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Sunday 15 February 2015

Life Extension: Health Concerns - Colorectal Cancer

Colorectal cancer remains the second most common cause of cancer death in the United States, although as much as 70% of cases thought to be preventable through moderate dietary and lifestyle modifications (Anand 2008; Thompson 2011).

This post is on Healthwise




Health Concerns

Colorectal Cancer

Colorectal cancer remains the second most common cause of cancer death in the United States, although as much as 70% of cases thought to be preventable through moderate dietary and lifestyle modifications (Anand 2008; Thompson 2011).
The colorectal cancer mortality rate has consistently declined in recent decades due largely to enhanced accuracy of early detection techniques, such as colonoscopy. However, the outlook for colon cancer patients rapidly diminishes if the cancer has metastasized to other organs or lymph nodes before detection.
If the cancer is detected while still localized in the colon, it is removed surgically and adjuvant techniques may be employed post-surgery to improve the chance for sustained disease-free survival. Treatment for advanced metastatic colon cancer usually encompasses multi-agent chemotherapy accompanied by palliative radiation.
Unfortunately, conventional standardized chemotherapy regimens may be ineffective for some patients due to genetic resistance against the drugs employed. Further, rarely do mainstream oncologists implement nutritional therapeutics or novel drug strategies to target genetic abnormalities associated with colon cancer growth, despite the fact that many peer-reviewed studies highlight the potential value of these agents.
Investigations have shown that several factors such as dietary habits, nutritional status, and inflammation influence the genetics involved in colon cancer development and progression, thus revealing multiple targets of interest in the prevention and management of colon cancer.
For example, a review of nine studies found that for every 10 ng/mL increase in serum vitamin D, the relative risk of colorectal cancer decreased 15% (Gandini 2011). Another landmark trial revealed that daily low dose aspirin reduced the risk of developing colon cancer by 24% and the risk of dying from the disease by 35% (Rothwell 2010).
In recent years, the introduction of advanced cancer analytical technology such as circulating tumor cell testing and chemosensitivity assays has improved outlook considerably by paving the way towards individually tailored treatments based upon the unique cellular characteristics of each patient’s cancer.
In this protocol, you will learn about several unappreciated risk factors for colorectal cancer, and gain insight into several genetic and molecular mechanisms that drive the evolution from healthy cells to cancerous cells in the colon. You will also discover evidence-based methods for targeting these risk factors and carcinogenic mechanisms using natural compounds and novel drug strategies. Life Extension will also present resources and guidance for thoroughly analyzing the unique biological characteristics of your cancer cells, which is a critical step towards establishing an effective, personalized cancer treatment regimen.

About the Colon

The colon is the third-to-last section of the gastrointestinal tract in humans, followed by the rectum and anus. Food is mostly digested by the time it reaches the colon, so the role of this segment of the large bowel is to absorb water, some short chain fatty acids from plant fiber and undigested starch, sodium, and chloride, and compact waste to be eliminated during defecation. Moreover, colonic bacteria play a central role in metabolic detoxification by secreting chemicals that encourage excretion of toxins and pathogens. Beneficial bacteria in the colon (probiotics) also ferment dietary fiber and generate compounds, such asbutyrate, which nourish cells in the colon wall and protect against carcinogenesis.

Causes of and Risk Factors for Colon Cancer

Risk factors for colorectal cancer include age (90% is found in those over 50), personal history of polyps or adenomas, family history of colorectal cancer, and diagnosis of inflammatory bowel disease (Crohn’s or ulcerative colitis). Other risks include a diet high in fat or low in fruits and vegetables, physical inactivity, obesity, smoking and excessive alcohol consumption (Benson 2007).

Lifestyle

As mentioned in the introduction of this protocol, as much as seventy percent of colon cancers are thought to be preventable through diet and lifestyle modification (Anand 2008).
Factors such as diet, physical activity level, tobacco use, alcohol consumption and sleep patterns are associated with increased risk of colorectal cancers (Schernhammer 2003). Obesity and physical inactivity are known to increase biomarkers of inflammatory processes, such as faecal calprotectin and serum C-reactive protein (CRP); elevated levels of inflammation are linked with higher rates of colorectal cancer. Simple changes such as increasing consumption of dietary fiber and vegetables effectively suppress inflammatory markers blunt colon cancer risk (Poullis 2004).
A colon cancer treatment or prevention plan should start with foundational lifestyle measures that include physical activity and a diet rich in plant foods; patients should also strive to attain a healthy body weight.

Genetics and Family History

Genetic alterations, both inherited and non-inherited, are responsible for the carcinogenic process in colon cancer. About 75% of colorectal cancers are “sporadic,” meaning that they arise in those without any family history of this disease, while the remaining 25% have an inherited predisposition that raises risk (NCI 2011).
Two familial disorders raise risk significantly, familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC, or Lynch syndrome). These inherited disorders are responsible for 1-2% and 3-5% of all colorectal cancers, respectively.
Familial adenomatous polyposis syndrome causes hundreds to thousands of polyps to form before age 30 and often leads to colon cancer at a young age (average age 39 years old). Familial adenomatous polyposis arises from inherited mutations of the adenomatous polyposis coli (APC) gene, a gene mutation that is also present in 60-80% of sporadic colon cancers.
Hereditary nonpolyposis colon cancer does not cause the multitude of polyps, but polyps are much more likely to become cancerous in those with this disorder. Those with hereditary nonpolyposis colon cancer have mutated mismatch repair genes (MMR genes), which fail to make necessary corrections to errors in DNA replication, allowing mistakes in the DNA to accumulate and colon cancer to ensue.

Metabolic Syndrome and Inactivity

Higher levels of insulin and glucose in the blood can increase the risk of developing colorectal cancers (Bruce 2005). An analysis of clinical data from 1966 through 2005 found that a diagnosis of diabetes raised the risk of colon cancer by more than 30% in both men and women (Larsson 2005).
A recent study, which looked at much of the previous data on diabetes and risk of colon cancer, concluded that diabetes is an independent risk factor for developing colon cancer (Yuhara, Steinmaus 2011).
The link between elevated insulin levels and colon cancer may be mediated though the insulin-like growth factor-1 receptor (IGF-1R). Insulin activates IGF-1R, which in turn functions to stimulate cellular growth and proliferation. Overexpression of IGF-1R has been observed in colon cancer cells, suggesting an increased sensitivity to the growth-promoting effects of insulin (Thompson 2011).
Obesity is a risk factor for developing cancers in general, and studies show that reducing weight can reduce inflammation in the colon, thereby reducing risk of colorectal cancers (Pendyala 2011). Adipose tissue (fat tissue) is not simply an inert storage system for excess calories - it actively produces manyadipokines, or chemical messengers, that circulate throughout the body. One such adipokine, leptin, is linked specifically to the increased risk of developing colon cancer (Drew 2011).
Regular physical activity, which combats all the components of metabolic syndrome, is associated with a decreased risk for colorectal cancer as well. One study compared those who did not have a sedentary job with those that worked a sedentary job for 10 years or more; the risk of cancer arising in the left (distal) colon was doubled, and the risk of developing rectal cancer increased 44% (Boyle 2011).

Inflammation

People with chronic inflammatory conditions of the bowel, such as Crohn’s disease or ulcerative colitis (UC), have up to a six times greater risk of developing colon cancer than those without the conditions (Mattar 2011). However, the inflammatory process is involved in the development of colorectal cancer growths even in those without Crohn’s or ulcerative colitis (Rhodes 2002; Terzić 2010).
Cyclooxygenase-2 (COX-2) is an enzyme that produces inflammatory end products by converting the omega-6 fatty acid arachidonic acid into prostaglandin E2, which promotes growth of cancerous cells; COX-2 is often overexpressed in colon cancer. Aspirin blocks COX-2 and has been shown to also lessen the development of colorectal cancers (Din 2010).
5-Lipoxygenase (5-LOX), similarly to COX-2, metabolizes arachidonic acid into metabolites that drive development and progression of cancer. In colorectal cancer, 5-LOX expression was shown to correlate with the density of blood vessel growth within tumors (Barresi 2008). Moreover, 5-LOX is overexpressed in pre-cancerous polyps, and inhibition of 5-LOX caused a suppression of tumor growth in a murine colorectal cancer model (Melstrom 2008). A compound extracted from Boswellia serrata, called 3-O-acetyl-11-keto-ß-boswellic acid (AKBA), is a powerful inhibitor of 5-LOX and may modulate the cellular properties of colorectal malignancies (Yadav 2011; Bishnoi 2007).
For a complete discussion of the roles of COX-2 and 5-LOX in cancer development and progression, see the Cancer Treatment Critical Factors protocol.
More recently, NF-Kappa B (NF-kB), a pro-inflammatory mediator that influences more than 500 genes involved in proliferation, angiogenesis, immune evasion and metastatic spread, has been the topic of intense research. Not surprisingly, NF-kB is a target for thwarting cancer’s growth and many natural agents act on NF-kB to prevent its signaling. The most notable natural agent able to suppress NF-kB signal transmission is curcumin (Gupta 2011). The high intake of curcumin, and resultant inhibition of NF-kB, may be one reason that the incidence of colon cancer in India is so much lower than in the US or Europe (Aggarwal 2009).

Low Vitamin D Levels

More akin to a hormone than a vitamin, vitamin D broadly influences the genome by activating the vitamin D receptor in the cell nucleus. Activation of the vitamin D receptor is estimated to modulate as many as 2,000 genes, many of which are related to inflammation and cellular mutation – initial drivers in all cancers (Smith 2010).
As mentioned in the introduction of this protocol, a review of nine studies found that for every 10 ng/mL increase in serum vitamin D, the relative risk of colorectal cancer decreases 15% (Gandini 2011). These findings are consistent with the conclusion of a large, case-control study across 10 European countries, which also found that as vitamin D blood levels rose, the risk for colorectal cancer declined considerably. Compared with those in the lowest quintile (1/5th) (<10 ng/mL), those in the highest (>40 ng/ml) had a40% lower risk of developing colorectal cancer (Jenab 2010).
Individuals with colon cancer appear to have lower levels of vitamin D at the time of diagnosis as well. Serum vitamin D levels were insufficient (less than 29 ng/mL) in 82% of patients with stage IV colon cancer at the time of diagnosis (Ng 2011).
Low levels of vitamin D may adversely impact prognosis as well. One large study found an inverse association between serum 25-hydroxyvitamin D at the time of diagnosis and colon cancer mortality (Freedman 2007). Individuals with 25-hydroxyvitamin D levels over 32 ng/mL had a 72% reduction in mortality compared to those with blood levels less than 20 ng/mL.
Life Extension encourages the maintenance of serum 25-hydroxyvitamin D levels between 50 – 80 ng/mLfor optimal health. This typically necessitates supplementation with 5,000 – 8,000 IU of vitamin D daily, but supplemental doses should always be determined by blood test results.

Low Folate and B-vitamin Intake

Homocysteine is an indirect marker for folate, B6 and B12 status. Homocysteine can be high when there is a deficiency in any of these B vitamins. Folate deficiency is associated with greater risk of developing colorectal cancers. In a large pooled analysis of data from 13 prospective studies including over 725,000 subjects, the highest quintile of folate intake was associated with a 15% reduced risk of colon cancer compared to the lowest quintile of intake (Kim 2010).

Pathology and Tumorogenesis

Colorectal cancers begin with epithelial cells that line the surface of the colon along finger-like projections called villi. The spaces between the villi are called crypts, and at the base of each crypt are immature stem cells that give rise to ever-renewing cells that migrate up the crypt and toward the tips of the villi. This normal cellular process is strictly governed by a balance of cellular renewal (normal proliferation) and cellular death (apoptosis), as well as elegantly choreographed expression of various genes along the path from immature stem cells to mature epithelial cells.
Early in the course of colon cancer development, however, the normal renewal of cells is disturbed. Cellular maturation (differentiation) is blocked and apoptosis is impaired leading to an accumulation of immature cells in the crypts. This is called an “aberrant crypt” and it is the first step in the carcinogenic process of colorectal cancers (Boman 2008; D’Errico 2008).These aberrant crypts almost always involve a genetic pathway that both embryos and colon cancer have in common, a pathway called Wnt (Abdul 2010). Many natural agents exert protective action through influencing this Wnt pathway, including components of black tea (Patel 2008a), green tea (Hao 2007) and turmeric (Mahmoud 2000).
Once the aberrant crypt forms, it may go on to become a polyp, which is a growth along the lining of the colon that can be seen during a colonoscopy exam. Polyps are benign, but they can progress to adenomas, which are considered precancerous. If further mutations occur, an adenoma can then progress to cancer over years or decades. This is the primary reason that screening colonoscopies are recommended, to remove the polyps or adenomas before they have a chance to become cancer.

Genetic Abnormalities in Colorectal Cancer

Several genes and/or genetic processes are frequently malfunctional in colon cancer cells, and therefore have become intriguing targets for treatment interventions. Some dietary compounds have been shown to influence these genes and may modulate colon cancer development and progression.

KRAS

KRAS is a gene that orchestrates cellular receptor sensitivity to a number of growth factors. When KRAS is activated, cellular proliferation is enhanced, while deactivated KRAS slows proliferation. In several types of cancer, including colorectal cancer, KRAS is mutated in such a way that causes it to be chronically activated, leading to unabated cellular proliferation. Mutations in KRAS are present in up to 40% of colorectal cancers (Thompson 2011).
While drugs that directly target KRAS are not yet available, the mutational status of this gene helps determine the likelihood that certain anticancer agents will be effective. For example, the anti-EGFR antibodies cetuximab and panitumumab may be ineffective if activating mutations in KRAS are present (Lin 2011).
Several natural compounds have been shown to target the KRAS pathway, including:
  • Perillyl alcohol, a substance extracted from citrus fruits (Bland 2001; Asamoto 2002);
  • Curcumin (Nautiyal 2011);
  • Fish oil (Morales 2007);
  • Tea polyphenols (Wark 2006).

EGFR

Epidermal growth factor receptor (EGFR) is a protein expressed on the surface of epithelial cells that variably regulates a number of pathways involved in cellular growth and proliferation. The KRAS pathway is among those that EGFR effects.
Overexpression of EGFR is observed in approximately 65 – 70% of colon cancers, and is associated with an advanced disease stage (Thompson 2011).
Activation of EGFR stimulates KRAS-induced signal transduction leading to proliferation. However, in KRAS mutant (upregulation; overexpression) cancer cells, binding of EGFR is not necessary to activate KRAS. Therefore, medications sometimes used to treat colon cancer, called anti-EGFR antibodies, are only effective in patients not harboring a KRAS mutation (Bohanes 2011). For example, cetuximab is a monoclonal antibody against EGFR indicated for metastatic colorectal cancer in patients not carrying a KRAS mutation.
Natural compounds shown to modulate EGFR include:
  • Genistein (an isoflavone from soy) (Yan 2010);
  • Curcumin (Lee 2011);
  • American ginseng (Dougherty 2011).
Note: Targeting EGFR directly may not be beneficial in a colorectal cancer patient overexpressing KRAS (constitutional activation). However, the aforementioned nutrients may also influence transcription downstream of EGFR and KRAS; thus they may be capable of inducing cell cycle arrest in KRAS mutant or wild type cancer cells. For example, curcumin was shown to act synergistically with dasatinib to reduce KRAS mutant colon cancer cell viability through alternative pathways (Nautiyal 2011); the other nutrients likely target additional pathways as well.

Microsatellite Instability (MSI) and Mismatch Repair Mutations

The human genome contains thousands of short, repeated base pair sequences called microsatellites, which vary in length from person to person, but are all the same length in an individual. DNA damage induced by factors such as oxidative stress and chemical carcinogens can cause dysfunction of genes responsible for ensuring that the microsatellites remain of consistent length; these genes are calledmismatch repair genes. Mismatch repair gene mutations lead to microsatellite instability (MSI) – the lengthening or shortening of microsatellites. This causes dysfunction in the region of the genome containing the unstable microsatellites. If this occurs in a tumor suppressor region, the consequence can be uncontrolled cell growth, the hallmark of cancer.
Microsatellite instability is found in about 15% of colorectal cancers (Boland 2010).
Ironically, MSI (versus stable microsatellites) is associated with a better prognosis in colorectal cancer (Bohanes 2011), likely for the same reasons that it leads to cancer in the first place – the cells are unable to repair major DNA damage and thus more readily succumb to apoptosis.
  • Tea polyphenols (Jin 2010; Dai 2008) have been shown to inhibit the proliferation of MSI colon cancer cells;
  • Cells with disrupted MMR function are highly sensitive to the apoptotic effects of curcumin (Jiang 2010).

Screening for Colorectal Cancer

Colonoscopy is an endoscopic process using a lens that allows a physician to visualize the mucosa from the rectum to the start of the colon (ileo-cecal junction). Removal of adenomatous polyps during colonoscopy has been proven to lower the risk of colorectal cancer (Cummings 2011; Winawer 1993).
Screening colonoscopies are recommended beginning at age 50, but those with any risk factors and/or a family history should consider screening at an earlier age.
How a colonoscopy is performed and by whom may influence whether or not adenomas or cancers are detected. During a 15 month period, analysis of 7,882 colonoscopies performed by 12 experienced gastroenterologists found that the time it took to withdraw the colonoscope influenced detection rates. Gastroenterologists who took less than 6 minutes to withdraw the scope were much less likely to detect cancer than those who withdrew the scope more slowly (up to over 16 minutes.). Even advanced cancers were more likely to be missed when the scope was withdrawn more quickly (Barclay 2006).
The time of day the colonoscopy is performed may also influence its reliability. In a chart review of a total of 2,087 colonoscopies at Metro Health Medical Center in Cleveland, Ohio, those done in the afternoon had a significantly higher failure rate compared to those done in the morning (Sanaka, 2006). The “failure” of a colonoscopy means that the scope could not reach the start of the colon (the cecum). This incomplete look at the colon often necessitates repeating the scoping procedure or undergoing further imaging, such as a CT scan.
The rate of incomplete colonoscopies may be influenced by who performs the procedure. In a study designed specifically to look at factors that lead to incomplete colonoscopies, the elderly, females, and those that have had prior abdominal or pelvic surgeries are more likely to have an incomplete colonoscopic evaluation. In this same study, the researchers found that having the colonoscopy done in an office rather than hospital setting tripled the risk of new or missed colon cancer in men and doubled it in women (Shah 2007).
Computer Tomographic Colonoscopy (CTC) is sometimes referred to as a “virtual colonoscopy”. It involves the use of CT imaging the colon. Preparation for CTC is much like a traditional colonoscopy with the use of laxatives to create an empty bowel. Carbon dioxide or air is infused through the rectum to create a smoother surface to assess. CTC’s are useful for larger polyps but may not pick up smaller or flattened polyps as well as traditional colonoscopy. If any polyps or suspicious areas are seen on CTC, the patient must then undergo a colonoscopy to visually assess and/or remove the polyps.
CTC is limited in some extent relative to a traditional colonoscopy in that if a polyp is detected, it cannot be removed during the procedure. This is a disadvantage as the patient will then need to undergo a traditional colonoscopy following the CTC to remove the polyp. Another disadvantage of virtual colonoscopies is the high levels of radiation needed to perform the procedure.
Fecal Occult Blood Test (FOBT) Occult blood in the stool can be detected with a simple test and is recommended as routine screening for colorectal cancers. Long before blood can be seen by the naked eye, minute quantities may signify the presence of cancer. The association of a positive FOBT with actual colorectal cancer, however, is fairly low, only 10% (Manfredi 2008). This is because occult blood more often comes from benign conditions, such as minor hemmorhoids; a FOBT may even detect bleeding associated with the upper gastrointestinal tract.
The FOBT is about 70% sensitive to the detection of colorectal cancer, while a colonoscopy performed by an experienced gastroenterologist is roughly 95% sensitive (Rex 1997; Niv 1995).

Indirect Tests for Colon Cancer and Emerging Techniques

Colon Cancer Specific Antigens (CCSA’s): A blood-based means of detecting colon cancer may be right around the corner. CCSA’s are nuclear matrix proteins that are unique to colon cancer cells. When circulating, these CCSA’s serve as a “fingerprint” indicating that either colon cancer or a premalignant adenoma is likely present (Leman 2008). Circulating levels of several of the CCSA’s, including CCSA-2, CCSA-3 and CCSA-4 have all been independently shown to be both sensitive and specific to colon cancer or premalignant adenomas (Leman 2007; Walgenbach-Brunagel 2008). While this test is not commercially available yet, ongoing research is looking at optimizing combinations of the different CCSA’s to predict the likelihood of colon cancer with great accuracy. In the future, this blood test may be used to gauge the urgency for colonoscopy screening.
Calprotectin in the stool has been used as a marker for IBD, and is a useful tool in determining the possibility of adenoma or colorectal cancer (Kronborg 2000; Roseth 1993). Fecal calprotectin is a product of granulocyte formation, a hallmark of chronic inflammation, and as such is not specific to the cancerous process but indicates that inflammation is present. In one study, of the patients referred for colonoscopy due to abdominal symptoms, elevated calprotectin was found in 85% of those with colorectal cancer, 81% of those with IBD and only 37% of those with normal findings (Meucci 2010).
Molecular Markers in the Stool: Since precancerous adenomas and colon cancer arise in the lining of the colon, the cells involved are shed with the stool on passing. With advances in technology and molecular biology, examining the stool for unique DNA changes that signify cancer is an area of interest.
The next generation of stool testing for colon cancer involves the stool DNA (sDNA) test, which was able to detect 64% of precancerous adenomas greater than 1 cm and 85% of colon cancers, and thefecal immunochemical test (FIT) (Ahlquist 2010). A patented stool DNA test called PreGen-Plus™ is approximately 65% sensitive to the detection of colorectal cancers (PreGen-Plus™ fact sheet 2011), but the high cost of this test may limit its utility for many consumers.
These non-invasive tests remain less sensitive than a colonoscopy, and have advantages and disadvantages that should be discussed with a healthcare provider (Cummings 2011).

Prognosis

Following diagnosis, oncologists and pathologists must analyze the extent to which the cancer has progressed and determine whether it has metastasized to other organs. This process, called “staging”, is crucial in guiding treatment.
Cancer confined to the mucosa of the colon wall is classified as stage I and is easily removable by surgery in the great majority of cases. When the cancer has penetrated deeper into the muscle layers of the colon, or has just perforated the colon wall, it is classified as stage II. Stage II colon cancer also carries a fairly good prognosis. Stage III is defined by detection of cancer in nearby lymph nodes, tissues or organs.Stage IV colorectal cancer defines metastasis to one or more distant organs, such as the lungs.
The outlook diminishes as stages advance; surgery is usually no longer a curative option for cancer not contained within the colon or isolated to nearby tissue (colon cancer with isolated liver or lung metastasis can rarely be treated effectively with surgery). Five-year survival rates for stage I colon cancer are very good, at about 90%, while the median survival plummets to just six months in advanced stage IV cancer (Crea 2011).
A valuable innovation in cancer prognostic technology is circulating tumor cell testing. Circulating Tumor Cell testing involves the detection of cancer cells in the bloodstream. These circulating tumor cells are the "seeds" that break away from the primary site of cancer and spread to other parts of the body. Understanding circulating tumor cells is critically important since it is the spread of cancer to other parts of the body—and not the primary cancer—that is very often responsible for the death of a person with cancer. For a detailed discussion of circulating tumor cell testing, please refer to section three of the Cancer Treatment: Critical Factors protocol.

Conventional Treatment of Colorectal Cancer

Colorectal cancer treatment is adjusted in accordance with the characteristics of each patient’s cancer. Surgery is a mainstay for treatment of stage I and most stage II cancers, while stage III and IV cancers are treated with chemotherapy and radiation. Advanced cancers are treated with an aim of reducing symptoms and improving quality of life, as they cannot be cured in most cases.
Surgery is the most common local treatment and usually the first-line treatment for patients diagnosed with localized colorectal cancer. Overall survival rates vary between 55 percent and 75 percent, with most recurrences of cancer seen within the first two years of follow-up. For patients whose cancer has not spread to the lymph nodes, survival with surgery alone varies from 75 percent to 90 percent. Surgery can also be performed for cancer metastases confined to the liver or lung whenever possible. Surgical removal of metastatic lesions results in long-term survival in a significant number of patients (Zeng 1992).
In some cases, the patient will require a colostomy, which is an opening into the colon from outside the body that provides an exit for fecal waste. A colostomy may be temporary or, if the surgery is very extensive, may be permanent. Total colonic resection is sometimes performed as a prophylactic measure for patients with familial polyposis and multiple colon polyps.
Nutritional supplementation and dietary modification should be considered before, during, and after surgery (for more information, refer to the protocol on Cancer Surgery).
Radiofrequency ablation (RFA) uses radiofrequency energy produced by an electrode that creates temperatures above 60°C (about 140°F) within the tumor, resulting in cancer cell death. RFA is used as an alternative to surgery in patients with inoperable colorectal liver metastases (Otsuka 2003; Pawlik 2003). Although RFA is unlikely to cure patients, it has a definite role in palliative therapy/ relieving symptoms (Lau 2003).
Radiation therapy (also known as radiotherapy) uses targeted, high-energy ionizing x-rays to destroy cancer cells. It is usually used after surgery to eliminate any remaining microscopic cancer cells in the vicinity. However, it may be used prior to surgery to reduce the tumor volume, which enables the removal of tumors previously considered inoperable. Intraoperative radiation therapy (IORT) has the advantage of maximally irradiating the tumor bed while reducing damage to surrounding, normal organ tissue from the field of radiation.
For more information regarding radiation therapy and prevention of its well-known side effects, refer to the chapter Cancer Radiation Therapy.

Adjuvant Therapy

The goal of adjuvant therapy is to eliminate any cancer cells that may have escaped the localized treatment. Adjuvant means "in addition to," and adjuvant therapy is used in combination with surgery and radiation (see the protocol Complementary Alternative Cancer Therapies). Several types of adjuvant treatments are usually used for early-stage colorectal cancer. These include chemotherapy, radiotherapy, immunotherapy, nutritional supplementation, and dietary intervention.

Chemotherapy

Chemotherapy uses drugs that can be taken orally or injected intravenously to kill cancer cells. Chemotherapy usually begins four to six weeks after the final surgery, though some oncologists may initiate chemotherapy sooner post-surgery. Typical chemotherapy for colon cancer consists of a combination of drugs that have been found to be the most effective, such as FOLFOX 4 (oxaliplatin, 5-fluorouracil (5-FU), and leucovorin) or FOLFIRI (folinic acid, 5-FU, and irinotecan), followed by FOLFOX6(folinic acid, 5-FU, and oxaliplatin) (Tournigand 2004).
For many tumors, the potential for eradication using chemotherapy is slight (Hahnfeldt 2003). However, chemotherapy using oxaliplatin may make metastatic colorectal cancer patients eligible for liver cancer removal (Zaniboni 2005). Nevertheless, chemotherapy drugs have many side effects that can damage or destroy some healthy tissues as well; for information on natural compounds that may help to reduce such adverse effects, refer to the protocol on Cancer Chemotherapy.
Chemoresistance is a major hurdle in the treatment of all cancers. This phenomenon occurs when genetic abnormalities make cancer cells resistant to chemotherapeutic drugs. Fortunately, some natural agents may combat chemoresistance.
Studies show that curcumin can inhibit the development of chemoresistance to FOLFOX through effects on insulin-like growth factor 1 receptor (IGF-1R) and/or endothelial growth factor receptor (EGFR) (Patel 2010). When curcumin was used in combination with the targeted drug dasatinib, colon cancer cells’ resistance to FOLFOX was eliminated (Nautiyal 2011). Curcumin has also been shown to sensitize colorectal cancer cells to the lethal effects of radiation therapy (Sandur 2009).

Anti-angiogenic therapies

Anti-angiogenic therapies stop tumors from forming new blood vessels (e.g., by inhibiting VEGF activity) and therefore impede tumor growth. A targeted anti-angiogenic agent, bevacizumab (Avastin®), which is a humanized monoclonal antibody targeting circulating VEGF, prolonged survival of metastatic colorectal cancer patients who had inoperable tumors (O'Neil 2003). Interestingly, in patients with metastatic colorectal cancer, the addition of Avastin® to irinotecan, fluorouracil, and leucovorin improves survival regardless of the level of VEGF expression (Jubb 2006). However, side effects from Avastin can be severe and improvements in survival seldom result in cures for advance cases.

Novel and Emergent Modalities in Colon Cancer Prevention and Management

COX-2 Inhibitor Drugs

  • Aspirin
It has long been known that aspirin may offer protection from developing a variety of cancers. Recently, a large retrospective look at data over a 20 year period showed that low dose aspirin (75-81mg) for longer than five years reduced the risk of colon cancer by 24%, and was most effective at reducing risk of right sided (proximal) colon cancer, a staggering 70% (Rothwell 2010)! Importantly, not just risk of being diagnosed, but also the risk dying from colon cancer was reduced by up to 40% in those that took aspirin (any dose) for over five years (Din 2010).
Aspirin’s anti-cancer properties stem in part from its capacity to inhibit the action of cyclooxygenase-2(COX-2), an enzyme that plays a central role in onset and progression of most cancers, and is overactive in 50% of adenomas and 80% of colorectal cancers (Chu 2004; Wang 2008; Moreira 2010). Aspirin also beneficially modulates activity of the protein complex nuclear factor-kappa B (NF-kB), the so-called “master switch” that stimulates the growth of a variety of cancers, including colorectal cancers (Luqman 2010).
  • Celecoxib
Celecoxib is a non-steroidal anti-inflammaotry drug (NSAID) that inhibits COX-2. In one study, 1,561 individuals with a history of adenomas were recruited to take either celecoxib (400mg/day) or placebo. Follow-up colonoscopies at three years found that the risk of developing adenomas was halved in the celecoxib group (Arber 2006). One study suggested a synergistic effect when celecoxib is taken with fish oil (Reddy 2005). However, while celecoxib can lessen adenoma formation, it is also well documented to raise the risk of cardiovascular events (Caldwell 2006; Bertagnolli 2009), leaving a risk/ benefit equation that should be seriously considered.
Note: additional information about inhibiting the COX-2 enzyme can be found in step four of the Cancer Treatment: Critical Factors protocol.

Metformin

Metformin is an oral antidiabetic drug that works by suppressing the production of glucose in the liver and boosting insulin sensitivity in peripheral tissues. Metformin is currently considered the treatment of choice for type 2 diabetes.
As with other malignancies, colorectal cancer risk is increased in diabetics, and there is a growing body of evidence that advanced glycation end products (AGEs), which are a consequence of elevated blood glucose, and insulin-receptor signaling are involved in the initiation and propagation of these common tumors (Yamagishi 2005; Mountjoy 1987).
Moreover, colorectal cancers are among those malignancies most closely associated with obesity. Obese individuals are deficient in the protective hormone adiponectin, which activates tumor-suppressing AMPK. Metformin, by independently activating AMPK, may circumvent this deficiency and help to reduce its impact on colorectal cancer risk (Zakikhani 2008). Naturally, these findings have piqued interest in investigating the potential role of metformin against colorectal cancer.
In 2011, researchers conducted a comprehensive review of observational data on the use of metformin and the risk of colorectal cancer in diabetic patients (Zhang 2011). This review encompassed 5 studies including nearly 110,000 subjects. Compared to all other antidiabetic treatments, the use of metformin was associated with a 37% lower risk of colorectal cancer.
While this review provides compelling data in support of the protective role of metformin against colorectal cancer, it should be noted that the trials included were observational in nature; the protective effects of metformin must still be substantiated in clinical intervention trials.
Nonetheless, Life Extension suggests that colorectal cancer patients, especially those who are overweight or have a fasting glucose level of greater than 85 mg/dL, ask their healthcare provider if metformin would be a positive addition to their regimen.

Cimetidine

Cimetidine, or Tagamet®, reduces the production of stomach acid by binding with H2 receptors on the acid-secreting cells of the stomach lining. These receptors normally bind with histamine to produce stomach acid, which helps to break down food. By competing with histamine to bind with H2 receptors, cimetidine reduces the stomach’s production of acid. This mechanism of action accounts for cimetidine’s use in managing gastroesophageal reflux disease (GERD), a condition marked by an excess of stomach acid. Before stronger anti-emetic drugs became available, cimetidine was prescribed to treat nausea associated with chemotherapy. As far back as 1988, scientists observed that colon cancer patients who had been treated with cimetidine had a notably better response to cancer therapy than those who did not receive cimetidine (Tonnesen 1988).
Cimetidine functions via several different pathways to inhibit growth of tumors. It inhibits proliferation of cells, blocks new blood vessel growth, and interferes with cell to cell adhesion, a necessary process in the spread of cancer (Kubecova 2011). It also has positive effects on immune function.
In a 1994 study, just seven days of cimetidine treatment (400 mg twice daily for five days preoperative and intravenously for two days post-operative) in colorectal cancer patients decreased their three-year mortality rate from 41% to 7%. In addition, tumors in the cimetidine-treated patients had a notably higher rate of infiltration by lymphocytes, a type of white blood cell (Adams 1994). These tumor-infiltrating lymphocytes, part of the body’s immune response to the tumor, serve as a good prognostic indicator.
Since cimetidine is a histamine receptor antagonist—that is, an agent that binds with a cell receptor without eliciting a biological response—it may help circumvent immunosuppression caused by increased histamine levels in a tumor’s microenvironment.(Adams 1994) While histamine appears to stimulate the growth and proliferation of certain types of cancer cells, inhibiting histamine’s action may be only one mechanism by which cimetidine fights cancer.
Cimetidine inhibits cancer cell adhesion by blocking the expression of an adhesive molecule—called E-selectin—on the surface of endothelial cells that line blood vessels (Platt 1992). Cancers cells latch onto E-selectin in order to adhere to the lining of blood vessels (Tremblay 2008). By preventing the expression of E-selectin on endothelial cell surfaces, cimetidine significantly limits the ability of cancer cell adherence to the blood vessel walls.
Administering cimetidine may enable the immune system to mount a more effective response, possibly minimizing the risk of growth and spread from surgical resection of the tumor. Recent studies suggest that cimetidine enhances local tumor response through the production of Interleukin-18 (IL-18) by immune cells (monocytes) (Takahashi 2006). IL-18 blocks new blood vessel growth and encourages apoptosis of cancer cells.
A report in the British Journal of Cancer examined findings of a collaborative colon cancer study conducted by 15 institutions in Japan. First, all participants had surgery to remove the primary colorectal tumor, followed by intravenous chemotherapy treatment. They were then divided into two groups: one group received 800 mg of oral cimetidine and 200 mg of fluorouracil (a cancer-fighting medication) daily for one year, while a control group received fluorouracil only. The patients were followed for 10 years. Cimetidine greatly improved the 10-year survival rate: 85% of the cimetidine-treated patients survived 10 years, compared to only 50% of the control group (Matsumoto 2002). Cimetidine produced the greatest survival-enhancing benefits in those whose cancer cells showed markers associated with the tendency to metastasize.
Several other studies have corroborated cimetidine’s benefits in colorectal cancer. For instance, in a Japanese study in 2006, colorectal cancer patients who received cimetidine following surgical removal of recurrent cancer had an improved prognosis compared to those treated with surgery alone (Yoshimatsu 2006).

Vaccines and Immunotherapies

An enlightened medical approach to cancer treatment involves the use of cancer vaccines. The concept is the same as using vaccines for infectious diseases, except that tumor vaccines target cancer cells instead of a virus. Another distinguishing feature of tumor vaccines is that while viral vaccines are created from a generic virus, tumor vaccines can be autologous, that is, they can be produced using a person’s own cancer cells that have been removed during surgery. This is a critical distinction since there can be considerable genetic differences between cancers. This highly individualized cancer vaccine greatly amplifies the ability of the immune system to identify and target any residual cancer cells present in the body. Cancer vaccines provide the immune system with the specific identifying markers of the cancer that can then be used to mount a successful attack against metastatic cancer cells.
Autologous cancer vaccines have been studied extensively, with the most encouraging results noted in randomized, controlled clinical trials including more than 1,300 colorectal cancer patients in which tumor vaccines were given after surgery. These trials reported reduced recurrence rates and improved survival (Mosolits 2005). Unlike chemotherapy, which can cause severe side effects and toxicity, cancer vaccines offer the hope of a “gentler” type of therapy with improved long-term safety (Choudhury 2006).
In a landmark study reported in 2003, 567 individuals with colon cancer were randomized to receive surgery alone, or surgery combined with vaccines derived from their own cancer cells. The median survival for the cancer vaccine group was over 7 years, compared to the median survival of 4.5 years for the group receiving surgery alone. The five-year survival was 66.5% in the cancer vaccine group, which dwarfed the 45.6% five-year survival for the group receiving surgery alone (Liang 2003). This glaring difference in five-year survival clearly displays the power of individually-tailored cancer vaccines to greatly focus a person’s own immunity to target and attack residual metastatic cancer cells.
Monoclonal antibody therapies currently employed in colorectal cancer therapy include bevacizumab, which targets VEGF, and panitumumab and cetuximab, which target EGFR.
For a detailed discussion of cancer vaccines, please review the protocol: Cancer Vaccines and Immunotherapy.

Personalizing Your Cancer Treatment Regimen

All cancers, including colon cancer, can have unique genetic characteristics from person to person. Gene expression profiles can highlight minute differences in the character of a cancer, and help identify which anti-cancer drugs will be most effective.
In one study, a 50-gene array conducted on resected colon cancers (stage I or II patients) determined that those with more “aggressive” patterns may be ideal candidates for interventions with specific preventative agents such as cox-2 inhibiting agents (Garman 2008). Such testing may be able to determine with great precision which natural or prescriptive agent to choose based on the molecular characteristics of the cancer. Specifically, tests for KRAS mutational status, EGFR expression, microsatellite instability, and other relevant tests are available currently.
Cancers have traditionally been treated as follows: if one therapy proves ineffective, then try another until a successful therapy is found or all options are exhausted. Evaluating the molecular biology of the tumor cell population helps to eliminate the need for this trial-and-error method by providing individualized information to help determine the optimal therapy before initiating treatment. This can save the patient time and money and most importantly, it may provide a better opportunity for "first strike" eradication.
Life Extension recognizes the value that advanced cancer testing delivers to cancer patients and suggests that every cancer patient test their cancers as extensively as possible. For more information on testing the unique biological characteristics of your cancer, refer to steps one and two of the Cancer Treatment: Critical Factors protocol.

Dietary and Lifestyle Considerations for Colon Cancer

There is a 25-fold difference in geographical areas in incidence of colorectal cancers, within North America, Australia, New Zealand, Western Europe, and select areas of Eastern Europe having the highest rates (Parkin 2004). People who migrate from low rate areas to high rate areas see an increase in development of colorectal cancers, indicating that the cultural environment and dietary habits contribute significantly to risk (Giovannucci 1994).
In general, Western diets contain too much red meat and not enough fruits and vegetables compared to Non-Western diets. Fruits and vegetables, in addition to the vitamins, minerals and fiber they provide, contain thousands of other compounds (phytochemicals) that have anti-cancer effects. One class of phytochemicals that lessen cancer risk are the phenolic compounds, including hesperdin, anthocyanins, quercetin, rutin, epigallocatechin-3-gallate (EGCG), and resveratrol, among others (Whitley 2005; Del Rio 2010; Linsalata 2010; Yang 2011).
Many cultures outside the US also use a more diverse and greater proportion of herbs and spices in their cooking. Many spices have anti-inflammatory effects and daily consumption of a variety of spices may contribute to the lower rates of colorectal cancers in non-Western cultures (Sinha 2003; Ferrucci 2010). Perhaps the most well studied spice with a potent anti-inflammatory action is turmeric, whose active ingredient is curcumin. Curcumin, through its modifying action of NF-kB, affects hundreds of molecules involved in proliferation, survival, migration and new blood vessel development.
While there is some controversy over the precise components of the diet that influence colorectal risk, there is no real debate that whole foods, with the nutrients and fibers intact, provide protection against colorectal cancers. A recent look at data from a study using the Dietary Approaches to Stop Hypertension (DASH) diet, which is high in whole grains, fruit, and vegetables; moderate amounts of low-fat dairy; and lower amounts of red or processed meats, desserts, and sweetened beverages, found the DASH diet reduced the risk of colon cancer by nearly 20% and rectal cancers by 27% (Fung 2010).
A healthy diet not only reduces risk, but appears to favorably affect outcomes once colon cancer has been diagnosed as well. A study of patients with stage III colon cancer divided their dietary habits into two dietary patterns. The “Prudent” pattern was characterized by high intakes of fruits and vegetables, poultry, and fish; and the “Western” pattern was characterized by high intakes of meat, fat, refined grains, and dessert. Those with Prudent diet had less recurrence of their colon cancer and were more likely to still be alive at the five year point (Meyerhardt 2007).
Exercise: Population studies show that those who exercise have a reduction in the risk of developing many cancers, including breast, prostate, lung, pancreatic and colon cancer (Na 2011). A study in the Journal of the American Medical Association showed that overweight survivors of cancer who took part in nutritional improvement, exercise and modest weight loss had less functional decline than non-participants (Morey 2009).
Exercise may protect against the development of cancers by reducing the likelihood of obesity and/or diabetes, but there are other, more direct effects as well. Fat, or adipose tissue, releases chemical messengers called adipokines. These adipokines increase inflammation and create glucose dysregulation and other metabolic disturbances. Recently, myokines from muscle have also been discovered. These myokines, which are made when muscles contract, appear to have a cross-talk with the adipokines, and the net effect is that myokines lead to improved glucose utilization and less fat deposition (Bente 2011). Therefore, usage of muscle and reduction of adipose through exercise results in a reduction of inflammation overall.
Maintaining normal weight protects against many cancers (Renehan 2008) and may be one reason that diet and exercise are linked so strongly to the reduction of risk of colorectal cancer (Nock 2008).

Nutritional Support for Colon Cancer

Multivitamin

Many nutrient deficiencies can increase risk of cancer, and biochemical variations in each person’s ability to utilize nutrients from food may lead to some harboring a nutrient deficiency despite eating well (Cahill 2010). Multivitamin supplements vary in forms and formulations of the nutrients they contain. All multivitamins contain folate, which is often cited as the nutrient responsible for conferring protection from colon cancer. Since several other nutrients have also been shown to lower risk, it is possible that there is synergy between nutrients that lead to protection.
Several studies indicate that multivitamin use is linked with a lower risk of colon and rectal cancers (White 1997; Giovannucci 1998; Jacobs 2001). Recently, a large pooled analysis of 13 clinical studies showed multivitamin use was associated with a 12% lower risk of colon cancer versus non-use (Park 2010). Moreover, an animal model revealed that experimental rats given a multivitamin in their drinking water were 84% less likely to developed chemical-induced aberrant crypt foci in their colons compared to their counterparts who received the chemical carcinogen without multivitamins (Arul 2012).
In addition, a three year clinical trial looked at a mixture of beta-carotene 15 mg, vitamin C 150 mg, vitamin E 75 mg, selenium 101 mcg, and calcium carbonate (1.6 g daily) versus placebo and found that the supplement group had significantly less adenoma formation (Hofstad 1998).

Vitamin D

The World Cancer Research Fund conducted a systematic review of studies on colorectal cancer and vitamin D intake and 25-hydroxyvitamin D status. They confirmed that higher vitamin D intake and 25-hydroxyvitamin D status were associated with reduced colon cancer risk (Touvier 2011).
The active form of vitamin D, 1,25-dihydroxycholicalciferol has been shown to directly increase the expression of tumor suppressor cystatin D in colon cancer (Alvarez-Díaz 2009). This is of interest because both normal and malignant colon epithelial cells have the enzyme required to transform circulating 25-hydroxycholicalciferol to the active 1,25-dihydroxycholicalciferol, which is then used intracellularly to thwart the growth of the colon cancer (Cross 2001).
In one study, 1,179 post-menopausal women were randomized to receive calcium (1,500 mg/day), calcium with vitamin D (1,500mg and 1,100 IU) or placebo. After four years, the incidence of cancers was less in women receiving the calcium + vitamin D, but not the calcium alone or placebo (Lappe 2007). These results were in keeping with earlier data in women (46-70 years old) showing that higher vitamin D status was associated with less risk of developing colon cancer (Feskanich 2004).
Precancerous lesions, or adenomas, are more likely to develop in those with lower circulating levels of vitamin D. A review of 12 studies of vitamin D consumption and 7 studies of circulating vitamin D found that high versus low dietary intake of vitamin D reduced the risk of adenoma development by 11% and high versus low circulating levels of vitamin D reduced the risk by 30% (Wei 2008).
Higher circulating levels of 25-hydroxycholicalciferol [25(OH)D] are protective against colorectal cancer. For example, pooled data from the Physician’s Health Study combined with eight prospective trials showed the risk of developing colorectal cancer was lower for those with higher 25(OH)D status (Lee 2011).

Vitamin E

Vitamin E is a family of eight naturally occurring compounds, four tocopherols and four tocotrienols. All forms of vitamin E are antioxidants, able to neutralize free radicals directly as well as recycle other antioxidants. Over the decades, studies have been predominantly on alpha-tocopherol, although more recent evidence suggests that gamma tocopherol is the more active cancer preventative agent, particularly for colon cancer (Campbell 2003; Campbell 2006; Ju 2010). Importantly, gamma tocopherol was more effective at inhibiting COX-2 than alpha-tocopherol, which may result in improved protection from colon cancer (Jiang 2000).
Oxidized compounds reach the epithelial cells of the colon and rectum both from dietary sources and from normal bacterial metabolism in the colon. Alpha and gamma tocopherol have been shown to mitigate the oxidative damage, thus lowering the carcinogenic potential of these compounds (Stone 1997). In an animal model, a mixture of tocopherols high in gamma tocopherol lessened colon cancer development through antioxidant, anti-inflammatory and other anti-carcinogenic mechanisms (Yang 2010).
Several clinical studies suggest a benefit attributable to vitamin E. In one study, intake of supplements containing alpha-tocopherol (>200IU/d) significantly reduced the risk of colon cancer development compared to no vitamin E intake (White 1997). In two other studies, those with the highest intakes of vitamin E had reduced risk of developing colorectal cancer as well (Bostick 1993; Ghadirian 1997).
Tocotrienols may have their own unique anti-cancer mechanisms. Tocotrienols were found to increase apoptosis in colon cancer cells through modulation of the balance between pro and anti-apoptotic mediators (Kannappan 2010; Agarwal 2004).

Calcium

Higher calcium intake appears to lower the risk of developing colorectal cancer (Wu 2002; Peters 2004). Calcium may protect the mucosa of the colon and rectum through binding carcinogenic bile acids (Bernstein 2005), or through encouraging proper maturation (differentiation) of colorectal cells. Supplemental calcium, as well as vitamin D, was shown to induce favorable cellular changes in colonic cells of patients with adenomas (Ahearn 2011).
A study of 92 men and women with a history of adenoma compared the effects of calcium and vitamin D alone and together on the normal cellular turnover of the colonic epithelium. Both calcium and vitamin D, alone and together, enhanced apoptosis of normal epithelial cells (Fedirko 2009). Interestingly, one study showed that up to five years after stopping the calcium supplementation, there was still less adenoma formation (Grau 2007). Another study showed that Vitamin D and calcium taken as a supplement was associated with reduced risk, but this benefit was not found from dietary sources alone, indicating that supplementation may be necessary to attain benefit (Hartman 2005). Two studies in men with previous adenomas showed a risk reduction of 36% for future adenomas with supplemental calcium (1200mg/day for four years in one study, 2000mg/day for three years in the other) (Weingarten 2008).

Selenium

Selenium deficiency has been linked to formation of many cancers, including colorectal cancer (Nelson 2005). Selenium is incorporated into proteins within cells, called “selenoproteins”, involved with protecting the cells from free radical accumulation that can lead to DNA damage. Some of these proteins include glutathione peroxidases (GPx), thioredoxin reductases (TrxR), and selenoprotein P (SePP). People that form adenomas are more likely to be deficient in selenium as well as the selenoproteins that protect DNA from damage. Repletion of selenium through supplementation restored both deficiencies, presumably leading to protection from further adenoma formation (Al-Taie 2003).
There have been a number of studies showing that selenium is lower in those with adenomas or colorectal cancer compared to controls (Mikac-Devic 1992; Ghadirian 2000; Fernández-Bañares 2002). Selenium may afford even more protection in current smokers and those that have quit less than 10 years previously (Peters 2006).
Selenium supplementation at the time of cancer surgery can increase local immune function, an effect which may reduce recurrence (Kiremidjian-Schumacher 2001). There may also be synergistic effects of selenium with other nutrients such as folate (Connelly-Frost 2009).
A clinical trial of 200mcg of selenium versus placebo found that the incidence of colorectal cancer was significantly less in those taking selenium (Clark 1996).
Selenium may also synergize with some cancer treatment drugs (Rudolf 2008). In a phase I clinical trial using high doses of selenomethionine alongside the chemotherapy drug irinotecan, the authors remarked “unexpected responses and disease stabilization were noted in a highly refractory population” (Fakih 2006). Selenium in high amounts can be toxic and evidence suggests that doses in the 200 – 400 mcg range are most beneficial (Reid 2008).

Folate

Folic acid is necessary for the synthesis of both S-adenosylmethionine (SAMe) and deoxythymidine monophosphate (dTMP). dTMP and SAMe are needed in the synthesis and function of DNA, respectively. Therefore, a deficiency of folic acid may disrupt proper DNA synthesis or function. A pooled analysis of 13 studies involving over 725,000 participants, found a 2% risk reduction for every 100 mcg/day increase of total folic acid intake (Kim 2010). In a large population study, those taking the highest amount of folate from diet and supplements (>900mcg/d) had a 30% reduced risk of developing colon cancer versus those with the lowest consumption (<200mcg/d) (Gibson 2011).
Alcohol consumption increases the risk of colon cancers, and evidence suggests this may be potentiated by polymorphisms in genes that produce enzymes involved in folate metabolism (Giovannucci 2003). Maintaining adequate levels of folate, and its co-nutrient methionine, may offer protection from colon adenoma development, particularly in those consuming alcohol or those with genetic polymorphisms in folate metabolism (Giovannucci 2002).

Green Coffee and Chlorogenic Acids

Greater coffee consumption has been linked with a lower rate of a variety of cancers, including colon cancer (Galeone 2010: Je 2009).
Coffee contains powerful antioxidant compounds, called chlorogenic acids, which have been shown to exert several potentially chemopreventive effects, including favorably modulating glucose metabolism, and quelling inflammation (dos Santos 2006; van Dijk 2009). In fact, a recent study found that chlorogenic acids were able to interfere with a variety of cellular processes that drive colon cancer metastasis, including NF-kB signaling (Kang 2011).
However, the roasting process used to prepare conventional coffee beverages destroys the majority of these beneficial chlorogenic acids. Therefore, drinking coffee is an inefficient means of obtaining these bioactive compounds.
Recent scientific innovation has led to the availability green coffee bean extract standardized to 50% chlorogenic acids. Supplementation with green coffee bean extract is a viable option for obtaining robust quantities of bioactive chlorogenic acids.

Garlic

Consumption of garlic has been linked with lower colon cancer risk (Fleischauer 2000). Garlic has been shown to reduce the carcinogenic potential of compounds such as nitrosamines, as well as exert anti-proliferative effects (Milner 2001a; Milner 2001b). Components that may be responsible for the cancer protective effects of garlic include organosulfur compounds and flavonoids.
There are many mechanisms that can explain how garlic reduces carcinogenesis in the colon and rectum.
  • Inhibition of cell growth and proliferation directly
  • Inhibition of new blood vessel growth
  • Increased cell death (apoptosis)
  • Increased detoxification of carcinogens
  • Suppression of carcinogen activating enzymes
  • Inhibition of cyclooxygenase-2 (thereby inhibition of inflammation)
  • Antioxidant action, squelching free radicals in the bowel (Ngo 2007)
One clinical trial showed that supplementing with aged garlic extract reduced the formation of pre-cancerous adenomas in patients with a history of adenomas (Tanaka 2006).

Ginger

Like garlic, ginger has been a mainstay of traditional medicine for more than 2,500 years. Ginger’s multiple chemopreventive benefits have been reported in a wide range of experimental models (Shukla 2007). Key compounds in ginger and its extracts limit the oxidative damage to cells caused by free radicals. They also lower levels of signaling molecules called cytokines, specifically those that provoke an inflammatory response. This dual mode of action may inhibit initiation of carcinogenesis and limit expansion of existing malignancies (Murakami 2002; Pan 2008). Some ginger components also increase the activity of vital enzymes that detoxify carcinogens present in the body (Nakamura 2004; Brandin 2007).
Indian researchers provided direct evidence of ginger’s chemopreventive power in rats with chemically induced colon cancers in two recent studies (Manju 2005; Manju 2006). After injection with a potent carcinogen, animals were either supplemented with ginger or given normal diets. In both studies the incidence of cancers and the number of individual tumors was significantly reduced in the supplemented groups. The first study also detected lower levels of oxidative agents and higher levels of natural antioxidants in supplemented animals, while the second study further showed a decrease in the activity of bacterial enzymes that release intestinal toxins and damage the colon’s natural protective mucous layer.
In recent clinical trial, 30 healthy subjects consumed 2 grams of ginger or a placebo each day for 28 days. Colon biopsies were taken at baseline and at day 28 and assessed for levels of inflammatory markers. The subjects that received ginger displayed significantly lower levels of PGE-2 and 5-HETE, two inflammatory fatty acid metabolites, in their tissue samples than those who received a placebo (Zick 2011). These findings are encouraging due to the role of inflammation in driving colon cancer growth.

Modified Citrus Pectin

Modified Citrus Pectin (MCP) is a type of soluble dietary fiber derived from citrus fruits that has been modified by pH and heat to form smaller units of absorbable galactose residues that are able to bind to cancer cells. Specifically, MCP binds to Galectin-3, a protein expressed by cancer cells that is involved in cell to cell adhesion, survival and spread to distant organs (metastasis) (Takenaka 2004; Nakahara 2005). Nullifying the effects of galectin-3 by finding agents to bind to it is one means of inhibiting these pro-cancerous mechanisms (Ingrassia 2006; Glinsky 2009). MCP has been shown to effectively bind galectin-3 and inhibit growth and metastasis of various cancers (Nangia-Makker 2002), including colon cancer (Liu 2008).
Interfering with galectin-3 and preventing metastasis is particularly important in colorectal cancer, where spread to the liver means a much worse prognosis than limited or local disease. Galectin-3 levels appear to be increased in colon cancer, and are associated with advanced disease stage (Irimura 1991; Schoeppner 1995), confirming that galectin-3 is an important molecule in the growth and spread of colon cancers.
Additional discussion on the role of MCP in combatting cancer metastasis can be found in the Life Extension Magazine article entitled “Fighting Cancer Metastasis and Heavy Metal Toxicities With Modified Citrus Pectin”.

Curcumin

Curcumin is derived from the spice turmeric (Curcuma longa), an ancient spice used throughout Asia. Cultures in which diets high in turmeric are consumed have much lower rates of colon cancer than Western cultures (Sinha 2003). Curcumin is a powerful anti-inflammatory compound that acts on NF-kB, a proinflammatory mediator that influences hundreds of genes involved in the growth and spread of cancer. In addition, curcumin regulates tumor suppressor pathways and triggers mitochondrial-mediated death in cancer cells (Ravindran 2009; Cheng 2010).
Despite aggressive surgical care and chemotherapy, nearly 50% of people with colorectal cancers develop recurrent tumors (Patel and Majumdar 2009). This may be due in part to the survival of dangerous colon cancer stem cells that resist conventional chemotherapy and act as “seeds” for subsequent cancers (Subramaniam 2010). There is evidence that combining curcumin with FOLFOX, the first line chemotherapy drug combination of 5-fluorouricil, leukovorin and oxaliplatin, eliminates the persistent pool of colon cancer stem cells (Yu 2009), and potentiates the lethality of FOLFOX on cancer cells (Sengupta 2008).
Finally, curcumin interferes with tumor invasiveness and blocks molecules that would otherwise open pathways to penetration of tissue (Anand 2008). It also helps to starve tumors of their vital blood supply and it can oppose many of the processes that permit metastases to spread (Bar-Sela 2010). These multi-targeted actions are central to curcumin’s capacity to block multiple forms of cancer before they manifest (Bachmeier 2010).
Curcumin also creates a gastrointestinal environment more favorable to optimal colon health by reducing levels of so-called secondary bile acids, natural secretions that contribute to colon cancer risk (Han 2009). That has a direct effect, inhibiting proliferation of cancer cells and further reducing their production (Wang 2009).
A novel feature of curcumin is its ability to bind to and activate vitamin D receptors (VDR) in colon cells (Bartik 2010). Binding to VDR elicits a host of anti-proliferative and anti-inflammatory actions.
Curcumin given to patients undergoing treatment for colon cancer led to weight gain, decreased circulating inflammatory mediator TNF-a, and increased apoptosis (He 2011).

Omega-3 Fatty Acids

There is a substantial amount of experimental, population-based studies and clinical trials showing that risk of colorectal cancer is reduced with higher intakes of omega-3 fatty acids (Anti 1992; Fernandez 1999; Rao 2001; Bancroft 2003; Cheng 2003; Hall 2008; Kim 2010).
EPA (2 grams/d for 3 months) reduced crypt cell proliferation and promoted proper apoptosis of colonic epithelial cells in patients with a history of colonic adenomas (Courtney 2007). Separately, a large population study of physicians found that those who consumed fish oil supplements during a 10-year period had a 35% reduction in the risk of developing colon cancer (Satia 2009).
Omega-3 fatty acids may prevent colorectal cancer through supporting normal turnover of the epithelial cells by encouraging apoptosis (Cheng 2003). Fish oils reduce the pro-tumor effects of many molecules involved in the growth and spread of colon cancer, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), platelet-derived endothelial cell growth factor (PDECGF), cyclo-oxygenase 2 (COX-2), prostaglandin-E2 (PGE2), nitric oxide, nuclear factor kappa B (NF-kB), matrix metalloproteinases and beta-catenin (Spencer 2009).
DHA, an omega-3 fatty acid found in fish oil, disrupts cell signaling in colon cancer and is synergistic with butyrate in inducing apoptosis (Kolar 2007; Chapkin 2008).
Fish oil (2.5 grams/d) normalized abnormal rectal proliferation patterns in patients with a history of adenomas, and this is thought to be through lessening the availability of the inflammatory omega-6 fatty acid arachidonic acid and modifying vitamin E availability (Anti 1994;Bartoli, Palozza 1993).
Chemotherapies induce cell death by inducing DNA damage in quickly dividing cells, tipping the death/survival pathways toward cellular self-destruction (apoptosis). Experiments have shown EPA and DHA can make cancer cells more vulnerable to damage from chemotherapy and radiation, thus encouraging the cells to turn on cell death pathways in lieu of repair pathways (Benais-Pont 2006; Dupertuis 2007; Slagsvold 2010). Eventual resistance of colon cancer cells to the cytotoxic effects of chemotherapy may also be lessened with EPA/DHA (Kuan 2011).

PSK

PSK is a mushroom polysaccharide complex used more commonly in other countries such as Japan and Australia for immune support in cancer care. Pure PSK cannot be obtained in the United States, but the mushroom Trametes versicolor (formerly called Coriolus versicolor) is high in this polysaccharide and is often substituted. Many mushrooms have some immune enhancing properties, but PSK can also suppress activation of NF-kB, therefore reducing the expression of hundreds of pro-cancerous genes (Yamashita 2007).
A review of three clinical trials in patients who had surgery and chemotherapy for their colon cancer showed that overall survival was improved by 29% with the addition of PSK (Sakamoto, Morita 2006).
A group of colon cancer patients were randomized to receive chemotherapy alone or chemotherapy plus PSK, which was taken for two years. The group receiving PSK had an exceptional 10-year survival of 82%. The group receiving chemotherapy alone had a 10-year survival of only 51% (Sakai 2008). In a similar trial reported in the British Journal of Cancer in 2004, colon cancer patients received chemotherapy alone or combined with PSK (3 grams per day) for two years. In the group with Stage 3 colon cancer, the five-year survival was 75% in the PSK group. This compared to a five-year survival of only 46% in the group receiving chemotherapy alone (Ohwada 2004).

Sulforaphane

Sulforaphane is a compound that is found in cruciferous vegetables, like broccoli and kale. It improves the elimination of toxic substances by the liver. It also may have a more direct role in thwarting the growth of cancers, including colorectal cancer, through re-activation of tumor suppressor genes that were formerly silenced (Myzak 2006; Dashwood 2007).
Sulforaphane inhibited the formation of colon tumors in an animal model (Myzak 2006). It is also able to induce apoptosis in colon cancer cells with impaired apoptosis capability (Rudolf 2011).
Sulforaphane appears to protect normal colon cells while encouraging self-destruction of colon cancer cells (Reuter 2008). When added to oxaliplatin, sulforaphane improved the ability of the drug to kill colon cancer cells (Kaminski 2011).
In one study, sulforaphane was synergistic with indole-3-carbinol, another compound from cruciferous vegetables. Together the compounds resulted in greater toxicity to colon cancer cells than either compound alone (Pappa 2007).

Resveratrol

Resveratrol is a polyphenol found in grapes, peanuts and mulberries. Resveratrol suppresses colitis and colitis associated colon cancer in mice (Cui 2010). Grape powder and resveratrol inhibited the carcinogenic Wnt pathway in normal colonic mucosa (Hope 2008; Nguyen 2009). Resveratrol also inhibits the COX-2 enzyme, suppressing inflammation (Zykova 2008). Resveratrol may synergize with butyrate in the colon as well (Wolter 2002).
Resveratrol has been shown to lessen aberrant crypt formation (Tessitore 2000; Sengottuvelan 2006) and adenoma formation (Schneider 2001) as well as induce apoptosis of colon cancer cells (Mahyar-Roemer 2002; Vanamala 2011).
A small study of twenty patients scheduled for colon resection to remove malignancy showed that a dose of 0.5-1.0 grams/day for eight days prior to surgery resulted in adequate levels of resveratrol in the tumors to have biological effects. This was particularly true for tumors on the right (proximal) side (Patel 2010).
Resveratrol may also increase the sensitivity of colon cancer cells to the killing effects of chemotherapy (Santandreu 2011).

Green Tea Extract

Green tea contains potent antioxidants known as catechins, the most well studied of which is epigallocatechin-3-gallate (EGCG), which has been found to inhibit carcinogenesis in various cancers, including colorectal cancers (Yang 2002; Issa 2007; Kumar 2007).
Green tea extract is well established to have anti-cancer actions on growth, survival, angiogenesis and metastatic processes of cancer cells (Yang, Lambert 2007; Singh 2011) and favorable effects on immune function (Butt 2009). Green tea has also been shown to reduce the carcinogenicity of nitrosamines, carcinogenic compounds from cooked meats (Dashwood 1999).
A meta-analysis of consumption of green tea across populations found that those consuming the highest levels of green tea had an 18% lower risk of developing colorectal cancer compared to those consuming the lowest amounts (Sun 2006). In a clinical study, green tea extract (equivalent of >10 cups/day, or about 150mg EGCG) lessened adenoma formation, both number and severity, in those with a prior history of adenomas (Shimizu 2008).

Milk Thistle

Milk thistle (Silybum marianum) contains silibinin and silymarin, flavonoid compounds shown to have numerous anticancer effects. Milk Thistle is generally used to improve the break down and elimination of chemicals and toxins, so it is not surprising that silymarin was able to prevent chemically induced colon cancer in mice (Kohno 2002). In another animal study, silymarin, along with quercitin, curcumin, rutin, all independently reduced aberrant crypt formation, an early process in colon cancer formation (Volate 2005). Silymarin also inhibits angiogenesis (Yang 2003), a necessary process for tumor growth.
Silibinin has been shown to inhibit colorectal carcinogenesis directly (Sangeetha 2010). Silibinin blocks proliferation, reduces new blood vessel growth and induces cell death (apoptosis) of colorectal cancer cells (Hogan 2007; Singh 2008; Kaur 2009; Kauntz 2011). It may achieve some of these anti-tumor effects through disruption of signaling pathways within cancer cells as well as by blocking activation of NF-kB (Li 2010).

Quercetin

Quercetin belongs to a class of potent antioxidants called flavonoids. These are what give apples their color. Onions, garlic, tea, red grapes, berries, broccoli, and leafy greens are also rich sources of quercetin.
It’s well known to nutritional scientists as a potent free radical-scavenger (Murakami 2008). Quercetin also happens to possess a singular cancer-fighting feature: it can prevent cancer caused by chemicals. Its unique molecular structure enables it to block receptors on the cell surface that interact with carcinogenic chemical compounds. This makes it a perfect anticancer agent for the colon, where carcinogenic chemicals tend to accumulate (Murakami 2008).
Researchers in Greece have also discovered that quercetin dramatically suppresses one particular cancer-causing gene in colon cells. This makes quercetin supplementation an ideal form of early prevention for individuals with a family history of colon cancer (Psahoulia 2007).
Dutch scientists uncovered even more evidence of its cancer-preventive power at the genetic level. In an animal study, quercetin reduced “cancer gene” activity and increased “tumor-suppressor gene” activity in colon cells after 11 weeks (Dihal 2008).
In yet another promising animal study, scientists in South Carolina were able to halt the development of aberrant crypts. Cancer-prone rats fed a diet high in quercetin (Mahmoud 2000) underwent a four-fold reduction in the number of aberrant crypts compared to a control group. Similar research has yielded additional evidence of quercetin’s capacity to reduce emerging aberrant crypts — a vital first step in preventing colon cancer from developing at all (Gee 2002).
In 2006, scientists at the Cleveland Clinic evaluated patients suffering from familial adeno-matous polyposis. They discovered that a combination of curcumin and quercetin could cause these growths to diminish substantially. The researchers supplemented the patients with 480 mg of curcumin and 20 mg of quercetin orally, three times a day, for six months. Every single patient experienced a remarkable decrease in polyp numbers and size, with average reductions of 60% and 51%, respectively (Cruz-Correa 2006).

N-Acetylcysteine

NAC is a slightly modified version of the sulfur-containing amino acid cysteine.
When taken internally, NAC replenishes intracellular levels of the natural antioxidant glutathione (GSH), helping to restore cells’ ability to avoid damage from reactive oxygen species. NAC suppresses the NF-kB, which in turn prevents activation of multiple inflammatory mediators (Kim 2000; Chen 2008). NAC also regulates the gene for COX-2, the enzyme that produces pain- and inflammation-inducing prostaglandins in a wide array of chronic conditions (Origuchi 2000).
NAC (800mg/day) lessened the rate of proliferation of the cells in the colonic crypts in patients with a history of adenomatous polyps (Estensen 1999). This is in keeping with a study that showed that those with a history of polyps had a 40% reduction in recurrence of their polyps using 600 mg of NAC daily (Ponz de Leon 1997).

Life Extension Suggestions

Life Extension’s approach includes avant-garde cancer testing technology coupled with evidenced-based regimen of natural compounds and novel drug strategies to complement conventional colon cancer treatment.
NOTE: This protocol should not be used in isolation. Individuals with colorectal cancer should also review the content in other Life Extension cancer protocols, including:

Primary Supplements

Secondary Supplements

Innovative Drug Strategies

  • Metformin: 250 – 500 mg two to three times daily before meals
  • Cimetidine: 800 mg daily
  • Aspirin: (low-dose): 81 mg daily
 
Disclaimer and Safety Information
This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information container herein.
The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.

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