators of tumor progression in pancreatic carcinoma cells. It downregulates matrix metalloproteinases, suggesting that it may decrease pancreatic cancer cell invasion. It also reduces tumor cell proliferation by cell cycle inhibition, via G2/M phase arrest (Funel 2010).

Seven randomized clinical trials suggest that Ukrain has curative effects on a range of cancers, including pancreatic cancer. However, the methodological quality of most studies was poor; therefore, independent rigorous studies are urgently needed (Ernst 2005).

Alpha-Lipoic Acid / Low-Dose Naltrexone (ALA/N)

The Integrative Medical Center of New Mexico, (located in Las Cruces) previously reported the long-term survival of a male patient with pancreatic cancer metastasized to the liver, treated with intravenous alpha-lipoid acid and oral low-dose naltrexone (ALA/N) (and a healthy lifestyle program) without any toxic adverse effects. The man was alive and well 78 months after initial treatment (Berkson 2006) even though he was told by a reputable oncology center in October 2002 that there was little hope for his survival.

Clinical Studies with ALA/N

Recently three new patients with metastatic pancreatic cancer were treated with the ALA/N protocol at the same center. In 2010, it was reported that the first patient is alive and well 39 months after presenting with pancreatic adenocarcinoma with metastases to the liver. The second patient, also with pancreatic adenocarcinoma with metastases to the liver, was treated with the ALA/N protocol and after 5 months of therapy, PET scan showed no evidence of disease. The third patient, in addition to his pancreatic cancer with liver and retroperitoneal metastases, has a history of B-cell lymphoma and prostate adenocarcinoma. After 4 months of the ALA/N protocol his PET scan showed no evidence of cancer. ALA/N exerts multiple anti-cancer effects including reducing oxidative stress, stabilizing NFkB, stimulating apoptosis, inhibiting tumor cell proliferation and modulating an immune response (Berkson 2009)

Berkson and colleagues (2009) believe that the results from their ALA/N integrative protocol warrant clinical trials, stating that “given its lack of toxicity at levels reported it may have the possibility of extending the life of a patient who would be customarily considered to be terminal.”

The ALA-LDN protocol comprises alpha-lipoic acid (ALA) (300 to 600 mg intravenously twice weekly), low-dose naltrexone (Vivitrol™) (3 to 4.5 mg at bedtime), and orally, ALA (300 mg twice daily), selenium (200 micrograms twice daily), silymarin (300 mg four times daily), and vitamin B complex (3 high-dose capsules daily). In addition, a strict dietary regimen, stress-reduction and exercise program, and a healthy lifestyle are essential.

References

Abou-Alfa GK, Chapman PB, Feilchenfeldt J, et al. Targeting mutated K-ras in pancreatic adenocarcinoma using an adjuvant vaccine. American Journal of Clinical Oncology. 2011;34(3):321-325.

Alcock RA, Dey S, Chendil D, et al. Farnesyltransferase inhibitor (L-744,832) restores TGF-beta type II receptor expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer cell line MIA PaCa-2. Oncogene 2002;21(51):7883-7890.

Aliustaoglu M, Bilici A, Seker M, et al. The association of pre-treatment peripheral blood markers with survival in patients with pancreatic cancer. Hepatogastroenterology 2010;57(99-100):640-645.

Andersen KM, Seed T, Vos M, et al. 5-lipoxygenase inhibitors reduce PC-3 cell proliferation and initiate nonnecrotic cell death. The Prostate. 1998;37(3):161-73.

Anderson KM, Seed T, Meng J, Ou D, Alrefai WA, Harris JE. Five-lipoxygenase inhibitors reduce Panc-1 survival: the mode of cell death and synergism of MK886 with gamma linolenic acid. Anticancer Res 1998a;18(2A):791-800.

Angelini C, Bovo G, Muselli P, Mussi C, Crippa S, Caprotti R, Uggeri F. Preoperative interleukin-2 immunotherapy in pancreatic cancer: preliminary results. Hepato-gastroenterology. Jan-Feb 2006;53(67):141-144.

Appel MJ, Woutersen RA. Effects of dietary beta-carotene and selenium on initiation and promotion of pancreatic carcinogenesis in azaserine-treated rats. Carcinogenesis 1996;17(7):1411-1416.

Armstrong T, Strommer L, Ruiz-Jasbon F, et al. Pancreaticoduodenectomy for peri-ampullary neoplasia leads to specific micronutrient deficiencies. Pancreatology 2007;7(1):37-44.

Arshad A, Al-Leswas D, Stephenson J, Metcalfe M, Dennison A. Potential applications of fish oils rich in n-3 fatty acids in the palliative treatment of advanced pancreatic cancer. Br J Nutr 2011;1-6.

Asaumi H, Watanabe S, Taguchi M, et al. Green tea polyphenol (-)-epigallocatechin-3-gallate inhibits ethanol-induced activation of pancreatic stellate cells. Eur J Clin Invest 2006;36(2):113-122.

Aschebrook-Kilfoy B, Cross AJ, Stolzenberg-Solomon RZ, et al. Pancreatic Cancer and Exposure to Dietary Nitrate and Nitrite in the NIH-AARP Diet and Health Study. Am J Epidemiol 2011;174(3):305-315.

Babu BI, Malleo G, Genovese T, et al. Green tea polyphenols ameliorate pancreatic injury in cerulein-induced murine acute pancreatitis. Pancreas 2009;38(8):954-967.

Bao Y, Ng K, Wolpin BM, et al. Predicted vitamin D status and pancreatic cancer risk in two prospective cohort studies. Br J Cancer 2010;102(9):1422-7.

Bao Y, Nimptsch K, Wolpin BM, et al. Dietary insulin load, dietary insulin index, and risk of pancreatic cancer. Am J Clin Nutr 2011;94(3):862-868.

Bao Y, Stolzenberg-Solomon R, Jiao L, et al. Added sugar and sugar-sweetened foods and beverages and the risk of pancreatic cancer in the National Institutes of Health-AARP Diet and Health Study. Am J Clin Nutr 2008;88(2):431-440.

Barber MD, Fearon KC, Tisdale MJ, McMillan DC, Ross JA. Effect of a fish oil-enriched nutritional supplement on metabolic mediators in patients with pancreatic cancer cachexia. Nutr Cancer 2001;40(2):118-124.

Bartsch DK, Sina-Frey M, Lang S, et al. CDKN2A germline mutations in familial pancreatic cancer. Ann Surg 2002;236(6):730-737.

Bauer C, Dauer M, Saraj S, Schnurr M, Bauernfeind F, Sterzik A, Junkmann J, Jakl V, Kiefl R, Oduncu F, Emmerich B, Mayr D, Mussack T, Bruns C, Rüttinger D, Conrad C, Jauch KW, Endres S, Eigler A. Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study. Cancer Immunol Immunother. 2011 Aug;60(8):1097-107.

Bauer J, Capra S, Battistutta D, Davidson W, Ash S. Compliance with nutrition prescription improves outcomes in patients with unresectable pancreatic cancer. Clin Nutr 2005;24(6):998-1004.

Belanger JT. Perillyl alcohol: applications in oncology. Altern Med Rev. 1998;3(6):448-57.

Berkson BM, Rubin DM, Berkson AJ. Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases. Integr Cancer Ther 2009;8(4):416-422.

Berkson BM, Rubin DM, Berkson AJ. The long-term survival of a patient with pancreatic cancer with metastases to the liver after treatment with the intravenous alpha-lipoic acid/low-dose naltrexone protocol. Integr Cancer Ther 2006;5(1):83-89.

Berner C, Aumuller E, Gnauck A, Nestelberger M, Just A, Haslberger AG. Epigenetic control of estrogen receptor expression and tumor suppressor genes is modulated by bioactive food compounds. Ann Nutr Metab 2010;57(3-4):183-189.

Bernhardt SL, Gjertsen MK, Trachsel S, et al. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study. British Journal of Cancer. 2006;95(11):1474–1482.

Berrington de Gonzalez A, Sweetland S, Spencer E. A meta-analysis of obesity and the risk of pancreatic cancer. Br J Cancer 2003;89(3):519-523.

Berrozpe G, Schaeffer J, et al. Comparative analysis of mutations in the p53 and K-ras genes in pancreatic cancer. Int J Cancer. 1994;58(2):185-91.

Bertuccio P, La VC, Silverman DT, et al. Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann Oncol 2011;22(6):1420-1426.

Bidoli E, Pelucchi C, Zucchetto A, et al. Fiber intake and pancreatic cancer risk: a case-control study. Ann Oncol 2011.

Bjelakovic G, Nikolova D, Simonetti RG, et al. Antioxidant supplements for prevention of gastrointestinal cancers: a systemic review and meta-analysis. Lancet. 2004;364(9441):1219-28.

Bo S, Ciccone G, Rosato R, et al. Cancer mortality reduction and metformin. A retrospective cohort study in type 2 diabetic patients. Diabetes Obes Metab 2011;10-1326.

Boadas J, Mora J, et al. Clinical usefulness of K-ras gene mutation detection and cytology in pancreatic juice in the diagnosis and screening of pancreatic cancer. Eur J Gastroenterol Hepatol 2001 Oct;13(10):1153-9.

Boik J. Natural Compounds in Cancer Therapy: Promising Nontoxic Antitumor Agents from Plants and Other Natural Sources. Princeton, MN: Oregon Medical Press; 2001.

Boros LG, Bassilian S, et al. Genistein inhibits nonoxidative ribose synthesis in MIA pancreatic adenocarcinoma cells: a new mechanism of controlling tumor growth. Pancreas 2001;22(1):1-7.

Braga M, Bissolati M, Rocchetti S, Beneduce A, Pecorelli N, Di Carlo V. Oral preoperative antioxidants in pancreatic surgery: A double-blind, randomized, clinical trial. Nutrition 2011 Sep 3.

Braga M, Cristallo M, De FR, et al. Correction of malnutrition and maldigestion with enzyme supplementation in patients with surgical suppression of exocrine pancreatic function. Surg Gynecol Obstet 1988;167(6):485-492.

Brand RE, Greer JB, Zolotarevsky E, et al. Pancreatic cancer patients who smoke and drink are diagnosed at younger ages. Clin Gastroenterol Hepatol 2009;7(9):1007-12.

Brand RE, Lynch HT. Hereditary pancreatic adenocarcinoma. A clinical perspective. Med Clin North Am 2000;84(3):665-675.

Brasiuniene B, Brasiunas V, Barauskas G, Juozaityte E. [Molecular factors of pancreatic cancer pathogenesis and prognosis]. Medicina (Kaunas) 2003;39(7):631-636.

Bravi F, Polesel J, Bosetti C, et al. Dietary intake of selected micronutrients and the risk of pancreatic cancer: an Italian case-control study. Ann Oncol 2011;22(1):202-206.

Brown KM, Domin C, Aranha GV, Yong S, Shoup M. Increased preoperative platelet count is associated with decreased survival after resection for adenocarcinoma of the pancreas. Am J Surg 2005;189(3):278-282.

Bruno MJ, Haverkort EB, Tytgat GN, van Leeuwen DJ. Maldigestion associated with exocrine pancreatic insufficiency: implications of gastrointestinal physiology and properties of enzyme preparations for a cause-related and patient-tailored treatment. Am J Gastroenterol 1995a;90(9):1383-1393.

Bruno MJ, Hoek FJ, Delzenne B, et al. Simultaneous assessments of exocrine pancreatic function by cholesteryl-[14C]octanoate breath test and measurement of plasma p-aminobenzoic acid. Clin Chem 1995b;41(4):599-604.

Buchler P, Reber HA, et al. Antiangiogenic activity of genistein in pancreatic carcinoma cells is mediated by the inhibition of hypoxia-inducible factor-1 and the down-regulation of VEGF gene expression. Cancer 2004;100(1):201-10.

Bulathsinghala P, Syrigos KN, Saif MW. Role of vitamin d in the prevention of pancreatic cancer. J Nutr Metab 2010;2010:721365.

Burke YD, Ayoubi AS, Werner SR, et al. Effects of the isoprenoids perillyl alcohol and farnesol on apoptosis biomarkers in pancreatic cancer chemoprevention. Anticancer Res 2002;22(6A):3127-3134.

Bussom S, Saif MW. Methods and rationale for the early detection of pancreatic cancer. Highlights from the "2010 ASCO Gastrointestinal Cancers Symposium". Orlando, FL, USA. January 22-24, 2010. JOP 2010;11(2):128-130.

Cai EP, Lin JK. Epigallocatechin gallate (EGCG) and rutin suppress the glucotoxicity through activating IRS2 and AMPK signaling in rat pancreatic beta cells. J Agric Food Chem 2009;57(20):9817-9827.

Caldas C, Hahn SA, Hruban RH, Redston MS, Yeo CJ, Kern SE. Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 1994;54(13):3568-3573.

Caprotti R, Brivio F, Fumagalli L, Nobili C, Degrate L, Lissoni P, . . . Uggeri F. Free-from-progression period and overall short preoperative immunotherapy with IL-2 increases the survival of pancreatic cancer patients treated with macroscopically radical surgery. Anticancer research. May-Jun 2008;28(3b):1951-1954.

Chen da W, Wei Fei Z, et al. Role of enteral immunonutrition in patients with gastric carcinoma undergoing major surgery. Asian J Surg 2005;28(2):121-124.

Chow HH, Salazar D, Hakim IA. Pharmacokinetics of perillic acid in humans after a single dose administration of a citrus preparation rich in d-limonene content. Cancer Epidemiol Biomarkers Prev 2002;11(11):1472-1476.

Chu J, Lloyd FL, et al. Potential involvement of the cyclooxygenase-2 pathway in the regulation of tumor-associated angiogenesis and growth in pancreatic cancer. Mol Cancer The 2003;2(1):1-7.

Clark LC, Combs GF Jr, Turnbull BW,… Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA. 1996 Dec 25;276(24):1957-63.

ClinicalTrials.gov. NCT00486460. Phase III Trial of Gemcitabine, Curcumin and Celebrex in Patients With Advance or Inoperable Pancreatic Cancer. Available at: http://clinicaltrials.gov/ct2/show/NCT00486460?term=00486460&rank=1 6/13/2007. Accessed 9/24/2012.

Combs GF Jr, Clark LC, Turnbull BW. Reduction of cancer risk with an oral supplement of selenium. Biomed Environ Sci. 1997 Sep;10(2-3):227-34.

Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011a;364(19):1817-1825.

Conroy T, Gavoille C, Adenis A. Metastatic pancreatic cancer: old drugs, new paradigms. Curr Opin Oncol 2011b Jul;23(4):390-5.

Cowgill SM, Muscarella P. The genetics of pancreatic cancer. Am J Surg 2003;186(3):279-286.

Crowell PL, Siar AA, Burke YD. Antitumorigenic effects of limonene and perillyl alcohol against pancreatic and breast cancer. Adv Exp Med Biol 1996;401:131-6.:131-136.

Cui J, Cui L, Liu Q, Sun Q. Dendritic cells transfected with lentiviral vector-encoding hTERT peptide augment antitumor T cell response in vitro. Mol Med Report 2011 Oct 3. doi: 10.3892/mmr.2011.610. [Epub ahead of print].

Cullen JJ. Ascorbate induces autophagy in pancreatic cancer. Autophagy 2010;6(3):421-422.

Cuoghi A, Farina A, Z'graggen K, et al. Role of proteomics to differentiate between benign and potentially malignant pancreatic cysts. J Proteome Res 2011;10(5):2664-2670.

Dandona M, Linehan D, Hawkins W, Strasberg S, Gao F, Wang-Gillam A. Influence of obesity and other risk factors on survival outcomes in patients undergoing pancreaticoduodenectomy for pancreatic cancer. Pancreas 2011;40(6):931-937.

Dauer M, Herten J, Bauer C, Renner F, Schad K, Schnurr M, Endres S, Eigler A. Chemosensitization of pancreatic carcinoma cells to enhance T cell-mediated cytotoxicity induced by tumor lysate-pulsed dendritic cells. J Immunother 2005 Jul-Aug;28(4):332-42.

de Albuquerque A, Kubisch I, rnst D, aul S, eier G, rsis N. Prognostic significance of multimarker circulating tumor cells analysis in patients with advanced pancreatic cancer. J Clin Oncol 2011;29(Suppl)(e14657).

Degrate L, Nobili C, Franciosi C, Caprotti R, Brivio F, Romano F, . . . Uggeri F. Interleukin-2 immunotherapy action on innate immunity cells in peripheral blood and tumoral tissue of pancreatic adenocarcinoma patients. Langenbeck's archives of surgery / Deutsche Gesellschaft fur Chirurgie. Jan 2009;394(1):115-121.

Dhillon N, Aggarwal BB, Newman RA, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 2008;14(14):4491-4499.

Domínguez-Muñoz JE. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency: when is it indicated, what is the goal and how to do it? Adv Med Sci 2011;56(1):1-5.

Dragovich T, Burris H 3rd, Loehrer P,… Gemcitabine plus celecoxib in patients with advanced or metastatic pancreatic adenocarcinoma: results of a phase II trial. Am J Clin Oncol. 2008 Apr;31(2):157-62.

Dumonceau JM, Polkowski M, Larghi A, et al. Indications, results, and clinical impact of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy 2011.

Edelman MJ, Watson D, Wang X,… Eicosanoid modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive predictive factor for celecoxib + chemotherapy--Cancer and Leukemia Group B Trial 30203. J Clin Oncol. 2008 Feb 20;26(6):848-55.

Elliott RL, Blobe GC. Role of transforming growth factor Beta in human cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Mar 20 2005;23(9):2078-2093.

El-Rayes BF, Philip PA, Sarkar FH, et al. A phase II study of isoflavones, erlotinib, and gemcitabine in advanced pancreatic cancer. Invest New Drugs 2011;29(4):694-699.

Epelbaum R, Schaffer M, Vizel B, Badmaev V, Bar-Sela G. Curcumin and gemcitabine in patients with advanced pancreatic cancer. Nutr Cancer 2010;62(8):1137-1141.

Ernst E, Schmidt K. Ukrain - a new cancer cure? A systematic review of randomised clinical trials. BMC Cancer 2005 Jul 1;5:69. Review.

Espey MG, Chen P, Chalmers B, et al. Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radic Biol Med 2011;50(11):1610-1619.

FDA. fda.gov. Correspondence to OSI Pharmaceuticals Inc. 11/2/2005. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021743s003ltr.pdf. Accessed 10/20/2011.

Fendrich V, Chen NM, Neef M, Waldmann J, Buchholz M, Feldmann G, Slater EP, Maitra A, Bartsch DK. The angiotensin-I-converting enzyme inhibitor enalapril and aspirin delay progression of pancreatic intraepithelial neoplasia and cancer formation in a genetically engineered mouse model of pancreatic cancer. Gut 2010 May;59(5):630-7.

Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127(12):2893-2917.

Ferrari V, Valcamonico F, Amoroso V, et al. Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase II trial. Cancer Chemother Pharmacol. 2006 Jan;57(2):185-90.

Ferrari V, Valcamonico F, et al. Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase II trial. Cancer Chemother Pharmacol 2005;1-6.

Fidler I. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 2003;3(6):453-458.

Fisher L, Byrnes E, Fisher AA. Prevalence of vitamin K and vitamin D deficiency in patients with hepatobiliary and pancreatic disorders. Nutr Res 2009;29(9):676-683.

Fisher WE, Boros LG, Schirmer WJ. Insulin promotes pancreatic cancer: evidence for endocrine influence on exocrine pancreatic tumors. J Surg Res 1996;63(1):310-313.

Fisher WE. The promise of a personalized genomic approach to pancreatic cancer and why targeted therapies have missed the mark. World J Surg 2011;35(8):1766-1769.

Fogelman DR, Pathak P, Qiao W, et al. Serum CA 19-9 level as a surrogate marker for prognosis in locally advanced pancreatic cancer (LAPC). J Clin Oncol (Meeting Abstracts) 2008;26(15514).

Friess H, Wang L, et al. Growth factor receptors are differentially expressed in cancers of the papilla of vater and pancreas. Ann Surg 1999;230(6):767-74.

Friso S, Choi SW. Gene-nutrient interactions and DNA methylation. J Nutr 2002;132(8 Suppl):2382S-2387S.

Froeling FE, Feig C, Chelala C, et al. Retinoic Acid-Induced Pancreatic Stellate Cell Quiescence Reduces Paracrine Wnt-beta-Catenin Signaling to Slow Tumor Progression. Gastroenterology 2011;141(4):1486-1497.e14.

Fujioka S, Sclabas GM, Schmidt C, et al. Function of nuclear factor kappaB in pancreatic cancer metastasis. Clin Cancer Res 2003;9(1):346-354.

Funahashi H, Satake M, Hasan S, et al. Opposing effects of n-6 and n-3 polyunsaturated fatty acids on pancreatic cancer growth. Pancreas 2008;36(4):353-362.

Funel N, Costa F, Pettinari L, et al. Ukrain affects pancreas cancer cell phenotype in vitro by targeting MMP-9 and intra-/extracellular SPARC expression. Pancreatology 2010;10(5):545-552.

Fyssas I, Syrigos KN, Konstandoulakis MM, et al. Sex hormone levels in the serum of patients with pancreatic adenocarcinoma. Horm Metab Res 1997;29(3):115-118.

Furukawa T, Sunamura M, Horii A. Molecular mechanisms of pancreatic carcinogenesis. Cancer science. Jan 2006;97(1):1-7.

Gallagher EJ, Fierz Y, Ferguson RD, LeRoith D. The pathway from diabetes and obesity to cancer, on the route to targeted therapy. Endocr Pract 2010 ; 16 (5) : 864 -873.

Ganepola GA, Gritsman AY, Asimakopulos N, Yiengpruksawan A. Are pancreatic tumors hormone dependent?: A case report of unusual, rapidly growing pancreatic tumor during pregnancy, its possible relationship to female sex hormones, and review of the literature. Am Surg 1999;65(2):105-111.

Gansauge F, Ramadani M, Pressmar J, et al. NSC-631570 (Ukrain) in the palliative treatment of pancreatic cancer. Results of a phase II trial. Langenbecks Arch Surg 2002;386(8):570-574.

Gapstur SM, Jacobs EJ, Deka A, McCullough ML, Patel AV, Thun MJ. Association of alcohol intake with pancreatic cancer mortality in never smokers. Arch Intern Med 2011;171(5):444-451.

Garcea G, Dennison AR, et al. Role of inflammation in pancreatic carcinogenesis and the implications for future therapy. Pancreatology 2005;5(6):514-29.

Gescher A. Polyphenolic phytochemicals versus non-steroidal anti-inflammatory drugs: which are better cancer chemopreventive agents? J Chemother 2004;16 Suppl 4:3-6.

Ghadirian P, Lynch HT, Krewski D. Epidemiology of pancreatic cancer: an overview. Cancer Detect Prev 2003;27(2):87-93.

Gjertsen MK, Buanes T, Rosseland AR, et al. Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: clinical and immunological responses in patients with pancreatic adenocarcinoma. International Journal of Cancer 2001;92(3):441–450.

Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as "Curecumin": from kitchen to clinic. Biochem Pharmacol 2008;75(4):787-809.

Gomez-Martin C, Hidalgo M, Tabernero J, Isla D. SEOM clinical guidelines for the treatment of pancreatic cancer. Clin Transl Oncol 2011;13(8):528-535.

Gonzalez A, del Castillo-Vaquero A, Miro-Moran A, Tapia JA, Salido GM. Melatonin reduces pancreatic tumor cell viability by altering mitochondrial physiology. J Pineal Res 2011;50(3):250-260.

Grant AG, McGlashan D, Hermon-Taylor J. A study of pancreatic secretory and intracellular enzymes in pancreatic cancer tissue, other gastrointestinal cancers, normal pancreas and serum. Clin Chim Acta 1978;90(1):75-82.

Greco E, Basso D, Fadi E, et al. Analogs of vitamin E epitomized by alpha-tocopheryl succinate for pancreatic cancer treatment: in vitro results induce caution for in vivo applications. Pancreas 2010;39(5):662-668.

Greer JB, Brand RE. New developments in pancreatic cancer. Curr Gastroenterol Rep 2011;13(2):131-139.

Greer JB, Whitcomb DC. Inflammation and pancreatic cancer: an evidence-based review. Curr Opin Pharmacol 2009;9(4):411-418.

Gregor JI, Kilian M, Heukamp I,… Effects of selective COX-2 and 5-LOX inhibition on prostaglandin and leukotriene synthesis in ductal pancreatic cancer in Syrian hamster. Prostaglandins Leukot Essent Fatty Acids. 2005 Aug;73(2):89-97.

Grutzmann R, Pilarsky C, et al. Systematic isolation of genes differentially expressed in normal and cancerous tissue of the pancreas. Pancreatology 2003;3(2):169-78.

Gupta S, Wang F, Holly EA, Bracci PM. Risk of pancreatic cancer by alcohol dose, duration, and pattern of consumption, including binge drinking: a population-based study. Cancer Causes Control 2010;21(7):1047-1059.

Habermehl D, Kammerer B, Handrick R, et al. Proapoptotic activity of Ukrain is based on Chelidonium majus L. alkaloids and mediated via a mitochondrial death pathway. BMC Cancer 2006;6:14.

Hansel DE, Kern SE, Hruban RH. Molecular pathogenesis of pancreatic cancer. Annual review of genomics and human genetics. 2003;4:237-256.

Heller AR, Rossel T, Gottschlich B, et al. Omega-3 fatty acids improve liver and pancreas function in postoperative cancer patients. Int J Cancer 2004;111(4):611-616.

Hennig R, Ding XZ, et al. 5-Lipoxygenase and leukotriene B(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. American Journal of Pathology 2002;161(2):421-8.

Hering J, Garrean S, Dekoj TR, et al. Inhibition of proliferation by omega-3 fatty acids in chemoresistant pancreatic cancer cells. Ann Surg Oncol 2007;14(12):3620-3628.

Hiura A, Tsutsumi M, et al. Inhibitory effect of green tea extract on the process of pancreatic carcinogenesis induced by N-nitrosobis-(2-oxypropyl)amine (BOP) and on tumor promotion after transplantation of N-nitrosobis-(2-hydroxypropyl)amine (BHP)-induced pancreatic cancer in Syrian hamsters. Pancreas 1997;15(3):272-7.

Hoffmann J, Junker H, Schmieder A, et al. EGCG downregulates IL-1RI expression and suppresses IL-1-induced tumorigenic factors in human pancreatic adenocarcinoma cells. Biochem Pharmacol 2011; Jul 20. [Epub ahead of print].

Hsu C, Saif MW. Diabetes and Pancreatic Cancer. Highlights from the "2011 ASCO Annual Meeting". Chicago, IL, USA; June 3-7, 2011. JOP 2011;12(4):330-333.

Huang C, Yang G, Jiang T, Cao J, Huang KJ, Qiu ZJ. Down-regulation of STAT3 expression by vector-based small interfering RNA inhibits pancreatic cancer growth. World J Gastroenterol 2011;17(25):2992-3001.

Huff J, Infante PF. Styrene exposure and risk of cancer. Mutagenesis 2011;26(5):583-584.

Hung Pham, Monica C, Chen HT, Hines OJ, Eibl G. Vitamin D3 Regulates 15-Hydroxyprostaglandin Dehydrogenase in Human Pancreatic Cancer Cells. Gastroenterology 2011;140(5(Suppl)1):S-861.

Hussein D, Mo H. d-delta-Tocotrienol-mediated suppression of the proliferation of human PANC-1, MIA PaCa-2, and BxPC-3 pancreatic carcinoma cells. Pancreas 2009;38(4):e124-e136.

Icli F, Akbulut H, Utkan G, Yalcin B, Dincol D, Isikdogan A, Demirkazik A, Onur H, Cay F, Büyükcelik A. Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer. J Surg Oncol 2007 May 1;95(6):507-12.

Iftimia N, Cizginer S, Deshpande V, et al. Differentiation of pancreatic cysts with optical coherence tomography (OCT) imaging: an ex vivo pilot study. Biomed Opt Express 2011;2(8):2372-2382.

Imrie CW, Connett G, Hall RI, Charnley RM. Review article: enzyme supplementation in cystic fibrosis, chronic pancreatitis, pancreatic and periampullary cancer. Aliment Pharmacol Ther 2010;32 Suppl 1:1-25.

Ito K, Nakazato H, Koike A, et al. Long-term effect of 5-fluorouracil enhanced by intermittent administration of polysaccharide K after curative resection of colon cancer. A randomized controlled trial for 7-year follow-up. Int J Colorectal Dis 2004;19(2):157-164.

Jaffee EM, Hruban RH, Biedrzycki B, et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. Journal of Clinical Oncology 2001;19(1)145–156.

Jaffee EM. Immunotherapy of cancer. Ann N Y Acad Sci 1999;886:67-72. Review.

James E, Waldron-Lynch MG, Saif MW. Prolonged survival in a patient with BRCA2 associated metastatic pancreatic cancer after exposure to camptothecin: a case report and review of literature. Anticancer Drugs 2009;20(7):634-638.

Jansa R, Prezelj J, Kocijancic A, et al. Androstanediol glucuronide in patients with pancreatic cancer and in those with chronic pancreatitis. Horm Metab Res. 1996;28(8):381-3.

Ji BT, Chow WH, et al. Green tea consumption and the risk of pancreatic and colorectal cancers. Int J Cancer 1997;70(3):255-8.

Jiang XT, Tao HQ, Zou SC. Detection of serum tumor markers in the diagnosis and treatment of patients with pancreatic cancer. Hepatobiliary Pancreat Dis Int 2004;3(3):464-468.

Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009;27(20):3297-3302.

Johnson J, de Mejia EG. Dietary factors and pancreatic cancer: the role of food bioactive compounds. Mol Nutr Food Res 2011;55(1):58-73.

Joshi SS, Kuszynski CA, et al. The cellular and molecular basis of health benefits of grape seed proanthocyanidin extract. Curr Pharm Biotechnol 2001;2(2):187-200.

Jutooru I, Chadalapaka G, Lei P, Safe S. Inhibition of NFkappaB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation. J Biol Chem 2010;285(33):25332-25344.

Kanai M, Yoshimura K, Asada M, et al. A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol 2011;68(1):157-164.

Kannappan R, Ravindran J, Prasad S, et al. Gamma-tocotrienol promotes TRAIL-induced apoptosis through reactive oxygen species/extracellular signal-regulated kinase/p53-mediated upregulation of death receptors. Mol Cancer Ther 2010;9(8):2196-2207.

Karlson J, Borg-Karlson AK, Unelius R, et al. Inhibition of tumor cell growth by monoterpenes in vitro: evidence of a Ras-independent mechanism of action. Anticancer Drugs 1996;7(4):422-429.

Katdare M, Osborne MP, et al. Inhibition of aberrant proliferation and induction of apoptosis in pre-neoplastic human mammary epithelial cells by natural phytochemicals. Oncol Rep 1998;5(2):311-5.

Kaufman HL, Kim-Schulze S, Manson K, DeRaffele G, Mitcham J, Seo KS, Kim DW, Marshall J. Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer. J Transl Med 2007 Nov 26;5:60.

Kim ER, Bae SY, Lee KH, e al. Is health screening beneficial for early detection and prognostic improvement in pancreatic cancer? Gut Liver. 2011;5(2):194-9.

Kim JE, Lee KT, Lee JK, Paik SW, Rhee JC, Choi KW. Clinical usefulness of carbohydrate antigen 19-9 as a screening test for pancreatic cancer in an asymptomatic population. J Gastroenterol Hepatol 2004a;19(2):182-186.

Kim R, Saif MW. Is there an optimal neoadjuvant therapy for locally advanced pancreatic cancer? JOP 2007;8(3):279-288.

Kimura Y, Tsukada J, Tomoda T, Takahashi H, Imai K, Shimamura K, Sunamura M, Yonemitsu Y, Shimodaira S, Koido S, Homma S, Okamoto M. Clinical and Immunologic Evaluation of Dendritic Cell-Based Immunotherapy in Combination With Gemcitabine and/or S-1 in Patients With Advanced Pancreatic Carcinoma. Pancreas 2011 Jul 22. [Epub ahead of print].

Kise Y, Yamamura M, Kogata M, et al. Inhibitory effect of selenium on hamster pancreatic cancer induction by N'-nitrosobis(2-oxopropyl)amine. Int J Cancer 1990;46(1):95-100.

Kisiel J. Digestive Disease Week conference. http://www medicalnewstoday com/articles/225130 php 2011.

Klek S, Kulig J, Szczepanik AM, Jedrys J, Kolodziejczyk P. The clinical value of parenteral immunonutrition in surgical patients. Acta Chir Belg 2005;105(2):175-179.

Koda K, Miyazaki M, Sarashina H, et al. A randomized controlled trial of postoperative adjuvant immunochemotherapy for colorectal cancer with oral medicines. Int J Oncol 2003;23(1):165-172.

Koido S, Homma S, Takahara A, Namiki Y, Tsukinaga S, Mitobe J, Odahara S, Yukawa T, Matsudaira H, Nagatsuma K, Uchiyama K, Satoh K, Ito M, Komita H, Arakawa H, Ohkusa T, Gong J, Tajiri H. Current immunotherapeutic approaches in pancreatic cancer. Clin Dev Immunol 2011;2011:267539.

Komoto M, Nakata B, Amano R, et al. HER2 overexpression correlates with survival after curative resection of pancreatic cancer. Cancer Sci 2009;100(7):1243-1247.

Kraft M, Kraft K, Gärtner S,… L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN) - a randomized multicentre trial. utr J. 2012 Jul 23;11:52.

Kranenburg O. The KRAS oncogene: past, present, and future. Biochim Biophys Acta 2005;1756(2):81-82.

Kudo Y, Kamisawa T, Anjiki H, Takuma K, Egawa N. Incidence of and risk factors for developing pancreatic cancer in patients with chronic pancreatitis. Hepatogastroenterology 2011;58(106):609-611.

Kunnumakkara AB, Sung B, Ravindran J, et al. {Gamma}-tocotrienol inhibits pancreatic tumors and sensitizes them to gemcitabine treatment by modulating the inflammatory microenvironment. Cancer Res 2010;70(21):8695-8705.

Kuroki-Suzuki S, Kuroki Y, Nasu K, et al. Pancreatic cancer screening employing noncontrast magnetic resonance imaging combined with ultrasonography. Jpn J Radiol 2011;29(4):265-271.

Laheru D, Lutz E, Burke J, et al., Allogeneic granulocyte macrophage colony-stimulating factor secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clinical Cancer Research 2008;14(5):1455–1463.

Lai KC, Hsu SC, Kuo CL, et al. Diallyl sulfide, diallyl disulfide, and diallyl trisulfide inhibit migration and invasion in human colon cancer colo 205 cells through the inhibition of matrix metalloproteinase-2, -7, and -9 expressions. Environ Toxicol 2011.

Lamerz R. Role of tumour markers, cytogenetics. Ann Oncol 1999;10 Suppl 4:145-149.

Langer P, Kann PH, Fendrich V, et al. Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer. Gut 2009;58(10):1410-1418.

Larsson SC, Bergkvist L, Wolk A. Consumption of sugar and sugar-sweetened foods and the risk of pancreatic cancer in a prospective study. Am J Clin Nutr 2006;84(5):1171-1176.

Larsson SC, Orsini N, Wolk A. Vitamin B6 and risk of colorectal cancer: a meta-analysis of prospective studies. JAMA. 2010 Mar 17;303(11):1077-83.

Lebedeva IV, Su ZZ, Vozhilla N, et al. Chemoprevention by perillyl alcohol coupled with viral gene therapy reduces pancreatic cancer pathogenesis. Mol Cancer Ther 2008;7(7):2042-2050.

Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer 2011;11:20.:20.

Leja-Szpak A, Jaworek J, Pierzchalski P, Reiter R. Melatonin induces pro-apoptotic signaling pathway in human pancreatic carcinoma cells (PANC-1). Journal of Pineal Research 2010;49(3):248-255.

Lepisto AJ, Moser AJ, Zeh H, et al. A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Therapy 2008;6(B):955–964.

Lev-Ari S, Vexler A, Starr A, et al. Curcumin augments gemcitabine cytotoxic effect on pancreatic adenocarcinoma cell lines. Cancer Invest 2007;25(6):411-418.

Levy MJ, Wiersema MJ. Endoscopic ultrasound in the diagnosis and staging of pancreatic cancer. Oncology (Williston Park) 2002;16(1):29-38, 43.

Li D, Morris JS, Liu J, et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA 2009a;301(24):2553-2562.

Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009b;137(2):482-488.

Li L, Aggarwal BB, Shishodia S, Abbruzzese J, Kurzrock R. Nuclear factor-kappaB and IkappaB kinase are constitutively active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis. Cancer 2004a;101(10):2351-2362.

Li Y, Ellis KL, Ali S, et al. Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-kappaB in BxPC-3 pancreatic cancer cell line. Pancreas 2004b;28(4):e90-e95.

Lian F, Li Y, Bhuiyan M, Sarkar FH. p53-independent apoptosis induced by genistein in lung cancer cells. Nutr Cancer 1999;33(2):125-131.

Lian JP, Word B, Taylor S, Hammons GJ, Lyn-Cook BD. Modulation of the constitutive activated STAT3 transcription factor in pancreatic cancer prevention: effects of indole-3-carbinol (I3C) and genistein. Anticancer Res 2004;24(1):133-137.

Lin Y, Tamakoshi A, Hayakawa T, Naruse S, Kitagawa M, Ohno Y. Nutritional factors and risk of pancreatic cancer: a population-based case-control study based on direct interview in Japan. J Gastroenterol 2005;40(3):297-301.

Lissoni P, Ardizzoia A, Barni S, et al. Efficacy and tolerability of cancer neuroimmunotherapy with subcutaneous low-dose interleukin-2 and the pineal hormone melatonin - a progress report of 200 patients with advanced solid neoplasms. Oncol Rep 1995a;2(6):1063-1068.

Lissoni P, Ardizzoia A, Meregalli S, et al. A clinical-study of immunotherapy versus endocrine therapy versus chemotherapy in the treatment of advanced pancreatic adenocarcinoma. Oncol Rep 1994;1(6):1277-1280.

Lissoni P, Barni S, Tancini G, et al. Immunoendocrine therapy with low-dose subcutaneous interleukin-2 plus melatonin of locally advanced or metastatic endocrine tumors. Oncology 1995b;52(2):163-166.

Lissoni P, Paolorossi F, Tancini G, et al. A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients. Br J Cancer 1996;74(9):1466-1468.

Liu H, Ma Q, Li J. High glucose promotes cell proliferation and enhances GDNF and RET expression in pancreatic cancer cells. Mol Cell Biochem 2011;347(1-2):95-101.

Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006;20(2):197-209.

Lu H, Yang Y, Gad E, et al. Polysaccharide krestin is a novel TLR2 agonist that mediates inhibition of tumor growth via stimulation of CD8 T cells and NK cells. Clin Cancer Res 2011a;17(1):67-76.

Lu H, Yang Y, Gad E, et al. TLR2 agonist PSK activates human NK cells and enhances the anti-tumor effect of HER2-targeted monoclonal antibody therapy. Clin Cancer Res 2011b.Sep 14 [Epub ahead of print].

Lucenteforte E, La VC, Silverman D, et al. Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann Oncol 2011.

Lutz E, Yeo CJ, Lillemoe KD, Biedrzycki B, Kobrin B, Herman J, Sugar E, Piantadosi S, Cameron JL, Solt S, Onners B, Tartakovsky I, Choi M, Sharma R, Illei PB, Hruban RH, Abrams RA, Le D, Jaffee E, Laheru D. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann Surg 2011 Feb;253(2):328-35.

Lyn-Cook BD, Rogers T, Yan Y, Blann EB, Kadlubar FF, Hammons GJ. Chemopreventive effects of tea extracts and various components on human pancreatic and prostate tumor cells in vitro. Nutr Cancer 1999;35(1):80-86.

Magruder JT, Elahi D, Andersen DK. Diabetes and pancreatic cancer: chicken or egg? Pancreas 2011;40(3):339-351.

Majima T, Tsutsumi M, Nishino H,… Inhibitory effects of beta-carotene, palm carotene, and green tea polyphenols on pancreatic carcinogenesis initiated by N-nitorsobis(2-oxopropyl)amine in Syrian golden hamsters. Pancreas. 1998 Jan;16(1):13-8.

Maki RG, Livingston PO, Lewis JJ, Janetzki S, Klimstra D, Desantis D, Srivastava PK, Brennan MF. A phase I pilot study of autologous heat shock protein vaccine HSPPC-96 in patients with resected pancreatic adenocarcinoma. Dig Dis Sci 2007 Aug;52(8):1964-72.

Mandalà M, Tondini C. The impact of thromboprophylaxis on cancer survival: focus on pancreatic cancer. Expert Rev Anticancer Ther 2011 Apr;11(4):579-88.

Masamune A, Satoh M, Kikuta K, Suzuki N, Satoh K, Shimosegawa T. Ellagic acid blocks activation of pancreatic stellate cells. Biochem Pharmacol 2005;70(6):869-878.

Matos JM, Schmidt CM, Thomas HJ, et al. A pilot study of perillyl alcohol in pancreatic cancer. J Surg Res 2008;147(2):194-199.

McIntyre BS, Sylvester PW. Genistein and erbstatin inhibition of normal mammary epithelial cell proliferation is associated with EGF-receptor down-regulation. Cell Prolif 1998;31(1):35-46.

McKenna WG, Muschel RJ. Targeting tumor cells by enhancing radiation sensitivity. Genes Chromosomes Cancer 2003;38(4):330-8.

Menapace LA, Khorana AA. The role of thromboprophylaxis in cancer patients: emerging data. Curr Opin Hematol 2010 Sep;17(5):450-6.

Meyer F, Galan P, Douville P,… Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial. Int J Cancer. 2005 Aug 20;116(2):182-6.

Michaud DS, Joshipura K, Giovannucci E, Fuchs CS. A prospective study of periodontal disease and pancreatic cancer in US male health professionals. J Natl Cancer Inst 2007;99(2):171-175.

Michaud DS, Liu S, Giovannucci E, Willett WC, Colditz GA, Fuchs CS. Dietary sugar, glycemic load, and pancreatic cancer risk in a prospective study. J Natl Cancer Inst 2002;94(17):1293-1300.

Michaud DS, Liu Y, Meyer M, Giovannucci E, Joshipura K. Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study. Lancet Oncol 2008;9(6):550-558.

Michaud DS, Vrieling A, Jiao L, et al. Alcohol intake and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan). Cancer Causes Control 2010;21(8):1213-1225.

Mihaljevic A, Buchler P, Harder J, et al. A prospective, non-randomized phase II trial of Trastuzumab and Capecitabine in patients with HER2 expressing metastasized pancreatic cancer. BMC Surg 2009;9:1.

Miltyk W, Craciunescu CN, Fischer L, et al. Lack of significant genotoxicity of purified soy isoflavones (genistein, daidzein, and glycitein) in 20 patients with prostate cancer. Am J Clin Nutr 2003;77(4):875-882.

Mirzoeva OK, Hann B, Hom YK, et al. Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma. J Mol Med (Berl) 2011;89(9):877-889.

Miyazawa M, Ohsawa R, Tsunoda T, Hirono S, Kawai M, Tani M, Nakamura Y, Yamaue H. Phase I clinical trial using peptide vaccine for human vascular endothelial growth factor receptor 2 in combination with gemcitabine for patients with advanced pancreatic cancer. Cancer Sci 2010 Feb;101(2):433-9.

Moore PS, Begheli S, Zamboni G, et al. Genetic abnormalities in pancreatic cancer. Mol Cancer. 2003;2:7.

Morales E, Porta M, Vioque J, et al. Food and nutrient intakes and K-ras mutations in exocrine pancreatic cancer. J Epidemiol Community Health 2007;61(7):641-649.

Morgan-Meadows S, Dubey S, Gould M, et al. Phase I trial of perillyl alcohol administered four times daily continuously. Cancer Chemother Pharmacol 2003;52(5):361-366.

Moses AW, Slater C, Preston T, Barber MD, Fearon KC. Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids. Br J Cancer 2004;90(5):996-1002.

Mountzios G, et al. A benefit-risk assessment of erlotinib in non-small-cell lung cancer and pancreatic cancer. Drug Saf. 2011 Mar 1;34(3):175-86. doi: 10.2165/11586540-000000000-00000.

Mousa SA. Antithrombotic effects of naturally derived products on coagulation and platelet function. Methods Mol Biol 2010;663:229-40.

Muc-Wierzgon M, Nowakowska-Zajdel E, Zubelewicz B, et al. Circadian fluctuations of melatonin, tumor necrosis factor-alpha and its soluble receptors in the circulation of patients with advanced gastrointestinal cancer. J Exp Clin Cancer Res 2003;22(2):171-178.

Nakamura M, Wada J, Suzuki H, Tanaka M, Katano M, Morisaki T. Long-term outcome of immunotherapy for patients with refractory pancreatic cancer. Anticancer Res 2009 Mar;29(3):831-6.

Nakamura T, Takebe K, et al. Effects of pancreatic digestive enzymes, sodium bicarbonate, and a proton pump inhibitor on steatorrhoea caused by pancreatic diseases. J Int Med Res 1995;23(1):37-47.

Nakchbandi IA, Löhr JM. Coagulation, anticoagulation and pancreatic carcinoma.Nat Clin Pract Gastroenterol Hepatol 2008 Aug;5(8):445-55.

Nakchbandi W, Müller H, Singer MV, Löhr M, Nakchbandi IA. Effects of low-dose warfarin and regional chemotherapy on survival in patients with pancreatic carcinoma. Scand J Gastroenterol 2006 Sep;41(9):1095-104.

Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32(1):193-203.

National Toxicology Program. Department of Health and Human Services (DHHS). About the Report on Carcinogens. Public Health page. Available at: http://ntp.niehs.nih.gov/?objectid=03C9B512-ACF8-C1F3-ADBA53CAE848F635. Last updated 9/7/2012. Accessed 7/16/2013.

Nava-Parada P, Emens LA. GV-1001, an injectable telomerase peptide vaccine for the treatment of solid cancers. Curr Opin Mol Ther 2007 Oct;9(5):490-7.

Neuhaus P, Riess H, Post S, et al. CONKO-001: final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer. J Clin Oncol 2008 ; 26 ((suppl)) : abstr LBA4504.

Nimptsch K, Rohrmann S, Linseisen J. Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). Am J Clin Nutr. 2008 Apr;87(4):985-92.

Nitsche C, Simon P, Weiss FU, et al. Environmental risk factors for chronic pancreatitis and pancreatic cancer. Dig Dis 2011;29(2):235-242.

Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, . . . Uggeri F. Prolonged survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. Tumori. May-Jun 2008;94(3):426-430.

Oaks BM, Dodd KW, Meinhold CL, Jiao L, Church TR, Stolzenberg-Solomon RZ. Folate intake, post-folic acid grain fortification, and pancreatic cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Clin Nutr 2010;91(2):449-455.

Ochi K, Harada H, Mizushima T, Tanaka J, Matsumoto S. Intraductal secretin test is as useful as duodenal secretin test in assessing exocrine pancreatic function. Dig Dis Sci 1997;42(3):492-496.

Oh DY, et al. A phase II trial of erlotinib in combination with gemcitabine and capecitabine in previously untreated metastatic/recurrent pancreatic cancer: combined analysis with translational research. Invest New Drugs. 2011 Mar 15. [Epub ahead of print].

Ohta T, Arakawa H, et al. [A new strategy for the therapy of pancreatic cancer by proton pump inhibitor]. Gan To Kagaku Ryoho 1996;23(12):1660-4.

Osada S, Carr BI. Mechanism of novel vitamin K analog induced growth inhibition in human hepatoma cell line. J Hepatol. 2001 May;34(5):676-82.

Ou YQ, Zhu W, Li Y, Qiu PX, Huang YJ, Xie J, He SM, Zheng XK, Leng TD, Xu D, Yan GM. Aspirin inhibits proliferation of gemcitabine-resistant human pancreatic cancer cells and augments gemcitabine-induced cytotoxicity. Acta Pharmacol Sin 2010 Jan;31(1):73-80.

Paquin SC, Gariepy G, Lepanto L, Bourdages R, Raymond G, Sahai AV. A first report of tumor seeding because of EUS-guided FNA of a pancreatic adenocarcinoma. Gastrointest Endosc 2005;61(4):610-611.

Parker LA, Lumbreras B, Lopez T, Hernandez-Aguado I, Porta M. How useful is it clinically to analyse the K-ras mutational status for the diagnosis of exocrine pancreatic cancer? A systematic review and meta-analysis. Eur J Clin Invest 2011;41(7):793-805.

Pecher G, H¨aring A, Kaiser L, Thiel E. Mucin gene (MUC1) transfected dendritic cells as vaccine: results of a phase I/II clinical trial. Cancer Immunology, Immunotherapy 2002;51(11-12):669–673.

Peluso G, Nicolai R, Reda E,… Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system. J Cell Physiol. 2000 Mar;182(3):339-50.

Persson C, Glimelius B, Ronnelid J, Nygren P. Impact of fish oil and melatonin on cachexia in patients with advanced gastrointestinal cancer: a randomized pilot study. Nutrition 2005;21(2):170-178.

Pisano C, Vesci L, Milazzo FM, Metabolic approach to the enhancement of antitumor effect of chemotherapy: a key role of acetyl-L-carnitine. Clin Cancer Res. 2010 Aug 1;16(15):3944-53. Epub 2010 Jun 18.

Plate JM, Plate AE, Shott S, Bograd S, Harris JE. Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunol Immunother 2005 Sep;54(9):915-25.

Prasad, A.S., Beck,F.W., Snell,D.C. and Kucuk,O. Zinc in cancer prevention, Nutr.Cancer.2009., 879-887, 1961.

Pruemer J. Prevalence, causes, and impact of cancer-associated thrombosis. Am J Health Syst Pharm 2005 Nov 15;62(22 Suppl 5):S4-6.

Ramanathan RK, Lee KM, McKolanis J, et al. Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer. Cancer Immunology, Immunotherapy 2005;54(3):254–264.

Recchia F, Sica G, et al. Advanced carcinoma of the pancreas: phase II study of combined chemotherapy, beta-interferon, and retinoids. Am J Clin Oncol 1998;21(3):275-8.

Risch HA, Yu H, Lu L, Kidd MS. ABO blood group, Helicobacter pylori seropositivity, and risk of pancreatic cancer: a case-control study. J Natl Cancer Inst 2010;102(7):502-505.

Robles-Diaz G, Duarte-Rojo A. Pancreas: a sex steroid-dependent tissue. Isr Med Assoc J. 2001;3(5):364-8.

Rogers KR, Kikawa KD, Mouradian M, et al. Docosahexaenoic acid alters epidermal growth factor receptor-related signaling by disrupting its lipid raft association. Carcinogenesis 2010;31(9):1523-1530.

Ross JA, Maingay JP, Fearon KC, Sangster K, Powell JJ. Eicosapentaenoic acid perturbs signalling via the NFkappaB transcriptional pathway in pancreatic tumour cells. Int J Oncol 2003;23(6):1733-1738.

Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011 Jan 1;377(9759):31-41.

Roy AM, Baliga MS, Elmets CA, Katiyar SK. Grape seed proanthocyanidins induce apoptosis through p53, Bax, and caspase 3 pathways. Neoplasia 2005;7(1):24-36.

Saif MW. Does erlotinib restore chemosensitivity to chemotherapy in pancreatic cancer? A case series. Anticancer Res. 2011a Mar;31(3):1039-42.

Schernhammer E, Wolpin B, Rifai N, et al. Plasma folate, vitamin B6, vitamin B12, and homocysteine and pancreatic cancer risk in four large cohorts. Cancer Res 2007;67(11):5553-5560.

Schibli S, Durie PR, et al. Proper usage of pancreatic enzymes. Curr Opin Pulm Med 2002;8(6):542-6.

Schusdziarra V, Holland A, Maier V, Pfeiffer EF. Effect of naloxone on pancreatic and gastric endocrine function in response to carbohydrate and fat-rich test meals. Peptides 1984;5(1):65-71.

Schutte M, Hruban R H, Geradts J, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Research 1997;57:3126.

Sclabas GM, Uwagawa T, Schmidt C, Hess KR, Evans DB, Abbruzzese JL, Chiao PJ. Nuclear factor kappa B activation is a potential target for preventing pancreatic carcinoma by aspirin. Cancer 2005 Jun 15;103(12):2485-90.

Shah MM, Saif MW. Pancreatic cancer and thrombosis. Highlights from the "2010 ASCO Annual Meeting". Chicago, IL, USA. June 4-8, 2010. JOP 2010 Jul 5;11(4):331-3.

Shankar S, Suthakar G, Srivastava RK. Epigallocatechin-3-gallate inhibits cell cycle and induces apoptosis in pancreatic cancer. Front Biosci 2007;12:5039-5051.

Shanmugam MK, Kannaiyan R, Sethi G. Targeting cell signaling and apoptotic pathways by dietary agents: role in the prevention and treatment of cancer. Nutr Cancer 2011;63(2):161-173.

Shehzad A, Wahid F, Lee YS. Curcumin in cancer chemoprevention: molecular targets, pharmacokinetics, bioavailability, and clinical trials. Arch Pharm (Weinheim) 2010;343(9):489-499.

Shi Y, Wu J, et al. Farnesyltransferase inhibitor effects on prostate tumor micro-environment and radiation survival. Prostate 2005;62(1):69-82.

Shin-Kang S, Ramsauer VP, Lightner J, et al. Tocotrienols inhibit AKT and ERK activation and suppress pancreatic cancer cell proliferation by suppressing the ErbB2 pathway. Free Radic Biol Med 2011.

Shirota T, Haji S, Yamasaki M, et al. Apoptosis in human pancreatic cancer cells induced by eicosapentaenoic acid. Nutrition 2005;21(10):1010-1017.

Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): Mechanisms, perspectives and clinical applications. Biochem Pharmacol 2011Jul 30. [Epub ahead of print].

Singh SV. Impact of garlic organosulfides on p21 (H-ras) processing. J Nutr. 2001;131(3s):1046S-8S.

Skinner HG. Vitamin D for the treatment and prevention of pancreatic cancer. Cancer Biol Ther 2008;7(3):437-439.

Skipworth RJ, Moses AG, Sangster K, Sturgeon CM, Voss AC, Fallon MT, Anderson RA, Ross JA, Fearon KC. Interaction of gonadal status with systemic inflammation and opioid use in determining nutritional status and prognosis in advanced pancreatic cancer. Support Care Cancer 2011 Mar;19(3):391-401.

Snady H, Bruckner HW, et al. Survival advantage of combined chemoradiotherapy compared with resection as the initial treatment of patients with regional pancreatic carcinoma. An outcomes trial. Cancer 2000;89(2):314-27.

Sohail MA, Saif MW. Role of anticoagulation in the management of pancreatic cancer. JOP 2009 Mar 9;10(2):82-7.

Sohma M, Kitagawa T, Okano S, et al. [Two cases of unresectable pancreatic cancer responding to combined chemotherapy with cisplatin, PSK and UFT]. Gan To Kagaku Ryoho 1987;14(6 Pt 1):1926-1929.

Solomon VR, Lee H. Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol 2009; 625(1-3): 220- 233.

Sperti C, Bonadimani B, Guolo P, Militello C, Cappellazzo F, Pasquali C, Pedrazzoli S. Androgen profile in patients with pancreatic carcinoma. Ital J Gastroenterol 1992 Jul-Aug;24(6):328-31

Stayrook KR, McKinzie JH, Barbhaiya LH, Crowell PL. Effects of the antitumor agent perillyl alcohol on H-Ras vs. K-Ras farnesylation and signal transduction in pancreatic cells. Anticancer Res 1998;18(2A):823-828.

Stingl JC, Ettrich T, Muche R, et al. Protocol for MInimizing the Risk of Metachronous Adenomas of the CoLorectum with Green Tea Extract (MIRACLE): a randomised controlled trial of green tea extract versus placebo for nutriprevention of metachronous colon adenomas in the elderly population. BMC Cancer 2011;11:360.

Stoita A, Penman ID, Williams DB. Review of screening for pancreatic cancer in high risk individuals. World J Gastroenterol 2011;17(19):2365-2371.

Stolzenberg-Solomon RZ, Albanes D, Nieto FJ,… Pancreatic cancer risk and nutrition-related methyl-group availability indicators in male smokers. J Natl Cancer Inst. 1999 Mar 17;91(6):535-41.

Stolzenberg-Solomon RZ, Dodd KW, Blaser MJ, Virtamo J, Taylor PR, Albanes D. Tooth loss, pancreatic cancer, and Helicobacter pylori. Am J Clin Nutr 2003;78(1):176-181.

Stolzenberg-Solomon RZ, Graubard BI, Chari S et al. Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers. JAMA 2005;294(22):2872-2878.

Stolzenberg-Solomon RZ. Vitamin D and pancreatic cancer. Ann Epidemiol 2009; 19 (2):89-95.

Strimpakos AS, Syrigos KN, Saif MW. Translational research in pancreatic cancer. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011. JOP 2011;12(2):120-122.

Strouch MJ, Ding Y, Salabat MR, et al. A high omega-3 fatty acid diet mitigates murine pancreatic precancer development. J Surg Res. 2011;165(1):75-81.

Sun J. D-Limonene: safety and clinical applications. Altern Med Rev 2007;12(3):259-264.

Suso EM, Dueland S, Rasmussen AM, Vetrhus T, Aamdal S, Kvalheim G, Gaudernack G. hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes. Cancer Immunol Immunother 2011 Jun;60(6):809-18.

Suzuki K, Aiura K, Ueda M, Kitajima M. The influence of platelets on the promotion of invasion by tumor cells and inhibition by antiplatelet agents. Pancreas 2004;29(2):132-140.

Swamy MV, Citineni B, Patlolla JM, Mohammed A, Zhang Y, Rao CV. Prevention and treatment of pancreatic cancer by curcumin in combination with omega-3 fatty acids. Nutr Cancer 2008;60 Suppl 1:81-9.:81-89.

Takimoto CH, Glover K, Huang X, et al. Phase I pharmacokinetic and pharmacodynamic analysis of unconjugated soy isoflavones administered to individuals with cancer. Cancer Epidemiol Biomarkers Prev 2003;12(11 Pt 1):1213-1221.

Talamini G, Falconi M, Bassi C, et al. Incidence of cancer in the course of chronic pancreatitis. Am J Gastroenterol 1999;94(5):1253-1260.

Tan XL, Reid-Lombardo KM, Bamlet WR, Oberg AL, Robinson DP, Anderson KE, Petersen GM. Aspirin, nonsteroidal anti-inflammatory drugs (NSAID), acetaminophen, and pancreatic cancer risk: A clinic-based case-control study. Cancer Prev Res (Phila) 2011 Jul 29. [Epub ahead of print].

Thiébaut AC, Jiao L, Silverman DT, et al. Dietary fatty acids and pancreatic cancer in the NIH-AARP diet and health study. J Natl Cancer Inst 2009;101(14):1001-1011.

Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM. Risk factors of vitamin B(12) deficiency in patients receiving metformin. Arch Intern Med 2006;166(18):1975-1979.

Toubaji A, Achtar M, Provenzano M, Herrin VE, Behrens R, Hamilton M, Bernstein S, Venzon D, Gause B, Marincola F, Khleif SN. Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers. Cancer Immunol Immunother 2008 Sep;57(9):1413-20.

Tranah GJ, Holly EA, Wang F, Bracci PM. Cigarette, cigar and pipe smoking, passive smoke exposure, and risk of pancreatic cancer: a population-based study in the San Francisco Bay Area. BMC Cancer 2011;11:138.:138.

Trikudanathan G, Philip A, Dasanu CA, Baker WL. Association between Helicobacter pylori infection and pancreatic cancer. A cumulative meta-analysis. JOP 2011;12(1):26-31.

Tsukagoshi S, Hashimoto Y, Fujii G, Kobayashi H, Nomoto K, Orita K. Krestin (PSK). Cancer Treat Rev 1984;11(2):131-155.

Tucker ON, Dannenberg AJ, et al. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res 1999;59(5):987-90.

Turner BG, Cizginer S, Agarwal D, Yang J, Pitman MB, Brugge WR. Diagnosis of pancreatic neoplasia with EUS and FNA: a report of accuracy. Gastrointest Endosc 2010;71(1):91-98.

Uggeri F, Caprotti R, De Grate L, Crippa S, Nobili C, Penati C, Romano F. Short-term preoperative IL-2 immunotherapy in operable pancreatic cancer: a randomized study. Hepato-gastroenterology. May-Jun 2009;56(91-92):861-865.

Uwagawa T, et al. Proton-pump inhibitor as palliative care for chemotherapy-induced gastroesophageal reflux disease in pancreatic cancer patients. J Palliat Med. 2010 Jul;13(7):815-8.

Vaccaro V, Melisi D, Bria E, et al. Emerging pathways and future targets for the molecular therapy of pancreatic cancer. Expert Opin Ther Targets 2011;Oct;15(10):1183-96.

van Doormaal FF, Di Nisio M, Otten HM, Richel DJ, Prins M, Buller HR. Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer. J Clin Oncol 2011 May 20;29(15):2071-6.

Vaquero EC, Edderkaoui M, Pandol SJ, et al. Reactive oxygen species produced by NAD(P)H oxidase inhibit apoptosis in pancreatic cancer cells. J Biol Chem. 2004;279(33):34643-54.

Vashi PG, Trukova K, Lammersfeld CA, Braun DP, Gupta D. Impact of oral vitamin D supplementation on serum 25-hydroxyvitamin D levels in oncology. Nutr J 2010;9:60.:60.

Vazquez-Martin A, Lopez-Bonetc E, Cufi S, et al. Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions. Drug Resist Updat 2011;14(4-5):212-223.

Vigushin DM, Poon GK, Boddy A et al. Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee. Cancer Chemother Pharmacol 1998;42(2):111-117.

Vu HA, Beppu Y, Chi HT, et al. Green tea epigallocatechin gallate exhibits anticancer effect in human pancreatic carcinoma cells via the inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor. J Biomed Biotechnol 2010;2010:290516.

Wang CJ, Wang C, Han J, Wang YK, Tang L, Shen DW, . . . Zhang H. Effect of combined treatment with recombinant interleukin-2 and allicin on pancreatic cancer. Molecular biology reports. Dec 2013;40(12):6579-6585.

Wang HY, Xiu DR, Li ZF, Wang G. Coagulation function in patients with pancreatic carcinoma. Chin Med J (Engl) 2009 Mar 20;122(6):697-700.

Wang Z, Ahmad A, Banerjee S, et al. FoxM1 is a novel target of a natural agent in pancreatic cancer. Pharm Res 2010;27(6):1159-1168.

Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH. Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer 2006;106(11):2503-2513.

Wedén S, Klemp M, Gladhaug IP, et al. Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. International Journal of Cancer. 2011;128(5):1120-1128.

Wei G, Wang M, Carr BI. Sorafenib combined vitamin K induces apoptosis in human pancreatic cancer cell lines through RAF/MEK/ERK and c-Jun NH2-terminal kinase pathways. J Cell Physiol. 2010 Jul;224(1):112-9.

Wendel M, Heller AR. Anticancer actions of omega-3 fatty acids--current state and future perspectives. Anticancer Agents Med Chem 2009;9(4):457-470.

Wenger FA, Kilian M, Achucarro P,… Effects of Celebrex and Zyflo on BOP-induced pancreatic cancer in Syrian hamsters. Pancreatology. 2002;2(1):54-60.

Wilentz RE, Chung CH, Sturm PD, et al. K-ras mutations in the duodenal fluid of patients with pancreatic carcinoma. Cancer 1998;82(1):96-103.

Wobser M, Keikavoussi P, Kunzmann V, Weininger M, Andersen MH, Becker JC. Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin. Cancer Immunology, Immunotherapy. 2006;55(10):1294–1298.

Woutersen RA, Appel MJ, et al. Modulation of pancreatic carcinogenesis by antioxidants. Food Chem Toxicol 1999;39(9-10):981-4.

Xu X, Strimpakos AS, Saif MW. Biomarkers and Pharmacogenetics in Pancreatic Cancer. Highlights from the "2011 ASCO Annual Meeting". Chicago, IL, USA; June 3-7, 2011. JOP 2011;12(4):325-329.

Yamaguchi K, Nakamura K, Kimura M, et al. Intraoperative radiation enhances decline of pancreatic exocrine function after pancreatic head resection. Dig Dis Sci 2000; 45(6):1084-1090.

Yamamoto K, Mine T, Katagiri K, et al. Immunological evaluation of personalized peptide vaccination for patients with pancreatic cancer. Oncology Reports 2005b;13(5):874–883.

Yamamoto K, Ueno T, Kawaoka T, et al. MUC1 peptide vaccination in patients with advanced pancreas or biliary tract cancer. Anticancer Research 2005a;25(5):3575–3579.

Yanagimoto H, Mine T, Yamamoto K, Satoi S, Terakawa N, Takahashi K, Nakahara K, Honma S, Tanaka M, Mizoguchi J, Yamada A, Oka M, Kamiyama Y, Itoh K, Takai S. Immunological evaluation of personalized peptide vaccination with gemcitabine for pancreatic cancer. Cancer Sci 2007 Apr;98(4):605-11.

Yanagimoto H, Shiomi H, Satoi S, Mine T, Toyokawa H, Yamamoto T, Tani T, Yamada A, Kwon AH, Komatsu N, Itoh K, Noguchi M. A phase II study of personalized peptide vaccination combined with gemcitabine for non-resectable pancreatic cancer patients. Oncol Rep 2010 Sep;24(3):795-801.

Yang S, Wang X, Contino G, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev 2011a;25(7):717-729.

Yang YX. Do diabetes drugs modify the risk of pancreatic cancer? Gastroenterology 2009;137(2):412-415.

Yates KR, Welsh J, Echrish HH, Greenman J, Maraveyas A, Madden LA. Pancreatic cancer cell and microparticle procoagulant surface characterization: involvement of membrane-expressed tissue factor, phosphatidylserine and phosphatidylethanolamine. Blood Coagul Fibrinolysis 2011 Sep 21. [Epub ahead of print].

Yu LL, et al. Curcumin reverses chemoresistance of human gastric cancer cells by downregulating the NF-κB transcription factor. Oncol Rep. 2011 Nov;26(5):1197-203. doi: 10.3892/or.2011.1410. Epub 2011 Aug 2.

Zeilhofer HU, Mollenhauer J, Brune K. Selective growth inhibition of ductal pancreatic adenocarcinoma cells by the lysosomotropic agent chloroquine. Cancer Lett 1989;44(1):61-66.

Zemskov V, Prokopchuk O, Susak Y. Efficacy of ukrainthe treatment of . Langenbecks Arch Surg. 2002;387(2):84-9.

Zemskov VS, Procopchuk OL, Susak YM, Zemskov SV, Hodysh YY, Zemskova MV. Ukrain (NSC-631570) in the treatment of pancreas cancer. Drugs Exp Clin Res 2000;26(5-6):179-190.

Zhang H, Morisaki T, Matsunaga H, et al. Protein-bound polysaccharide PSK inhibits tumor invasiveness by down-regulation of TGF-beta1 and MMPs. Clin Exp Metastasis. 2000;18(4):343-52.

Zhang H, Morisaki T, Nakahara C, et al. PSK-mediated NF-kappaB inhibition augments docetaxel-induced apoptosis in human pancreatic cancer cells NOR-P1. Oncogene 2003;22(14):2088-2096.

Zhang J, Dhakal IB, Gross MD, et al. Physical activity, diet, and pancreatic cancer: a population-based, case-control study in Minnesota. Nutr Cancer 2009;61(4):457-465.

Zhang J, Zhang X, Dhakal IB, Gross MD, Kadlubar FF, Anderson KE. Sequence variants in antioxidant defense and DNA repair genes, dietary antioxidants, and pancreatic cancer risk. Int J Mol Epidemiol Genet 2011;2(3):236-244.

Zhou JH, Cheng HY, Yu ZQ, He DW, Pan Z, Yang DT. Resveratrol induces apoptosis in pancreatic cancer cells. Chin Med J (Engl) 2011;124(11):1695-1699.

Zubarik R, Gordon SR, Lidofsky SD, et al. Screening for pancreatic cancer in a high-risk population with serum CA 19-9 and targeted EUS: a feasibility study. Gastrointest Endosc. 2011;74(1):87-95.