A Review on Colorectal Cancer

Cancers of the colon and rectum are the second leading cause of cancer death. Fifty percent of the colorectal cancer occurs in either the lower (sigmoid) colon or the rectum and should be easy to detect at an early stage. The majority of the colon cancers are not inherited, but rather are considered sporadic, having developed from an accumulation of mutations throughout the course of a lifetime. The epidemiological risk factors for cancers, other than genetic risk factors, include dietary components, such as the amount of fat and fiber in the diet, intake of calcium, vitamins of the antioxidant class, NSAIDS such as aspirin and specific inhibitors of cyclo-oxygenase. The risk of colon cancer increases with age, the history of previous polyps or cancer, family history of cancer, history of long standing inflammatory bowel disease including ulcerative colitis and Crohn’s disease. Colonoscopy plays an important role in the medical care of patients with colorectal cancer. It is generally used for both the diagnosis of different stages of colorectal cancer and the treatment of early colorectal cancers and its precursors.


Introduction 1,2
Colon cancer is the most common type of gastrointestinal cancer which can be derived from either inherited or somatic genetic alterations that develop over the course of a lifetime. This type of cancer begins in the cells of the glandular structures in the inner layers of the colon and spreads first into the wall of the colon and potentially into the lymphatic system and the other organs. Colon cancer stems from colon polyps that turn cancerous, and individuals who develop polyps are at the highest risk of colon cancer.
The adenoma-carcinoma sequence refers to a traditional view that colorectal malignancies develop from adenomatous polyps and, indeed, a large amount of evidence has been accumulated indicating that carcinomas of the large intestine arise from pre-existing, premalignant lesions, especially when associated with dysplastic changes. However, only few adenomas actually develop invasive cancer (progressive adenomas), although every adenoma has the capacity of malignant evolution. Most adenomas stabilize their progression or even regress. In addition, the earliest phases of colorectal tumorigenesis presumably initiate in normal mucosa, with a disorder of cell replication and renewal, and with the appearance of clusters of enlarged crypts showing proliferative, biochemical, and biomolecular abnormalities. Although several lines of evidence indicate that carcinomas usually originate from pre-existing adenomas, this does not imply that all polyps undergo malignant changes, and does not exclude "de novo" carcinogenesis (i.e., the development of cancer from flat mucosa). Thus, defining progression risk of adenomas, even in the long-term follow-up, remains an ongoing research for which few good predictors are available.

Epidemiology and Incidence Rates 3-6
Colorectal cancer (CRC) incidence and mortality rates vary markedly around the world. Globally, CRC is the third most commonly diagnosed cancer in males and the second in females, with over 1.2 million new cases and 608,700 deaths estimated to have occurred in 2008. Rates are substantially higher in males than in females. Colorectal cancer incidences and the mortality rates are highest in African American men and women. The rates among other major racial/ ethnic groups are lower than those among whites. Globally, the incidence of CRC varies over 10-fold. The highest incidence rates are in Australia and New Zealand, Europe and North America, and the lowest rates are found in Africa and South-Central Asia. In the United States, both the incidence and mortality have been slowly but steadily decreasing. Annually approximately 142,820 new cases of large bowel cancer are diagnosed, of which 102,480 are colon and the remainder rectal cancers. The colorectal cancer incidence rates by race, ethnicity and gender is illustrate in fig.1.
According to the Rajiv Gandhi Cancer Institute and Research Centre, colorectal cancer is the sixth most prevalent cancer in India. Hospital based and population based data show that the incidence rates for rectal cancer is higher than colon cancer in all parts of India. However, the incidence rates of rectal cancer are disproportionately higher in rural India. Population based time trend studies show a Advances in Pharmacology and Pharmacy 1(3): 124-134, 2013 125 rising trend in the incidence of CRC in India. Worrisome is the finding that the incidence rates of CRC in Indian immigrants to the United Kingdom and USA are much higher, suggesting that life styles and dietary habits are important in the causation of the CRC.

Risk Factors
There are many known factors that increase or decrease the risk of colorectal cancer; some of these factors are modifiable and the others are not.
 Non-Modifiable Risk Factors: The non-modifiable risk factors include family or personal history of colorectal cancer or adenomatous polyps, and a personal history of chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. 7 The non-modifiable risk factors of colorectal cancer are shown in table 1.  Modifiable Risk Factors: The modifiable risk factors that are associated with colorectal cancers include physical activity, obesity, high consumption of red or processed meats, smoking, and alcohol consumption. Studies suggest that increasing calcium intake lowers the risk of colorectal cancer. It has also been found that the regular use of aspirin and other NSAIDS lower the risk of colorectal cancer and adenomatous polyp. A recent study revealed that a quarter of colorectal cancer could be avoided by following a healthy diet and lifestyle. 8,9 The evidence of diet and lifestyle risk factors is shown in table 2.  Detecting the signs of colon cancer and nipping colon cancer in the bud at an early stage increases the patient's survival rate.

Screening 7,10-15
Colorectal cancers may shed blood and other tissue components that can be detected in the feces long before the development of clinical symptoms. Hence screening is intended for asymptomatic individuals. Screening needs to be applied within the framework of a program that includes: primary prevention (diet and lifestyle), timely diagnostic work up with colonoscopy in those screened positive, and timely treatment (polypectomy, surgery). Any patient with symptoms or signs suggesting the presence of colorectal cancer falls outside the domain of screening and requires diagnostic workup. Several different screening tests can be used to find the polyps or colorectal cancer. Each can be used alone or in combination with each other. 10  The double-contrast barium enema (DCBE) is also called an air-contrast barium enema or a barium enema with air contrast. It may also be referred to as a lower GI series. It is basically a type of x-ray test. In this the patient receives an enema with liquid barium, followed by air enema. This creates an outline around the colon, allowing seeing the outline of colon on the X-ray. The sensitivity for detection of colorectal cancer is approximately 82% for double contrast barium enemas.  Computed Tomographic Colonography (CTC): This imaging procedure may also be referred to as virtual colonoscopy.
Thin-section helical computed-tomographic scanning of the abdomen and pelvis, followed by digital processing and interpretation of the images, can display two-dimensional and three-dimensional reconstructions of the colonic lumen. CTC technique does not require sedation. CTC is less invasive than the other screening techniques, requires no recovery time and takes 10-15 minutes for completion. Invasive cancer and polyps approximately 1 cm or larger in size can be detected by CTC.  The different screening methods for colon cancer are briefed in the table 3. abnormal changes in deoxyribonucleic acid, when DNA is making a copy of its own. MSI is caused by methylated genes as an epigenetic feature called CpG Island Methylator Phenotype (CIMP). The gold standard for MSI testing is polymerase chain reaction (PCR), and the type of markers used for highest sensitivity is currently being scrutinized.  Non-inherited changes in genes which affect the colon cancer treatment are also tested (K-ras gene and BRAF gene). The K-ras proto-oncogene encodes guanosine 5'-triphosphate (GTP) binding protein at the beginning of the MAPK signaling pathway. K-ras is found to be mutated in about 40% of people with colorectal cancer. People who do not have the mutated gene are said to have the "wild type" K-ras gene. Research shows that people who have the K-ras mutation do not respond to drugs called EGFR inhibitors, such as cetuximab (Erbitux) and panitumumab (Vectibix). Thus, EGFR inhibitors may be an option for those with a "wild type" K-ras gene. BRAF gene encodes a serine-threonine protein kinase that is downstream of K-ras in the MAPK signaling pathway. BRAF mutations occur in 5-22% of all colorectal cancers. The most frequently reported BRAF mutation is a valine-to-glutamic acid amino acid substitution. BRAF mutations are mutually exclusive with K-ras mutations.  Oncotype DX colon cancer assay test is for people with stage II colon cancer. This test analyzes 12 different genes to give a "recurrence score." The score (a number between zero and 100) estimates the chance of the cancer returning after surgery. A low score indicates a low risk of recurrence, and a high score, a high risk of recurrence.

Stages of Colon Cancer 18,19
Stage of disease is the most important determinant of prognosis in colorectal cancer. Once a cancer diagnosis is made, the cancer will be described by a stage and grade. Colorectal cancer staging describes the size of the tumor, how far it has grown into the colon or rectum wall, and whether the cancer has spread to lymph nodes or other places in the body past the place where it began to grow. The

Treatment 20-25
The treatment plan for colon cancer is generally based on the state of the disease, location of the disease and the functional status of the patient. There are several terms used to describe when the treatment is given, which are shown in table 5. The main treatment for cancer Treatments given to qualify for surgery Treatments given before the primary treatment Treatments that follows primary treatment The first treatment given The treatment given after the first treatment fails Treatment for colorectal cancer includes one or more of the following:  Surgery: Surgery is often the main treatment for the earlier stages of colorectal cancers.  Open colectomy: A colectomy (sometimes called a hemicolectomy, partial colectomy, or segmental resection) removes part of the colon, as well as nearby lymph nodes. The surgery is referred to as an open colectomy, if it is done through a single incision in the abdomen.  Laparoscopic assisted colectomy: This newer approach to removing part of the colon and nearby lymph nodes may be an option for some earlier stage cancers. Instead of making one long incision in the abdomen, the surgeon makes several smaller incisions. One of the instruments, called a laparoscope, has a small video camera on the end, is inserted through these incisions and it allows the surgeon to see inside the abdomen. Once the diseased part of the colon has been freed, one of the incisions is made larger to allow for its removal.  Polypectomy and local excision: For a polypectomy, the cancer is removed as part of the polyp, which is cut at its stalk. Local excision removes superficial cancers and a small amount of nearby tissue.  Local transanal resection: Local transanal resection is done with instruments inserted through the anus, without making an opening in the skin of the abdomen. This operation cuts through all layers of the rectum to remove cancer as well as some surrounding normal rectal tissue, and then closes the hole in the rectal wall. This procedure can be used to remove stage I rectal cancers.  Endoscopic treatments include hot biopsy, snare polypectomy, endoscopic submucosal resection (EMR), piecemeal EMR (EPMR) and endoscopic submucosal dissection (ESD). Hot biopsy is performed cautiously in the cecum using a low amplitude and brief duration of current because the colonic wall is the thinnest and most vulnerable to transmural necrosis in this region. Snare polypectomy is chiefly applied to pedunculated and sessile lesions of 0.5 to 2.0 cm in diameter. Sessile polyps between 2 and 3 cm in diameter may be removed by snare polypectomy after creating a pseudopedicle by injecting normal saline or other solution into the polyp base. Sessile polyps more than 3 cm in diameter may be unamenable to conventional snare polypectomy but can be removed by sequential piecemeal polypectomy over several colonoscopies  Transanal endoscopic microsurgery (TEM)  Low anterior resection  Proctectomy with colo-anal anastomosis  Abdominoperineal resection  Radiofrequency ablation  Ethanol ablation  Cryosurgery  Lymph node surgery: The surgery to remove lymph nodes is called lymphecomy. A lymphectomy is often done during a colectomy.  Radiation therapy: During radiation therapy, high doses of special type of energy (radiation) are aimed at the area where the cancer is growing and destroy cells, making it impossible for them to grow and divide. There are two types of radiation therapy that can be used:  External beam radiation therapy, where beam of radiation is directed at the tumor.  Brachytherapy, where radioactive material is placed inside the tumor, making it possible to treat the cancer in a focused manner.  Systemic therapy: This therapy uses drugs to treat the cancer cells that have spread through the body. Chemotherapy and targeted therapy are the systemic therapies for colon cancer. The systemic drugs used for colon cancer are shown in Table 6:  Chemotherapy is the use of anti-cancer medicines that are typically given by injection, or sometimes as pills, to destroy the cancer cells.  Targeted therapy: It is a type of medication that blocks the growth of cancer cells by interfering with the specific targeted molecules needed for carcinogenesis and tumor growth rather than simply interfering with all rapidly dividing cells.  Complementary and alternate medicine (CAM) such as vitamins, herbs, or stress reduction may be suggested as a treatment for cancer or to make feel better. CAM is a group of treatments that aren't usually given by doctors. Complementary medicines are treatments given along with usual medical treatments. Examples include acupuncture for pain management or yoga for relaxation. Alternative medicine is used in place of usual medicine.

Newer Treatment Options for Colorectal Cancer 26-30
 Immunotherapy: It is a type of treatment that uses the body's own immune system to fight cancer. The therapy mainly consists of stimulating the immune system to help it do its job effectively. The various types of immunotherapy include:  Biological response modifiers: It includes cytokines such as interferons and interleukins. These substances do not directly destroy the cancer, but they are able to trigger the immune system to indirectly affect tumors.  Colony-stimulating factors: These are substances that stimulate the production of bone marrow cells, which include both red and white blood cells and platelets. the T-cells. c) Antigen vaccines: The antigens are usually proteins or pieces of protein called peptides. These vaccines boost the immune system by using only one antigen, rather than whole tumor cells.  Monoclonal antibodies: These are substances produced in the lab that can locate and bind to cancer cells wherever they are in the body. These antibodies can be used to see where the tumor is in the body (detection of cancer), or as therapy to deliver drugs, toxins, or radioactive material directly to a tumor. Eg: cetuximab, bevacizumab, panitumumab.  Targeted therapy:  Anti-angiogenic agents: It is a promising approach for colon cancer therapy, as it is less toxic and has a lower risk of drug resistance. Cancer cells depend on angiogenesis to obtain nutrients and oxygen for their outgrowth and metastasis. Some anti-angiogenic agents currently approved by the FDA include bevacizumab (targets VEGF-A), tyrosine kinase inhibitors sunitinib (targets VEGF and PDGF receptors) and sorafenib (targets Raf, VEGF and PDGF receptors). In this approach, tissue inhibitors of metalloproteinases (TIMPs), integrin antagonist, monoclonal antibodies, endogenous angiogenesis inhibitors (eg: Endostatin, Vasohibin-an endothelium derived negative feedback regulator of angiogenesis) are also used.  Agents targeted at EGFR: a) Anti-EGFR antibodies: Eg. Cetuximab and panitumumab. Cetuximab is a recombinant human/ chimeric IgG 1 monoclonal antibody which binds to the extracellular domain of both normal and tumor cells and competitively inhibits the binding of epidermal growth factor and other ligands. It also mediates antibody dependent cell cytotoxicity. Cetuximab was approved by the FDA for use in patients whose disease is refractory to irinotecan with tumors expressing EGFR. Panitumumab is a human IgG2 monoclonal antibody that targets EGFR. The FDA approved panitumumab for the treatment of patients with CRC that has metastasized following standard chemotherapy. b) EGFR tyrosine kinase inhibitors: Gefitinib and erlotinib prevent ATP binding both selectively and reversibly, and autophosphorylation of EGFR tyrosine kinase.  Apoptosis induction: Apoptosis, or programmed cell death, plays an important role in maintaining tissue homeostasis and permitting the controlled deletion of potentially harmful cells within the adult organism.

Clinical Trials 32
Ongoing researches in colorectal cancer have lead to advances in treatment and new ways to manage side effects related to treatment. Always in search of more effective treatments, many clinical trials are done to test different combinations of drugs that are already used separately to treat colorectal cancer.

Conclusion
Colon cancer is that it usually starts from a pre-cancerous growth called a polyp and grows slowly, usually in a predictable way. It therefore can be preventable with screening, and when diagnosed at an early stage, it is often curable. Regular colorectal cancer screening or testing is one of the most powerful weapons for preventing colorectal cancer. Screening is the process of looking for cancer in people who have no symptoms of the disease. Screening needs to be applied within the framework of a program that includes: primary prevention (diet and lifestyle), timely diagnostic work up with colonoscopy in those screened positive, and timely treatment (polypectomy, surgery).