Colorectal Cancer Basics
Colorectal cancer (CRC) can be divided into two basic types, hereditary or sporadic.
Â Â Â Hereditary CRC are germlineterm (passed to offspring) mutations (a damaging change in DNA) with two well described forms. These hereditary mutations are thought to reduce the time it takes for the cells to turn cancerous. Mutations can be thought of in terms of â€œhitsâ€. One hit is one mutation. It is thought that a normal cell needs 3 to 6 hits to become cancerous. With an inherited mutation, there is one fewer hit needed to reach the correct number to transform the cell to cancer. One odd aspect to CRC is that there is a relatively well defined set of events for the progression from adenomaterm to carcinomaterm.
Â Â Â Familial adenomatous (FAP) refers to a mutation in the adenomatous polyposis coli (APC) gene. The gene is on the 5th chromosome arm q (long arm), 21st segment. It is said that mutations in exon 15 are the most severe forms. It is not known what the APC protein does but its role is related to cell adhesion and contact. This is a rare disease with <1% of all cases of CRC being FAP. Patients of FAP form numerous polyps (abnormal bulbous tumor growth) in the colon. It is the excess number of polyps that increases the relative risk for CRC since these polyps precede CRC.
Â Â Â Hereditary non-polyposis colorectal cancer (HNPCC) is also called Lynch syndrome. It is more common with 5% of CRC attributed to this form. HNPCC is also associated with an increased risk in other cancers including ovary, urinary tract and stomach. The genes associated with HNPCC are found on chromosome 2 on the short arm (p arm). hMSH2, hMLH1(3p), hPMS1 (2q), and hPMS2 (7p) are genes associated with HNPCC and are part of DNA mismatch repair (keeps DNA integrity and prevents mutations). It is thought that mutations in these genes lead to genetic instability, other mutations, and loss of apoptosis (a controlled cell death mechanism). It is also shown that Tumor growth factor B receptor (a tumor suppressor) is affected in HNPCC.
Sporadic CRC and Screening
Â Â Â Sporadic CRC is the most common with some factors known to influence the cancer occurrence involving diet, exercise, inflammatory bowel disease, and family history including genetics. Commonly, lesions (abnormal growths) can be found on the large-bowel that are the main source of sporadic CRC. Again, it is thought that there are multiple mutations needed for these lesions to transform in to cancer. Current screening for CRC includes tests to determine if blood is present in the stool. This is done in faecal occult blood tests (FOB) by different methodologies including Haemoccult test, haemporphyrin, and immunological assays. Even though FOB has a low sensitivity to detect CRC, it has been shown that it lowers mortality rates for those being screened because it helps catch CRC earlier. Sigmoidoscopy and Colonoscopy are other methods used to screen for CRC by visualizing the colon, with sigmoidoscopy being limited to the sigmoid of the colon (the last part) and colonoscopy visualizing the entire colon.
Â Â Â Colon cancers can be staged (categorized) according to the Modified Dukesâ€™ Staging or the Tumor, Node, Metastasistermterm (TNM) Staging where characteristics of the cancer are examined to conclude the next line of treatment for a patient. A pathologist is one who examines resected tumors and determines its staging. Molecular markers are also used in prognosis which further influences treatment options. Serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, and p53 serum levels are a few.
Â Â Â Two types of gastrointestinal cancers are distinguished in this topic, carcinoma of the rectum (the part of the colon that connects the anus) and colonic cancer. 50% of patients undergoing rectal adenocarcinomaterm surgery are cured, although there is a wide range of survival rates in studies. Recurrence of cancer correlates with survival, but this rate varies as well in different studies. Rectal surgery is more complex since it is near the anus. Keeping bowel functions normal is difficult with resection (removal) in the rectal region. It has been concluded from studies that there is large variability on survival of rectal cancer since this surgery is more complex, surgeon expertise varies, and the current optimal technique for resection is not established. It has been noted that rectal surgery should be done by experienced surgeons in specialist centers.
Â Â Â Colonic cancer surgery is not as technically challenging as rectal cancers so local recurrent rates of cancer are lower and survival is higher.
Â Â Â Â 80% of patients with recurrent cancer will have liver involvement. The liver is the sole metastaticterm site in 20-30% of these patients. Up to one third of patients with the liver as the sole metastatic site can be cured with resection. Surgical resection of liver metastases improves median survival of patients with hepatic metastatic disease from 4.5 months to 24 months. 25% of those patients with resection curable liver metastasis had a 5-year survival rate. One problem with liver resection is there must be at least 30% of the liver left after resection that is in good health, but liver metastasis is usually spread throughout the liver and resection is not an option.
Â Â Â Follow-up visits to the doctor for possible detection of recurrence of the cancer has not reached a consensus since it has been shown that those with vigorous follow-ups have failed to show an overall survival increase from more frequent follow-ups.
Â Â Â Non-resectable CRC is given a variety of chemotherapy depending on staging and prognosis. Chemotherapy is a treatment of a drug(s) that is toxic to all cells and does not distinguish cancerous cells from normal cells. The key to chemotherapy is exploiting the differences in cancer cells versus normal cells in order to optimize the killing effect on cancer cells and minimize the damage to normal cells. These differences include cancerous cells overexpressing certain proteins, uncontrolled growth, and increased need for a blood supply.
Â Â Â 5-fluorouraciltermtermtermterm (5-FUterm) is a halogenated form of uracil that is a prodrug which must be changed within the cell to active metabolites (processed molecules). 5-FU active metabolites act by inhibiting thymidylate synthase and this stops thymidine creation. The stopping of thymidine creation leads to a stopping of DNA and RNA synthesis. 5-FU has been a main treatment for CRC for the past 40 years. As a single agent, the response rate of 5-FU is 11% with main toxicities being nausea, vomiting, diarrhea, mucositisterm, myelosuppression, and sometimes cardiac and neurologic effects. To augment the efficacy (amount of effect) folinic acid (FAterm, can be given as leucovorintermterm) is given as this increases the degree of thymidylate synthase inhibition. Oral fluoropyrimidines are sources of 5-FU that can be taken orally and are more cost-efficient. Xelodaterm (capecitabinetermterm) is a prodrug form of 5-FU that is sometimes used as well.
Â Â Â Irinotecantermterm, a topoisomerase 1 inhibitor which causes apoptosis, is used to treat patients who have progressed on 5-FU. Median survival was improved from 10.8 months with irinotecan versus 8.5 months on infusional 5-FU.
Oxaliplatintermterm is another drug used, which damages DNA resulting in cellular apoptosis.
Â Â Â After surgery, 20% of patients with CRC relapse with cancer confined to the liver. Tumors in the liver with a size of 1-3mm are almost solely supported by the hepatic artery where normal liver cells derive their blood supply from the portal vein. This difference in blood supply allows hepatic arterial infusion of 5-FU to concentrate the drug and give a better response rate of 41% versus 14% in systemic therapy in CRC from 6 randomized trials.
Â Â Â Adjuvant therapy is extra treatment (chemo, radiation, etc.) given to patients after surgery to prevent recurrence of a cancer. In colonic tumors, the recurrence (sometimes termed relapse) is usually at distant sites from the colon. In CRC, approximately half of the 80% of patients who undergo curative resection relapse. These sites can be in the liver, lungs or bones so the current guidelines suggests systemic (the entire body) chemotherapy for colon adjuvant therapy. In Dukesâ€™ C CRC, patients receiving 5-FU/levamisoletermterm had a 41% less recurrence risk after surgery compared to those receiving no adjuvant chemotherapy.
Â Â Â Rectal tumors are a different guideline for adjuvant therapy, since 50% of recurrent tumors occur in the pelvis. The adjuvant therapy is local radiotherapy for rectal tumors. One question has been raised as whether to have pre- or postoperative radiotherapy. In an analysis of 22 randomized controlled trials, there was no gain in overall survival of receiving adjuvant radiotherapy, but the yearly risk of recurrence in those receiving preoperative treatment was 46% lower than no treatment. The recurrence rate was 37% lower in postoperative treatment than in no treatment.
Targeting Invasion, Metastasis, and Angiogenesis
Â Â Â The step limiting tumor progression is believed to be the ability of the tumor to grow blood vessels and increase its blood supply. There are a few drugs approved that target this process known as angiogenesis. Avastinterm (bevacizumabtermterm) is an antibodyterm that binds and inhibits Vascular Endothelial Growth Factor (VEGFterm). VEGF plays a role in angiogenesis and blood vessel formation.
Â Â Â Other steps to tumor progression include invasion and metastasis. Invasion is the process where the tumor begins to invade the surrounding tissue, breaking through certain membrane barriers that normal cells do not cross. Metastasis is the spreading of cancer from the primary or original tumor site to distant sites. Epidermal growth factor receptor (EGRF) is a protein that binds another protein called Epidermal growth factor (EGF). This binding turns on the receptor which results in cell proliferation and growth. Erbituxterm (cetuximabtermterm) is a selective monoclonal antibody that binds to EGRF to stop its actions of proliferation. Vectibixterm (panitumumabtermterm) is another antibody that bind to EGRF to inhibit its action.
Â Â Â Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) is a class of drugs that has pain-relief and anti-inflammation properties but is not of the steroid molecular structure. Aspirin, Ibuprofen, Naproxen, and Celecoxib are a few. The main effect of NSAIDs is to block the COX1 and COX2 enzymes that are responsible for making various molecules that signal the body to produce the inflammation response. A medium size clinical trial has shown that taking a daily aspirin (81mg) can substantially reduce the occurrence of advanced colorectal adenomas as well as a less but still significant reduction in non-advanced adenomas. (See article on Aspirin preventing Colorectal Cancer in the Forums)
Current National Comprehensive Cancer Network (NCCN) guidelines for Advanced or
Metastatic Colon or Rectal Cancer include:
Â Â Â First-line therapy of FOLFOXterm and Avastin or FOLFIRIterm and Avastin or IFLterm and Avastin or 5-FU/FA and Avastin or CAPOXtermtermterm and Avastin. For those patients who cannot tolerate the first line therapy mentioned above since it is intensive, they are given only Xeloda or Bolus 5-FU and FA or Infusional 5-FU and FA and Avastin or Protracted (a long-term intravenous device) 5-FU and FA.
Â Â Â Second-line therapy is FOLFIRI or FOLFOX or Camptosarterm (irinotecan) depending on first-line treatment.
FOLFIRI is a regimen that consists of irinotecan, folinic acid, and 5-fluorouracil.
FOLFOX is a regimen that consists of 5-FU, FA, and oxaliplatin.
This in formation was compiled from a review and other research articles. This is the abstract for the review about colon cancer treatments and causes. These are the other abstract links about colon cancer treatments and colorectal cancer basics.
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