Pancreatic cancer is the fourth leading cause of cancer death in the United States, accounting for approximately 30,000 deaths each year (Michaud DS 2004). Worldwide, more than 200,000 people die from this cancer each year.
Little is known about the causes of pancreatic cancer. The disease is difficult to diagnose in its early stages, as it presents few symptoms and there are few tests to screen for it. As a result, most patients have incurable disease by the time they are diagnosed. Fewer than 5 percent of pancreatic cancer patients survive five years beyond diagnosis of the disease. Surgery is the only hope for cure; however, due to the aggressive nature of pancreatic tumors, only 5 percent to 20 percent of patients are candidates for surgery (Cleary SP et al. 2004). Chemotherapy and radiation therapy produce only minor increases in survival rates. Conventional medicine's inability to treat pancreatic cancer effectively is illustrated by the fact that more than 90 percent of patients die within 12 months of diagnosis. Along with lifestyle changes and nutritional approaches, novel therapeutic strategies are needed for the treatment of pancreatic cancer.
About the Pancreas
The pancreas is a pear-shaped gland located across the back of the belly, behind the stomach. It comprises the exocrine pancreas, which produces pancreatic enzymes that help break down carbohydrates, fats, and proteins, and the endocrine pancreas, which produces hormones such as insulin and glucagon that regulate how the body stores and uses food.
Risk Factors for Pancreatic Cancer
Age, sex, race, and ethnicity. The disease is more common in the elderly and among men, and there is a higher incidence rate among African-Americans (Ghadirian L et al 2003).
a)Smoking (Lowenfels AB et al 2002; Michaud DS 2004).
Exposure to chemicals such as gasoline, petroleum products, and DDT (Alguacil J et al 2003; Hoppin JA et al 2000; Simon B et al 2001).
Inherited pancreatic disease and inherited breast cancer (Cowgill SM et al 2003; Ghadirian P et al 2003; Lowenfels AB et al 2004).
Chronic pancreatitis and diabetes mellitus (Truninger K 2000).
Insulin resistance (Berrington de Gonzalez A et al 2003).
Diet: excess calorie intake; high intake of saturated fats and oils, including omega-6 fatty acids, meat, and dairy products; and high intake of fried foods, carbohydrates, cholesterol, salt, nitrites from animal products, and nitrosamines (Coss A et al 2004).
About 95 percent of pancreatic cancers begin in the exocrine pancreas, where enzymes are produced. The remaining 5 percent are cancers of the endocrine pancreas, where hormones are produced; these are also called islet cell cancers. Typically, pancreatic cancer spreads first to nearby lymph nodes, then to the liver and, less commonly, the lungs. It can also directly invade surrounding organs such as the upper region of the small intestine, stomach, and colon.
Alterations of Function in Pancreatic Cancer
Pancreatic cancer can alter the normal function of the pancreas by:
Creating a deficiency of pancreatic enzymes, bicarbonate, and bile salt.
Causing poor absorption of nutrients from food.
Impairing the use of pancreatic enzymes.
The activity of pancreatic enzymes is impaired by an acidic environment, which is partly determined by dietary intake. Each day, the exocrine tissue secretes about 2 liters of bicarbonate (a buffer) to neutralize stomach acid in the small intestine. Reduced bicarbonate levels create an acidic microenvironment that weakens the activity of pancreatic enzymes. Some evidence suggests that antacids, alkaline diet, and essential fatty acids may be beneficial in treating pancreatic cancer (Nakamura T et al 1995; Ohta T et al 1996; Ravichandran D et al 1998).
Causes of and Risk Factors for Pancreatic Cancer
While the exact cause of pancreatic cancer is not known with certainty, several factors—including smoking, nutrition, glucose levels, hormones, and genetics—are thought to be involved in its initiation and development.
Smoking. Smoking is a major risk factor, accounting for 25-30 percent of all cases. Heavy smokers are two to three times more at risk for cancer than are nonsmokers (Lowenfels AB et al 2002). Several studies have observed a reduction in pancreatic cancer risk within a decade after smoking cessation (Michaud DS 2004).
Nutritional influences on pancreatic cancer. DNA damage caused by exposure to free radicals has been found in human pancreatic tissues (Uden S et al 1992). In pancreatic cancer cells, antioxidant levels are much lower compared to those in non-cancerous pancreatic cells. Nutritional supplements such as alpha-tocopherol (Ferreira PR et al 2004; Hernaandez J et al 2005; Rautalahti MT et al 1999), ascorbic acid (Zullo A et al 2000), zinc (Ertekin MV et al 2004; Prasad AS et al 2004; Uden S et al 1992), and selenium may be beneficial in elevating antioxidant levels (Zhan CD et al 2004).
Glucose levels and pancreatic cancer. Abnormal sugar metabolism, diabetes (DeMeo MT 2001 Gapstur SM et al 2000), and foods that elevate after-meal blood sugar levels are associated with increased pancreatic cancer risk in individuals with insulin resistance (Michaud DS et al 2002). Increasing soluble fiber intake has been shown to improve after-meal glucose levels and insulin response in healthy subjects (Aller R et al 2004; Lu ZX et al 2000). Thus, supplemental fiber may help to stabilize glucose levels (Rayes N et al 2002; Tsai AC et al 1987).
Phytoestrogens. Evidence suggests that the increased incidence of pancreatic cancer in Western nations may be related to the relatively low dietary content and qualities of naturally occurring plant hormones (phytoestrogens) (Stephens FO 1999). Daidzein, a phytoestrogen found in soybeans, chickpeas, and dietary supplements, has been shown to slow the growth of pancreatic cell lines (Guo JM et al 2004).
Folate. Maintaining adequate blood folate levels or increasing folate intake from dietary or vitamin sources may reduce pancreatic cancer risk significantly (Kim YI 1999). In a study of 27,101 healthy male smokers, 157 developed pancreatic cancer during 13 years of follow-up. Those with the lowest folate intake showed a 48 percent increased risk of pancreatic cancer (Stolzenberg-Solomon RZ et al 2001).
Lycopene. Data support an association between reduced lycopene levels and pancreatic cancer (Comstock GW et al 1991). In a clinical study, low levels of lycopene, retinol, and beta-carotene were strongly associated with pancreatic cancer (Abiaka CD et al 2001). Tomatoes are a rich dietary source of lycopene, which is also available as a dietary supplement (Ansari MS et al 2004).
Olive Oil. Olive oil contains several antioxidants and a protective fat called oleic acid that diminish the risk of cell damage (Owen RW et al 2004) by scavenging free radicals (Alarcon de la Lastra C et al 2001). In a study of 362 pancreatic cancer cases and 1502 controls in Italy, olive oil had a comparatively more favorable impact on pancreatic cancer risk than did other types of fats (La Vecchia C et al 1997).
Are Hormones Involved?Testosterone:
A low serum testosterone/dihydrotestosterone (DHT) ratio has been observed in some patients with pancreatic carcinoma (Corbishley TP et al 1986; Robles-Diaz G et al 2001). Based on findings that hormone receptors are contained in human pancreatic adenocarcinomas (Andren-Sandberg A et al 1990) and on experimental studies showing that pancreatic cancer development is influenced by sex hormones (Robles-Diaz G et al 2001), it is possible that hormonal manipulation might be of value in treating pancreatic cancer (Ganepola GA et al 1999). In one study, an anti-androgen was shown to prolong life significantly in patients with inoperable pancreatic carcinoma (Andren-Sandberg A et al 1990).
Parathyroid hormone-related protein (PTHrP):
PTHrP regulates the growth and division of experimental pancreatic cancer (Grzesiak JJ et al 2004; Grzesiak JJ et al 2005). PTHrP is produced in pancreatic adenocarcinoma tumor specimens, suggesting that it may be a useful marker in monitoring the growth of pancreatic cancer in the body (Bouvet M et al 2002).
Genetic and Protein Changes
Genetic damage is highly associated with pancreatic cancer (Shiraishi K et al 2001). People with immediate family members affected by the disease are at increased risk for pancreatic cancer (Rulyak SJ et al 2003) and should consider pancreatic cancer screening if it becomes available.
At least 222 genes are overproduced and active in pancreatic cancer, and may be valuable in discovering novel ways to stop tumor growth (Grutzmann R et al 2003). Readers with neuroendocrine tumors are referred to Genzyme Genetics (www.genzymegenetics.com) for more information on how to obtain an analysis of genes found in their tumors, which may be beneficial in determining an optimal, individualized treatment plan.
Activation of cancer-associated genes (oncogenes)
K-ras and HER2/neu are cancer-associated genes (oncogenes) that acquire mutations resulting in the inactivation of genes that typically prevent tumor formation. These include p16, p53, DPC4, BRCA2, and FHIT (Moore PS et al 2003).
Ras genes.
Ras proteins play a central role in regulating cell growth, multiplication, and life cycle. Mutations in the ras genes can transform normal cells into cancerous cells that grow rapidly and form tumors. Ras oncogene mutations have been identified in up to 95 percent of pancreatic cancers (Brasiuniene B et al 2003). Smoking and alcohol and coffee consumption have been linked with the occurrence of ras mutations in pancreatic tumors (Li D et al 2003).
Detection of K-ras mutations.
The detection of K-ras mutations may help to predict treatment outcome. K-ras mutations are relatively easy to detect in different human tissues, including blood, intestinal fluid (Wilentz RE et al 1998), pancreatic fluid (Boadas J et al 2001), stool (Caldas C et al 1994), regional lymph nodes and other bodily fluids, and the tumor itself (Brasiuniene B et al 2003).
Ras gene activity can be slowed by:
1)Fish oil containing the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Singh J et al 1997).
2)Garlic’s natural component, diallyl disulfide (Gail MH et al 1998; Singh SV 2001).
3)d-Limonene and perillyl alcohol, natural monoterpenes (Chen X et al 1999) from citrus fruits and essential oils.
4)Green tea extract containing epigallocatechin gallate (EGCG) (Lyn-Cook BD et al 1999a).
5)Black tea extract containing black tea polyphenol (BTP) (Lyn-Cook BD et al 1999a).
Tumor cells with a mutant ras are more difficult to kill with radiation than are cells with normal ras (McKenna WG et al 2003). However, laboratory experiments have shown that the FTI (farnesyl transferase inhibitor) drug L-744,832 makes pancreatic cancer cells with a K-ras mutation more sensitive to the killing effects of radiation (Alcock RA et al 2002). Therefore, the combination of an FTI and radiation may offer therapeutic advantages for those undergoing radiotherapy (Shi Y et al 2005).
HER2. HER2 is found in many pancreatic cancers and is associated with poor patient survival rates. In one study, patients with HER2 lived for only 7 months, whereas those without it lived at least 19 months (Lei S et al 1995).
A flavonoid called apigenin reduces the growth of cancer cells containing HER2 significantly (Way TD et al 2004).
HER2 can be targeted specifically by the neutralizing antibody drug Herceptin®.
EGF-R (epidermal growth factor receptor). In pancreatic cancer cells, EGF-R is turned on and levels are 4-fold higher than in normal healthy pancreatic cells (Friess H et al 1999).
The green tea polyphenol EGCG has been shown to block EGF-R activity (Liang YC et al 1997), as have luteolin and quercetin (Baker CH et al 2002a).
Curcumin prevents activation of EGF-R (Korutla L et al 1995).
Genistein from soy is powerful in reducing levels of EGF-R (McIntyre BS et al 1998) and may disable the EGF-R signaling pathway (Bai J et al 2004).
Important genes turned off in pancreatic cancer
Compared to other major types of cancer, pancreatic cancer evinces a loss of activity of genes known to suppress tumor development, such as p16, DPC4, BRCA2, and p53.
p16 is turned off in virtually all pancreatic ductal cancers (Bartsch DK et al 2002; Cowgill SM et al 2003) and in 40 percent to 75 percent of all pancreatic cancers.
DPC4 is absent from approximately 50 percent of pancreatic cancers and is associated with more-invasive cancer growth (Cowgill SM et al 2003).
BRCA2 mutations have been clearly associated with pancreatic cancer development (Naderi A et al 2002).
p53: Because p53 is involved in repairing damaged DNA, when this gene is inactive (turned off) or malfunctions, damaged DNA is able to proliferate and form cancerous cells (Berrozpe G et al 1994). Nutritional supplements known to change levels or restore function of the p53 gene include:
Red grape seed proanthocyanidins (Joshi SS et al 2001).
Folate (Kim YI et al 2001).
Phytochemicals such as genistein from soy (Lian F et al 1999), indole-3-carbinol (I3C) from cruciferous vegetables, and the green tea polyphenol EGCG (Katdare M et al 1998).
Regulation of Transcription Factors. A transcription factor controls whether a particular gene is turned on (active) or turned off (inactive). Transcription factors can be activated or deactivated selectively by other proteins, often as a final step in the process of transmitting their signals. The presence and activity of these factors can differ in normal and cancerous tissues.
STAT3 is a dormant transcription factor activated in pancreatic cancer but not in normal pancreatic tissue.
Nutritional agents such as I3C and genistein inhibit STAT3 from functioning (Lian JP et al 2004).
NF-kappa B is another transcription factor activated in human pancreatic cancer but not in normal pancreatic tissue. Blocking NF-kappa B activity prevents cancer invasion and spread (metastasis) in animals with tumors. Furthermore, preventing NF-kappa B activity reduces levels of molecules involved in tumor blood-vessel development, thereby retarding tumor growth and slowing cancer spread (Fujioka S et al 2003).
Genistein and curcumin both reduce NF-kappa B activation (Li L et al 2004; Li Y et al 2004).
What You Have Learned So Far
-When pancreatic cells do not die when they should, pancreatic cancer results (called carcinoma of the pancreas or, rarely, islet cell tumor).
-Pancreatic cancer has the lowest five-year survival rate of any cancer.
-Conventional treatment does not appreciably extend survival.
-Surgery is the only hope for cure.
-Smoking, obesity, exposure to chemicals, genetics, and eating red meat, refined sugar, and fried foods increase pancreatic cancer risk.
-Diet and lifestyle modifications may improve outcomes.
-Genetic analysis of tumors provides information for customized treatment.
Possible Signs and Symptoms of Pancreatic Cancer
1)Jaundice (yellowing of the skin and whites of the eyes) due to blockage of the bile duct or liver malfunction.
2)A gnawing pain from the stomach to the back.
3)Unexplained weight loss from malabsorption of nutrients or loss of appetite.
4)Fatigue or chronic tiredness.
Laboratory Testing
Early diagnosis of pancreatic cancer is difficult, even with recent advances in diagnostic methods. Symptoms develop gradually and steadily, and are often present for many months before diagnosis. Physicians typically use a range of imaging studies to confirm the diagnosis (see sidebar on “Diagnostic Imaging”). The development of improved early-detection methods is essential (Brand R 2001). No standard for pancreatic cancer screening exists, but strategies employing endoscopic, radiologic, and molecular methods to screen high-risk individuals are under investigation (Konner J et al 2002). Tumor markers (substances in the body that indicate the presence of tumors) do not permit early diagnosis of pancreatic cancer, but on follow-up are used to indicate the presence of tumors. Endoscopic ultrasound has been used to detect abnormal pancreatic cells in family members of pancreatic cancer patients; in high-risk patients, it has revealed cystic masses that were not detected by spiral CT scan (McBride 2004; Pezzilli 2004; Rulyak SJ et al 2004).
Blood Tests
CA 19-9 (carbohydrate antigen 19-9) is the mainstay tumor marker and is ordered when pancreatic cancer is suspected, particularly if the patient shows signs of jaundice (yellowing of the skin). CA 19-9 levels match the course of the disease following surgery, chemotherapy, or radiotherapy, normalizing or decreasing soon after treatment (Lamerz R 1999). Additional diagnostic methods are required because this test is only 70 percent sensitive and 87 percent specific for pancreatic cancer.
Among the serum tumor markers that may be measured by a blood test and can be used in conjunction with other tests for the diagnosis and follow-up of surgically treated pancreatic cancer are CA19-9, CA-50, CA72-4, and CA242 (Jiang XT THZSC 2004).
High platelet counts may be associated with a poor outcome and a shortening of the disease-free survival interval (Suzuki K et al 2004).
Tumor Markers
In a prospective study of 58 patients with pancreatic cancer, 40 with alcoholic pancreatitis, and 40 healthy controls, CA 19-9, tissue plasminogen activator (TPA), and carbohydrate antigen 50 (CA-50) were found to be useful in identifying differences between pancreatic cancer and chronic pancreatitis. The specificity of TPA, CA 19-9, and CA-50 in differentiating between pancreatic cancer and chronic pancreatitis was 87.5 percent, 90 percent, and 95 percent, respectively, with a sensitivity of nearly 90 percent (Irigoyen Oyarzabal AM et al 2003).
Assessment of pancreatic function.
In pancreatic cancer, abnormal digestion associated with inadequate pancreatic enzymes and function (insufficiency) can occur (Bruno MJ et al 1995a; Grant AG et al 1978). When pancreatic enzyme levels fall below 1 percent to 2 percent of normal, poor nutrient digestion and incorporation occur. Poor digestion can cause significant weight loss, nutritional deficiencies, and foul-smelling or greasy bowel movements. It is also associated with changes in gastrointestinal function, such as changes in acid-base balance, bile acid metabolism, stomach emptying, and motility of the intestine.
Tests for pancreatic enzyme function. These tests are sensitive for moderate-to-severe pancreatic insufficiency, but are of limited value in mild pancreatic impairment.
Bicarbonate secretion is probably the single most useful measure of pancreatic
enzyme function (Ochi K et al 1997). Indirect estimation can be done via the 72-hour fat balance test, which determines fat losses as a percentage of daily fat intake.
Measuring the activity of pancreatic chymotrypsin (a pancreatic enzyme).
A test in which oral fluorescein dilaurate is broken down by esterase, a pancreatic enzyme.
Fecal elastase-1 is a simple, non-invasive, and robust test (Sonwalkar SA et al 2003) of fat balance in the body.
Cholesteryl-[14C]octanoate breath test (Bruno MJ et al 1995b).
With enzyme supplementation (for example, with pancrelipase, enteric-coated microspheres), body weight loss and biochemical indices of malnutrition can be greatly improved (Braga M et al 1988).
Thursday, January 31, 2008
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
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
Pancreatic Cancer-3
Clinical Studies: Fish Oil and Pancreatic Cancer
Many clinical studies have shown that fish oil supplementation stabilizes the rate of weight loss, as well as adipose tissue and muscle mass, in pancreatic cancer patients, who often suffer from wasting (Tisdale MJ 1999).
Protein supplements enriched with EPA increased total energy expenditure and physical activity levels in advanced pancreatic cancer patients, thereby increasing their quality of life (Klek S et al 2005; Moses AW et al 2004).
Twenty pancreatic cancer patients were asked to consume two cans of a fish oil-enriched nutritional supplement daily in addition to their normal food intake. Each can contained 16.1 grams of protein and 1.09 grams of EPA. At the study’s onset, all patients were losing weight at a median rate of 2.9 kg a month. After administration of the fish oil-enriched supplement, patients had a significant weight gain at both three and seven weeks (Barber MD et al 1999).
In another study, after three weeks of consuming an EPA-enriched supplement, the body weight of cancer patients had increased, and their energy expenditure in response to feeding had risen significantly to levels no different from baseline healthy control values (Barber MD et al 2000).
In a study of 18 pancreatic cancer patients who supplemented with fish oil capsules (1 gram each containing EPA 18 percent and DHA 12 percent), patients had a median weight loss of 2.9 kg a month before supplementation; three months after beginning fish oil supplementation, patients had a median weight gain of 0.3 kg a month (Wigmore SJ et al 1996).
Food-Derived Polyphenols
Genistein prevents pancreatic cancer cell growth primarily by regulating sugar metabolism (Boros LG et al 2001). In addition, genistein inactivates NF-kappa B (Li Y et al 2005), thus sensitizing cancer cells to chemotherapeutic agents such as Gemzar® (Banerjee S et al 2005), cisplatin and docetaxel (Li Y et al 2004), and VP-16 and doxorubicin (Sato T et al 2003). In laboratory experiments, genistein has been shown to improve survival, reduce tumor blood-vessel development (Buchler P et al 2004), almost completely inhibit cancer metastasis, and increase cancer cell suicide (Buchler P et al 2003).
If the pathology report shows that the pancreatic cancer cells have a mutated p53 oncogene, or if there is no p53 detected, then high-dose genistein therapy may be appropriate (Choi YH et al 2000; Wilson LC et al 2003). If the pathology report shows a functional p53, then genistein is less effective in stopping cancer growth. The suggested dose of genistein is approximately 500 mg daily (Miltyk W et al 2003; Takimoto CH et al 2003).
Green Tea. Tea is particularly rich in polyphenols such as epigallocatechin gallate (EGCG) that act as antioxidants. Black and green tea extracts reduce pancreatic tumor cell growth by approximately 90 percent while preventing angiogenesis (Maiti TK et al 2003; Masamune A et al 2005; Roomi MW et al 2005). They also decrease the expression of the K-ras gene (Lyn-Cook BD et al 1999a) and the invasiveness of pancreatic cancer cells (Takada M et al 2002). Animal experiments of pancreatic cancer show that tea polyphenols restrain carcinogen-induced increases in oxidative DNA damage (Frei B et al 2003).
Green tea extract curbs the process of pancreatic cancer development (Lyn-Cook BD et al 1999b) and the promotion of transplanted human pancreatic cancer in animals, and also causes pancreatic cancer cell death (Hiura A et al 1997; Qanungo S et al 2005).
In humans, an inverse relationship was observed between the amount of green tea consumed and the risk of developing pancreatic cancer; the highest intake was associated with the lowest risk of cancer (Ji BT et al 1997). In clinical studies, green tea supplementation has been shown to be safe and protective (Ahn WS et al 2003; Chow HH et al 2001; Chow HH et al 2003).
Antioxidants. Free radicals can cause repeated damage to normal cells and reduce the function of injured tissues. When sufficient antioxidants are available, free radicals are removed before excess damage occurs. Antioxidant levels are reduced in pancreatic cancer compared to other pancreatic diseases and healthy pancreatic tissue, resulting in increases in reactive oxygen (Cullen JJ et al 2003) that are capable of stimulating cancer cell division (Garcea G et al 2005; Vaquero EC et al 2004).
Increased levels of some antioxidants may be useful in slowing the growth of pancreatic cancer (Weydert C et al 2003). Vitamins A, C, and E, as well as selenium, increase antioxidants in the body needed to reduce free-radical damage (Woutersen RA et al 1999).
Vitamins A, C, and E. In animals in which pancreatic cancer was caused by chemicals, cancer incidence was decreased by 64.3 percent by vitamin A and by 71.4 percent with vitamin C. Both vitamins increased SOD (superoxide dismutase) activity and were toxic to tumor cells but not to normal healthy cells (Wenger FA et al 2001).
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 G et al 2004).
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 F et al 1998).
Retinoids curb the growth and adhesion of a variety of pancreatic cancer types, even those that previously have been documented to be resistant to retinoids (El-Metwally TH et al 1999). Vitamin E succinate restrained pancreatic cancer cell growth in laboratory experiments (Heisler T et al 2000).
Ascorbyl stearate, a fat-soluble form of ascorbic acid (vitamin C), markedly restrained the growth of—and even killed—pancreatic cancer cells (Naidu KA et al 2003).
Selenium. Selenium and beta-carotene were found to restrain the growth of pancreatic tumors caused by carcinogen exposure in mice (Appel MJ et al 1996). Selenium levels were found to be reduced in pancreatic cancer patients who underwent surgery to remove the upper portion of their intestine (Armstrong T et al 2002). In preclinical studies, a diet high in selenium reduced the number of carcinogen-induced pancreatic cancers significantly (Kise Y et al 1990).
Curcumin has many anticancer effects. It is a selective inhibitor of the COX-2 enzyme and may be beneficial in preventing and treating pancreatic cancer (Cuendet M et al 2000). It decreases NF-kappa B activity, which is involved in controlling the growth of pancreatic cancer cells (Li L et al 2004). It also inhibits interleukin-8 (IL-8) production, which affects invasiveness, cell growth, and tumor blood-vessel development (Hidaka H et al 2002).
Complementary Alternative Therapies
PSK (Polysaccharide K). PSK is a protein-bound polysaccharide derived from the mycelium of the mushroom Coriolus versicolor (Tsukagoshi S et al 1984). In Japan, PSK is used as a non-specific biological response modifier to enhance the immune system in cancer patients (Koda K et al 2003; Noguchi K et al 1995; Yokoe T et al 1997). PSK suppresses tumor cell invasiveness by down-regulating several invasion-related factors (Zhang H et al 2000). Also, PSK can enhance pancreatic cancer cell death induced by Taxotere® (docetaxel) (Zhang H et al 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 M et al 1987). PSK has been used as adjuvant immunotherapy for cancer at a dose of 3 grams daily (Ito K et al 2004; Ohwada S et al 2004; Toge T et al 2000).
Ukrain (NSC-631570). Ukrain, a semisynthetic agent, has been used in complementary medicine for more than 20 years to treat benign and malignant tumors. In a phase II trial of advanced pancreatic cancer patients, Ukrain either alone or together with Gemzar® (gemcitabine) was found to be well-tolerated with only moderate toxicity, and doubled median survival times (Gansauge F et al 2002). In another study, Ukrain improved the quality of life of patients suffering from advanced pancreatic cancer while significantly prolonging their survival time (Zemskov V et al 2002).
For More Information
Pancreatic cancer is usually associated with weight loss (catabolic wasting) and pain. The following protocols may be useful in designing a program that will address specific needs:
Catabolic Wasting
Pain
Cancer Surgery
Complementary Adjuvant Therapies
Cancer Chemotherapy
Cancer Radiation
Diabetes
Life Extension Foundation Recommendations
Pancreatic cancer is a rapidly progressive disease with generally poor survival time. The goal of therapy is to strengthen pancreatic function, impede cancer growth and spread, and reduce the severity of symptoms. Various nutritional supplements outlined in this chapter have been shown to help pancreatic cancer patients by slowing disease progression or increasing quality of life.
Guidelines for Reducing Pancreatic Cancer Risk
Stop smoking and drinking alcohol.
Avoid or reduce exposure to toxic chemicals and petroleum products.
Maintain a healthy body weight.
Reduce dietary intake of fried foods, red meat, and meat products.
Increase intake of fresh fruit and vegetables, fiber, minerals, and vitamins.
Reduce sugar consumption (glycemic load).
Increase physical activity.
Maintain a diet suitable for diabetics that restricts simple carbohydrates such as sugar and emphasizes complex carbohydrates (fibers) and proteins (refer to the Diabetes protocol). Protein supplements such as soy and essential fatty acids such as borage and fish oils will help by altering the dietary intake ratio of carbohydrates, proteins, and fats.
If pancreatic cancer patients are to improve their odds of achieving a remission or long-term survival, they should attempt to integrate into their conventional therapy as many of the following dietary changes and supplements as possible, but only under a physician’s supervision.
Aged Garlic Extract—1200 milligram (mg) daily
Alpha-tocopherol—400 international units (IU) daily
Ascorbic acid—500 to 3000 mg daily
Beta-carotene—20 mg daily
Curcumin—2400 mg daily, two hours apart from medications
d-Limonene—7.3 to 14.4 grams (g) daily
Fiber—4 to 12 g daily before meals
Fish oil concentrate—700 to 4200 mg of EPA, 500 to 2000 mg of DHA daily
Life Extension Booster—1 capsule daily
Gamma-linolenic acid (GLA)—700 to 900 mg daily
Grape seed extract—100 mg daily
Green tea extract (EGCG)—800 mg daily
Life Extension Mix multivitamin/multi-mineral formula without copper—follow label directions
Lycopene—15 to 30 mg daily
Perillyl alcohol—2050 mg, four times daily
PSK (Coriolus versicolor)—3 grams daily
Selenium—600 micrograms (mcg) daily
Silymarin—100 to 420 mg daily
Soy extract (genistein)—656 mg daily
Vitamin A—10,000 IU daily
Zinc—45 to 50 mg daily.
Innovative Drug Strategies
The following should be used only under a physician’s supervision:
Pancreatic enzymes (by prescription)—1000 to 10,000 U lipase per kg of body weight per meal (Schibli S et al 2002). Delayed-release preparations (capsules containing enteric-coated microspheres, such as Creon®) are reportedly less susceptible to acid inactivation.
Antacids or a histamine H2-receptor antagonist (cimetidine, Tagamet®) have been used to decrease the inactivation of pancreatic enzyme activity.
Celebrex® (celecoxib)—400 mg twice daily.
Zyflo® (zileuton)—400 to 800 mg twice daily (except for those with active liver disease).
Ukrain (NSC-631570). Ukrain is supplied as a solution ready for injection. A Ukrain therapy cycle consists of 10 mg taken intravenously every other day for 20 days. A vitamin C cycle is added to the Ukrain cycle, 3 grams taken intravenously every other day, and 2.4 grams taken orally in three divided doses on the same days, for 20 days (Zemskov V et al 2002).
Product Availability
All the nutrients and supplements discussed in this section are available through the Life Extension Foundation Buyers Club, Inc. For ordering information, call anytime toll-free 1-800-544-4440, or visit us online at www.LifeExtension.com.
The blood tests discussed in this section are available through Life Extension National Diagnostics, Inc. For ordering information, call anytime toll-free 1-800-208-3444, or visit us online at www.LifeExtension.com.
Pancreatic Cancer Safety Caveats
An aggressive program of dietary supplementation should not be launched without the supervision of a qualified physician. Several of the nutrients suggested in this protocol may have adverse effects. These include:
Beta-Carotene
Do not take beta-carotene if you smoke. Daily intake of 20 milligrams or more has been associated with a higher incidence of lung cancer in smokers.
Taking 30 milligrams or more daily for prolonged periods can cause carotenoderma, a yellowish skin discoloration (carotenoderma can be distinguished from jaundice because the whites of the eyes are not discolored in carotenoderma).
Curcumin
Do not take curcumin if you have a bile duct obstruction or a history of gallstones. Taking curcumin can stimulate bile production.
Consult your doctor before taking curcumin if you have gastroesophageal reflux disease (GERD) or a history of peptic ulcer disease.
Consult your doctor before taking curcumin if you take warfarin or antiplatelet drugs. Curcumin can have antithrombotic activity.
Always take curcumin with food. Curcumin may cause gastric irritation, ulceration, gastritis, and peptic ulcer disease if taken on an empty stomach.
Curcumin can cause gastrointestinal symptoms such as nausea and diarrhea.
EPA/DHA
Consult your doctor before taking EPA/DHA if you take warfarin (Coumadin). Taking EPA/DHA with warfarin may increase the risk of bleeding.
Discontinue using EPA/DHA 2 weeks before any surgical procedure.
Fiber
Take fiber supplements with a full 8-ounce glass of water.
Drink eight 8-ounce glasses of water daily while taking fiber.
Garlic
Garlic has blood-thinning, anticlotting properties.
Discontinue using garlic before any surgical procedure.
Garlic can cause headache, muscle pain, fatigue, vertigo, watery eyes, asthma, and gastrointestinal symptoms such as nausea and diarrhea.
Ingesting large amounts of garlic can cause bad breath and body odor.
Genistein
Consult your doctor before taking genistein/genistin if you have prostate cancer.
Do not take genistein/genistin if you have estrogen receptor–positive tumors.
Genistein/genistin can cause hypothyroidism in some people.
GLA
Consult your doctor before taking GLA if you take warfarin (Coumadin). Taking GLA with warfarin may increase the risk of bleeding.
Discontinue using GLA 2 weeks before any surgical procedure.
GLA can cause gastrointestinal symptoms such as nausea and diarrhea.
Green Tea
Consult your doctor before taking green tea extract if you take aspirin or warfarin (Coumadin). Taking green tea extract and aspirin or warfarin can increase the risk of bleeding.
Discontinue using green tea extract 2 weeks before any surgical procedure. Green tea extract may decrease platelet aggregation.
Green tea extract contains caffeine, which may produce a variety of symptoms including restlessness, nausea, headache, muscle tension, sleep disturbances, and rapid heartbeat.
Selenium
High doses of selenium (1000 micrograms or more daily) for prolonged periods may cause adverse reactions.
High doses of selenium taken for prolonged periods may cause chronic selenium poisoning. Symptoms include loss of hair and nails or brittle hair and nails.
Selenium can cause rash, breath that smells like garlic, fatigue, irritability, and nausea and vomiting.
Vitamin A
Do not take vitamin A if you have hypervitaminosis A.
Do not take vitamin A if you take retinoids or retinoid analogues (such as acitretin, all-trans-retinoic acid, bexarotene, etretinate, and isotretinoin). Vitamin A can add to the toxicity of these drugs.
Do not take large amounts of vitamin A. Taking large amounts of vitamin A may cause acute or chronic toxicity. Early signs and symptoms of chronic toxicity include dry, rough skin; cracked lips; sparse, coarse hair; and loss of hair from the eyebrows. Later signs and symptoms of toxicity include irritability, headache, pseudotumor cerebri (benign intracranial hypertension), elevated serum liver enzymes, reversible noncirrhotic portal high blood pressure, fibrosis and cirrhosis of the liver, and death from liver failure.
Vitamin C
Do not take vitamin C if you have a history of kidney stones or of kidney insufficiency (defined as having a serum creatine level greater than 2 milligrams per deciliter and/or a creatinine clearance less than 30 milliliters per minute.
Consult your doctor before taking large amounts of vitamin C if you have hemochromatosis, thalassemia, sideroblastic anemia, sickle cell anemia, or erythrocyte glucose-6-phosphate dehydrogenase (G6PD) deficiency. You can experience iron overload if you have one of these conditions and use large amounts of vitamin C.
Zinc
High doses of zinc (above 30 milligrams daily) can cause adverse reactions.
Zinc can cause a metallic taste, headache, drowsiness, and gastrointestinal symptoms such as nausea and diarrhea.
High doses of zinc can lead to copper deficiency and hypochromic microcytic anemia secondary to zinc-induced copper deficiency.
High doses of zinc may suppress the immune system. High doses of zinc may be immunosuppressive.
Many clinical studies have shown that fish oil supplementation stabilizes the rate of weight loss, as well as adipose tissue and muscle mass, in pancreatic cancer patients, who often suffer from wasting (Tisdale MJ 1999).
Protein supplements enriched with EPA increased total energy expenditure and physical activity levels in advanced pancreatic cancer patients, thereby increasing their quality of life (Klek S et al 2005; Moses AW et al 2004).
Twenty pancreatic cancer patients were asked to consume two cans of a fish oil-enriched nutritional supplement daily in addition to their normal food intake. Each can contained 16.1 grams of protein and 1.09 grams of EPA. At the study’s onset, all patients were losing weight at a median rate of 2.9 kg a month. After administration of the fish oil-enriched supplement, patients had a significant weight gain at both three and seven weeks (Barber MD et al 1999).
In another study, after three weeks of consuming an EPA-enriched supplement, the body weight of cancer patients had increased, and their energy expenditure in response to feeding had risen significantly to levels no different from baseline healthy control values (Barber MD et al 2000).
In a study of 18 pancreatic cancer patients who supplemented with fish oil capsules (1 gram each containing EPA 18 percent and DHA 12 percent), patients had a median weight loss of 2.9 kg a month before supplementation; three months after beginning fish oil supplementation, patients had a median weight gain of 0.3 kg a month (Wigmore SJ et al 1996).
Food-Derived Polyphenols
Genistein prevents pancreatic cancer cell growth primarily by regulating sugar metabolism (Boros LG et al 2001). In addition, genistein inactivates NF-kappa B (Li Y et al 2005), thus sensitizing cancer cells to chemotherapeutic agents such as Gemzar® (Banerjee S et al 2005), cisplatin and docetaxel (Li Y et al 2004), and VP-16 and doxorubicin (Sato T et al 2003). In laboratory experiments, genistein has been shown to improve survival, reduce tumor blood-vessel development (Buchler P et al 2004), almost completely inhibit cancer metastasis, and increase cancer cell suicide (Buchler P et al 2003).
If the pathology report shows that the pancreatic cancer cells have a mutated p53 oncogene, or if there is no p53 detected, then high-dose genistein therapy may be appropriate (Choi YH et al 2000; Wilson LC et al 2003). If the pathology report shows a functional p53, then genistein is less effective in stopping cancer growth. The suggested dose of genistein is approximately 500 mg daily (Miltyk W et al 2003; Takimoto CH et al 2003).
Green Tea. Tea is particularly rich in polyphenols such as epigallocatechin gallate (EGCG) that act as antioxidants. Black and green tea extracts reduce pancreatic tumor cell growth by approximately 90 percent while preventing angiogenesis (Maiti TK et al 2003; Masamune A et al 2005; Roomi MW et al 2005). They also decrease the expression of the K-ras gene (Lyn-Cook BD et al 1999a) and the invasiveness of pancreatic cancer cells (Takada M et al 2002). Animal experiments of pancreatic cancer show that tea polyphenols restrain carcinogen-induced increases in oxidative DNA damage (Frei B et al 2003).
Green tea extract curbs the process of pancreatic cancer development (Lyn-Cook BD et al 1999b) and the promotion of transplanted human pancreatic cancer in animals, and also causes pancreatic cancer cell death (Hiura A et al 1997; Qanungo S et al 2005).
In humans, an inverse relationship was observed between the amount of green tea consumed and the risk of developing pancreatic cancer; the highest intake was associated with the lowest risk of cancer (Ji BT et al 1997). In clinical studies, green tea supplementation has been shown to be safe and protective (Ahn WS et al 2003; Chow HH et al 2001; Chow HH et al 2003).
Antioxidants. Free radicals can cause repeated damage to normal cells and reduce the function of injured tissues. When sufficient antioxidants are available, free radicals are removed before excess damage occurs. Antioxidant levels are reduced in pancreatic cancer compared to other pancreatic diseases and healthy pancreatic tissue, resulting in increases in reactive oxygen (Cullen JJ et al 2003) that are capable of stimulating cancer cell division (Garcea G et al 2005; Vaquero EC et al 2004).
Increased levels of some antioxidants may be useful in slowing the growth of pancreatic cancer (Weydert C et al 2003). Vitamins A, C, and E, as well as selenium, increase antioxidants in the body needed to reduce free-radical damage (Woutersen RA et al 1999).
Vitamins A, C, and E. In animals in which pancreatic cancer was caused by chemicals, cancer incidence was decreased by 64.3 percent by vitamin A and by 71.4 percent with vitamin C. Both vitamins increased SOD (superoxide dismutase) activity and were toxic to tumor cells but not to normal healthy cells (Wenger FA et al 2001).
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 G et al 2004).
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 F et al 1998).
Retinoids curb the growth and adhesion of a variety of pancreatic cancer types, even those that previously have been documented to be resistant to retinoids (El-Metwally TH et al 1999). Vitamin E succinate restrained pancreatic cancer cell growth in laboratory experiments (Heisler T et al 2000).
Ascorbyl stearate, a fat-soluble form of ascorbic acid (vitamin C), markedly restrained the growth of—and even killed—pancreatic cancer cells (Naidu KA et al 2003).
Selenium. Selenium and beta-carotene were found to restrain the growth of pancreatic tumors caused by carcinogen exposure in mice (Appel MJ et al 1996). Selenium levels were found to be reduced in pancreatic cancer patients who underwent surgery to remove the upper portion of their intestine (Armstrong T et al 2002). In preclinical studies, a diet high in selenium reduced the number of carcinogen-induced pancreatic cancers significantly (Kise Y et al 1990).
Curcumin has many anticancer effects. It is a selective inhibitor of the COX-2 enzyme and may be beneficial in preventing and treating pancreatic cancer (Cuendet M et al 2000). It decreases NF-kappa B activity, which is involved in controlling the growth of pancreatic cancer cells (Li L et al 2004). It also inhibits interleukin-8 (IL-8) production, which affects invasiveness, cell growth, and tumor blood-vessel development (Hidaka H et al 2002).
Complementary Alternative Therapies
PSK (Polysaccharide K). PSK is a protein-bound polysaccharide derived from the mycelium of the mushroom Coriolus versicolor (Tsukagoshi S et al 1984). In Japan, PSK is used as a non-specific biological response modifier to enhance the immune system in cancer patients (Koda K et al 2003; Noguchi K et al 1995; Yokoe T et al 1997). PSK suppresses tumor cell invasiveness by down-regulating several invasion-related factors (Zhang H et al 2000). Also, PSK can enhance pancreatic cancer cell death induced by Taxotere® (docetaxel) (Zhang H et al 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 M et al 1987). PSK has been used as adjuvant immunotherapy for cancer at a dose of 3 grams daily (Ito K et al 2004; Ohwada S et al 2004; Toge T et al 2000).
Ukrain (NSC-631570). Ukrain, a semisynthetic agent, has been used in complementary medicine for more than 20 years to treat benign and malignant tumors. In a phase II trial of advanced pancreatic cancer patients, Ukrain either alone or together with Gemzar® (gemcitabine) was found to be well-tolerated with only moderate toxicity, and doubled median survival times (Gansauge F et al 2002). In another study, Ukrain improved the quality of life of patients suffering from advanced pancreatic cancer while significantly prolonging their survival time (Zemskov V et al 2002).
For More Information
Pancreatic cancer is usually associated with weight loss (catabolic wasting) and pain. The following protocols may be useful in designing a program that will address specific needs:
Catabolic Wasting
Pain
Cancer Surgery
Complementary Adjuvant Therapies
Cancer Chemotherapy
Cancer Radiation
Diabetes
Life Extension Foundation Recommendations
Pancreatic cancer is a rapidly progressive disease with generally poor survival time. The goal of therapy is to strengthen pancreatic function, impede cancer growth and spread, and reduce the severity of symptoms. Various nutritional supplements outlined in this chapter have been shown to help pancreatic cancer patients by slowing disease progression or increasing quality of life.
Guidelines for Reducing Pancreatic Cancer Risk
Stop smoking and drinking alcohol.
Avoid or reduce exposure to toxic chemicals and petroleum products.
Maintain a healthy body weight.
Reduce dietary intake of fried foods, red meat, and meat products.
Increase intake of fresh fruit and vegetables, fiber, minerals, and vitamins.
Reduce sugar consumption (glycemic load).
Increase physical activity.
Maintain a diet suitable for diabetics that restricts simple carbohydrates such as sugar and emphasizes complex carbohydrates (fibers) and proteins (refer to the Diabetes protocol). Protein supplements such as soy and essential fatty acids such as borage and fish oils will help by altering the dietary intake ratio of carbohydrates, proteins, and fats.
If pancreatic cancer patients are to improve their odds of achieving a remission or long-term survival, they should attempt to integrate into their conventional therapy as many of the following dietary changes and supplements as possible, but only under a physician’s supervision.
Aged Garlic Extract—1200 milligram (mg) daily
Alpha-tocopherol—400 international units (IU) daily
Ascorbic acid—500 to 3000 mg daily
Beta-carotene—20 mg daily
Curcumin—2400 mg daily, two hours apart from medications
d-Limonene—7.3 to 14.4 grams (g) daily
Fiber—4 to 12 g daily before meals
Fish oil concentrate—700 to 4200 mg of EPA, 500 to 2000 mg of DHA daily
Life Extension Booster—1 capsule daily
Gamma-linolenic acid (GLA)—700 to 900 mg daily
Grape seed extract—100 mg daily
Green tea extract (EGCG)—800 mg daily
Life Extension Mix multivitamin/multi-mineral formula without copper—follow label directions
Lycopene—15 to 30 mg daily
Perillyl alcohol—2050 mg, four times daily
PSK (Coriolus versicolor)—3 grams daily
Selenium—600 micrograms (mcg) daily
Silymarin—100 to 420 mg daily
Soy extract (genistein)—656 mg daily
Vitamin A—10,000 IU daily
Zinc—45 to 50 mg daily.
Innovative Drug Strategies
The following should be used only under a physician’s supervision:
Pancreatic enzymes (by prescription)—1000 to 10,000 U lipase per kg of body weight per meal (Schibli S et al 2002). Delayed-release preparations (capsules containing enteric-coated microspheres, such as Creon®) are reportedly less susceptible to acid inactivation.
Antacids or a histamine H2-receptor antagonist (cimetidine, Tagamet®) have been used to decrease the inactivation of pancreatic enzyme activity.
Celebrex® (celecoxib)—400 mg twice daily.
Zyflo® (zileuton)—400 to 800 mg twice daily (except for those with active liver disease).
Ukrain (NSC-631570). Ukrain is supplied as a solution ready for injection. A Ukrain therapy cycle consists of 10 mg taken intravenously every other day for 20 days. A vitamin C cycle is added to the Ukrain cycle, 3 grams taken intravenously every other day, and 2.4 grams taken orally in three divided doses on the same days, for 20 days (Zemskov V et al 2002).
Product Availability
All the nutrients and supplements discussed in this section are available through the Life Extension Foundation Buyers Club, Inc. For ordering information, call anytime toll-free 1-800-544-4440, or visit us online at www.LifeExtension.com.
The blood tests discussed in this section are available through Life Extension National Diagnostics, Inc. For ordering information, call anytime toll-free 1-800-208-3444, or visit us online at www.LifeExtension.com.
Pancreatic Cancer Safety Caveats
An aggressive program of dietary supplementation should not be launched without the supervision of a qualified physician. Several of the nutrients suggested in this protocol may have adverse effects. These include:
Beta-Carotene
Do not take beta-carotene if you smoke. Daily intake of 20 milligrams or more has been associated with a higher incidence of lung cancer in smokers.
Taking 30 milligrams or more daily for prolonged periods can cause carotenoderma, a yellowish skin discoloration (carotenoderma can be distinguished from jaundice because the whites of the eyes are not discolored in carotenoderma).
Curcumin
Do not take curcumin if you have a bile duct obstruction or a history of gallstones. Taking curcumin can stimulate bile production.
Consult your doctor before taking curcumin if you have gastroesophageal reflux disease (GERD) or a history of peptic ulcer disease.
Consult your doctor before taking curcumin if you take warfarin or antiplatelet drugs. Curcumin can have antithrombotic activity.
Always take curcumin with food. Curcumin may cause gastric irritation, ulceration, gastritis, and peptic ulcer disease if taken on an empty stomach.
Curcumin can cause gastrointestinal symptoms such as nausea and diarrhea.
EPA/DHA
Consult your doctor before taking EPA/DHA if you take warfarin (Coumadin). Taking EPA/DHA with warfarin may increase the risk of bleeding.
Discontinue using EPA/DHA 2 weeks before any surgical procedure.
Fiber
Take fiber supplements with a full 8-ounce glass of water.
Drink eight 8-ounce glasses of water daily while taking fiber.
Garlic
Garlic has blood-thinning, anticlotting properties.
Discontinue using garlic before any surgical procedure.
Garlic can cause headache, muscle pain, fatigue, vertigo, watery eyes, asthma, and gastrointestinal symptoms such as nausea and diarrhea.
Ingesting large amounts of garlic can cause bad breath and body odor.
Genistein
Consult your doctor before taking genistein/genistin if you have prostate cancer.
Do not take genistein/genistin if you have estrogen receptor–positive tumors.
Genistein/genistin can cause hypothyroidism in some people.
GLA
Consult your doctor before taking GLA if you take warfarin (Coumadin). Taking GLA with warfarin may increase the risk of bleeding.
Discontinue using GLA 2 weeks before any surgical procedure.
GLA can cause gastrointestinal symptoms such as nausea and diarrhea.
Green Tea
Consult your doctor before taking green tea extract if you take aspirin or warfarin (Coumadin). Taking green tea extract and aspirin or warfarin can increase the risk of bleeding.
Discontinue using green tea extract 2 weeks before any surgical procedure. Green tea extract may decrease platelet aggregation.
Green tea extract contains caffeine, which may produce a variety of symptoms including restlessness, nausea, headache, muscle tension, sleep disturbances, and rapid heartbeat.
Selenium
High doses of selenium (1000 micrograms or more daily) for prolonged periods may cause adverse reactions.
High doses of selenium taken for prolonged periods may cause chronic selenium poisoning. Symptoms include loss of hair and nails or brittle hair and nails.
Selenium can cause rash, breath that smells like garlic, fatigue, irritability, and nausea and vomiting.
Vitamin A
Do not take vitamin A if you have hypervitaminosis A.
Do not take vitamin A if you take retinoids or retinoid analogues (such as acitretin, all-trans-retinoic acid, bexarotene, etretinate, and isotretinoin). Vitamin A can add to the toxicity of these drugs.
Do not take large amounts of vitamin A. Taking large amounts of vitamin A may cause acute or chronic toxicity. Early signs and symptoms of chronic toxicity include dry, rough skin; cracked lips; sparse, coarse hair; and loss of hair from the eyebrows. Later signs and symptoms of toxicity include irritability, headache, pseudotumor cerebri (benign intracranial hypertension), elevated serum liver enzymes, reversible noncirrhotic portal high blood pressure, fibrosis and cirrhosis of the liver, and death from liver failure.
Vitamin C
Do not take vitamin C if you have a history of kidney stones or of kidney insufficiency (defined as having a serum creatine level greater than 2 milligrams per deciliter and/or a creatinine clearance less than 30 milliliters per minute.
Consult your doctor before taking large amounts of vitamin C if you have hemochromatosis, thalassemia, sideroblastic anemia, sickle cell anemia, or erythrocyte glucose-6-phosphate dehydrogenase (G6PD) deficiency. You can experience iron overload if you have one of these conditions and use large amounts of vitamin C.
Zinc
High doses of zinc (above 30 milligrams daily) can cause adverse reactions.
Zinc can cause a metallic taste, headache, drowsiness, and gastrointestinal symptoms such as nausea and diarrhea.
High doses of zinc can lead to copper deficiency and hypochromic microcytic anemia secondary to zinc-induced copper deficiency.
High doses of zinc may suppress the immune system. High doses of zinc may be immunosuppressive.
Thursday, January 17, 2008
Prostate Cancer-1
a)General Introduction
b)2003 Edition
c)Preventing PC
d)Getting Help
e)Medical Records
f)Early Diagnosis
j)Risk Assessment
h)Treatment Options
i)Tumor Growth
j)Dietary Changes
k)Bone Integrity
l)Supportive Care
m)Empowering The Patient
n)Where To Go From Here
o)Glossary Of Terms
p)Reading
INTRODUCTION TO DR. STRUM'S PROSTATE CANCER UPDATE
When I was diagnosed with advanced prostate cancer in September 1991, I thought my life, as I had envisioned it, was over. Instead, I have found a whole new universe of living and, in doing so, have come to terms with my own mortality.
Transformation is what is possible when we are faced with a life-threatening illness. When the unthinkable happens to us and we are faced with our mortality, we have an opportunity to transform our lives.
Acceptance of our situation is the first milestone we must pass before we can truly begin the process of healing. For me this translates into doing everything I can to understand the entire process of my illness and what I can do to become well. While I do not blame myself for my diagnosis, it has been valuable for me to take an introspective look at my life in relation to the kinds of stressors or environmental exposures that may have played a role. Sometimes it is not until we are on the reef that we realize it is there.
Fortunately for us, the cancer patient today has many more resources available than there were just a few years ago. What follows by Dr. Stephen Strum is an update of the treatment of prostate cancer. I have known Steve for over 10 years. He is one of the precious few who have brought a new and compassionate dimension to the patient/physician relationship.
Frederick Mills
Prostate Cancer Survivor
Founding Member of Educational Council
for Prostate Cancer Patients
PROSTATE CANCER UPDATE 2003
Stephen B. Strum, M.D., F.A.C.P.
GENERAL INTRODUCTION
In this, the year 2003 edition of Disease Prevention and Treatment, I will discuss prostate cancer (PC), using the metaphor of a military incursion--needing to have a focused, strategic approach, deployed in a systematic, problem-solving manner. The purpose of such a metaphor is to bring to the student of this disease a different perspective that will hopefully provide new insights that will lead to victories in our battles against this disease. The reason for such a departure from the conventional formal discussion of PC is that this latter academic approach is not being translated into winning strategies for the man with PC. The battle is being lost because we, the generals, are not translating what has been published in medical journals and discussed at national meetings into real-time preventive, diagnostic, evaluatory, and treatment tactics. Medical pragmatism--the art of being practical and using common sense--is not being practiced.
The battle to prevent this disease, to diagnose it earlier, and to treat it effectively is also not occurring at the proper pace largely because men are not taking an active role in winning this war. As we are learning in our war against terrorism, you defeat the enemy by recognizing their presence early (not late), preventing their buildup, learning their location, and eradicating them with the proper weaponry. There are too many men, already diagnosed with PC, who are not taking an active role in their own recovery. Many believe that because they are consulting a professional with a medical degree (who may also command a generous salary), all or part of this equates with getting the very best advice and treatment. Wrong. In today's world of rapid pace, where medicine is practiced with 15-minute office visits and where physicians are too busy to read and translate much of what is being published, the patient and his partner must not take a passive role and assume that all that can be done is being done.
My recommendations, therefore, either to patients with PC or to their loved ones, will be those of a counselor or guide, offering practical advice based on 20 years of working on the front lines of PC management. I do not hesitate in telling you that for the vast majority of men diagnosed with PC, a successful outcome can be realized. But the principles you are about to learn must become part and parcel of the strategic approach used by the patient/partner/physician (PPP) team. The patient and his partner have the most to gain as well as the most to lose when encountering PC. They must expend serious energy to win this particular war. In doing so, they learn the art of battle; they are brought closer together and evolve in their lives; and other intertwined health issues are brought to light and healed. This is the beauty of such an approach. Are you willing to invest in the time to help yourself? Are you worth it?
THE 2003 DISEASE PREVENTION AND TREATMENT EDITION
The most important take-home lesson that I can relate to you within the pages that follow relates to your ability to use concepts. It is through the use of concepts--the structural framework of our thinking--that we intelligently plan a strategy of success.
Comparison of a Military Campaign with Prostate Cancer Strategy
A)Winning a Military Campaign:1 Preventing War
Defeating Prostate Cancer (PC):1 Preventing PC
B)Winning a Military Campaign:Basic Military Training
Defeating Prostate Cancer (PC):Getting Help to Understand Biological Principles
C)Winning a Military Campaign:Military Information (Intel)
Defeating Prostate Cancer (PC):The Importance of the Medical Record
D)Winning a Military Campaign:Early Recognition of Enemy Activity
Defeating Prostate Cancer (PC):Early Diagnosis of PC
E)Winning a Military Campaign:Assessment of the Enemy
Defeating Prostate Cancer (PC):Risk Assessment of the PC Patient
F)Winning a Military Campaign:Knowing Pros and Cons of Weaponry
Defeating Prostate Cancer (PC):Understanding Pros and Cons of Treatment Options
G)Winning a Military Campaign:Understanding Enemy Vulnerability
Defeating Prostate Cancer (PC):Learning Principles Underlying Tumor Growth
H)Winning a Military Campaign:Stopping Supply Lines to the Enemy
Defeating Prostate Cancer (PC):Antiangiogenesis Treatments, Dietary Changes
I)Winning a Military Campaign:Stabilizing Key Arenas of Conflict
Defeating Prostate Cancer (PC):Focus on Bone Integrity, Biomarkers, etc.
J)Winning a Military Campaign:
b)2003 Edition
c)Preventing PC
d)Getting Help
e)Medical Records
f)Early Diagnosis
j)Risk Assessment
h)Treatment Options
i)Tumor Growth
j)Dietary Changes
k)Bone Integrity
l)Supportive Care
m)Empowering The Patient
n)Where To Go From Here
o)Glossary Of Terms
p)Reading
INTRODUCTION TO DR. STRUM'S PROSTATE CANCER UPDATE
When I was diagnosed with advanced prostate cancer in September 1991, I thought my life, as I had envisioned it, was over. Instead, I have found a whole new universe of living and, in doing so, have come to terms with my own mortality.
Transformation is what is possible when we are faced with a life-threatening illness. When the unthinkable happens to us and we are faced with our mortality, we have an opportunity to transform our lives.
Acceptance of our situation is the first milestone we must pass before we can truly begin the process of healing. For me this translates into doing everything I can to understand the entire process of my illness and what I can do to become well. While I do not blame myself for my diagnosis, it has been valuable for me to take an introspective look at my life in relation to the kinds of stressors or environmental exposures that may have played a role. Sometimes it is not until we are on the reef that we realize it is there.
Fortunately for us, the cancer patient today has many more resources available than there were just a few years ago. What follows by Dr. Stephen Strum is an update of the treatment of prostate cancer. I have known Steve for over 10 years. He is one of the precious few who have brought a new and compassionate dimension to the patient/physician relationship.
Frederick Mills
Prostate Cancer Survivor
Founding Member of Educational Council
for Prostate Cancer Patients
PROSTATE CANCER UPDATE 2003
Stephen B. Strum, M.D., F.A.C.P.
GENERAL INTRODUCTION
In this, the year 2003 edition of Disease Prevention and Treatment, I will discuss prostate cancer (PC), using the metaphor of a military incursion--needing to have a focused, strategic approach, deployed in a systematic, problem-solving manner. The purpose of such a metaphor is to bring to the student of this disease a different perspective that will hopefully provide new insights that will lead to victories in our battles against this disease. The reason for such a departure from the conventional formal discussion of PC is that this latter academic approach is not being translated into winning strategies for the man with PC. The battle is being lost because we, the generals, are not translating what has been published in medical journals and discussed at national meetings into real-time preventive, diagnostic, evaluatory, and treatment tactics. Medical pragmatism--the art of being practical and using common sense--is not being practiced.
The battle to prevent this disease, to diagnose it earlier, and to treat it effectively is also not occurring at the proper pace largely because men are not taking an active role in winning this war. As we are learning in our war against terrorism, you defeat the enemy by recognizing their presence early (not late), preventing their buildup, learning their location, and eradicating them with the proper weaponry. There are too many men, already diagnosed with PC, who are not taking an active role in their own recovery. Many believe that because they are consulting a professional with a medical degree (who may also command a generous salary), all or part of this equates with getting the very best advice and treatment. Wrong. In today's world of rapid pace, where medicine is practiced with 15-minute office visits and where physicians are too busy to read and translate much of what is being published, the patient and his partner must not take a passive role and assume that all that can be done is being done.
My recommendations, therefore, either to patients with PC or to their loved ones, will be those of a counselor or guide, offering practical advice based on 20 years of working on the front lines of PC management. I do not hesitate in telling you that for the vast majority of men diagnosed with PC, a successful outcome can be realized. But the principles you are about to learn must become part and parcel of the strategic approach used by the patient/partner/physician (PPP) team. The patient and his partner have the most to gain as well as the most to lose when encountering PC. They must expend serious energy to win this particular war. In doing so, they learn the art of battle; they are brought closer together and evolve in their lives; and other intertwined health issues are brought to light and healed. This is the beauty of such an approach. Are you willing to invest in the time to help yourself? Are you worth it?
THE 2003 DISEASE PREVENTION AND TREATMENT EDITION
The most important take-home lesson that I can relate to you within the pages that follow relates to your ability to use concepts. It is through the use of concepts--the structural framework of our thinking--that we intelligently plan a strategy of success.
Comparison of a Military Campaign with Prostate Cancer Strategy
A)Winning a Military Campaign:1 Preventing War
Defeating Prostate Cancer (PC):1 Preventing PC
B)Winning a Military Campaign:Basic Military Training
Defeating Prostate Cancer (PC):Getting Help to Understand Biological Principles
C)Winning a Military Campaign:Military Information (Intel)
Defeating Prostate Cancer (PC):The Importance of the Medical Record
D)Winning a Military Campaign:Early Recognition of Enemy Activity
Defeating Prostate Cancer (PC):Early Diagnosis of PC
E)Winning a Military Campaign:Assessment of the Enemy
Defeating Prostate Cancer (PC):Risk Assessment of the PC Patient
F)Winning a Military Campaign:Knowing Pros and Cons of Weaponry
Defeating Prostate Cancer (PC):Understanding Pros and Cons of Treatment Options
G)Winning a Military Campaign:Understanding Enemy Vulnerability
Defeating Prostate Cancer (PC):Learning Principles Underlying Tumor Growth
H)Winning a Military Campaign:Stopping Supply Lines to the Enemy
Defeating Prostate Cancer (PC):Antiangiogenesis Treatments, Dietary Changes
I)Winning a Military Campaign:Stabilizing Key Arenas of Conflict
Defeating Prostate Cancer (PC):Focus on Bone Integrity, Biomarkers, etc.
J)Winning a Military Campaign:
Wednesday, January 16, 2008
Prostate Cancer-2
Lycopenes and Their Critical Role in Cancer Prevention
a)Tomato-Based Products
b)Tissue Lycopene Levels
c)Assimilation
d)Lycopenes And Strawberries Lower Risk
e)Gene Up-regulation of Connexin 43
f)Lycopene and Vitamin D
g)Reduce Cardiovascular Risk Factors
h)Decreases Insulin-like Growth Factor Levels
i)Increase Lycopene Consumption and Plasma Levels
Of all nutritional literature currently in existence relating to PC, the relationship between lycopene ingestion and the health of the prostate is the clearest. Lycopene consumption been found to decrease not only the risk of PC in multiple studies,14-16 but also the risk of BC17 and pancreatic and stomach cancer,16 as well as lung cancer.18
Tomato-Based Products Are the Richest Sources of Lycopene
In these positive studies that correlated lycopene consumption with decreased risk of PC, the lycopene sources were tomato-based products. The richest sources of lycopene in the U.S. diet are ketchup, tomato juice, and pizza sauce; these account for over 80% of the total lycopene intake of Americans.19 In one study from Athens, Greece, the authors concluded that the incidence of prostate cancer in Greece could be reduced by about 40% if the population increased the consumption of tomatoes, reduced the intake of dairy products, and substituted olive oil for other added lipids.20
Lycopene Consumption Correlates with Blood and Tissue Lycopene Levels
The correlation between increased tomato-based consumption of lycopenes and the decreased risk of PC and other cancers is also found in the laboratory, where serum levels of lycopene are correlated with lycopene intake. The same holds true in studies in which tissue levels of lycopene have been studied in prostate pathology specimens.16,17
Lycopene concentrations in the serum of healthy men are typically 0.60-1.9 nmol/mL (nanomoles per milliliter).21 Biochemically, lycopene is composed of two main chemical structures or isomers: all-trans-lycopene and cis-isomers. Tomato sauce contains primarily all-trans-lycopene (83% of total lycopene). The ingestion of tomato sauce results in substantial increases in total lycopene levels in both the serum and prostate tissue and a substantial increase in all-trans-lycopene in prostate tissue but with relatively smaller increases in the serum.22 Serum lycopene levels are predominantly composed of the cis-isomer of lycopene, which represents 58-73% of the total serum lycopene, while the all-trans-isomer composes 27-42% of the serum lycopene.21
Among 72 studies identified, 57 reported that higher tomato intake or blood lycopene levels reduced the risk of cancer at a defined anatomic site; 35 of these associations were statistically significant.23 The evidence for a benefit was strongest for cancers of the prostate, lung, and stomach. Data were also suggestive of a benefit for cancers of the pancreas, colon and rectum, esophagus, oral cavity, breast, and cervix. The relative risk (RR) was determined, comparing high tomato intake or high lycopene levels with low tomato intake or low lycopene levels. In such comparisons, about half of the RR was close to 0.6 or lower.23 In another study, the odds of contracting aggressive PC were significantly lower when plasma lycopene levels were high. Plasma lycopene levels were divided into five quintiles. The highest level, the fifth quintile, showed an odds ratio (OR) of 0.56.14 These findings add up to about a 40% reduction in risk of being diagnosed with these cancer types for those with high tomato intake or the highest plasma lycopene levels.
The Proof of the Pudding Is Not in the Eating but in the Assimilation
The proof of the pudding, in the matter of dietary issues, relates more to how we assimilate what we have eaten rather than to just a history of having eaten something. It should not be surprising then that the correlation between serum or plasma lycopene levels and a lower incidence of PC is greater than the correlation between the oral intake of lycopenes and PC incidence. In a study by Lu et al., significant reductions in PC incidence were observed with higher plasma concentrations of the following carotenoids: lycopene, OR 0.17; and zeaxanthin, OR 0.22, when comparing highest and lowest quartiles.24 This translates into about an 80% reduction in PC incidence when the highest blood levels of either lycopene or zeaxanthin are achieved.
Lycopenes and Strawberries Lower Risk, Especially for Aggressive and Extra-Prostatic PCA dietary history of significant lycopene and/or strawberry consumption correlated with a lower risk of aggressive and extra-prostatic PC.14 The lycopene source that was found to be most significant in most epidemiologic studies was the tomato, in the form of tomato sauce, stewed tomatoes, and pizza. In one large-scale study involving 812 new cases of PC over the years 1986-1992 with matched controls, of the 46 vegetables and fruits or related products significantly associated with lower PC risk, three of the four identified were related to lycopenes--tomato sauce, tomatoes, and pizza. In this study, the combined intake of tomatoes, tomato sauce, tomato juice, and pizza (accounting for 82% of lycopene intake) was associated with a reduced risk of PC for consumption frequency greater than 10 versus less than 1.5 servings a week. Lycopene intake was also associated with a 53% reduced risk for advanced PC (Stages III and IV). The other nonlycopene product identified with significantly lower PC risk was strawberries.15
The largest relevant dietary study, a prospective study in male health professionals, found that consumption of 2-4 servings of tomato sauce a week was associated with about a 35% risk reduction of total PC and a 50% reduction of advanced (extra-prostatic) PC. Tomato sauce was by far the strongest predictor of plasma lycopene levels in this study.25 These associations persisted in analyses controlling for fruit consumption, vegetable consumption, and olive oil use and were observed separately in men of Southern European or other Caucasian ancestry.26
Lycopene Inhibits Cancer Cell Growth by Gene Up-regulation of Connexin 43Lycopene functions as a very potent antioxidant. In this regard, lycopene can trap singlet oxygen and reduce mutagenesis (gene mutations) in the Ames test. Other mechanisms of lycopene action may be operative as well. Lycopene at physiological concentrations can inhibit human cancer cell growth by interfering with growth factor receptor signaling and cell-cycle progression--specifically in PC cells--without evidence of toxic effects or apoptosis of cells.27 Studies of human and animal cells have identified connexin 43, a gene, whose expression is up-regulated by lycopene and which allows direct intercellular gap junctional communication (GJC). GJC is deficient in many human tumors and its restoration or up-regulation is associated with decreased proliferation.
Lycopene Is Synergistic with Vitamin D, Inhibiting Tumor Cell Proliferation and Enhancing Differentiation
The combination of low concentrations of lycopene with 1,25-dihydroxyvitamin D3 exhibits a synergistic effect on inhibition of cell proliferation, and differentiation, and an additive effect on cell-cycle progression in the HL-60 promyelocytic leukemia cell line, suggesting some interaction at a nuclear or subcellular level.18
Lycopenes Reduce Cardiovascular Risk Factors
Lycopene levels decrease with advancing age. However, in contrast to other carotenoids, they are not found to be reduced by smoking or alcohol consumption.16,19 Lycopenes also have an inhibitory effect on cholesterol synthesis and may enhance LDL degradation. Available evidence suggests that intimal wall thickness and risk of myocardial infarction are reduced in persons with higher adipose tissue concentrations of lycopene.19
Lycopene Levels May Be Associated with Decreased Insulin-like Growth Factor Levels
The consumption of cooked tomatoes was substantially and significantly associated with reduced insulin-like growth factor-1 (IGF-1) levels, with a mean change of -31.5% for an increment of 1 serving a day. The authors concluded that the strongest known dietary risk factor for PC (lycopene deficit, as reflected in a reduced intake of cooked tomatoes) is somehow related to an important endocrine factor (IGF-1) in the cause of this disease.28 However, in another study, IGF-1 was not associated with any dietary factor studied, such as total fat, carbohydrate, protein, dairy products, tomatoes, or calcium.29
Suggested Ways to Increase Lycopene Consumption and Plasma Levels
The easiest way I have found to combine a healthy intake of lycopenes into my diet is by using marinara sauce on various foods. For example, at breakfast, an egg-white omelet containing eggplant and bell peppers (ratatouille omelet) covered with marinara sauce is a healthy source of protein, contains a substantial fiber content, and is restricted in the amount of simple carbohydrates. Stewed tomatoes can be served as a vegetable side dish with lunch or dinner.
Dietary Fat Increases PC Growth Rates
There are studies that show that dietary fat increases tumor growth rates in an animal model of human PC. In a mouse model of PC involving androgen-sensitive human prostatic adenocarcinoma cells (LNCaP cells), mice fed a 40.5% fat diet had mean tumor weights more than 2 times greater than mice fed a 21% fat diet. The 40.5% fat diet approximates that found in the average American male diet, which has been determined to be 36%.30
The slower tumor growth associated with the low-fat diet occurred even after the formation of measurable tumors when the diets were changed from 40% fat to 21% fat. Serum PSA levels also were highest in the 40.5 kcal% fat group and lowest in another group fed only 2.3 kcal% fat.30
Reduction of Total Calorie Consumption Decreases Tumor Size by Decreasing VEGF, Angiogenesis, and IGF-1 and by Increasing Apoptosis
The emphasis on dietary fat, per se, has lessened our focus on the importance of caloric over-consumption. Fat excess, however, is linked to excessive calorie consumption, since fat contains twice as many calories, gram for gram, as protein or carbohydrate.
I believe that diet should be regarded as having serious biochemical relevance to the health of the individual. You are, for the most part, what you eat (or at least what you assimilate). Western societies, especially the United States, are consumers of excessive calories. Excessive caloric consumption, especially coupled with a sedentary lifestyle, is a significant factor that adversely affects longevity.
An important study demonstrated that energy intake (caloric intake) modulates the growth of prostate tumors in two animal models: the androgen-dependent Dunning R3327-H adenocarcinoma in rats and the androgen-sensitive LNCaP human adenocarcinoma in severe combined immunodeficiency (SCID) mice.31 Specifically, decreasing calorie consumption (energy restriction) by 20-40% from the control animals fed ad libitum resulted in:
Increased PC cell apoptosis (programmed cell death)
A two- to threefold reduction in PC angiogenesis as measured by microvessel density
A decrease in vascular endothelial growth factor (VEGF) expression
A decrease in circulating levels of IGF-1
A significant decrease in tumor size
Therefore, all of these findings were benefits observed in the calorie-restricted group. This study showed that the nutritional status directly or indirectly influenced interaction between tumor cells and local blood vessels by changing the expression of angiogenic growth factors. In the Dunning model, energy (calorie) restriction resulted in a striking inhibition of VEGF expression. In the LNCaP model, there was little baseline expression of VEGF. However, there was an almost threefold reduction from the baseline IGF-1 levels in blood samples from LNCaP-bearing mice that were subjected to energy restriction.
IGF-1 Levels Stimulate PC Growth, Up-regulate uPA, and Stimulate Angiogenesis
a)IGF-1 and uPA Increases Aggressive PC Growth
b)GLA and EPA Inhibit uPA
Higher IGF-1 levels are associated with a fourfold greater risk of developing PC.32 IGF-1 is a known mitogen (stimulator of cell division and tumor growth) for PC. IGF-1 receptors are found on the PC cell as well as on osteoblasts.33 IGF-1 stimulates the PC cell to make uPA (urokinase-type plasminogen activator), a cell product implicated in the invasiveness and metastasis of PC. The uPA receptors are on the PC cell and on osteoblasts. IGF-1 adds further insult by also acting as an angiogenic growth factor.34 A detailed illustration of these and other interactions is shown in Figure 1.
Gene expression of IGF-1 and its receptor are inhibited by 5-alpha-reductase inhibitors such as Proscar.35
IGF-1 and uPA Act Together to Increase Aggressive PC Growth
There are studies demonstrating that elevations of uPA and its receptor are associated with nonorgan-confined PC at radical prostatectomy (RP), disease progression with metastases, and a poorer overall survival.36 uPA works closely with IGF-1 and its receptors, cleaving IGF-1 from its binding proteins. uPA is also part of an autocrine pathway for the PC cell, allowing uPA to stimulate PC cell growth and make more uPA at the same time.
Good News! GLA and EPA Inhibit uPA
Of interest is the fact that uPA production is inhibited by gamma-linolenic acid (GLA) and eicosapentenoic acid (EPA).37 GLA and EPA, which are essential fatty acids, are among the important players in the prevention of disease and in maintenance of health. This is discussed by Barry Sears, Ph.D., in Omega Rx Zone.38 Sears beautifully presents the interconnection between restriction of calories, along with dietary adjustments of carbohydrate, protein, and fat intake, and the production of a class of fatty acids called eicosanoids. An understanding of these issues is fundamental to our ability to prevent disease and maintain or recapture health.
More Advantages to Caloric Restriction and Avoidance of Hyperinsulinemia
a)Carbohydrates Should Be Minimized
b)Glycemic Index
c)Volume of Food
Sears stresses the importance of caloric restriction by means of limiting the intake of high-density carbohydrates such as bread, pasta, grains in most cereals, and starches such as those found in potatoes. This reduction of caloric intake by lowering high-density carbohydrate intake decreases the stimulation of the pancreas to make insulin and limits all the adverse side effects associated with increased insulin levels (hyperinsulinemia).
Caloric restriction has been shown to be an important factor in augmenting the immune system and improving longevity. It reduces free radical production, which if otherwise unchecked, damages DNA and oxidizes polyunsaturated fats. Caloric restriction increases levels of superoxide dismutase (SOD), glutathione, melatonin, DHEA, peroxidase, and catalase. The latter substances are important defense mechanisms in our body that are known to decrease with aging. Caloric restriction is instrumental in lowering the production of cortisol. Cortisol is associated with increased stress levels, and an imbalance in cortisol production leads to immune deficiency and bone loss through resorption, leading to osteopenia and osteoporosis, as well as muscle breakdown and aging of the skin.
Calorie restriction, as proposed by Sears and others, has been shown to also reduce advanced glycosylated end-products (AGE). These are carbohydrate-protein complexes associated with hyperinsulinemic states and with cardiovascular disease, Alzheimer's disease, kidney disease, and other degenerative states.
We need to rethink how much food we need to eat. Our ideal body weight should be taken seriously. If we were to do this alone, we would eliminate most cases of diabetes, hypertension, hypercholesterolemia, stroke, heart disease, and a significant amount of cancer from our lives and those of our loved ones. healthy people should consume 500 calories permeal and 100 calories persnack. Modifications of this are based on the level of disease activity, age, and body surface area. Nutritional software and nutritional counseling should be an integral part of our approach to good health.
Insulin-Stimulating Carbohydrate Is the Damaging Subcomponent of Carbohydrate
If hyperinsulinemia is crucial to the development of many of our biochemical problems--from arthritis to neurodegenerative disease to cancer--then controlling the carbohydrate loads we subject our bodies to should be a major tool in maintaining good health. Carbohydrates can be characterized by the amount of insulin-stimulating carbohydrate (ISC) that they contain. The ISC is the total carbohydrate content (in grams) minus the amount of fiber (in grams) it contains. An example is 1 cup of broccoli containing a total of 7 grams of carbohydrate, of which 4 grams are fiber. The difference between the two equals the ISC content or 3 grams. Fruits and vegetables, which are high in fiber, generally have a lower ISC content than do starches, grains, and pasta. Therefore, analogous to PSA (benign-related versus cancer-related) and to cholesterol (total cholesterol versus LDL versus HDL), any intelligent discussion on carbohydrates must specify the components in question.
a)Tomato-Based Products
b)Tissue Lycopene Levels
c)Assimilation
d)Lycopenes And Strawberries Lower Risk
e)Gene Up-regulation of Connexin 43
f)Lycopene and Vitamin D
g)Reduce Cardiovascular Risk Factors
h)Decreases Insulin-like Growth Factor Levels
i)Increase Lycopene Consumption and Plasma Levels
Of all nutritional literature currently in existence relating to PC, the relationship between lycopene ingestion and the health of the prostate is the clearest. Lycopene consumption been found to decrease not only the risk of PC in multiple studies,14-16 but also the risk of BC17 and pancreatic and stomach cancer,16 as well as lung cancer.18
Tomato-Based Products Are the Richest Sources of Lycopene
In these positive studies that correlated lycopene consumption with decreased risk of PC, the lycopene sources were tomato-based products. The richest sources of lycopene in the U.S. diet are ketchup, tomato juice, and pizza sauce; these account for over 80% of the total lycopene intake of Americans.19 In one study from Athens, Greece, the authors concluded that the incidence of prostate cancer in Greece could be reduced by about 40% if the population increased the consumption of tomatoes, reduced the intake of dairy products, and substituted olive oil for other added lipids.20
Lycopene Consumption Correlates with Blood and Tissue Lycopene Levels
The correlation between increased tomato-based consumption of lycopenes and the decreased risk of PC and other cancers is also found in the laboratory, where serum levels of lycopene are correlated with lycopene intake. The same holds true in studies in which tissue levels of lycopene have been studied in prostate pathology specimens.16,17
Lycopene concentrations in the serum of healthy men are typically 0.60-1.9 nmol/mL (nanomoles per milliliter).21 Biochemically, lycopene is composed of two main chemical structures or isomers: all-trans-lycopene and cis-isomers. Tomato sauce contains primarily all-trans-lycopene (83% of total lycopene). The ingestion of tomato sauce results in substantial increases in total lycopene levels in both the serum and prostate tissue and a substantial increase in all-trans-lycopene in prostate tissue but with relatively smaller increases in the serum.22 Serum lycopene levels are predominantly composed of the cis-isomer of lycopene, which represents 58-73% of the total serum lycopene, while the all-trans-isomer composes 27-42% of the serum lycopene.21
Among 72 studies identified, 57 reported that higher tomato intake or blood lycopene levels reduced the risk of cancer at a defined anatomic site; 35 of these associations were statistically significant.23 The evidence for a benefit was strongest for cancers of the prostate, lung, and stomach. Data were also suggestive of a benefit for cancers of the pancreas, colon and rectum, esophagus, oral cavity, breast, and cervix. The relative risk (RR) was determined, comparing high tomato intake or high lycopene levels with low tomato intake or low lycopene levels. In such comparisons, about half of the RR was close to 0.6 or lower.23 In another study, the odds of contracting aggressive PC were significantly lower when plasma lycopene levels were high. Plasma lycopene levels were divided into five quintiles. The highest level, the fifth quintile, showed an odds ratio (OR) of 0.56.14 These findings add up to about a 40% reduction in risk of being diagnosed with these cancer types for those with high tomato intake or the highest plasma lycopene levels.
The Proof of the Pudding Is Not in the Eating but in the Assimilation
The proof of the pudding, in the matter of dietary issues, relates more to how we assimilate what we have eaten rather than to just a history of having eaten something. It should not be surprising then that the correlation between serum or plasma lycopene levels and a lower incidence of PC is greater than the correlation between the oral intake of lycopenes and PC incidence. In a study by Lu et al., significant reductions in PC incidence were observed with higher plasma concentrations of the following carotenoids: lycopene, OR 0.17; and zeaxanthin, OR 0.22, when comparing highest and lowest quartiles.24 This translates into about an 80% reduction in PC incidence when the highest blood levels of either lycopene or zeaxanthin are achieved.
Lycopenes and Strawberries Lower Risk, Especially for Aggressive and Extra-Prostatic PCA dietary history of significant lycopene and/or strawberry consumption correlated with a lower risk of aggressive and extra-prostatic PC.14 The lycopene source that was found to be most significant in most epidemiologic studies was the tomato, in the form of tomato sauce, stewed tomatoes, and pizza. In one large-scale study involving 812 new cases of PC over the years 1986-1992 with matched controls, of the 46 vegetables and fruits or related products significantly associated with lower PC risk, three of the four identified were related to lycopenes--tomato sauce, tomatoes, and pizza. In this study, the combined intake of tomatoes, tomato sauce, tomato juice, and pizza (accounting for 82% of lycopene intake) was associated with a reduced risk of PC for consumption frequency greater than 10 versus less than 1.5 servings a week. Lycopene intake was also associated with a 53% reduced risk for advanced PC (Stages III and IV). The other nonlycopene product identified with significantly lower PC risk was strawberries.15
The largest relevant dietary study, a prospective study in male health professionals, found that consumption of 2-4 servings of tomato sauce a week was associated with about a 35% risk reduction of total PC and a 50% reduction of advanced (extra-prostatic) PC. Tomato sauce was by far the strongest predictor of plasma lycopene levels in this study.25 These associations persisted in analyses controlling for fruit consumption, vegetable consumption, and olive oil use and were observed separately in men of Southern European or other Caucasian ancestry.26
Lycopene Inhibits Cancer Cell Growth by Gene Up-regulation of Connexin 43Lycopene functions as a very potent antioxidant. In this regard, lycopene can trap singlet oxygen and reduce mutagenesis (gene mutations) in the Ames test. Other mechanisms of lycopene action may be operative as well. Lycopene at physiological concentrations can inhibit human cancer cell growth by interfering with growth factor receptor signaling and cell-cycle progression--specifically in PC cells--without evidence of toxic effects or apoptosis of cells.27 Studies of human and animal cells have identified connexin 43, a gene, whose expression is up-regulated by lycopene and which allows direct intercellular gap junctional communication (GJC). GJC is deficient in many human tumors and its restoration or up-regulation is associated with decreased proliferation.
Lycopene Is Synergistic with Vitamin D, Inhibiting Tumor Cell Proliferation and Enhancing Differentiation
The combination of low concentrations of lycopene with 1,25-dihydroxyvitamin D3 exhibits a synergistic effect on inhibition of cell proliferation, and differentiation, and an additive effect on cell-cycle progression in the HL-60 promyelocytic leukemia cell line, suggesting some interaction at a nuclear or subcellular level.18
Lycopenes Reduce Cardiovascular Risk Factors
Lycopene levels decrease with advancing age. However, in contrast to other carotenoids, they are not found to be reduced by smoking or alcohol consumption.16,19 Lycopenes also have an inhibitory effect on cholesterol synthesis and may enhance LDL degradation. Available evidence suggests that intimal wall thickness and risk of myocardial infarction are reduced in persons with higher adipose tissue concentrations of lycopene.19
Lycopene Levels May Be Associated with Decreased Insulin-like Growth Factor Levels
The consumption of cooked tomatoes was substantially and significantly associated with reduced insulin-like growth factor-1 (IGF-1) levels, with a mean change of -31.5% for an increment of 1 serving a day. The authors concluded that the strongest known dietary risk factor for PC (lycopene deficit, as reflected in a reduced intake of cooked tomatoes) is somehow related to an important endocrine factor (IGF-1) in the cause of this disease.28 However, in another study, IGF-1 was not associated with any dietary factor studied, such as total fat, carbohydrate, protein, dairy products, tomatoes, or calcium.29
Suggested Ways to Increase Lycopene Consumption and Plasma Levels
The easiest way I have found to combine a healthy intake of lycopenes into my diet is by using marinara sauce on various foods. For example, at breakfast, an egg-white omelet containing eggplant and bell peppers (ratatouille omelet) covered with marinara sauce is a healthy source of protein, contains a substantial fiber content, and is restricted in the amount of simple carbohydrates. Stewed tomatoes can be served as a vegetable side dish with lunch or dinner.
Dietary Fat Increases PC Growth Rates
There are studies that show that dietary fat increases tumor growth rates in an animal model of human PC. In a mouse model of PC involving androgen-sensitive human prostatic adenocarcinoma cells (LNCaP cells), mice fed a 40.5% fat diet had mean tumor weights more than 2 times greater than mice fed a 21% fat diet. The 40.5% fat diet approximates that found in the average American male diet, which has been determined to be 36%.30
The slower tumor growth associated with the low-fat diet occurred even after the formation of measurable tumors when the diets were changed from 40% fat to 21% fat. Serum PSA levels also were highest in the 40.5 kcal% fat group and lowest in another group fed only 2.3 kcal% fat.30
Reduction of Total Calorie Consumption Decreases Tumor Size by Decreasing VEGF, Angiogenesis, and IGF-1 and by Increasing Apoptosis
The emphasis on dietary fat, per se, has lessened our focus on the importance of caloric over-consumption. Fat excess, however, is linked to excessive calorie consumption, since fat contains twice as many calories, gram for gram, as protein or carbohydrate.
I believe that diet should be regarded as having serious biochemical relevance to the health of the individual. You are, for the most part, what you eat (or at least what you assimilate). Western societies, especially the United States, are consumers of excessive calories. Excessive caloric consumption, especially coupled with a sedentary lifestyle, is a significant factor that adversely affects longevity.
An important study demonstrated that energy intake (caloric intake) modulates the growth of prostate tumors in two animal models: the androgen-dependent Dunning R3327-H adenocarcinoma in rats and the androgen-sensitive LNCaP human adenocarcinoma in severe combined immunodeficiency (SCID) mice.31 Specifically, decreasing calorie consumption (energy restriction) by 20-40% from the control animals fed ad libitum resulted in:
Increased PC cell apoptosis (programmed cell death)
A two- to threefold reduction in PC angiogenesis as measured by microvessel density
A decrease in vascular endothelial growth factor (VEGF) expression
A decrease in circulating levels of IGF-1
A significant decrease in tumor size
Therefore, all of these findings were benefits observed in the calorie-restricted group. This study showed that the nutritional status directly or indirectly influenced interaction between tumor cells and local blood vessels by changing the expression of angiogenic growth factors. In the Dunning model, energy (calorie) restriction resulted in a striking inhibition of VEGF expression. In the LNCaP model, there was little baseline expression of VEGF. However, there was an almost threefold reduction from the baseline IGF-1 levels in blood samples from LNCaP-bearing mice that were subjected to energy restriction.
IGF-1 Levels Stimulate PC Growth, Up-regulate uPA, and Stimulate Angiogenesis
a)IGF-1 and uPA Increases Aggressive PC Growth
b)GLA and EPA Inhibit uPA
Higher IGF-1 levels are associated with a fourfold greater risk of developing PC.32 IGF-1 is a known mitogen (stimulator of cell division and tumor growth) for PC. IGF-1 receptors are found on the PC cell as well as on osteoblasts.33 IGF-1 stimulates the PC cell to make uPA (urokinase-type plasminogen activator), a cell product implicated in the invasiveness and metastasis of PC. The uPA receptors are on the PC cell and on osteoblasts. IGF-1 adds further insult by also acting as an angiogenic growth factor.34 A detailed illustration of these and other interactions is shown in Figure 1.
Gene expression of IGF-1 and its receptor are inhibited by 5-alpha-reductase inhibitors such as Proscar.35
IGF-1 and uPA Act Together to Increase Aggressive PC Growth
There are studies demonstrating that elevations of uPA and its receptor are associated with nonorgan-confined PC at radical prostatectomy (RP), disease progression with metastases, and a poorer overall survival.36 uPA works closely with IGF-1 and its receptors, cleaving IGF-1 from its binding proteins. uPA is also part of an autocrine pathway for the PC cell, allowing uPA to stimulate PC cell growth and make more uPA at the same time.
Good News! GLA and EPA Inhibit uPA
Of interest is the fact that uPA production is inhibited by gamma-linolenic acid (GLA) and eicosapentenoic acid (EPA).37 GLA and EPA, which are essential fatty acids, are among the important players in the prevention of disease and in maintenance of health. This is discussed by Barry Sears, Ph.D., in Omega Rx Zone.38 Sears beautifully presents the interconnection between restriction of calories, along with dietary adjustments of carbohydrate, protein, and fat intake, and the production of a class of fatty acids called eicosanoids. An understanding of these issues is fundamental to our ability to prevent disease and maintain or recapture health.
More Advantages to Caloric Restriction and Avoidance of Hyperinsulinemia
a)Carbohydrates Should Be Minimized
b)Glycemic Index
c)Volume of Food
Sears stresses the importance of caloric restriction by means of limiting the intake of high-density carbohydrates such as bread, pasta, grains in most cereals, and starches such as those found in potatoes. This reduction of caloric intake by lowering high-density carbohydrate intake decreases the stimulation of the pancreas to make insulin and limits all the adverse side effects associated with increased insulin levels (hyperinsulinemia).
Caloric restriction has been shown to be an important factor in augmenting the immune system and improving longevity. It reduces free radical production, which if otherwise unchecked, damages DNA and oxidizes polyunsaturated fats. Caloric restriction increases levels of superoxide dismutase (SOD), glutathione, melatonin, DHEA, peroxidase, and catalase. The latter substances are important defense mechanisms in our body that are known to decrease with aging. Caloric restriction is instrumental in lowering the production of cortisol. Cortisol is associated with increased stress levels, and an imbalance in cortisol production leads to immune deficiency and bone loss through resorption, leading to osteopenia and osteoporosis, as well as muscle breakdown and aging of the skin.
Calorie restriction, as proposed by Sears and others, has been shown to also reduce advanced glycosylated end-products (AGE). These are carbohydrate-protein complexes associated with hyperinsulinemic states and with cardiovascular disease, Alzheimer's disease, kidney disease, and other degenerative states.
We need to rethink how much food we need to eat. Our ideal body weight should be taken seriously. If we were to do this alone, we would eliminate most cases of diabetes, hypertension, hypercholesterolemia, stroke, heart disease, and a significant amount of cancer from our lives and those of our loved ones. healthy people should consume 500 calories permeal and 100 calories persnack. Modifications of this are based on the level of disease activity, age, and body surface area. Nutritional software and nutritional counseling should be an integral part of our approach to good health.
Insulin-Stimulating Carbohydrate Is the Damaging Subcomponent of Carbohydrate
If hyperinsulinemia is crucial to the development of many of our biochemical problems--from arthritis to neurodegenerative disease to cancer--then controlling the carbohydrate loads we subject our bodies to should be a major tool in maintaining good health. Carbohydrates can be characterized by the amount of insulin-stimulating carbohydrate (ISC) that they contain. The ISC is the total carbohydrate content (in grams) minus the amount of fiber (in grams) it contains. An example is 1 cup of broccoli containing a total of 7 grams of carbohydrate, of which 4 grams are fiber. The difference between the two equals the ISC content or 3 grams. Fruits and vegetables, which are high in fiber, generally have a lower ISC content than do starches, grains, and pasta. Therefore, analogous to PSA (benign-related versus cancer-related) and to cholesterol (total cholesterol versus LDL versus HDL), any intelligent discussion on carbohydrates must specify the components in question.
Prostate Cancer-3
High Density Carbohydrates Should Be Minimized
An important variable in nutrition relates to the quantity or volume of food that we eat at each meal. Therefore, we need to specify carbohydrate intake as a function of ISC per unit volume of food. A serving of mashed potatoes (1 cup) containing a total of 40 grams of carbohydrate, with 2 grams being fiber, would have the difference--38 grams--as ISC. The same serving of broccoli containing a total of 7 grams of carbohydrate, with 4 grams being fiber, would have 3 grams of ISC per serving. The ISC per unit serving, comparing mashed potatoes to broccoli is therefore 38 versus 3. Carbohydrates that deliver a high insulin-stimulating effect per unit serving are termed high-density carbohydrates. Carbohydrates that are proportionally higher in fiber and lower in ISC per unit serving are called low-density carbohydrates. In our PC analogy, PSA density would relate to carbohydrate density.
Glycemic Index Further Modifies the Concept of ISC Content: The Glycemic LoadInsulin release is also related to the rapidity of increase of the blood sugar after ingestion of carbohydrates. The concept of glycemic index is used to account for this variable. The glycemic index measures the rate of carbohydrate entry into the bloodstream. Factors relating to the glycemic index of a particular food include the following:
The amount of fiber it contains
The amount of fructose the carbohydrate contains relative to the amount of glucose
The amount of fat eaten with the carbohydrate
High fiber and increased amounts of fructose (sugar from fruits) both function to lower the glycemic index. Fat consumed with carbohydrates will also mollify the glycemic effect and lower the glycemic index. Sears ties this nicely together by using the concept of glycemic load (GL): the amount of insulin-stimulating carbohydrate multiplied by the glycemic index of the carbohydrate (ISC × GI).
Volume of Food Eaten
An additional factor that must also be accounted for is the volume of carbohydrate ingested. You might be looking intelligently at the total carbohydrate content, noting the fiber content and determining the grams of ISC. You might even be smart enough to have memorized the glycemic indices of many of the foods you eat to determine the GL. However, if you double or triple the volume of carbohydrate you eat, you can still be over-stimulating the production of insulin. These topics relating to balancing protein, carbohydrate, and healthy fats, are discussed in the Omega Rx Zone by Sears.
Eicosanoid Balance
a)Metabolites Increase PC Growth, Invasion, and Metastasis
b)Inhibition Causes Apoptosis
c)EPA and DHA
Eicosanoids are hormones that are made within the cell membrane of each and every cell--all 60 trillion cells in the human body. Eicosanoids are 20-carbon structures. Eicosanoids have autocrine, paracrine, and endocrine effects. That is, they affect the very cell that produces the eicosanoid (autocrine effect), as well as nearby cells (paracrine effect) and distant cells (endocrine effect). As with every aspect of biology, balance is a critical issue relating to good health as well as the development and progression of various diseases. Likewise, eicosanoid balance plays a central role that puts this desired biological endpoint at the hub of the integrative medicine wheel. Eicosanoids, and the balance of good versus bad eicosanoids, can be seen as the heart and soul, muscle, bone, and sinew, literally and figuratively, of holistic medicine.
Clearly pertinent to a discussion of PC is the fact that the first eicosanoids isolated in 1936 by Ulf von Euler were prostaglandins--eicosanoids isolated from the prostate gland. Eicosanoids are the oldest hormones, tracing their origin back 500 million years ago to production by sponges. Hormones are messengers involved in communication between cells. A hormone is formally defined as a substance, usually a peptide or steroid, produced by one tissue and conveyed by the bloodstream to another to affect physiological activity, such as growth or metabolism. All of medicine--in fact, all of life--represents issues of communication and balance. Such is the case at every level of existence. This is true for the cell, tissues, an organism, a human individual, a family, a community, a society, a nation, a planet, and the universe. If there was ever a guiding principle that is truly holistic, it is the principle of communication and balance.
Arachidonic Acid Metabolites Increase PC Growth, Invasion, and Metastasis
Eicosanoid synthesis involves the release of arachidonic acid (AA) from cell membrane phospholipids by an enzyme called phospholipase A2 (PLA2). AA then undergoes metabolism by cyclooxygenases (COXs) and lipoxygenases (LOXs). AA is an omega-6 fatty acid that is known to generate free radicals and is considered an unfavorable eicosanoid. Specific metabolites of AA, for example, PGE2 and 5-HETE, are created through the actions of the enzymes COX-2, 5-LOX, 12-LOX, and 15-LOX. These metabolites are examples of bad eicosanoids and have been implicated in PC growth and metastasis.39,40 In a study of human PC in which 5-LOX and its metabolite 5-HETE were evaluated in both malignant and benign prostate tissue within the same patient, both 5-LOX and 5-HETE were significantly over-expressed in the PC tissue.41 In other words, specific eicosanoids are modulators of tumor cell interactions with certain host components within the context of cancer growth, invasion, and spread.
The administration of PGE2 to prostate, breast, and colon cancer cells resulted in increased cellular proliferation. Some studies have shown that stimulation of PC growth is related more to COX-2 and a resultant increase in angiogenesis than to PGE2.42
Inhibition of AA and Its Metabolites Causes PC Apoptosis
Laboratory studies have shown a significant reduction in cancer cell invasiveness by inhibitors of PLA2, as well as by general COX inhibitors such as ibuprofen (Motrin) and also by specific COX-2 inhibitors.43 In this particular study, the mechanism of action was related to a reduction in angiogenesis factors called matrix metalloproteinases (MMPs). Other studies have shown a significant role for COX-2 inhibition in PC with demonstration of reduction in microvessel density of the tumor related to a decrease in VEGF, a potent angiogenesis factor.44 Apparently, within the center of PC tumors a state of lower oxygen tension exists (hypoxic center) which stimulates VEGF. COX-2 inhibition seems to be able to prevent this hypoxia-induced up-regulation of VEGF and angiogenesis. An ibuprofen derivative called Flurbiprofen® inhibited PGE2 and reduced PC cell growth by inhibiting up-regulation of COX-2.45
Multiple papers have shown that inhibition of 5-LOX leads to PC apoptosis.46-49
EPA and DHA Lower PC Risk
EPA, an omega-3 fatty acid, has been shown to suppress AA formation by inhibiting the enzyme delta-5-desaturase.50 Some epidemiologic studies have shown that high intakes of EPA and DHA lower PC risk substantially.51 Other studies have shown a reduction in PC risk only with a decrease in the ratio of AA to EPA (AA:EPA).52 A combination of GLA and EPA administered to humans was shown to strongly increase serum EPA and DGLA levels and to reduce AA formation and AA metabolites such as leuko-trienes.50
Foods rich in EPA include coldwater fish such as tuna, sardines, herring, swordfish, and salmon. Commercially available pharmaceutical-grade fish oils also contain large amounts of EPA and DHA.
Selenium Prevents PC in Select Patients
a)Enhances Cell Kill
b)Vitamin E Isomers
Measures to prevent PC must be a routine part of the counsel that general practitioners and internists give their patients. Selenium intake of at least 200 mcg a day should be a consideration in the prevention of PC. Low plasma selenium is associated with a four- to fivefold increased risk of PC.53 In addition, levels of plasma selenium also decrease with age, resulting in middle-aged to older men being at a higher risk for low selenium levels. Ideally, baseline levels of selenium should be obtained before beginning routine selenium supplementation. It would make sense to begin such a micronutrient and mineral assessment at age 25 and perhaps every 10 years thereafter.
The studies of selenium supplementation and its role in preventing PC need continued clarification. In one study, selenium supplements provided benefit only for those individuals who had lower baseline plasma selenium levels.54 Other subjects with normal or higher levels did not benefit and had a slightly increased risk for PC. The studies by Clark et al. showed that selenium reduced the incidence of PC in men 63%.54,55 The mechanism of selenium anti-PC activity appears related to selenium's antiproliferative effect against PC. Selenium affects the cell cycle (see Figure 3) with up-regulation of cell-cycle regulators such as p21 and p27, resulting in a decrease in PC growth due to G1 arrest and up to an 80% reduction in the S-phase of PC growth.56
Selenium Enhances Cell Kill with Taxol and Adriamcyin Chemotherapy
Selenium also has been shown to have a significant antineoplastic effect on breast, lung, liver, and small intestinal tumor cells. Supplementation with selenium enhanced the chemotherapeutic effects of Taxol (paclitaxel) and Adriamycin (doxorubicin) in these cells beyond that seen when the chemotherapeutic drugs were used alone. In studies of the PC cell lines LNCaP and PC-3, the addition of Taxol or Adriamycin, in combination with selenium, caused small but significant inhibition of the PC cell growth. In the cited studies, the optimal inhibition of tumor growth occurred when the plasma selenium level was between 4 -40 ng/mL after 72 hours of treatment.57
Vitamin E Isomers Alpha- and Gamma-Tocopherol plus Selenium Combine to Reduce PC Risk
A large-scale study of almost 11,000 men in Maryland showed that the protective effects of high selenium levels, and similarly that of the alpha-tocopherol isomer of vitamin E, were only observed when the concentrations of the gamma tocopherol isomer of vitamin E were also high.58 In this study, the risk of PC declined with increasing concentrations of alpha-tocopherol, with the highest concentration associated with a 68% PC risk reduction. For gamma-tocopherol, men with levels in the highest fifth of the distribution had a fivefold greater reduction in the risk of developing PC than men in the lowest fifth (p = .002). The observed interaction between alpha-tocopherol, gamma-tocopherol, and selenium suggested that combined alpha- and gamma-tocopherol supplements, used in conjunction with selenium, should be considered in future PC prevention trials.
Vitamin E Succinate Inhibits PC Cell Growth and PSA Expression
a)In Smokers
b)VEGF Levels
c)Dietary Fat
d)Implementing
In another study, vitamin E succinate inhibited cell growth of PC cells in the LNCaP line by suppressing androgen receptor expression and PSA expression. The combination of Eulexin (flutamide) with vitamin E succinate resulted in a more significant inhibition of LNCaP cell growth.59 The same investigators demonstrated that selenomethionine also showed an inhibitory effect on LNCaP cell growth but that this appeared to be independent of androgen receptor or PSA pathways.
Vitamin E Reduces Incidence of PC in Smokers in Two Separate Studies
A study of over 29,000 male smokers in Finland, ages 50-69, disclosed a 32% decrease in the incidence of PC (95% confidence interval [CI] = -47% to -12%). This was observed among the subjects who had received 50 mg a day of alpha-tocopherol (n = 14,564) in contrast with those not receiving it (n = 14,569). Mortality from PC was 41% lower among men receiving alpha-tocopherol (95% CI = -65% to -1%). Among subjects receiving beta-carotene (n = 14,560), PC incidence was 23% higher (95% CI = -4% to 59%) and mortality was 15% higher (95% CI = -30% to 89%) compared with those not receiving it (n = 14,573). In this study, long-term supplementation with alpha-tocopherol substantially reduced PC incidence and mortality in male smokers.60
An important issue is whether this benefit of alpha-tocopherol, and possibly other tocopherols, is limited to smokers or those who have recently quit smoking. A report by Chan et al. (1999) showed significant benefit only to smokers or those recently quitting smoking in a study involving 47,780 U.S. male health professionals who received at least 100 IU of supplemental alpha-tocopherol. In this population, the risk of metastatic or fatal PC was reduced 56%. In the nonsmoking population, there were no beneficial findings of statistical significance.61 In a study on the relationship of green and yellow vegetable consumption to risk reduction in cancer development, a significant reduction was again found to occur only in smokers. The cancers studied included those of the mouth and pharynx, esophagus, stomach, liver, larynx, lung, and urinary bladder.62
Vitamin E Reduces VEGF LevelsA follow-up study involving the Finnish smokers compared VEGF levels in patients receiving alpha-tocopherol with those in the placebo group. There was an 11% reduction in VEGF levels in the alpha-tocopherol group as compared with a 10% increase in the placebo group (p = 0.03).63
Vitamin E Lessens Adverse Effects on PC Growth Due to Dietary Fat In vitro
Research studies have shown that vitamin E reduces growth rates of PCs resulting from a high fat diet. Tumor growth rates were highest in the animals fed a 40.5%-kcal fat diet (the typical American diet). Tumors in animals fed 40.5%-kcal fat plus vitamin E were the same as those fed a 21.2%- kcal fat diet (an ideal fat level).64
One Recommendation for Implementing Some of the These Finding
Each Life Extension (LE) Booster softgel contains 210 mg of gamma-tocopherol plus 200 mcg of selenium in addition to 10 mg of lycopene. The full supplement facts on LE Booster softgels can be reviewed at http://www.lef.org/newshop/items/item00579.html. Combining one LE Booster softgel with one LE Vitamin E capsule containing 400 IU of d-alpha-tocopherol succinate, in conjunction with the dietary approaches detailed in previous paragraphs, should contribute significantly to both the prevention and active nutritional treatment of PC.
High Consumption of Dairy Products and Calcium Increase Risk of PC
A study in Sweden examined the relationship of dairy products, dietary calcium, phosphorus, and vitamin D with risk of total, extraprostatic, and metastatic PC. The results indicated that calcium intake was an independent predictor of PC [relative risk (RR) = 1.91] for calcium intakes of greater than or equal to 1183 mg a day versus less than 825 mg a day. This was especially the case for metastatic tumors with a RR equal to 2.64, controlling for age, family history of PC, smoking, and total energy and phosphorus intakes. The authors concluded that high consumption of dairy products was associated with a 50% increased risk of PC.65
A second study in the United States involved 1012 cases of PC among 20,885 men over an 11-year follow-up period. Men consuming greater than 2.5 servings a day of dairy products had a RR of 1.34 for PC after adjustment for baseline age, body mass index, smoking, exercise, and randomized treatment assignment in the original placebo-controlled trial. Compared with men consuming less than or equal to 150 mg calcium a day from dairy products, men consuming greater than 600 mg of calcium a day had a 32% higher risk of PC. The results support the hypothesis that dairy products and calcium are associated with a greater risk of PC.
Also noted was that at baseline men who consumed greater than 600 mg of calcium a day from skim milk had lower plasma 1,25(OH)(2)D(3) concentrations than did those consuming less than or equal to 150 mg of calcium a day (71 compared with 85 pmol/L or 30.06 pg/mL compared with 35.64 pg/mL; p = 0.005).66
The RR for the diagnosis of advanced PC was noted to be 2.97 in men with daily calcium consumption of greater than or equal to 2000 mg a day versus intakes of less than 500 mg a day.67 The same was true for the risk of metastatic PC, but with a stronger RR of 4.57. (A RR of 4.57 means a 4.57 times greater risk of contracting PC.) Calcium from food sources and from supplements independently increased risk of PC.
High Fructose Consumption Decreases Risk of PC
In the same study referenced above, high fructose intake was found to be related to a lower risk of advanced PC (multivariate RR, 0.51). Fruit intake was associated with a RR of advanced PC (RR = 0.63; 5 versus %1 serving a day), and this association was accounted for by fructose intake. Nonfruit sources of fructose similarly predicted lower risk of advanced PC.67
Boron Consumption Lowers PC Occurrence
Men who ate the greatest amount of boron were 54% less likely to develop PC compared to men who consumed the least amount of boron. This information was presented in the annual Experimental Biology Conference in Florida in 2001. The study was led by Cui et al. from the UCLA Medical Center and compared dietary patterns of 95 men with PC with those of 5720 males without cancer. 67a The more boron-rich foods consumed, the greater the reduction in risk of being diagnosed with PC. Those men in the highest quartile of boron consumption had a 54% reduction in PC. Boron-rich foods include plums, grapes, prunes, avocados, and nuts such as almonds and peanuts. A serving of 100 grams of prunes (6 dried prunes) has 2-3 mg of boron and 6.1 grams of fiber.68
Diet and Supplement Studies Versus Cancer Risk: Confounding Findings Affecting Interpretation
The lifestyle characteristics of supplement users are certainly a potential bias in studies investigating the benefits versus risks of vitamins, minerals, and dietary habits. A study by Patterson et al. evaluated supplement users and found that, among men, supplement users had the characteristics detailed in Table 2.69
The health-minded nature of users of vitamins, mineral supplements, and dietary plans may well confound what we think we know about the relationship of such integrative health measures and investigations dealing with relative risks (RR) and odds ratios (OR) of diseases such as PC as well as other malignant and nonmalignant processes.
An important variable in nutrition relates to the quantity or volume of food that we eat at each meal. Therefore, we need to specify carbohydrate intake as a function of ISC per unit volume of food. A serving of mashed potatoes (1 cup) containing a total of 40 grams of carbohydrate, with 2 grams being fiber, would have the difference--38 grams--as ISC. The same serving of broccoli containing a total of 7 grams of carbohydrate, with 4 grams being fiber, would have 3 grams of ISC per serving. The ISC per unit serving, comparing mashed potatoes to broccoli is therefore 38 versus 3. Carbohydrates that deliver a high insulin-stimulating effect per unit serving are termed high-density carbohydrates. Carbohydrates that are proportionally higher in fiber and lower in ISC per unit serving are called low-density carbohydrates. In our PC analogy, PSA density would relate to carbohydrate density.
Glycemic Index Further Modifies the Concept of ISC Content: The Glycemic LoadInsulin release is also related to the rapidity of increase of the blood sugar after ingestion of carbohydrates. The concept of glycemic index is used to account for this variable. The glycemic index measures the rate of carbohydrate entry into the bloodstream. Factors relating to the glycemic index of a particular food include the following:
The amount of fiber it contains
The amount of fructose the carbohydrate contains relative to the amount of glucose
The amount of fat eaten with the carbohydrate
High fiber and increased amounts of fructose (sugar from fruits) both function to lower the glycemic index. Fat consumed with carbohydrates will also mollify the glycemic effect and lower the glycemic index. Sears ties this nicely together by using the concept of glycemic load (GL): the amount of insulin-stimulating carbohydrate multiplied by the glycemic index of the carbohydrate (ISC × GI).
Volume of Food Eaten
An additional factor that must also be accounted for is the volume of carbohydrate ingested. You might be looking intelligently at the total carbohydrate content, noting the fiber content and determining the grams of ISC. You might even be smart enough to have memorized the glycemic indices of many of the foods you eat to determine the GL. However, if you double or triple the volume of carbohydrate you eat, you can still be over-stimulating the production of insulin. These topics relating to balancing protein, carbohydrate, and healthy fats, are discussed in the Omega Rx Zone by Sears.
Eicosanoid Balance
a)Metabolites Increase PC Growth, Invasion, and Metastasis
b)Inhibition Causes Apoptosis
c)EPA and DHA
Eicosanoids are hormones that are made within the cell membrane of each and every cell--all 60 trillion cells in the human body. Eicosanoids are 20-carbon structures. Eicosanoids have autocrine, paracrine, and endocrine effects. That is, they affect the very cell that produces the eicosanoid (autocrine effect), as well as nearby cells (paracrine effect) and distant cells (endocrine effect). As with every aspect of biology, balance is a critical issue relating to good health as well as the development and progression of various diseases. Likewise, eicosanoid balance plays a central role that puts this desired biological endpoint at the hub of the integrative medicine wheel. Eicosanoids, and the balance of good versus bad eicosanoids, can be seen as the heart and soul, muscle, bone, and sinew, literally and figuratively, of holistic medicine.
Clearly pertinent to a discussion of PC is the fact that the first eicosanoids isolated in 1936 by Ulf von Euler were prostaglandins--eicosanoids isolated from the prostate gland. Eicosanoids are the oldest hormones, tracing their origin back 500 million years ago to production by sponges. Hormones are messengers involved in communication between cells. A hormone is formally defined as a substance, usually a peptide or steroid, produced by one tissue and conveyed by the bloodstream to another to affect physiological activity, such as growth or metabolism. All of medicine--in fact, all of life--represents issues of communication and balance. Such is the case at every level of existence. This is true for the cell, tissues, an organism, a human individual, a family, a community, a society, a nation, a planet, and the universe. If there was ever a guiding principle that is truly holistic, it is the principle of communication and balance.
Arachidonic Acid Metabolites Increase PC Growth, Invasion, and Metastasis
Eicosanoid synthesis involves the release of arachidonic acid (AA) from cell membrane phospholipids by an enzyme called phospholipase A2 (PLA2). AA then undergoes metabolism by cyclooxygenases (COXs) and lipoxygenases (LOXs). AA is an omega-6 fatty acid that is known to generate free radicals and is considered an unfavorable eicosanoid. Specific metabolites of AA, for example, PGE2 and 5-HETE, are created through the actions of the enzymes COX-2, 5-LOX, 12-LOX, and 15-LOX. These metabolites are examples of bad eicosanoids and have been implicated in PC growth and metastasis.39,40 In a study of human PC in which 5-LOX and its metabolite 5-HETE were evaluated in both malignant and benign prostate tissue within the same patient, both 5-LOX and 5-HETE were significantly over-expressed in the PC tissue.41 In other words, specific eicosanoids are modulators of tumor cell interactions with certain host components within the context of cancer growth, invasion, and spread.
The administration of PGE2 to prostate, breast, and colon cancer cells resulted in increased cellular proliferation. Some studies have shown that stimulation of PC growth is related more to COX-2 and a resultant increase in angiogenesis than to PGE2.42
Inhibition of AA and Its Metabolites Causes PC Apoptosis
Laboratory studies have shown a significant reduction in cancer cell invasiveness by inhibitors of PLA2, as well as by general COX inhibitors such as ibuprofen (Motrin) and also by specific COX-2 inhibitors.43 In this particular study, the mechanism of action was related to a reduction in angiogenesis factors called matrix metalloproteinases (MMPs). Other studies have shown a significant role for COX-2 inhibition in PC with demonstration of reduction in microvessel density of the tumor related to a decrease in VEGF, a potent angiogenesis factor.44 Apparently, within the center of PC tumors a state of lower oxygen tension exists (hypoxic center) which stimulates VEGF. COX-2 inhibition seems to be able to prevent this hypoxia-induced up-regulation of VEGF and angiogenesis. An ibuprofen derivative called Flurbiprofen® inhibited PGE2 and reduced PC cell growth by inhibiting up-regulation of COX-2.45
Multiple papers have shown that inhibition of 5-LOX leads to PC apoptosis.46-49
EPA and DHA Lower PC Risk
EPA, an omega-3 fatty acid, has been shown to suppress AA formation by inhibiting the enzyme delta-5-desaturase.50 Some epidemiologic studies have shown that high intakes of EPA and DHA lower PC risk substantially.51 Other studies have shown a reduction in PC risk only with a decrease in the ratio of AA to EPA (AA:EPA).52 A combination of GLA and EPA administered to humans was shown to strongly increase serum EPA and DGLA levels and to reduce AA formation and AA metabolites such as leuko-trienes.50
Foods rich in EPA include coldwater fish such as tuna, sardines, herring, swordfish, and salmon. Commercially available pharmaceutical-grade fish oils also contain large amounts of EPA and DHA.
Selenium Prevents PC in Select Patients
a)Enhances Cell Kill
b)Vitamin E Isomers
Measures to prevent PC must be a routine part of the counsel that general practitioners and internists give their patients. Selenium intake of at least 200 mcg a day should be a consideration in the prevention of PC. Low plasma selenium is associated with a four- to fivefold increased risk of PC.53 In addition, levels of plasma selenium also decrease with age, resulting in middle-aged to older men being at a higher risk for low selenium levels. Ideally, baseline levels of selenium should be obtained before beginning routine selenium supplementation. It would make sense to begin such a micronutrient and mineral assessment at age 25 and perhaps every 10 years thereafter.
The studies of selenium supplementation and its role in preventing PC need continued clarification. In one study, selenium supplements provided benefit only for those individuals who had lower baseline plasma selenium levels.54 Other subjects with normal or higher levels did not benefit and had a slightly increased risk for PC. The studies by Clark et al. showed that selenium reduced the incidence of PC in men 63%.54,55 The mechanism of selenium anti-PC activity appears related to selenium's antiproliferative effect against PC. Selenium affects the cell cycle (see Figure 3) with up-regulation of cell-cycle regulators such as p21 and p27, resulting in a decrease in PC growth due to G1 arrest and up to an 80% reduction in the S-phase of PC growth.56
Selenium Enhances Cell Kill with Taxol and Adriamcyin Chemotherapy
Selenium also has been shown to have a significant antineoplastic effect on breast, lung, liver, and small intestinal tumor cells. Supplementation with selenium enhanced the chemotherapeutic effects of Taxol (paclitaxel) and Adriamycin (doxorubicin) in these cells beyond that seen when the chemotherapeutic drugs were used alone. In studies of the PC cell lines LNCaP and PC-3, the addition of Taxol or Adriamycin, in combination with selenium, caused small but significant inhibition of the PC cell growth. In the cited studies, the optimal inhibition of tumor growth occurred when the plasma selenium level was between 4 -40 ng/mL after 72 hours of treatment.57
Vitamin E Isomers Alpha- and Gamma-Tocopherol plus Selenium Combine to Reduce PC Risk
A large-scale study of almost 11,000 men in Maryland showed that the protective effects of high selenium levels, and similarly that of the alpha-tocopherol isomer of vitamin E, were only observed when the concentrations of the gamma tocopherol isomer of vitamin E were also high.58 In this study, the risk of PC declined with increasing concentrations of alpha-tocopherol, with the highest concentration associated with a 68% PC risk reduction. For gamma-tocopherol, men with levels in the highest fifth of the distribution had a fivefold greater reduction in the risk of developing PC than men in the lowest fifth (p = .002). The observed interaction between alpha-tocopherol, gamma-tocopherol, and selenium suggested that combined alpha- and gamma-tocopherol supplements, used in conjunction with selenium, should be considered in future PC prevention trials.
Vitamin E Succinate Inhibits PC Cell Growth and PSA Expression
a)In Smokers
b)VEGF Levels
c)Dietary Fat
d)Implementing
In another study, vitamin E succinate inhibited cell growth of PC cells in the LNCaP line by suppressing androgen receptor expression and PSA expression. The combination of Eulexin (flutamide) with vitamin E succinate resulted in a more significant inhibition of LNCaP cell growth.59 The same investigators demonstrated that selenomethionine also showed an inhibitory effect on LNCaP cell growth but that this appeared to be independent of androgen receptor or PSA pathways.
Vitamin E Reduces Incidence of PC in Smokers in Two Separate Studies
A study of over 29,000 male smokers in Finland, ages 50-69, disclosed a 32% decrease in the incidence of PC (95% confidence interval [CI] = -47% to -12%). This was observed among the subjects who had received 50 mg a day of alpha-tocopherol (n = 14,564) in contrast with those not receiving it (n = 14,569). Mortality from PC was 41% lower among men receiving alpha-tocopherol (95% CI = -65% to -1%). Among subjects receiving beta-carotene (n = 14,560), PC incidence was 23% higher (95% CI = -4% to 59%) and mortality was 15% higher (95% CI = -30% to 89%) compared with those not receiving it (n = 14,573). In this study, long-term supplementation with alpha-tocopherol substantially reduced PC incidence and mortality in male smokers.60
An important issue is whether this benefit of alpha-tocopherol, and possibly other tocopherols, is limited to smokers or those who have recently quit smoking. A report by Chan et al. (1999) showed significant benefit only to smokers or those recently quitting smoking in a study involving 47,780 U.S. male health professionals who received at least 100 IU of supplemental alpha-tocopherol. In this population, the risk of metastatic or fatal PC was reduced 56%. In the nonsmoking population, there were no beneficial findings of statistical significance.61 In a study on the relationship of green and yellow vegetable consumption to risk reduction in cancer development, a significant reduction was again found to occur only in smokers. The cancers studied included those of the mouth and pharynx, esophagus, stomach, liver, larynx, lung, and urinary bladder.62
Vitamin E Reduces VEGF LevelsA follow-up study involving the Finnish smokers compared VEGF levels in patients receiving alpha-tocopherol with those in the placebo group. There was an 11% reduction in VEGF levels in the alpha-tocopherol group as compared with a 10% increase in the placebo group (p = 0.03).63
Vitamin E Lessens Adverse Effects on PC Growth Due to Dietary Fat In vitro
Research studies have shown that vitamin E reduces growth rates of PCs resulting from a high fat diet. Tumor growth rates were highest in the animals fed a 40.5%-kcal fat diet (the typical American diet). Tumors in animals fed 40.5%-kcal fat plus vitamin E were the same as those fed a 21.2%- kcal fat diet (an ideal fat level).64
One Recommendation for Implementing Some of the These Finding
Each Life Extension (LE) Booster softgel contains 210 mg of gamma-tocopherol plus 200 mcg of selenium in addition to 10 mg of lycopene. The full supplement facts on LE Booster softgels can be reviewed at http://www.lef.org/newshop/items/item00579.html. Combining one LE Booster softgel with one LE Vitamin E capsule containing 400 IU of d-alpha-tocopherol succinate, in conjunction with the dietary approaches detailed in previous paragraphs, should contribute significantly to both the prevention and active nutritional treatment of PC.
High Consumption of Dairy Products and Calcium Increase Risk of PC
A study in Sweden examined the relationship of dairy products, dietary calcium, phosphorus, and vitamin D with risk of total, extraprostatic, and metastatic PC. The results indicated that calcium intake was an independent predictor of PC [relative risk (RR) = 1.91] for calcium intakes of greater than or equal to 1183 mg a day versus less than 825 mg a day. This was especially the case for metastatic tumors with a RR equal to 2.64, controlling for age, family history of PC, smoking, and total energy and phosphorus intakes. The authors concluded that high consumption of dairy products was associated with a 50% increased risk of PC.65
A second study in the United States involved 1012 cases of PC among 20,885 men over an 11-year follow-up period. Men consuming greater than 2.5 servings a day of dairy products had a RR of 1.34 for PC after adjustment for baseline age, body mass index, smoking, exercise, and randomized treatment assignment in the original placebo-controlled trial. Compared with men consuming less than or equal to 150 mg calcium a day from dairy products, men consuming greater than 600 mg of calcium a day had a 32% higher risk of PC. The results support the hypothesis that dairy products and calcium are associated with a greater risk of PC.
Also noted was that at baseline men who consumed greater than 600 mg of calcium a day from skim milk had lower plasma 1,25(OH)(2)D(3) concentrations than did those consuming less than or equal to 150 mg of calcium a day (71 compared with 85 pmol/L or 30.06 pg/mL compared with 35.64 pg/mL; p = 0.005).66
The RR for the diagnosis of advanced PC was noted to be 2.97 in men with daily calcium consumption of greater than or equal to 2000 mg a day versus intakes of less than 500 mg a day.67 The same was true for the risk of metastatic PC, but with a stronger RR of 4.57. (A RR of 4.57 means a 4.57 times greater risk of contracting PC.) Calcium from food sources and from supplements independently increased risk of PC.
High Fructose Consumption Decreases Risk of PC
In the same study referenced above, high fructose intake was found to be related to a lower risk of advanced PC (multivariate RR, 0.51). Fruit intake was associated with a RR of advanced PC (RR = 0.63; 5 versus %1 serving a day), and this association was accounted for by fructose intake. Nonfruit sources of fructose similarly predicted lower risk of advanced PC.67
Boron Consumption Lowers PC Occurrence
Men who ate the greatest amount of boron were 54% less likely to develop PC compared to men who consumed the least amount of boron. This information was presented in the annual Experimental Biology Conference in Florida in 2001. The study was led by Cui et al. from the UCLA Medical Center and compared dietary patterns of 95 men with PC with those of 5720 males without cancer. 67a The more boron-rich foods consumed, the greater the reduction in risk of being diagnosed with PC. Those men in the highest quartile of boron consumption had a 54% reduction in PC. Boron-rich foods include plums, grapes, prunes, avocados, and nuts such as almonds and peanuts. A serving of 100 grams of prunes (6 dried prunes) has 2-3 mg of boron and 6.1 grams of fiber.68
Diet and Supplement Studies Versus Cancer Risk: Confounding Findings Affecting Interpretation
The lifestyle characteristics of supplement users are certainly a potential bias in studies investigating the benefits versus risks of vitamins, minerals, and dietary habits. A study by Patterson et al. evaluated supplement users and found that, among men, supplement users had the characteristics detailed in Table 2.69
The health-minded nature of users of vitamins, mineral supplements, and dietary plans may well confound what we think we know about the relationship of such integrative health measures and investigations dealing with relative risks (RR) and odds ratios (OR) of diseases such as PC as well as other malignant and nonmalignant processes.
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