Drugs Expert

Colorectal cancer, also called colon cancer or large bowel cancer, includes cancerous growths in the colon, rectum and appendix. With 655,000 deaths worldwide per year, it is the fourth most common form of cancer in the United States and the third leading cause of cancer-related death in the Western world. Colorectal cancers arise from adenomatous polyps in the colon. These mushroom-shaped growths are usually benign, but some develop into cancer over time. Localized colon cancer is usually diagnosed through colonoscopy.

Invasive cancers that are confined within the wall of the colon (TNM stages I and II) are curable with surgery. If untreated, they spread to regional lymph nodes (stage III), where up to 73% are curable by surgery and chemotherapy. Cancer that metastasizes to distant sites (stage IV) is usually not curable, although chemotherapy can extend survival, and in rare cases, surgery and chemotherapy together have seen patients through to a cure. Radiation is used with rectal cancer.

On the cellular and molecular level, colorectal cancer starts with a mutation to the Wnt signaling pathway. When Wnt binds to a receptor on the cell, that sets in motion a chain of molecular events that ends with β-catenin moving into the nucleus and activating a gene on DNA. In colorectal cancer, genes along this chain are damaged. Usually, a gene called APC, which is a “brake” on the Wnt pathway, is damaged. Without a working APC brake, the Wnt pathway is stuck in the “on” position.

What are the Causes for Colorectal Cancer?

Doctors are certain that colorectal cancer is not contagious (a person cannot catch the disease from a cancer patient). Some people are more likely to develop colorectal cancer than others. Factors that increase a person’s risk of colorectal cancer include high fat intake, a family history of colorectal cancer and polyps, the presence of polyps in the large intestine, and chronic ulcerative colitis.

Diet and colon cancer

Diets high in fat are believed to predispose humans to colorectal cancer. In countries with high colorectal cancer rates, the fat intake by the population is much higher than in countries with low cancer rates. It is believed that the breakdown products of fat metabolism lead to the formation of cancer-causing chemicals (carcinogens). Diets high in vegetables and high-fiber foods such as whole-grain breads and cereals may rid the bowel of these carcinogens and help reduce the risk of cancer.

Colon polyps and colon cancer

Doctors believe that most colon cancers develop in colon polyps. Therefore, removing benign colon polyps can prevent colorectal cancer. Colon polyps develop when chromosome damage occurs in cells of the inner lining of the colon. Chromosomes contain genetic information inherited from each parent. Normally, healthy chromosomes control the growth of cells in an orderly manner. When chromosomes are damaged, cell growth becomes uncontrolled, resulting in masses of extra tissue (polyps). Colon polyps are initially benign. Over years, benign colon polyps can acquire additional chromosome damage to become cancerous.

Ulcerative colitis and colon cancer

Chronic ulcerative colitis causes inflammation of the inner lining of the colon. For further information, please read the Ulcerative Colitis article. Colon cancer is a recognized complication of chronic ulcerative colitis. The risk for cancer begins to rise after eight to 10 years of colitis. The risk of developing colon cancer in a patient with ulcerative colitis also is related to the location and the extent of his or her disease.

Current estimates of the cumulative incidence of colon cancer associated with ulcerative colitis are 2.5% at 10 years, 7.6% at 30 years, and 10.8% at 50 years. Patients at higher risk of cancer are those with a family history of colon cancer, a long duration of colitis, extensive colon involvement, and those with primary sclerosing cholangitis (PSC).

Since the cancers associated with ulcerative colitis have a more favorable outcome when caught at an earlier stage, yearly examinations of the colon often are recommended after eight years of known extensive disease. During these examinations, samples of tissue (biopsies) can be taken to search for precancerous changes in the lining cells of the colon. When precancerous changes are found, removal of the colon may be necessary to prevent colon cancer.

Genetics and colon cancer

A person’s genetic background is an important factor in colon cancer risk. Among first-degree relatives of colon cancer patients, the lifetime risk of developing colon cancer is 18% (a threefold increase over the general population in the United States).

Even though family history of colon cancer is an important risk factor, majority (80%) of colon cancers occur sporadically in patients with no family history of colon cancer. Approximately 20% of cancers are associated with a family history of colon cancer. And 5 % of colon cancers are due to hereditary colon cancer syndromes. Hereditary colon caner syndromes are disorders where affected family members have inherited cancer-causing genetic defects from one or both of the parents.

Chromosomes contain genetic information, and chromosome damages cause genetic defects that lead to the formation of colon polyps and later colon cancer. In sporadic polyps and cancers (polyps and cancers that develop in the absence of family history), the chromosome damages are acquired (develop in a cell during adult life). The damaged chromosomes can only be found in the polyps and the cancers that develop from that cell. But in hereditary colon cancer syndromes, the chromosome defects are inherited at birth and are present in every cell in the body. Patients who have inherited the hereditary colon cancer syndrome genes are at risk of developing large number of colon polyps, usually at young ages, and are at very high risk of developing colon cancer early in life, and also are at risk of developing cancers in other organs.

FAP (familial adenomatous polyposis) is a hereditary colon cancer syndrome where the affected family members will develop countless numbers (hundreds, sometimes thousands) of colon polyps starting during the teens. Unless the condition is detected and treated (treatment involves removal of the colon) early, a person affected by familial polyposis syndrome is almost sure to develop colon cancer from these polyps. Cancers usually develop in the 40s. These patients are also at risk of developing other cancers such as cancers in the thyroid gland, stomach, and the ampulla (the part where the bile ducts drain into the duodenum just beyond the stomach).

AFAP (attenuated familial adenomatous polyposis) is a milder version of FAP. Affected members develop less than 100 colon polyps. Nevertheless, they are still at very high risk of developing colon cancers at young ages. They are also at risk of having gastric polyps and duodenal polyps.

HNPCC (hereditary nonpolyposis colon cancer) is a hereditary colon cancer syndrome where affected family members can develop colon polyps and cancers, usually in the right colon, in their 30s to 40s. Certain HNPCC patients are also at risk of developing uterine cancer, stomach cancer, ovarian cancer, and cancers of the ureters (the tubes that connect the kidneys to the bladder), and the biliary tract (the ducts that drain bile from the liver to the intestines).

MYH polyposis syndrome is a recently discovered hereditary colon cancer syndrome. Affected members typically develop 10-100 polyps occurring at around 40 years of age, and are at high risk of developing colon cancer.

What are the Risk Factors?

The lifetime risk of developing colon cancer in the United States is about 7%. Certain factors increase a person’s risk of developing the disease. These include:

• Age. The risk of developing colorectal cancer increases with age. Most cases occur in the 60s and 70s, while cases before age 50 are uncommon unless a family history of early colon cancer is present.
• Polyps of the colon, particularly adenomatous polyps, are a risk factor for colon cancer. The removal of colon polyps at the time of colonoscopy reduces the subsequent risk of colon cancer.
• History of cancer. Individuals who have previously been diagnosed and treated for colon cancer are at risk for developing colon cancer in the future. Women who have had cancer of the ovary, uterus, or breast are at higher risk of developing colorectal cancer.
• Heredity:
  • Family history of colon cancer, especially in a close relative before the age of 55 or multiple relatives.
  • Familial adenomatous polyposis (FAP) carries a near 100% risk of developing colorectal cancer by the age of 40 if untreated
  • Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome
  • Gardner syndrome
• Smoking. Smokers are more likely to die of colorectal cancer than non-smokers. An American Cancer Society study found that “Women who smoked were more than 40% more likely to die from colorectal cancer than women who never had smoked. Male smokers had more than a 30% increase in risk of dying from the disease compared to men who never had smoked.”
• Diet. Studies show that a diet high in red meat and low in fresh fruit, vegetables, poultry and fish increases the risk of colorectal cancer. In June 2005, a study by the European Prospective Investigation into Cancer and Nutrition suggested that diets high in red and processed meat, as well as those low in fiber, are associated with an increased risk of colorectal cancer. Individuals who frequently eat fish showed a decreased risk. However, other studies have cast doubt on the claim that diets high in fiber decrease the risk of colorectal cancer; rather, low-fiber diet was associated with other risk factors, leading to confounding. The nature of the relationship between dietary fiber and risk of colorectal cancer remains controversial.
• Lithocholic acid. Lithocholic acid is a bile acid that acts as a detergent to solubilize fats for absorption. It is made from chenodeoxycholic acid by bacterial action in the colon. It has been implicated in human and experimental animal carcinogenesis. Carbonic acid type surfactant easily combine with calcium ion and become detoxication.
• Physical inactivity. People who are physically active are at lower risk of developing colorectal cancer.
• Virus. Exposure to some viruses (such as particular strains of human papilloma virus) may be associated with colorectal cancer.
• Primary sclerosing cholangitis offers a risk independent to ulcerative colitis
• Low levels of selenium.
• Inflammatory bowel disease. About one percent of colorectal cancer patients have a history of chronic ulcerative colitis. The risk of developing colorectal cancer varies inversely with the age of onset of the colitis and directly with the extent of colonic involvement and the duration of active disease. Patients with colorectal Crohn’s disease have a more than average risk of colorectal cancer, but less than that of patients with ulcerative colitis.
• Environmental factors. Industrialized countries are at a relatively increased risk compared to less developed countries that traditionally had high-fiber/low-fat diets. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers.
• Exogenous hormones. The differences in the time trends in colorectal cancer in males and females could be explained by cohort effects in exposure to some gender-specific risk factor; one possibility that has been suggested is exposure to estrogens.  There is, however, little evidence of an influence of endogenous hormones on the risk of colorectal cancer. In contrast, there is evidence that exogenous estrogens such as hormone replacement therapy (HRT), tamoxifen, or oral contraceptives might be associated with colorectal tumors.
• Alcohol. Drinking, especially heavily, may be a risk factor.
• Vitamin B₆ intake is inversely associated with the risk of colorectal cancer.

Alcohol

The WCRF panel report Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective finds the evidence “convincing” that alcoholic drinks increase the risk of colorectal cancer in men.

The NIAAA reports that: “Epidemiologic studies have found a small but consistent dose-dependent association between alcohol consumption and colorectal cancer even when controlling for fiber and other dietary factors. Despite the large number of studies, however, causality cannot be determined from the available data.”

“Heavy alcohol use may also increase the risk of colorectal cancer” (NCI). One study found that “People who drink more than 30 grams of alcohol per day (and especially those who drink more than 45 grams per day) appear to have a slightly higher risk for colorectal cancer.” Another found that “The consumption of one or more alcoholic beverages a day at baseline was associated with approximately a 70% greater risk of colon cancer.”

One study found that “While there was a more than twofold increased risk of significant colorectal neoplasia in people who drink spirits and beer, people who drank wine had a lower risk. In our sample, people who drank more than eight servings of beer or spirits per week had at least a one in five chance of having significant colorectal neoplasia detected by screening colonoscopy.”.

Other research suggests that “to minimize your risk of developing colorectal cancer, it’s best to drink in moderation.”

On its colorectal cancer page, the National Cancer Institute does not list alcohol as a risk factor; however, on another page it states, “Heavy alcohol use may also increase the risk of colorectal cancer”.

Drinking may be a cause of earlier onset of colorectal cancer.

What are the Symptoms of Colorectal Cancer?

The symptoms of colorectal cancer depend on the location of tumor in the bowel, and whether it has spread elsewhere in the body (metastasis). Most of the symptoms may occur in other diseases as well, and hence none of the symptoms mentioned here is diagnostic of colorectal cancer. Symptoms and signs are divided into local, constitutional (affecting the whole body) and metastatic (caused by spread to other organs).

Local

Local symptoms are more likely if the tumor is located closer to the anus. There may be a change in bowel habit (new-onset constipation or diarrhea in the absence of another cause), and a feeling of incomplete defecation (rectal tenesmus) and reduction in diameter of stool; tenesmus and change in stool shape are both characteristic of rectal cancer. Lower gastrointestinal bleeding, including the passage of bright red blood in the stool, may indicate colorectal cancer, as may the increased presence of mucus. Melena, black stool with a tarry appearance, normally occurs in upper gastrointestinal bleeding (such as from a duodenal ulcer), but is sometimes encountered in colorectal cancer when the disease is located in the beginning of the large bowel.

A tumor that is large enough to fill the entire lumen of the bowel may cause bowel obstruction. This situation is characterized by constipation, abdominal pain, abdominal distension and vomiting. This occasionally leads to the obstructed and distended bowel perforating and causing peritonitis.

Certain local effects of colorectal cancer occur when the disease has become more advanced. A large tumor is more likely to be noticed on feeling the abdomen, and it may be noticed by a doctor on physical examination. The disease may invade other organs, and may cause blood or air in the urine (invasion of the bladder) or vaginal discharge (invasion of the female reproductive tract).

Constitutional

If a tumor has caused chronic occult bleeding, iron deficiency anemia may occur; this may be experienced as fatigue, palpitations and noticed as pallor (pale appearance of the skin). Colorectal cancer may also lead to weight loss, generally due to a decreased appetite.

More unusual constitutional symptoms are an unexplained fever and one of several paraneoplastic syndromes. The most common paraneoplastic syndrome is thrombosis, usually deep vein thrombosis.

Metastatic

Colorectal cancer most commonly spreads to the liver. This may go unnoticed, but large deposits in the liver may cause jaundice and abdominal pain (due to stretching of the capsule). If the tumor deposit obstructs the bile duct, the jaundice may be accompanied by other features of biliary obstruction, such as pale stools.

Diagnosis of Colorectal Cancer

Colorectal cancer can take many years to develop and early detection of colorectal cancer greatly improves the chances of a cure. The National Cancer Policy Board of the Institute of Medicine estimated in 2003 that even modest efforts to implement colorectal cancer screening methods would result in a 29 percent drop in cancer deaths in 20 years. Despite this, colorectal cancer screening rates remain low. Therefore, screening for the disease is recommended in individuals who are at increased risk. There are several different tests available for this purpose.

• Digital rectal exam (DRE): The doctor inserts a lubricated, gloved finger into the rectum to feel for abnormal areas. It only detects tumors large enough to be felt in the distal part of the rectum but is useful as an initial screening test.
• Fecal occult blood test (FOBT): a test for blood in the stool. Two types of tests can be used for detecting occult blood in stools i.e. guaiac based (chemical test) and immunochemical. The sensitivity of immunochemical testing is superior to that of chemical testing without an unacceptable reduction in specifity.
• Endoscopy:
  • Sigmoidoscopy: A lighted probe (sigmoidoscope) is inserted into the rectum and lower colon to check for polyps and other abnormalities.
  • Colonoscopy: A lighted probe called a colonoscope is inserted into the rectum and the entire colon to look for polyps and other abnormalities that may be caused by cancer. A colonoscopy has the advantage that if polyps are found during the procedure they can be removed immediately. Tissue can also be taken for biopsy.

In the United States, colonoscopy or FOBT plus sigmoidoscopy are the preferred screening options.

Other screening methods

• Double contrast barium enema (DCBE): First, an overnight preparation is taken to cleanse the colon. An enema containing barium sulfate is administered, then air is insufflated into the colon, distending it. The result is a thin layer of barium over the inner lining of the colon which is visible on X-ray films. A cancer or a precancerous polyp can be detected this way. This technique can miss the (less common) flat polyp.
• Virtual colonoscopy replaces X-ray films in the double contrast barium enema (above) with a special computed tomography scan and requires special workstation software in order for the radiologist to interpret. This technique is approaching colonoscopy in sensitivity for polyps. However, any polyps found must still be removed by standard colonoscopy.
• Standard computed axial tomography is an x-ray method that can be used to determine the degree of spread of cancer, but is not sensitive enough to use for screening. Some cancers are found in CAT scans performed for other reasons.
• Blood tests: Measurement of the patient’s blood for elevated levels of certain proteins can give an indication of tumor load. In particular, high levels of carcinoembryonic antigen (CEA) in the blood can indicate metastasis of adenocarcinoma. These tests are frequently false positive or false negative, and are not recommended for screening, it can be useful to assess disease recurrence. CA19-9 and CA 242 biomarkers can indicate e-selectin related metastatic risks, help follow therapeutic progress, and assess disease recurrence.
• Genetic counseling and genetic testing for families who may have a hereditary form of colon cancer, such as hereditary nonpolyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP).
• Positron emission tomography (PET) is a 3-dimensional scanning technology where a radioactive sugar is injected into the patient, the sugar collects in tissues with high metabolic activity, and an image is formed by measuring the emission of radiation from the sugar. Because cancer cells often have very high metabolic rates, this can be used to differentiate benign and malignant tumors. PET is not used for screening and does not (yet) have a place in routine workup of colorectal cancer cases.
• Whole-body PET imaging is the most accurate diagnostic test for detection of recurrent colorectal cancer, and is a cost-effective way to differentiate resectable from nonresectable disease. A PET scan is indicated whenever a major management decision depends upon accurate evaluation of tumour presence and extent.
• Stool DNA testing is an emerging technology in screening for colorectal cancer. Premalignant adenomas and cancers shed DNA markers from their cells which are not degraded during the digestive process and remain stable in the stool. Capture, followed by PCR amplifies the DNA to detectable levels for assay. Clinical studies have shown a cancer detection sensitivity of 71%–91%.
• High C-Reactive Protein levels is risk marker.

Monitoring

Carcinoembryonic antigen (CEA) is a protein found on virtually all colorectal tumors. CEA may be used to monitor and assess response to treatment in patients with metastatic disease. CEA can also be used to monitor recurrence in patients post-operatively.

Pathology

The pathology of the tumor is usually reported from the analysis of tissue taken from a biopsy or surgery. A pathology report will usually contain a description of cell type and grade. The most common colon cancer cell type is adenocarcinoma which accounts for 95% of cases. Other, rarer types include lymphoma and squamous cell carcinoma.

Cancers on the right side (ascending colon and cecum) tend to be exophytic, that is, the tumour grows outwards from one location in the bowel wall. This very rarely causes obstruction of feces, and presents with symptoms such as anemia. Left-sided tumours tend to be circumferential, and can obstruct the bowel much like a napkin ring.

Adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the colorectal mucosa. It invades the wall, infiltrating the muscularis mucosae, the submucosa and thence the muscularis propria. Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma (“back to back” aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus/colloid (optically “empty” spaces) – mucinous (colloid) adenocarcinoma, poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery – “signet-ring cell.” Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of differentiation: well, moderately, and poorly differentiated.

Most colorectal cancer tumors are thought to be cyclooxygenase-2 (COX-2) positive. This enzyme is generally not found in healthy colon tissue, but is thought to fuel abnormal cell growth.

Staging

Colon cancer staging is an estimate of the amount of penetration of a particular cancer. It is performed for diagnostic and research purposes, and to determine the best method of treatment. The systems for staging colorectal cancers depend on the extent of local invasion, the degree of lymph node involvement and whether there is distant metastasis.

Definitive staging can only be done after surgery has been performed and pathology reports reviewed. An exception to this principle would be after a colonoscopic polypectomy of a malignant pedunculated polyp with minimal invasion. Preoperative staging of rectal cancers may be done with endoscopic ultrasound. Adjunct staging of metastasis include Abdominal Ultrasound, CT, PET Scanning, and other imaging studies.

The most common staging system is the TNM (for tumors/nodes/metastases) system, from the American Joint Committee on Cancer (AJCC). The TNM system assigns a number based on three categories. “T” denotes the degree of invasion of the intestinal wall, “N” the degree of lymphatic node involvement, and “M” the degree of metastasis. The broader stage of a cancer is usually quoted as a number I, II, III, IV derived from the TNM value grouped by prognosis; a higher number indicates a more advanced cancer and likely a worse outcome.

Dukes system

Micrograph of a colorectal adenocarcinoma metastasis to a lymph node. The cancerous cells are at the top center-left of the image, in glands (circular/ovoid structures) and eosinophilic (bright pink). H&E stain.

Dukes classification is an older and less complicated staging system, that predates the TNM system, and was first proposed by Dr. Cuthbert Dukes in 1932; it identifies the stages as:

• A – Tumour confined to the intestinal wall
• B – Tumour invading through the intestinal wall
• C – With lymph node(s) involvement (this is further subdivided into C1 lymph node involvement where the apical node is not involved and C2 where the apical lymph node is involved)
• D – With distant metastasis

A few cancer centers still use this staging system.

Methods of Treatment

The treatment depends on the staging of the cancer. When colorectal cancer is caught at early stages (with little spread) it can be curable. However, when it is detected at later stages (when distant metastases are present) it is less likely to be curable.

Surgery remains the primary treatment while chemotherapy and/or radiotherapy may be recommended depending on the individual patient’s staging and other medical factors.

Because colon cancer primarily affects the elderly, it can be a challenge to determine how aggressively to treat a particular patient, especially after surgery. Clinical trials suggest that “otherwise fit” elderly patients fare well if they have adjuvant chemotherapy after surgery, so chronological age alone should not be a contraindication to aggressive management.

Surgery

Surgeries can be categorised into curative, palliative, bypass, fecal diversion, or open-and-close.

Curative Surgical treatment can be offered if the tumor is localized.

• Very early cancer that develops within a polyp can often be cured by removing the polyp (i.e., polypectomy) at the time of colonoscopy.
• In colon cancer, a more advanced tumor typically requires surgical removal of the section of colon containing the tumor with sufficient margins, and radical en-bloc resection of mesentery and lymph nodes to reduce local recurrence (i.e., colectomy). If possible, the remaining parts of colon are anastomosed together to create a functioning colon. In cases when anastomosis is not possible, a stoma (artificial orifice) is created.
• Curative surgery on rectal cancer includes total mesorectal excision (lower anterior resection) or abdominoperineal excision.

In case of multiple metastases, palliative (non curative) resection of the primary tumor is still offered in order to reduce further morbidity caused by tumor bleeding, invasion, and its catabolic effect. Surgical removal of isolated liver metastases is, however, common and may be curative in selected patients; improved chemotherapy has increased the number of patients who are offered surgical removal of isolated liver metastases.

If the tumor invaded into adjacent vital structures which makes excision technically difficult, the surgeons may prefer to bypass the tumor (ileotransverse bypass) or to do a proximal fecal diversion through a stoma.

The worst case would be an open-and-close surgery, when surgeons find the tumor unresectable and the small bowel involved; any more procedures are thought by some to do more harm than good to the patient. This is uncommon with the advent of laparoscopy and better radiological imaging. Most of these cases formerly subjected to “open and close” procedures are now diagnosed in advance and surgery avoided.

Laparoscopic-assisted colectomy is a minimally invasive technique that can reduce the size of the incision and may reduce post-operative pain.

As with any surgical procedure, colorectal surgery may result in complications including

• wound infection, Dehiscence (bursting of wound) or hernia
• anastomosis breakdown, leading to abscess or fistula formation, and/or peritonitis
• bleeding with or without hematoma formation
• adhesions resulting in bowel obstruction. A 5-year study of patients who had surgery in 1997 found the risk of hospital readmission to be 15% after panproctocolectomy, 9% after total colectomy, and 11% after ileostomy.
• adjacent organ injury; most commonly to the small intestine, ureters, spleen, or bladder
• Cardiorespiratory complications such as myocardial infarction, pneumonia, arrythmia, pulmonary embolism etc.

Chemotherapy

Chemotherapy is used to reduce the likelihood of metastasis developing, shrink tumor size, or slow tumor growth. Chemotherapy is often applied after surgery (adjuvant), before surgery (neo-adjuvant), or as the primary therapy (palliative). The treatments listed here have been shown in clinical trials to improve survival and/or reduce mortality rate and have been approved for use by the US Food and Drug Administration. In colon cancer, chemotherapy after surgery is usually only given if the cancer has spread to the lymph nodes (Stage III).

• Adjuvant (after surgery) chemotherapy.
  • 5-fluorouracil (5-FU) or Capecitabine (Xeloda)
  • Leucovorin (LV, Folinic Acid)
  • Oxaliplatin (Eloxatin)

• Chemotherapy for metastatic disease. Commonly used first line chemotherapy regimens involve the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) with bevacizumab or infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab or the same chemotherapy drug combinations with cetuximab in KRAS wild type tumors
  • 5-fluorouracil (5-FU) or Capecitabine
  • UFT or Tegafur-uracil
  • Leucovorin (LV, Folinic Acid)
  • Irinotecan (Camptosar)
  • Oxaliplatin (Eloxatin)
  • Bevacizumab (Avastin)
  • Cetuximab (Erbitux)
  • Panitumumab (Vectibix)

• In clinical trials for treated/untreated metastatic disease.
  • Bortezomib (Velcade)
  • Oblimersen (Genasense, G3139)
  • Gefitinib and Erlotinib (Tarceva)
  • Topotecan (Hycamtin)

At the 2008 annual meeting of the American Society of Clinical Oncology, researchers announced that colorectal cancer patients that have a mutation in the KRAS gene do not respond to certain therapies, those that inhibit the epidermal growth factor receptor (EGFR)–namely Erbitux (cetuximab) and Vectibix (panitumumab). Following recommendations by ASCO, patients should now be tested for the KRAS gene mutation before being offered these EGFR-inhibiting drugs. In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.

However, having the normal KRAS version does not guarantee that these drugs will benefit the patient.

“The trouble with the KRAS mutation is that it’s downstream of EGFR,” says Richard Goldberg, MD, director of oncology at the Lineberger Comprehensive Cancer Center at the University of North Carolina. “It doesn’t matter if you plug the socket if there’s a short downstream of the plug. The mutation turns [EGFR] into a switch that’s always on.” But this doesn’t mean that having normal, or wild-type, KRAS is a fail-safe. “It isn’t foolproof,” cautions Goldberg. “If you have wild-type KRAS, you’re more likely to respond, but it’s not a guarantee.” Tumors shrink in response to these drugs in up to 40 percent of patients with wild-type KRAS, and progression-free and overall survival is increased.

The cost benefit of testing patients for the KRAS gene could potentially save about $740 million a year by not providing EGFR-inhibiting drugs to patients who would not benefit from the drugs. “With the assumption that patients with mutated Kras (35.6% of all patients) would not receive cetuximab (other studies have found Kras mutation in up to 46% of patients), theoretical drug cost savings would be $753 million; considering the cost of Kras testing, net savings would be $740 million.”

Radiation therapy

Radiotherapy is not used routinely in colon cancer, as it could lead to radiation enteritis, and it is difficult to target specific portions of the colon. It is more common for radiation to be used in rectal cancer, since the rectum does not move as much as the colon and is thus easier to target. Indications include:

• Colon cancer
  • pain relief and palliation – targeted at metastatic tumor deposits if they compress vital structures and/or cause pain
• Rectal cancer
  • neoadjuvant – given before surgery in patients with tumors that extend outside the rectum or have spread to regional lymph nodes, in order to decrease the risk of recurrence following surgery or to allow for less invasive surgical approaches (such as a low anterior resection instead of an abdomino-perineal resection). In locally advanced adenocarcinoma of middle and lower rectum, regional hyperthermia added to chemoradiotherapy achieved good results in terms of rate of sphincter sparing surgery.
  • adjuvant – where a tumor perforates the rectum or involves regional lymph nodes (AJCC T3 or T4 tumors or Duke’s B or C tumors)
  • palliative – to decrease the tumor burden in order to relieve or prevent symptoms

Sometimes chemotherapy agents are used to increase the effectiveness of radiation by sensitizing tumor cells if present.

Immunotherapy

Bacillus Calmette-Guérin (BCG) is being investigated as an adjuvant mixed with autologous tumor cells in immunotherapy for colorectal cancer.

Cancer Vaccine

TroVax, a cancer vaccine, produced by Oxford BioMedica, is in Phase III trials for renal cancers, and phase III trials are planned for colon cancers.

Treatment of liver metastases

According to the American Cancer Society statistics in 2006, over 20% of patients present with metastatic (stage IV) colorectal cancer at the time of diagnosis, and up to 25% of this group will have isolated liver metastasis that is potentially resectable. Lesions which undergo curative resection have demonstrated 5-year survival outcomes now exceeding 50%.

Resectability of a liver metastasis is determined using preoperative imaging studies (CT or MRI), intraoperative ultrasound, and by direct palpation and visualization during resection. Lesions confined to the right lobe are amenable to en bloc removal with a right hepatectomy (liver resection) surgery. Smaller lesions of the central or left liver lobe may sometimes be resected in anatomic “segments”, while large lesions of left hepatic lobe are resected by a procedure called hepatic trisegmentectomy. Treatment of lesions by smaller, non-anatomic “wedge” resections is associated with higher recurrence rates. Some lesions which are not initially amenable to surgical resection may become candidates if they have significant responses to preoperative chemotherapy or immunotherapy regimens. Lesions which are not amenable to surgical resection for cure can be treated with modalities including radio-frequency ablation (RFA), cryoablation, and chemoembolization.

Patients with colon cancer and metastatic disease to the liver may be treated in either a single surgery or in staged surgeries (with the colon tumor traditionally removed first) depending upon the fitness of the patient for prolonged surgery, the difficulty expected with the procedure with either the colon or liver resection, and the comfort of the surgery performing potentially complex hepatic surgery.

Aspirin

A study published in 2009 found that Aspirin reduces risk of colorectal neoplasia in randomized trials and inhibits tumor growth and metastases in animal models. The influence of aspirin on survival after diagnosis of colorectal cancer is unknown. Several reports including a prospective cohort of 1,279 people diagnosed with stages I-III (non-metastatic) colorectal cancer have suggested a significant improvement in cancer-specific survival in a subset of patients using aspirin.

Cimetidine

Cimetidine is being investigated in Japan as an adjuvant for adenocarcinomas,  including for stage III and stage IV colorectal cancers biomarked with overexpressed sialyl Lewis X and A epitopes. Multiple small trials suggest a significant survival improvement in the subset of patients with the sLeX and sLeA biomarkers that take cimetidine treatment perioperatively, through several mechanisms.

Support therapies

Cancer diagnosis very often results in an enormous change in the patient’s psychological wellbeing. Various support resources are available from hospitals and other agencies which provide counseling, social service support, cancer support groups, and other services. These services help to mitigate some of the difficulties of integrating a patient’s medical complications into other parts of their life.

Drugs rating:

Prognosis

Survival is directly related to detection and the type of cancer involved. Survival rates for early stage detection is about 5 times that of late stage cancers. CEA level is also directly related to the prognosis of disease, since its level correlates with the bulk of tumor tissue.

Follow-up

Micrograph of a colorectal villous adenoma. These lesions are considered pre-cancerous. H&E stain.

The aims of follow-up are to diagnose in the earliest possible stage any metastasis or tumors that develop later but did not originate from the original cancer (metachronous lesions).

The U.S. National Comprehensive Cancer Network and American Society of Clinical Oncology provide guidelines for the follow-up of colon cancer. A medical history and physical examination are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen blood level measurements follow the same timing, but are only advised for patients with T2 or greater lesions who are candidates for intervention. A CT-scan of the chest, abdomen and pelvis can be considered annually for the first 3 years for patients who are at high risk of recurrence (for example, patients who had poorly differentiated tumors or venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A colonoscopy can be done after 1 year, except if it could not be done during the initial staging because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a villous polyp, polyp >1 centimeter or high grade dysplasia is found, it can be repeated after 3 years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year.

Routine PET or ultrasound scanning, chest X-rays, complete blood count or liver function tests are not recommended. These guidelines are based on recent meta-analyses showing that intensive surveillance and close follow-up can reduce the 5-year mortality rate from 37% to 30%.

Colorectal Cancer Prevention

Unfortunately, colon cancers can be well advanced before they are detected. The most effective prevention of colon cancer is early detection and removal of precancerous colon polyps before they turn cancerous. Even in cases where cancer has already developed, early detection still significantly improves the chances of a cure by surgically removing the cancer before the disease spreads to other organs. Multiple world health organizations have suggested general screening guidelines.

Digital rectal examination and stool occult blood testing

It is recommended that all individuals over the age of 40 have yearly digital examinations of the rectum and their stool tested for hidden or “occult” blood. During digital examination of the rectum, the doctor inserts a gloved finger into the rectum to feel for abnormal growths. Stool samples can be obtained to test for occult blood (see below). The prostate gland can be examined at the same time.

An important screening test for colorectal cancers and polyps is the stool occult blood test. Tumors of the colon and rectum tend to bleed slowly into the stool. The small amount of blood mixed into the stool is usually not visible to the naked eye. The commonly used stool occult blood tests rely on chemical color conversions to detect microscopic amounts of blood. These tests are both convenient and inexpensive. A small amount of stool sample is smeared on a special card for occult blood testing. Usually, three consecutive stool cards are collected. A person who tests positive for stool occult blood has a 30% to 45% chance of having a colon polyp and a 3% to 5% chance of having a colon cancer. Colon cancers found under these circumstances tend to be early and have a better long-term prognosis.

It is important to remember that having stool tested positive for occult blood does not necessarily mean the person has colon cancer. Many other conditions can cause occult blood in the stool. However, patients with a positive stool occult blood should undergo further evaluations involving barium enema x-rays, colonoscopies, and other tests to exclude colon cancer, and to explain the source of the bleeding. It is also important to realize that stool which has tested negative for occult blood does not mean the absence of colorectal cancer or polyps. Even under ideal testing conditions, at least 20% of colon cancers can be missed by stool occult blood screening. Many patients with colon polyps are tested negative for stool occult blood. In patients suspected of having colon tumors, and in those with high risk factors for developing colorectal polyps and cancer, flexible sigmoidoscopies or screening colonoscopies are performed even if the stool occult blood tests are negative.

Flexible sigmoidoscopy and colonoscopy

Beginning at age 50, a flexible sigmoidoscopy screening tests is recommended every three to five years. Flexible sigmoidoscopy is an exam of the rectum and the lower colon using a viewing tube (a short version of colonoscopy). Recent studies have shown that the use of screening flexible sigmoidoscopy can reduce mortality from colon cancer. This is a result of the detection of polyps or early cancers in people with no symptoms. If a polyp or cancer is found, a complete colonoscopy is recommended. The majority of colon polyps can be completely removed by colonoscopy without open surgery. Recently doctors are recommending screening colonoscopies instead of screening flexible sigmoidoscopies for healthy individuals starting at ages 50-55. Please read the Colon Cancer Screening article.

Patients with a high risk of developing colorectal cancer may undergo colonoscopies starting at earlier ages than 50. For example, patients with family history of colon cancer are recommended to start screening colonoscopies at an age 10 years before the earliest colon caner diagnosed in a first-degree relative, or five years earlier than the earliest precancerous colon polyp discovered in a first-degree relative. Patients with hereditary colon cancer syndromes such as FAP, AFAP, HNPCC, and MYH are recommended to begin colonoscopies early. The recommendations differ depending on the genetic defect, for example in FAP; colonoscopies may begin during teenage years to look for the development of colon polyps. Patients with a prior history of polyps or colon cancer may also undergo colonoscopies to exclude recurrence. Patients with a long history (greater than 10 years) of chronic ulcerative colitis have an increased risk of colon cancer, and should have regular colonoscopies to look for precancerous changes in the colon lining.

Genetic counseling and testing

Blood tests are now available to test for FAP, AFAP, MYH, and HNPCC hereditary colon cancer syndromes. Families with multiple members having colon cancers, members with multiple colon polyps, members having cancers at young ages, and having other cancers such as cancers of the ureters, uterus, duodenum, etc., should be referred for genetic counseling followed possibly by genetic testing. Genetic testing without prior counseling is discouraged because of the extensive family education that is involved and the complicated nature of interpreting the test results.

The advantages of genetic counseling followed by genetic testing include: (1) identifying family members at high risk of developing colon cancer to begin colonoscopies early; (2) identifying high risk members so that screening may begin to prevent other cancers such as ultrasound tests for uterine cancer, urine examinations for ureter cancer, and upper endoscopies for stomach and duodenal cancers; and (3) alleviating concern for members who test negative for the hereditary genetic defects.

Diet and colon cancer to prevent colon cancer

People can change their eating habits by reducing fat intake and increasing fiber (roughage) in their diet. Major sources of fat are meat, eggs, dairy products, salad dressings, and oils used in cooking. Fiber is the insoluble, nondigestible part of plant material present in fruits, vegetables, and whole-grain breads and cereals. It is postulated that high fiber in the diet leads to the creation of bulky stools which can rid the intestines of potential carcinogens. In addition, fiber leads to the more rapid transit of fecal material through the intestine, thus allowing less time for a potential carcinogen to react with the intestinal lining.