Nguyen,+Tim

Colorectal cancer is the third leading cancer in the United States, with over 130,000 new cases, and second leading cause of cancer death, with over 50,000 deaths, in the last year1. About one in every 20 Americans will develop colorectal cancer at some point in their lives. Of these cases, roughly 65 percent will be diagnosed in the colon and 35 percent in the rectum. Once diagnosed with colorectal cancer, it can be easy to succumb to the fear of cancer and forget that cancer, like any other disease, can be defeated. With early detection and today’s treatments, colorectal cancer patients have among the highest five year survival rates of all cancer patients. In the following, we will shadow the life of a cancer patient named Doug Sheldon, as he is diagnosed, treated, and freed of colon cancer. -- At the time, Doug was a 54 year old, Caucasian male who had no known family history of cancer. He lived in Stockton, California where he worked as a crane operator in the Port of Stockton. Doug was once married with two children, but divorced at the age of 32. His wife divorced him because Doug was an avid smoker and heavy drinker, and refused to stop these habits for his two young children. Following the divorce, Doug began to smoke and binge drink even more. After his family moved out, he lived alone with his dog, Scooter, and spent the majority of his free time sitting on the couch watching movies. Doug first suspected something wrong when he began to experience frequent cramps in his lower abdomen which was often followed by constipation. Doug also noticed that when he finally was able to pass the stool, there was traces of blood. At first he thought it might have been something he ate, but when these symptoms failed to subside, Doug was afraid that his symptoms were a result of a more serious health issue. Doug made a visit to the doctor’s office and told the doctor what he was experiencing. To his dismay, the doctor told Doug that all the symptoms he can be a product of colon cancer2. -- The most common form of colon cancer is adenocarcinoma in which a tumor forms along the inner wall of the colon. These tumors begin as polyps—harmless growths from the mucus membrane—that can develop into cancer if left untreated3. Polyps mature into two forms of adenomas, tubular or villous. A tubular adenoma is a mushroom shaped polyp that protrudes from colon wall and has positive risk for becoming cancer. A villous adenoma is a flat polyp that grows within the colon wall and has an extremely high risk for developing into cancer. Tubular adenomas are much more common, making up about 70 percent of the polyps that are removed during cancer diagnosis and treatment, while villous adenomas only make up 15 percent4. Figure 1. Cancer progression from a benign polyp to a malignant tumor26.

Like many cancers, early detection of colon cancer has a major effect on five year survival rates. For patients whose cancers were diagnosed in stage I, the five year survival rate is 90 percent5. At this point the cancer is localized to one tumor and can be easily removed with surgery. At stage II and III, the five year survival rate of colon cancer is still relatively high at 70 percent. Cancers in stages II and III have spread to nearby lymph nodes, but have yet to affect other organs. The five year survival rate sees a large decrease to just 12 percent in stage IV patients where the tumor has metastasized to other organs such as the liver or lungs.

Symptoms of colon cancer vary between each patient and stage of the cancer. In early stages, symptoms may not show, but as the cancer progresses, symptoms become more severe. The most common symptoms include changes in bowel habits-constipation or diarrhea, blood in stool, abdominal or gas pains, fatigue, and weight loss6. Constipation is an indication of a large tubular adenoma that obstructs the pathway of waste material through the colon or rectum. Similarly, diarrhea is a result of cancerous polyps which reduce the intestine’s ability to absorb water from digested food. Bleeding occurs when tubular adenomas are partially torn while stool is passing through. When tumors bleed, the loss of red blood cells reduces the amount of oxygen transported to muscles resulting in fatigue. Furthermore, tumors that create blockages lead to abdominal pains when gas and feces are unable to be released and build up in the colon. Lastly, unexplained weight loss is a result of chemicals which are released from tumors and increase metabolism.

Risk factors for colon cancer include some lifestyle habits as well as some bowel disorders. Diets that are high in red meats and low in fruits and vegetables increase the risk of colon cancer. In an English study, researchers found that people who ate mostly meats had high amounts of N-nitroso compounds, DNA damaging chemicals that can lead to cancerous mutations6. Another study showed an increased amount of alcohol consumption led to adenocarcinoma in the colon7. Moreover, long-term smoking increases the risk of colon cancer because the carcinogenic compounds found in cigarette smoke are exposed to the colon and induce DNA damage8. Obesity or lack of exercise is another risk factor for colon cancer in that insulin resistance has been linked to increased instances of cancer9. Other risk factors, such as Crohn’s disease or colon ulcers, promote tumor growth by causing inflammation. Those with a personal history or hereditary disposition of developing adenomatous polyps are likely to develop colon cancer. Finally, old age is risk factor because abnormal growths spawning from the previously mentioned risk factors take several years to develop into cancer.

The colon cancer screening and diagnosis process begins with a colonoscopy10. During the procedure, the patient is sedated and a doctor inserts a tube equipped with a camera into colon through the rectal opening. The doctor then searches the entire colon for any polyps or tumors. If the doctor finds a growth, he or she can insert a wire loop into the tube, place the loop around the polyp, and send an electrical current through the wire to cut off the polyp. The cut off tissue is then sent to a lab where a biopsy is performed to determine if the polyp is cancerous. If the polyp is too large, a portion of it can be cut off in order to do the biopsy. Here, the pathologist can determine where the genetic variance is occurring in the tumor of the given patient. A CT scan is then performed on the patient to see if the cancer has spread to other lymph nodes or organs and is important in stage diagnosis. -- After introducing the possible risk of cancer, the doctor performed a colonoscopy on Doug. The doctor found a three centimeter tubular adenomatous polyp at the beginning of the colon and was able to remove a portion of it. The tissue was sent to a pathologist for a biopsy and then performed a CT scan on Doug. The CT scan revealed that the cancer had begun to spread to nearby lymph nodes, but had not yet metastasized. The doctor diagnosed Doug with stage IIIA adenocarcinoma of the colon. -- Colon cancer treatment has shown to be very effective and can even begin before diagnosis. During a colonoscopy, the doctor can remove any tumors or polyps which develop into cancer. If the cancer is at an early enough stage, this is often all it takes to cure the patient. The procedure can last anywhere from 30 minutes to a few hours depending on the size and number of tumors that need to be removed. One of the side effects of a colonoscopy is bloating or gas pains due to air that is pumped into the colon to allow room to operate11. Another side effect of colonoscopy is bleeding. Bleeding may occur for up to two days past the procedure, but is seldom serious enough require further treatment.

If the cancer has progressed to further stages, the tumor may be too large to remove during a colonoscopy. In these cases, a partial colectomy is required to remove the tumor12. In order to perform this surgery, called a radical bowel resection, doctors make a small incision in the patient's abdomen granting access to the colon. Carbon dioxide is then pumped into the opening to make room to insert a camera attached to a tube and other tools. The doctors then remove the tumor and nearby affected lymph nodes. Afterwards, the colon is resealed using surgical staples. Although the surgery is relatively safe, several complications can arise. Side effects can either be described as early, within 30 days of procedure, or late, between 30 days and six months following procedure. Of the early complications, a couple of the most common include abscess and infection. Later complications include pneumonia, bacteremia, and bowel obstruction. Despite these side effects, partial colectomies are still extremely effective in curing colon cancer.

For patients with multiple adenomatous polyps, things become increasingly complicated. In rare cases of the hereditary colon cancer, a mutated gene causes the growth of hundreds to thousands of polyps inside the colon wall13. All of these polyps can develop into cancer and therefore must all be removed in order to prevent tumor growth. The necessary surgery for these patients is a subtotal colectomy14. The surgery follows a very similar procedure to the partial colectomy; however, the entire colon is removed instead of just a portion. The side effects of this surgery are also very similar to those of a partial colectomy. A 2003 study on surgical treatment of colon cancer found that a subtotal colectomy resulted in a 2.3 year, one year, and 0.3 years gain in life expectancy over a partial colectomy in patients 27, 47, and 67 years old, respectively.

In later stages of colon cancer, chemotherapy is often recommended before and/or after surgical treatment to increase the effectiveness of surgery or prevent secondary tumor formation. The most common chemotherapy regimen is FOLFOX, which consists of oxaliplatin, leucovorin, and fluorouracil15. This treatment is administered with two day infusions that are repeated every two weeks for up to 12 cycles. On the first day, patients are given a two hour infusion of oxaliplatin and leucovorin. Immediately after, patients are given a 22 hour infusion of fluorouracil. On the second day, patients are given another two hour infusion of leucovorin and 22 hour infusion of fluorouracil. FOLFOX is effective at tumor suppression, but presents other adverse health effects in patients. The therapy itself can be painful for some people and create nerve damage. In addition, the drop in white blood cells, red blood cells, and platelets leave patients vulnerable to infection, fatigue, and bruising.

 Radiation therapy is another option of treatment for patients with colon cancer. The radiation therapy used most often for colon cancer patients is external-beam radiation therapy, where patients are given radiation to the targeted area for a few minutes16. This process is repeated five days a week for several weeks. For radiation therapy, it is important for doctors to use proper dosage and angles to fight the tumors. Several side effects of the radiation therapy for colon cancer include skin, rectal, and bladder irritation, nausea, and fatigue. Rectal and bladder irritation can become permanent in some patients and cause diarrhea or burning sensations during urination. Radiation therapy can also result in new forms of cancer by causing mutation in normal cells. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">--- In a return visit, the doctors performed a partial colectomy on Doug to remove the tumor and nearby lymph nodes. A partial colectomy was chosen over a subtotal colectomy because the tumor only affected one small region of the colon and the full removal of the colon was not necessary. The doctors also recommended for Doug to undergo the FOLFOX chemotherapy regimen to reduce risk of cancer recurrence. However, the doctors opted out of radiation therapy. They found that surgery and chemotherapy would be sufficient in treating and curing stage IIIA colon cancer and the additional risks of radiation therapy unnecessary. The biopsy of Doug’s cancerous tissue revealed that he had acquired a mutation in the adenomatous polyposis coli (APC) gene. This particular gene mutation is associated with a rare form of hereditary colon cancer; however, Doug’s mutant APC gene was a result of a spontaneous mutation. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">--- <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">In patients with colon cancer, tumor cells in the colon are able to thrive by sustaining proliferative signaling. In some cases, mutations in the Ras gene can lead to permanently activated Ras proteins, which promote cell growth17. In other cases, the APC gene is mutated18. The APC protein, coded by the APC gene, is a tumor suppressor which keeps cells from growing uncontrollably. The APC protein forms a complex with glycogen synthase kinase 3-beta that phosphorylates β-catenin19. This marks β-catenin for ubiquitination when it is then degraded by proteasomes. If β-catenin is not degraded, it is translocated to the nucleus of the cell and acts as a transcription factor for proliferative genes. Therefore, when the APC gene is mutated, the APC protein no longer functions properly and tumor cells can sustain proliferative signaling.

<span style="font-family: 'Times New Roman',serif; font-size: 10pt;">The FOLFOX treatment chosen for many colon cancers combats cell proliferation by inducing cell apoptosis and disrupting DNA and RNA synthesis. Oxaliplatin activates a cascade of events which create DNA damage ultimately leading to cell apoptosis20. Fluorouracil blocks the regular binding of nucleotides resulting in misincorporation of nucleotides in RNA and DNA synthesis21. Folinic acid enhances the effects of fluorouracil by stabilizing the inactive form of thymidylate synthase created by fluorouracil22. FOLFOX is widely used for colon cancer and can reduce the risk of cancer recurrence. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">Oxaliplatin, a platinum compound, can induce cell cycle arrest and apoptosis by inducing DNA damage such as DNA crosslinking23. DNA degradation increases the amount of p53 protein in the cell which can recognizes damage in the DNA sequence24. P53 will then halt the cell cycle and induce DNA repair or cell apoptosis. In the presence of oxaliplatin, cytochrome C is released into the cytoplasm where it activates apoptotic protease-activating factor one (APAF1) dimerization. This then leads to increased caspase 3 activity which cleaves inhibitor-CAD off of CAD. The CAD protein is now able to move from the cytoplasm to the nucleus of the cells where it leads to crosslinking of DNA.

<span style="font-family: 'Times New Roman',serif; font-size: 10pt;">The anti-cancer properties of fluorouracil (5-FU) lie in its ability to inhibit both DNA and RNA from their normal functions through thymidylate synthase inhibition25. 5-FU enters the cell using the same transport mechanisms as uracil. Once inside the cell, it is converted to fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP). In its normal function, thymidylate synthase catalyses the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) during DNA replication. In patients given 5-FU, FdUMP binds to the normal binding site of thymidylate synthase and blocks the binding of dUMP. An increased level of dUMP in the cell also leads to increased levels of dUTP. Both dUTP and FdUTP can be misincorporated in DNA and cause breaks in the DNA strand, ultimately leading to cell cycle arrest and cell death. FUTP is also misincorporated into RNA which caused disruptions in many of the RNA processes. The effects of 5-FU on cancer cells are limited when it is converted to dihydrofluorouracil by the protein, dihydropyrimidine dehydrogenase. However, oxaliplatin can inhibit dihydropyrimidine dehydrogenase and is therefore often administered along with fluorouracil. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">Figure 2. Metabolic pathway of fluorouracil (5-FU) within cancer cells leading to RNA and DNA dysfunction21.

<span style="font-family: 'Times New Roman',serif; font-size: 10pt;">Folinic acid is administered in chemotherapies to enhance the effects of drugs such as fluorouracil. It stabilizes the inactive form of thymidylate synthase therefore increasing the effects of FdUMP and misincorporation of FdUTP into DNA strands. Although folinic acid is known to reduce side effects of certain chemotherapeutic drugs, it has been found to increase the severity of the side effects of 5-FU. Because of this, it is not always advised to administer folinic acid alongside 5-FU in colorectal cancer patients. In Doug’s case, we have advised to do so because at this stage, the benefits of being able to increase the disruption cell proliferation outweigh the negatives of more severe side effects. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">-- Doug finished the twelve cycles of his chemotherapy regimen roughly five months after initial diagnosis. Subsequent testing showed that the treatment was able to remove all cancerous tumors. The doctors advised Doug to return every couple years for a routine colonoscopy in case of new adenomatous growth. In the meantime, Doug has quit smoking and reduced his alcohol consumption to just one drink a day. He also adopted a Mediterranean diet that is high in fruits, vegetables, and whole grains. Now, Doug spends his free time taking his dog on walks along the San Joaquin River bank. With these simple lifestyle changes, Doug hopes to prevent any future tumor development and live a long, healthy life. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">--

<span style="font-family: 'Times New Roman',serif; font-size: 10pt;"> Although colon cancer is not easy to overcome, current treatments are extremely effective in patients whose cancers are detected at an early stage. Early screening along with healthy eating and exercising habits are the strongest tools we have against colon cancer development and recurrence.

<span style="font-family: 'Times New Roman',serif; font-size: 10pt;">References <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">1 "What Are the Key Statistics about Colorectal Cancer?" American Cancer Society, 27 Feb. 2015. Web. 15 May 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">2 "Colorectal Cancer - Risk Factors and Prevention." //Cancer.Net//. American Society of Clinical Oncology, Sept. 2014. Web. 24 May 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">3 "Colon Polyps and Cancer." //Endoscopy// 36.1 (2004): 3-7. College of American Pathologists. Web. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">4 "Colorectal Cancer Diagnosis." //Colorectal Cancer Diagnosis//. Colon Cancer Alliance, n.d. Web. 08 June 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">5 "What Are the Survival Rates for Colorectal Cancer by Stage?" //Cancer.org//. American Cancer Society, 15 Oct. 2014. Web. 08 June 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">6 "Red Meat and Colon Cancer - Harvard Health." //Harvard Health//. Harvard Medical School, Mar. 2008. Web. 08 June 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">7 Bardou, M. "Excessive Alcohol Consumption Favours High Risk Polyp or Colorectal Cancer Occurrence among Patients with Adenomas: A Case Control Study." //Gut// 50.1 (2002): 38-42. //Excessive Alcohol Consumption Favours High Risk Polyp or Colorectal Cancer Occurrence among Patients with Adenomas: A Case Control Study//. BMJ Group, 1 May 2001. Web. 08 June 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">8 Chao, A. "Cigarette Smoking and Colorectal Cancer Mortality in the Cancer Prevention Study II." //Journal of the National Cancer Institute// 92.23 (2000): 1888-896. Web. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">9 Frezza, E. E. "Influence of Obesity on the Risk of Developing Colon Cancer." //Gut// 55.2 (2006): 285-91. Web. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">10 "How Is Colorectal Cancer Diagnosed?" //Cancer.org//. American Cancer Society, 15 Oct. 2014. Web. 08 June 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">11 "Colonoscopy." //Johns Hopkins Medicine//. The Johns Hopkins University, n.d. Web. 08 June 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">12 "Partial Colectomy Procedure, Recovery, Complications." //WebMD//. WebMD, 25 Oct. 2012. Web. 08 June 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">13 "Do We Know What Causes Colorectal Cancer?" //Cancer.org//. American Cancer Society, 15 Oct. 2014. Web. 08 June 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">14 W H De Vos Tot Nederveen Cappel. "Decision Analysis in the Surgical Treatment of Colorectal Cancer Due to a Mismatch Repair Gene Defect." //Gut// 52.12 (2003): 1752-755. Web. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">15 "FOLFOX." Cancer Research UK, n.d. Web. 08 June 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">16 "Radiation Therapy for Colorectal Cancer." //Cancer.org//. American Cancer Society, 15 Oct. 2015. Web. 08 June 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">17 Ciardiello, Fortunato, Sabine Tejpar, and Demetris Papamichael. "Implications of KRAS Mutation Status for the Treatment of Metastatic Colorectal Cancer." //Targ Oncol Targeted Oncology// 4.4 (2009): 311-22. Web. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">18 "APC Gene." //Genetics Home Reference//. U.S. National Library of Medicine, 1 June 2015. Web. 08 June 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">19 Navaratnam, R. M. "The Molecular Biology of Colorectal Cancer Development and the Associated Genetic Events." //The Annals of the Royal College of Surgeons of England// 81.5 (1999): 312-19. Web. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">20 Murata, Soichiro. "Enhanced Antitumor Activity of Cerulenin Combined with Oxaliplatin in Human Colon Cancer Cells." //International Journal of Oncology Int J Oncol// (2013): n. pag. Web. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">21 Tamatani, Tetsuya. "Antitumor Efficacy of Sequential Treatment with Docetaxel and 5-fluorouracil against Human Oral Cancer Cells."//International Journal of Oncology Int J Oncol// (2012): n. pag. Web. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">22 "Biochemical Rationale for the 5-fluorouracil Leucovorin Combination and Update of Clinical Experience." //Journal of Chemotherapy// 2.1 (1990): 5-11. Web. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">23 Alcindor, T., and N. Beauger. "Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy." //Current Oncology Curr. Oncol.// 18.1 (2011): n. pag. Web. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">24 "TP53 Gene." //Genetics Home Reference//. U.S. National Library of Medicine, 1 June 2015. Web. 08 June 2015. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">25 Longley, Daniel B., D. Paul Harkin, and Patrick G. Johnston. "5-FLUOROURACIL: MECHANISMS OF ACTION AND CLINICAL STRATEGIES." //Nature Reviews: Cancer// 3 (2003): 331-38. Web. <span style="font-family: 'Times New Roman',serif; font-size: 10pt;">26 "From Polyp to Cancer." //Johns Hopkins Medicine//. Johns Hopkins Colon Cancer Center, n.d. Web. 08 June 2015.