Colorectal Cancer-2

Prognostic Markers

Factors that affect survival of colorectal cancer patients include age and gender, tumor type and grade, cancer stage, presence of symptoms (versus asymptomatic), presence of obstruction or perforation, low Bcl-2 levels, p53 and ras gene mutations, low cancer-cell death rate, and vascular endothelial growth factor (VEGF) levels (Stoeltzing O et al 2003; Kos M et al 2002). VEGF levels may be useful in predicting whether cancer will recur in patients who do not have cancer in their lymph nodes (Hanrahan V et al 2003; Broll R et al 1998; Takahashi Y et al 1997).

Serum p53 antibodies. Approximately half of all colorectal cancers do not have a normal p53 tumor-suppressor gene; on the contrary, they have p53 gene mutations that are associated with poorer survival (Pricolo VE et al 1997). When a mutation in the p53 gene occurs, p53 loses its ability to block cancer growth. More important, mutation of p53 renders cancer cells more resistant to current cancer treatments due to lack of p53-mediated cancer cell death (He TC et al. 1999b; Jalving M et al. 2005i; Sun Y 2006). High levels of p53 protein produce antibodies, which can be measured by a blood test (Takeda A et al 1999).

Curcumin reduces the activity of mutant p53 in cancer cells, which may underlie its cancer-preventive action. Curcumin treatment causes p53-independent cell death in colon cancer cells (Jaiswal AS et al 2002). The anti-cancer activities of genistein depend on the presence of p53 (Wilson LC et al 2003).

Ras gene mutations occur in 21 percent to 60 percent of primary colorectal cancers (Wang JY et al 2003) and contribute to tumor initiation and progression (Pretlow TP et al. 2005); thus, they may be of clinical value in the prognosis of colorectal cancer (Castagnola P et al. 2005); Okulczyk B et al 2003). K-ras mutations increase gastrin gene levels in colon cancer cells, which stimulate cell growth in some colorectal cancers (Hori H et al 2003). Furthermore, K-ras gene increases VEGF levels and thus may increase tumor angiogenesis (Zhong SS et al 2003).

Unfortunately, clinical trials using drugs that target Ras—such as tipifarnib, a farnesyl transferase inhibitor (FTI)—have been disappointing even in patients whose tumors harbor Ras mutations (Mesa RA 2006; Rao S et al. 2004). However, Ras gene activity can be slowed by:

1)Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil ((Collett ED et al. 2001; Singh J et al. 1998)

2)d-Limonene and perillyl alcohol from citrus fruits and essential oils (Broitman SA et al. 1995; Gelb MH et al. 1995)

3)Epigallocatechin gallate (EGCG) from green tea extract (Lyn-Cook BD et al. 1999)

4)Black tea polyphenol (BTP) from black tea extract (Lyn-Cook BD et al. 1999)

5)Diallyl disulfide, from garlic (Singh SV 2001).
Deleted in colorectal cancer gene (DCC), a gene frequently deleted in colon cancer, is associated with a worse prognosis in certain patients with colorectal adenocarcinoma (Vogelstein B et al 1988).

Determining Whether Cancer Has Spread
Removal and examination of at least 12 lymph nodes during surgery can determine whether colorectal cancer has spread to nearby lymph nodes. For the first two years after surgery, the patient should have the following procedures performed every three months to assess for possible recurrence: determination of tumor markers; fecal occult blood test (FOBT); ultrasound of the upper abdomen and CT of the lower abdomen; and total colonoscopy every six months (Griesenberg D et al 1999; Stangl R et al 1994).

If the cancer spreads, surgical removal is the only treatment that can ensure long-term survival and cure in some patients. New treatment modalities, including blocking off the liver (portal) vein (embolization), chemotherapy, and local eradication with cryotherapy or radiofrequency ablation, may help to increase the number of patients suitable for surgical resection of their hepatic metastases, and may prolong survival in cases not suitable for surgery.

Conventional Treatment of Colorectal Cancer

The course of treatment for colorectal cancer is largely determined by the stage of the cancer. Possible treatments include surgery, chemotherapy, radiation therapy, radiofrequency ablation (RFA), vaccines, and immunotherapy. Nutritional supplementation and dietary modification may be considered in addition to any of these conventional therapies.

Local Treatments

Surgery is the most common local treatment and usually the first treatment for patients diagnosed with 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 must 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 Z et al 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 colon resection is performed for patients with familial polyposis and multiple colon polyps.

Nutritional supplementation and dietary modification should be considered both before, during, and after surgery (for more information, refer to the chapter Cancer Surgery).

Radiofrequency ablation (RFA) uses radiofrequency energy produced by an electrode that creates temperatures above 60° C within the tumor, resulting in cancer cell death. RFA is used as an alternative to surgery in patients with inoperable colorectal liver metastases (Otsuka S et al 2003; Pawlik TM et al 2003). Although RFA is unlikely to cure patients, it has a definite role in relieving symptoms (Lau TN et al 2003).

Radiation therapy (also known as radiotherapy) uses targeted, high-energy x-rays to prevent cancer cells from growing and dividing. 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 eliminating surrounding normal organs 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 chapter Complementary Alternative Cancer Therapies). Several types of adjuvant treatments are usually used for early-stage colorectal cancer. These include chemotherapy, immunotherapy, nutritional supplementation, and dietary intervention.

Chemotherapy uses drugs that can be taken orally in tablet or capsule form or injected intravenously to kill cancer cells. Chemotherapy usually begins four to six weeks after the final surgery and is given as a combination of drugs (sometimes two to three 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, FU, and irinotecan) followed by FOLFOX6 (folinic acid, FU, and oxaliplatin) (Tournigand C et al 2004). For many tumors, the potential for eradication using chemotherapy is slight (Hahnfeldt P et al 2003). However, chemotherapy using oxaliplatin may make metastatic colorectal cancer patients eligible for liver cancer removal (Zaniboni A et al. 2005). Nevertheless, chemotherapy drugs have many side effects that can damage or destroy healthy normal tissues throughout the body; for information on nutritional supplements that help to reduce such adverse effects, refer to the chapter Cancer Chemotherapy.

Immunotherapy. Colorectal carcinoma can be detected by the immune system and thus can be targeted by immunotherapy (Dalerba P et al 2003) and vaccine therapy. For more information, refer to the chapter Cancer Vaccines and Immunotherapy.

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 the circulating VEGF (O'Neil BH et al 2003), prolonged survival of metastatic colorectal cancer patients who had inoperable tumors. Avastin® is now an FDA-approved drug to treat colon cancer. Interestingly, in patients with metastatic colorectal cancer, the addition of Avastin® to irinotecan, fluorouracil, and leucovorin improves survival regardless of the level of VEGF (Jubb AM et al. 2006).

Innovative Drug Strategies

Cimetidine (Tagamet®) is an over-the-counter ulcer medication that has beneficial effects in treating colorectal cancer and improving survival. Cimetidine prevents cancer growth and spread by several different mechanisms, including enhancing the immune response via stimulation of natural killer (NK) cells and interleukin-2 (IL-2) production, preventing histamine activity and thus immunosuppression, and reducing cancer-cell adhesion molecule expression (Tang NH et al 2004; Kubota T et al 2002; Kobayashi K et al 2000).

Colorectal cancers secrete histamine in high concentrations, enough to be locally immunosuppressive (Reynolds JL et al 1997; Melmon KL et al 1972). Histamine’s suppression of the immune response (immunosuppression) prevents the body from mounting a desirable attack against the tumor (Rocklin RE et al 1979). Cimetidine helps restore natural killer cells (Bai D et al 1999) and thus prevents this immune suppression (Adams et al 1993,1994a,b; Hansbrough JF et al 1986), resulting in prolonged survival of patients who undergo colorectal cancer surgery (Matsumoto S et al 2002).

In just seven days of treatment with 800 mg of cimetidine twice daily (Kelly MD et al 1999)—five days prior to surgery and two days post-surgery—the three-year mortality rate decreased from 41 percent to 7 percent in colorectal cancer patients (Tavani A et al 1998; Uchida A et al 1993). Furthermore, cimetidine improves survival in patients with noncurative surgery for stage IV colorectal cancer (Yoshimatsu K et al 2003). Indeed, cimetidine used in conjunction with chemotherapy can significantly improve survival rates. Patients with aggressive colon cancer had a remarkable 84.6 percent 10-year survival rate when treated with cimetidine (800 mg per day) together with 200 mg per day of 5-fluorouracil (5-FU) for one year starting two weeks after surgery, compared to a 49.8 percent 10-year survival rate for patients who were not treated with cimetidine as an adjuvant therapy (Matsumoto S et al 2002). Patients who had tumors with high expression of the Lewis antigen and were treated with cimetidine had a 10-year cumulative survival rate of 95.5 percent compared to 35.1 percent for those who had tumors with low expression of the Lewis antigens (Matsumoto S et al 2002).

The FDA, however, has not approved cimetidine for use in cancer treatment, which means that colorectal cancer patients should discuss the off-label use of cimetidine with their treating physician. While cimetidine can be purchased over the counter, it may be covered by insurance if prescribed by a physician.

Preventing Colorectal Cancer

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the few agents known to prevent the development of colorectal cancer (Chan TA 2006). Aspirin or NSAID use results in an impressive reduction in the risk of developing colorectal cancer (Janne PA et al. 2000). In two randomized, placebo-controlled trials, aspirin decreased the risk of polyp recurrence, considered a precursor to cancer (Baron JA et al. 2003; Sandler RS et al. 2003); Moran EM 2002; Nakatsugi S et al 1997). Other trials have shown that NSAIDs such as sulindac (Clinoril®) and celecoxib (Celebrex®) decrease the frequency of colorectal adenomas in patients with familial adenomatous polyposis (Jalving M et al. 2005h).

How Do NSAIDs Exert Their Anti-cancer Effects?

NSAIDs inhibit cyclooxygenase (COX) enzymes and prostaglandin synthases, which is at least partly responsible for their anti-cancer effects. Colon cancers have excessive levels of COX-2, which increases production of PGE2 in colon tumors (Sheehan KM et al 1999), promoting tumor progression (Eberhart CE et al. 1994; Jalving M et al. 2005f; Jalving M et al. 2005g; Oshima M et al. 1996) Rigas B et al 1993). NSAID treatment of cancer cells leads to inhibition of COX enzymes and consequent reduction of levels of prostaglandin E2 (PGE2), which in turn suppresses tumor development (Chan TA et al. 1998b; Jalving M et al. 2005e; Tsujii M et al. 1998). PGE2 regulates cancer cell proliferation by modulating the ß-catenin-axin signaling pathway, which is essential for the development of colorectal cancer (Castellone MD et al. 2005; Jalving M et al. 2005d). PGE2 also regulates cancer cell death (apoptosis) by transactivating the nuclear receptor NR4A2 (Holla VR et al. 2006; Jalving M et al. 2005c).

However, COX-independent mechanisms are also involved, as NSAIDs such as sulindac sulfone suppress proliferation, prevent tumor growth, and cause the death of cells that do not express COX enzymes (Hanif R et al. 1996; Jalving M et al. 2005b; Stoner GD et al. 1999). NSAIDs also act via prostaglandin-independent pathways involving ceramide, nuclear factor-?B (NF-?B), or peroxisome proliferator-activated receptors (PPARs) (Chan TA et al. 1998a; He TC et al. 1999a; Jalving M et al. 2005a; Yamamoto Y et al. 1999).


A 9.4-year epidemiological study showed that COX-2 activation was related to more advanced tumor stage, tumor size, and lymph node metastasis, as well as diminished survival rates among colorectal cancer patients (Sheehan KM et al 1999). With regular use of aspirin (a nonspecific COX-2 inhibitor, but also an anticoagulant), the risk of dying from the disease decreased (Thun MJ et al 1991).

Thus, COX inhibitors have a pivotal role in the prevention and adjuvant treatment of colon cancer. However, the benefits observed with taking prescription COX-2 inhibitors such as Celebrex® (100-200 mg taken every 12 hours) for prolonged periods are accompanied by side effects (Tsujii M et al 1998). Therefore, nutritional supplements that naturally suppress COX-2 such as curcumin (3600 mg/day) could be considered (Gescher A 2004); others include bioflavonoids (250 to 1800 mg/day) and silymarin (420 mg/day) (Pares A et al 1998; Boari C et al 1981).

Intervention for Those at High Risk

Interventions that can prevent the development of colorectal cancer include screening for adenomas, removal of polyps by endoscopic polypectomy, excision of the large bowel (in FAP) (Munkholm P 2003; Watson P et al 1998), and regular NSAID use (Reeves MJ et al 1996; Giardiello FM et al 1993), in addition to the following dietary interventions:

Fiber from bran and cellulose is effective in reducing the risk of colorectal cancer development (Gonzalez CA 2006b); Greenwald P et al 1986). In those with low intake of dietary fiber, doubling of total fiber intake could reduce the risk of colorectal cancer by 40 percent (Bingham S 2006). Fruit fiber consumption, as opposed to vegetable fiber, reduces the risk of colorectal adenomas (Platz EA et al 1997). High-fiber foods include legumes, beans, seeds, nuts, wild rice, and oatmeal.

Calcium reduces the growth rate of rectal and colon epithelial cells both directly and by binding bile acids and fatty acids in the stool, resulting in compounds that are less likely to adversely affect the colon (Rozen P et al 1989). Calcium’s beneficial effects may occur only in individuals who have a low level of fat intake (Cats A et al 1995). Oral calcium supplementation reduces benign tumor (adenoma) formation by 19 percent (Baron JA et al 1999) and slightly reduces cell proliferation in the rectum (Cats A et al 1995). Foods such as broccoli, kale, Chinese cabbage, milk, cheese, and yogurt are good sources of calcium.

Curcumin is currently being investigated in human clinical trials for the prevention and treatment of colorectal cancer (Jiao Y et al. 2006a). Curcumin may be effective in preventing the development of colon cancer related to Apc mutations (Corpet DE et al 2003; Pierre F 2003; Reddy BS et al 1994, 2002). The suggested daily dose is 1.6 grams (Perkins S et al 2002). Curcumin is extracted from turmeric root and is used as a spice in cooking.

Multivitamin use reduces the risk of benign tumor (adenoma) formation in high-risk individuals (Whelan RL et al 1999). Vitamins C, E, and A reduce the risk of developing colorectal cancer (Howe GR et al 1992; Newberne PM et al 1990).


Nutritional Therapies for Colorectal Cancer

PSK (polysaccharide K) extracted from the mushroom Coriolus versicolor is a unique polysaccharide that has been used as a chemo-immunotherapy agent to treat cancer in Asia for over 30 years (Fisher M et al. 2002).

Several randomized clinical trials have demonstrated that PSK has great potential as an adjuvant colorectal cancer therapeutic. In one such trial, PSK was effective in prolonging survival in colorectal cancer patients who underwent curative surgery. Patients took PSK (3 grams daily) for one year from the second week after surgery, along with rectal suppositories of the chemotherapy drug FT-207 (750 mg twice a day); now know as tegafur, or tegafur alone. The five-year survival rate was 88.6 percent in the tegafur-only group and 93.0 percent in the PSK-plus-tegafur group (Takashima S et al 1988).

In another randomized study of stage II or III colorectal cancer patients who were treated with either UFT (tegafur/uracil) alone or the combination of UFT and PSK, PSK prevented lung metastases, decreased the risk of recurrence by 43.6 percent, and increased the five-year disease-free survival rate (to 73.0 percent versus 58.8 percent). The five-year survival rate was 82 percent in the PSK group and 72 percent in the control group (Ohwada S et al. 2004).

PSK’s multifold anti-cancer activity includes its ability to improve the immune response through natural killer and lymphocyte-activated killer (LAK) cell activation (Matsunaga K et al. 1986), its potential to inhibit cancer spread through several different mechanisms (Kobayashi H et al. 1995), and its effects on cancer cell differentiation or normalization (Kanazawa M et al. 2004).

Fermented wheat germ extract (Avemar®), registered in Hungary since 2002 as a “medical nutriment” standardized to methoxy-substituted benzoquinones, is effective in the supportive therapy of colorectal cancer patients undergoing surgery or chemotherapy (Farkas E 2005a; Jakab F et al. 2000). Specifically, it significantly improves the incidence of metastasis and overall and progression-free survival of colorectal cancer patients when continuously supplemented (9 grams once daily) for more than six months, with no toxicity (Jakab F et al 2003; (Illmer C et al. 2005). When used in combination with chemotherapy, Avemar® reduces the occurrence of febrile neutropenia, or the low count of specialized white blood cells (Garami M et al. 2004).

One of Avemar®’s anti-cancer mechanisms is a highly cancer cell-specific activation of caspase-3-mediated cleavage of poly-(ADP-ribose)-polymerase (PARP) (Farkas E 2005b). Avemar® also has metastasis-inhibiting effects (Hidvegi M et al. 1998b; Hidvegi M et al. 1999; Szende B et al. 1998) and works synergistically with 5-fluorouracil (5-FU) and dacarbazine (DTIC) under experimental conditions (Hidvegi M et al. 1998a).

Aged garlic extract (AGE). A preliminary, double-blind, randomized clinical trial using high-dose aged garlic extract (2.4 ml/day) as an active treatment and low-dose AGE (0.16 ml/day) as a control was performed on 51 patients diagnosed with pre-cancerous lesions of the large bowel (adenomas). The number of adenomas increased linearly in the control group from the beginning, but AGE significantly suppressed both the size and number of colon adenomas in patients after 12 months of high-dose treatment. AGE seems to suppress the progression of colorectal adenomas through its effects on their growth and proliferation (Tanaka S et al. 2004; Tanaka S et al. 2006).

In another double-blind, randomized trial of advanced-cancer patients, AGE was administered for six months, resulting in a significant increase in natural killer cell number and activity, without adverse effects (Ishikawa H et al. 2006).

The mechanisms by which garlic prevents colorectal cancer growth and spread include immunomodulatory and antioxidant effects, as well as suppression of cell motility and invasion by inhibition of angiogenesis, through the suppression of endothelial cell motility, proliferation, and tube formation (Matsuura N et al. 2006).

Wheat grass (Triticum aestivum) juice is extracted from the pulp of wheat grass and has been used to treat various gastrointestinal disorders. Wheat grass therapy is associated with significant reductions in overall disease activity and the severity of rectal bleeding, without side effects (Ben-Arye E et al 2002).

Wheat grass is reported to contain all the amino acids (except tryptophan), minerals and trace minerals, essential fatty acids, vitamins A and C, iron, B vitamins, vitamin K, and chlorophyll. Chlorophyll is thought to be an immune system booster and antioxidant (Mata JE et al 2004; Robey RW et al 2004; Tajmir-Riahi HA et al 2004). Indeed, wheat grass contains superoxide dismutase (SOD) and displays antioxidant activity (Kulkarni SD et al. 2006).