Pancreatic Cancer-2

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

Diagnostic Imaging

1)CT (computed tomography).A spiral CT detects tumor presence and cancer spread, and assesses the feasibility of surgically removing the growth (Dimagno EP et al 1999).

2)Ultrasound. If the patient is jaundiced, an ultrasound (US) will be performed.

3)EUS (endoscopic ultrasonography) can differentiate between pancreatic cancer and pancreatitis (Levy MJ et al 2002), and can detect pancreatic lesions of less than 20 mm in size and small islet cell tumors of less than 10 mm (Yamao K et al 2003).

4)IDUS (intraductal ultrasonography) is useful in detecting carcinoma in situ, identifying small tumors, differentiating non-cancerous (benign) from cancerous (malignant) cases, and assessing cancer spread (Yamao K et al 2003).

5)MRI (magnetic resonance imaging.)MRI between the chest and hips has a sensitivity of 100 percent (Schima W et al 2002). Enhanced MRI offers improved detection of small pancreatic spread and liver metastases.

6)PET (positron emission tomography). PET with 18-fluorodeoxyglucose (18-FDG PET) is an experimental technique that can detect cancers as small as 7 mm in diameter and distant cancer spread in approximately 40 percent of cases. False positives (tests indicating that cancer is present when it is not) can occur in inflamed tissues (Saisho H et al 2004) and in chronic and autoimmune pancreatitis (Higashi T et al 2003).


Typical Medical Treatments for Pancreatic Cancer
Conventional cancer treatments include surgery and various types of radiation therapy and chemotherapy. Apart from surgery, standard treatments do not prolong survival significantly. However, adjuvant systemic chemotherapy using gemcitabine showed some survival benefit in stage IV pancreatic cancer patients. The respective survival rates of the gemcitabine and surgery-only groups were 86 percent and 70 percent at one year, and 50 percent and 12 percent at two years, with a median survival time of 20 months and 14 months. The disease-free interval was improved, and the occurrence of hepatic metastasis was reduced in the gemcitabine group compared to the surgery-only group (Kurosaki I et al 2005).

Experimental treatments under investigation should be explored, including:

Targeted antibodies (HER2/neu, EG-FR) that bind to unique proteins on pancreatic cancer cells and alert the immune system to attack them (Hansel DE et al 2005; Kim T 2004; Xiong HQ et al 2004b).
Drugs known as antiangiogenics that prevent new tumor blood vessels from developing, which is necessary for tumor survival (Sangro B et al 2004).
Drugs known as anti-metastatic agents that prevent cancer from invading healthy tissues (Blumenthal RD et al 2005).
Vaccines such as Oncophage and GM-CSF (Jaffee EM et al 1998).
New drugs that were not originally developed for pancreatic cancer treatment but have incidentally been shown to hinder its growth, including drugs that eliminate the activity of the enzymes COX-2 (cyclooxygenase-2) (for example, Celebrex®) and 5-LOX (5-lipoxygenase) (Anderson KM et al 1998b; Crane CH et al 2003; Ding XZ et al 2001; Hennig R et al 2002; Kokawa A et al 2001; Tong WG et al 2002; Tucker ON et al 1999).
Replenishing the body with pancreatic enzymes that may not be produced because of the cancer may also be a beneficial strategy to consider (Novak JF et al 2005).

Surgery
Only 15 percent 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 percent and a five-year survival rate of only 10 percent (Snady H et al 2000). The median survival time for the inoperable 85-90 percent 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 often is used in the conventional treatment of pancreatic cancer (Snady H et al 2000).

Radiation
Radiation therapy alone can improve pain and may prolong survival (Goldstein D et al 2004). Precision external-beam techniques are required. For patients with advanced pancreatic cancer, a radiation procedure known as IMRT (intensity modulated radiation therapy) combined with the drug 5-fluorouracil (5-FU) can provide symptom relief with tolerable short-term toxicity (Bai YR et al 2003). Please refer to the Cancer Radiation protocol for information on supporting healthy tissues during radiation therapy.

Radioimmunotherapy (RAIT, RIT) is a novel approach in which radiation is delivered to known and unknown tumor sites by chemically linking the radiation source to an antibody (a type of protein) that specifically targets a tumor marker.

The PAM4 antibody targets the MUC1 mucin produced in more than 85 percent of human pancreatic cancers (Gold DV et al 1994).
MUC4, another mucin that is overproduced in pancreatic cancer, is associated with cancer that spreads and with altered growth of tumor cells (Singh AP et al 2004). Anti-MUC4 monoclonal antibodies have been developed and may represent a powerful tool for diagnosing and treating pancreatic tumors (Moniaux N et al 2004; Saitou M et al 2005). When mice with pancreatic tumors were treated with a radioiodine-linked antibody, tumors decreased to approximately 15 percent of their initial volume, while untreated tumors grew 16.5-fold over the same period (Gold DV et al 1997).
A similar radioantibody approach using yttrium-90 as the radiation source in combination with the drug Gemzar® was found to be more effective than either treatment method alone, with minimal toxicity to normal tissues (Gold DV et al 2003).

Chemotherapy
While many chemotherapy drugs have been evaluated, no single drug has produced a significant response rate or greatly improved the average survival rate. One chemotherapy approach for pancreatic cancer is a combination of 5-FU, streptozotocin, and cisplatin (Snady H et al 2000). Understandably, every chemotherapy treatment plan must be individualized according to the type, location, and progression of the patient's pancreatic cancer. Please refer to Genzyme Genetics (www.genzymegenetics.com) for more information on individual tumor analysis, which may be beneficial in determining an optimal, individualized treatment plan.

Evidence suggests that the proper combination of cell-differentiating agents (agents that convert cancer cells to normal cells) and chemotherapy drugs may slow pancreatic cancer progression (Missiaglia E et al 2005). In order to have a realistic chance of achieving a significant remission (a complete or partial disappearance of cancer), the use of nutritional supplementation together with experimental or investigational therapies, including clinical trials (www.clinicaltrials.gov), is highly recommended (Modrak DE et al 2004).

Long-Term Survival with Alpha-Lipoic Acid (Intravenous), Multiple Antioxidants, and Low-Dose Naltrexone
A recent case report describes the long-term survival (>3 years) of a 46-year-old man who was diagnosed with a very aggressive cancer of the pancreas (adenocarcinoma) which had spread to the liver (Berkson BM et al 2006). The patient had a 3.9 x 3.9 cm tumor in the head of the pancreas and 4 tumors in the liver, one of which was 5 to 6 cm in diameter. He was told there was not much that could be done for him, yet he was treated with one round of a typical chemotherapy regimen (Gemzar® (gemcitabine) and Paraplatin® (carboplatin)), which caused reduced blood cell counts but no tumor regression. He received a second opinion that any further treatment would be in vain, so he opted for an integrative medical approach (via the Integrative Medical Center of New Mexico).

For his non-cancer medical conditions he was given several antacids (Prevacid® 30 mg, Rolaids®), antibiotics (Primsol™/Gantanol®), antiulcer agents (Mylanta®, Pepto-Bismol®), and the anti-anxiety drug, Xanax®, and then he started an integrative therapy program, the ALA-LDN (Intravenous Alpha-Lipoic Acid- Low-Dose Naltrexone) protocol.

The ALA-LDN protocol comprised 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, he maintained a strict dietary regimen, performed a stress-reduction and exercise program, and led a healthy lifestyle. Remarkably, after just one treatment of intravenous ALA his symptoms began to disappear, his quality of life improved, and he had no unwanted side effects.

His pancreatic cancer has remained stable for more than 3-years and he is free from symptoms. Several other patients are being treated with this protocol and, to date, with success (Berkson BM et al 2006). Thus, the ALA-LDN protocol could possibly extend the lives of those pancreatic cancer patients who have been led to believe that their cancer is terminal.

So How Does It Work? Alpha-lipoic acid is a potent antioxidant (Baraboi VA 2005), improves immune cells’ functions (Mantovani G et al 2000), increases homocysteine levels in cancer cells which is toxic to them (Hultberg B 2003), and prevents the activation of nuclear factor kappaB (NF-kappaB) a key regulator of tumor development and progression (Sokoloski JA et al 1997;Suzuki YJ et al 1992;Vermeulen L et al. 2006). Selenium is useful in elevating antioxidant levels (Woutersen RA et al 1999; Zhan CD et al 2004) and silymarin is a selective COX-2 inhibitor (Cuendet M et al 2000a).

Low-dose naltrexone blocks opiate receptors causing the body to make large amounts of opiates in response, which in turn improve the immune response; specifically, natural killer cell cytotoxicity, B-cell and T-cell proliferation, and IFN-gamma production are maintained during times of immune suppression (Nelson CJ et al 2000).

Prevacid® is an antacid that also improves cell-mediated immunity, prevents immune suppression, and may also exert anti-inflammatory activity, all of which are important for cancer patients with impaired immune systems (Dattilo M et al 1998; Peddicord TE et al 1999).


Innovative Drug Strategies
Several therapeutic strategies are being explored for the treatment of pancreatic cancer, including:

Pancreatic enzymes, by prescription, pancrelipase powder, or enteric-coated preparations (Braga M et al 1988; Gonzalez NJ et al 1999; Novak JF et al 2005).
COX-2 (cyclooxygenase-2) inhibitors, such as Celebrex® (celecoxib) in combination with chemotherapy (Crane CH et al 2003; Ding XZ et al 2000; Lipton A et al 2004; Tseng WW et al 2002; Wei D et al 2004).
Lipoxygenase inhibitors, such as zileuton, a 5-LOX (5-lipoxygenase) inhibitor.
Pancreatic Enzyme Replacement Therapy
Dr. John Beard, who published The Enzyme Theory of Cancer in 1911, was the first to propose using pancreatic digestive enzymes to treat cancer. Later, Dr. William Donald Kelley treated his cancer patients with enzymes for more than 20 years, and many lived far beyond expectations. By comparison, in a trial of 126 pancreatic cancer patients treated with the drug Gemzar®, not one patient lived longer than 19 months (Burris HA3 1996). Treating patients with pancreatic extract containing enzymes resulted in significantly improved absorption in those with moderate-to-severe fat or protein malabsorption (Perez MM et al 1983).

In a remarkable study by Dr. Nicholas Gonzalez, 11 patients with pancreatic cancer were treated with large doses of pancreatic enzymes, nutritional supplements, "detoxification" procedures, and an organic diet. Of the 11 patients, nine survived for one year, five survived two years, and four survived three years. This pilot study suggests that aggressive nutritional therapy with large doses of pancreatic enzymes significantly increased survival over what would normally be expected for patients with inoperable pancreatic cancer (Gonzalez NJ et al 1999). An experimental animal study found that treating tumors in mice with pancreatic enzyme extract (PPE) significantly prolonged their survival and slowed tumor growth (Saruc M et al 2004).

As a result of the pilot study, the National Cancer Institute and the National Center for Complementary and Alternative Medicine approved funding for a large-scale phase III clinical trial comparing Dr. Gonzalez's nutritional regimen against Gemzar® in treating inoperable pancreatic cancer. This study has full FDA approval and is being conducted under the Department of Surgical Oncology at New York Presbyterian Hospital, Columbia Campus (www.clinicaltrials.gov):

“In the nutritional arm: Patients receive pancreatic enzymes orally every four hours and at meals daily on days 1-16, followed by five days of rest. Patients receive magnesium citrate and Papaya Plus with the pancreatic enzymes. Additionally, patients receive nutritional supplementation with vitamins, minerals, trace elements, and animal glandular products four times per day on days 1-16, followed by five days of rest. Courses repeat every 21 days. Patients consume a moderate vegetarian metabolizer diet during the course of therapy, which excludes red meat, poultry, and white sugar. Coffee enemas are performed twice a day, along with skin brushing daily, skin cleansing once a week with castor oil during the first six months of therapy, and a salt-and-soda bath each week. Patients also undergo a complete liver flush and a clean sweep and purge on a rotating basis each month during the five days of rest.”
To learn more about the study and its objectives, call Cara Visser in the office of John Chabot, M.D., Chief of Surgical Oncology at Columbia University, 212-305-0787.

Several factors contribute to the effectiveness of pancreatic enzyme replacement therapy. These include:

Patient compliance and adherence to scheduled dose and timing of intake.
Individual weight perception versus actual weight measurement.
Type of pancreatic enzyme preparations, that is, pancrelipase powder versus enteric-coated products (Schibli S et al 2002). Delayed-release preparations (capsules containing enteric-coated microspheres, such as Creon®) are reportedly less susceptible to acid inactivation in the stomach and duodenum, as they are designed to disintegrate at a relatively high gastrointestinal pH (greater than 5.5 to 6). Antacids or a histamine H2-receptor antagonist (cimetidine, Tagamet®) have been used to decrease the inactivation of enzyme activity.

COX-2 (Cyclooxygenase-2) Inhibitors
The COX-2 enzyme is elevated in pancreatic cancer (Tucker ON et al 1999) and indirectly prevents cancer cells from dying (Chu J et al 2003). The COX-2 inhibitor Celebrex® reduces levels of the COX-2 enzyme and is now being investigated for use in cancer treatment (Ferrari V et al 2005; Fosslien E 2000; Lipton A et al 2004).

The combination of Celebrex® and 5-FU by prolonged intravenous injection was well tolerated and capable of producing long-lasting, measurable responses, even in patients with advanced pancreatic cancer (Milella M et al 2004). Selective reduction of COX-2 levels improves response to both chemotherapy and radiotherapy without being toxic to normal healthy tissues (Ferrari V et al 2005; Lipton A et al 2004). COX-2 inhibition sensitizes tumor cells to death by radiation and is now being studied in clinical trials (Rich TA et al 2004). However, COX-2 inhibitors may cause heart attack or stroke, as well as kidney damage. Because of these concerns, the FDA-approved drugs Vioxx® and Bextra® have been taken off the market by their manufacturers. Celebrex®, however, is still available.

Suppressing the COX-2 enzyme may inhibit pancreatic cancer cell propagation. In the past, COX-2 inhibitors such as Celebrex® (100-200 mg taken every 12 hours) were considered. However, with recent observations that people taking COX-2 inhibitors for prolonged periods have a higher incidence of cardiac and vascular problems, some of these drugs may no longer be available in the future. Instead, bioflavonoids could be considered at a dose of 250-1800 mg a day, or silymarin (420 mg/day) (Boari C et al 1981; Pares A et al 1998) and/or curcumin (3600 mg/day), which have demonstrated the ability to naturally suppress COX-2 (Gescher A 2004).

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 et al 2002). Reducing levels of 5-LOX prevents human pancreatic cancer cell lines from multiplying and induces apoptosis (cell death). In a phase II study, the 5-LOX inhibitor CV6504 was well tolerated and maintained stable disease. The predicted one-year survival time was approximately 25 percent (Ferry DR et al 2000).

Zileuton, a 5-LOX inhibitor, was approved in the United States in September 2005 for the prevention and chronic treatment of asthma in patients 12 years and older. The drug is contraindicated in patients with active liver disease.

Investigational/Experimental Therapies

Oncophage Vaccine. Antigenics (866-805-8994, www.antigenics.com) manufactures personalized vaccines or general vaccines, based on the use of heat-shock proteins (BioDrugs et al 2002; Hoos A et al 2003; Oki Y et al 2004).


GM-CSF Vaccine. Targets tumor cell lines that produce the immune system-stimulating growth factor known as granulocyte-macrophage colony-stimulating factor (GM-CSF) (Jaffee EM et al 2001; Jaffee EM et al 1998). GM-CSF with synthetic mutant ras peptides resulted in prolonged survival (148 versus 61 days) (Gjertsen MK et al 2001; Gjertsen MK et al 2003).

Angiogenesis Inhibitors (tumor-blocker drugs) under testing include PTK787/ZK 222584 (a VEGFR2 inhibitor) (Baker CH et al 2002b; Wiedmann MW et al 2005), VEGF antisense, and TNP-470 (Hotz HG et al 2005; Jia L et al 2005).

Herceptin® (trastuzumab) is an antibody that binds to HER2 and may be appropriate for those who have excess HER2 (Safran H et al 2004).

EGFR-Targeted Therapy: Produces antibodies against the epidermal growth factor receptor, such as Erbitux™(cetuximab) or panitumumab (ABX-EGF) (Needle MN 2002; Yang XD et al 2001). In a phase II trial, 41 patients were treated with anti-EGF antibody and Gemzar®. One-year progression-free survival and overall survival rates were 12 percent and 31.7 percent, respectively (Xiong HQ et al 2004a).


Nutritional Therapy and Supplements
Nutritional intervention aims to:

a)Reduce the occurrence of pancreatic cancer.
b)Decrease treatment-related disease and deaths.
c)Enhance response to radiation and chemotherapy.
d)Improve long-term survival via direct therapeutic effects.

Consuming a diet rich in fruit and vegetables, plus controlling calories by dietary measures or exercise, will help to prevent pancreatic cancer (Lowenfels AB et al 2004). A constituent of cruciferous vegetables such as watercress called phenethyl isothiocyanate (PEITC) stopped pancreatic cancer from developing in a hamster model that was given a cancer-causing agent (a carcinogen known as BOP) (Nishikawa A et al 2004).

Monoterpenes.
Monoterpenes are found in the essential oils of citrus fruits and other plants. The monoterpenes limonene and perillyl alcohol demonstrate intense antitumor activity against pancreatic cancer cells (Crowell PL et al 1996; Gelb MH et al 1995). They counter cancer by:

Jump-starting enzymes that are able to break down cancer-causing chemicals.
Preventing cancer cell growth by reducing ras activity and causing cancer cell death.
Restraining liver enzyme actions (hepatic HMG-CoA reductase activity), which controls cholesterol production and thus cancer cell growth.

Limonene.
Found in citrus fruits, limonene reduces the growth of pancreatic cancer cells by 50 percent (Karlson J et al 1996). The tentative dose recommendation for limonene is 7.3 to 14.4 grams per day (Boik J 2001; Igimi H et al 1976; Vigushin DM et al 1998). According to studies, limonene is well tolerated in cancer patients at doses that may have clinical activity (Salazar D et al 2002). One partial response in a breast cancer patient at a dose of 8 grams taken twice daily was maintained for 11 months, and three additional patients with colorectal cancer showed disease stabilization for longer than six months on d-limonene at .5 or 1 gram taken twice daily (Vigushin DM et al 1998).

Perillyl Alcohol.
Perillyl alcohol is found in small concentrations in the essential oils of lavender, peppermint, spearmint, sage, cherries, cranberries, perilla, lemongrass, celery, and caraway seeds (Belanger JT 1998). Perillyl alcohol exhibits powerful effects in minimizing cancer cell growth (Hardcastle IR et al 1999; Stark MJ et al 1995) and preventing the mutated ras proteins from continuously stimulating cancer cell growth (Broitman SA et al 1995; Burke YD et al 2002).

Twelve clinical trials have investigated the use of perillyl alcohol in various types of cancer treatments. A 2050-mg dose administered four times daily was found to be easily tolerated (Morgan-Meadows S et al 2003). In one clinical trial, perillyl alcohol was administered four times a day to 16 patients with advanced cancers not responding to treatment. Evidence of antitumor activity was seen in a patient with metastatic colorectal cancer who had an ongoing near-complete response of greater than two years’ duration. Several patients had stable disease for as long as or greater than six months (Ripple GH et al 2000). The predominant toxicity of perillyl alcohol seen during most trials was gastrointestinal (nausea, vomiting, and belching), limiting the dose. The minimum required antitumor dose is 1.3 grams per day (Boik J 2001).

Gamma Linolenic Acid (GLA).GLA, a fatty acid found in borage oil, slows the growth and spread of pancreatic cancer by hindering tumor blood-vessel development (Cai J et al 1999). GLA treatment changes tissue blood flow dramatically in pancreatic tumors, even at low doses (Kairemo KJ et al 1998; Ravichandran D et al 1998).

Intravenous administration of the lithium salt of GLA (Li-GLA) to 48 patients with inoperable pancreatic cancer was associated with longer survival times (Fearon KC et al 1996).

A cell-culture study investigated possible interactions between GLA and 5-FU or Gemzar®. GLA had a synergistic effect with Gemzar® at concentrations that correspond to therapeutic doses in the body. However, GLA with 5-FU was synergistic only within a tight range of high concentrations of 5-FU (Whitehouse PA et al 2003).

Fish Oil. Patients with advanced pancreatic cancer usually experience weight loss (catabolic wasting or cachexia) and often fail to gain weight with conventional nutritional support. EPA, an essential fatty acid found in fish oil, restrains pancreatic cancer cell growth in laboratory experiments at low doses and decreases the number of cancer cells at higher doses (Lai PB et al 1996). The maximum tolerated daily dose of fish oil was found to be 0.3 grams per kilogram (kg) of body weight. This means that a 70-kg (154-lb.) patient can generally tolerate up to 21 grams of fish oil containing 13.1 grams of EPA and DHA (Burns CP et al 1999). However, 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 new high-purity preparation of EPA as a 20 percent oil and water diester emulsion was tolerated (Barber MD et al 2001).

Several studies have shown that supplementation with fish oils containing EPA and DHA is helpful and may even reverse weight loss caused by cancer (Merendino N et al 2003; Wigmore SJ et al 2000). Moreover, consumption of a protein- and energy-dense oral nutritional supplement containing omega-3 fatty acids (such as EPA) improves body weight, lean body mass, and quality of life in patients undergoing chemotherapy (Bauer JD et al 2004; Chen da W et al 2005; Klek S et al 2005).

Fish oil supplements providing at least 2400 mg of EPA and 1800 mg of DHA daily have been recommended (Anderson KM et al 1998a). To reduce cachexia, an estimated 2 to 12 grams per day of EPA is needed (Gogos CA et al 1998; Persson C et al 2005; Rosenstein ED et al 2003; Thies