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.
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 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 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
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 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 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, 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.
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
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).
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 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).
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 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).