Gramps

Colon Cancer Irwin was 75 when he was diagnosed with colon cancer. Irwin grew up in Honolulu, Hawaii and moved to San Francisco, California when he was 25 with his wife Elaine. There they bought and opened a 76 gas station where he worked for 40 years until retirement. When his wife was 38, she was diagnosed with breast cancer, fought the disease, and won. This was Irwin’s first experience with cancer, and it was not until 34 years later that he had his own encounter with cancer. Many who knew Irwin thought of him as a meat and potatoes kind of guy, and throughout Irwin’s life, he greatly enjoyed barbequing steaks. His love of barbequing may have impacted his cancer’s development because of all the carcinogens in grilled foods. Carcinogens from burnt food greatly increase the risk of cancer because they act as mutagens. When meat is cooked at high temperatures, the amino acids and sugars form heterocyclic amines (HCAs), and when the fats of the meat are vaporized by the flames, the chemical released, polycyclic aromatic hydrocarbons (PACs), stick to the meat. Both HCAs and PACs have been found to damage DNA. [ ] Irwin was not a fan of eating a diverse diet, commonly excluding fruits and vegetables. Fruits and vegetables have been shown to induce apoptosis as well as protect cells from DNA damage from carcinogens. [ ] Irwin had very little physical activity due to his arthritis, but when he was able, he gardened and rode bicycles with his grandchildren. Physical activity is important in protecting against cancer development because it helps maintain metabolic balance. [ ] Throughout his life, he has sustained many injuries from doing construction at his house. One time, he fell off a ladder and broke a couple of his ribs. Another time, he drilled a bit through his finger. Furthermore, Irwin also suffered from type II diabetes that was most likely caused by his obesity and had a heart arrhythmia that doctors had previously fixed. Type II diabetes is caused by either a desensitization to insulin on cell membranes or a failure to release insulin in response to glucose. Either way, glucose is not being properly regulated. Studies have shown that hyperglycemia promotes the growth and development of cancer in colon cells. [ ] Also, by inhaling many of the harmful chemicals at the gas station may have further developed his cancer. Irwin’s first sign of colon cancer was when he found blood in his stool and he went to the doctor to figure out what was wrong. The doctor’s first test was a colonoscopy and the doctor noted some inflamed nodes in his intestines. The doctor proceeded to run more tests such as an MRI, CT scan, and a biopsy. They found he had stage IIB colon cancer where the tumor has grown into the wall of the intestine, but has not traveled to the lymph nodes and metastasized. [ ] Within a few months of being diagnosed with colon cancer, Irwin had multiple surgeries, but the doctors were not able to fully eradicate the cancer from his colon. The doctors then relied on chemotherapy and radiation to help eliminate the rest of his cancer. These treatments, however, were ultimately ineffective. The doctor informed Irwin that of the many types of cancer, colon cancer is the third most common and fatal type of cancer in both men and women. 8 percent of men and women who were diagnosed with cancer contracted colon cancer, and of those who died of cancer, 8 percent died of colon cancer. Irwin lived 7 years after his initial diagnosis of colon cancer, which had spread to his bladder before the doctor preformed surgery. The doctor removed his bladder, but the cancer had already metastasized through his lymph nodes. At the age of 82, Irwin eventually succumbed to cancer.[ ] Irwin’s family researched the disease to get a better understanding of it, and learned colon cancer has a deep biological cause that is extremely complicated. Many of the mechanisms that lead to colon cancer are heavily involved with genetics. The doctor informed Irwin that he suffered from Lynch syndrome, which is when the gene that repairs mismatched base-base mutations is inactive. When the gene is inherited it is also known as hereditary nonpolyposis colon cancer (HNPCC). Because Lynch syndrome is hereditary, the doctor recommended all of Irwin’s family members above the age of 45 have a yearly colonoscopy to have a proactive approach against possible colon cancer. Cancer prevention is extremely important especially if there is familial history. Methylation is another factor that plays a key role in colon cancer, and general cancer, development. Methylation is when the DNA of the cell is constricted and tightly bound so that portion of the genome will not be expressed. Methylation is key to how humans are able to have specific portions of their DNA expressed by methylating the parts of DNA that codes for all non-functional parts of the cell [ ]. Because of its importance within the genetic code, it is important to control methylation of DNA. Losing control of methylation in a cell will have severe consequences. When cells are hypermethylated, vital growth and tumor regulators maybe silenced in the process leading to abnormal growth of cells. When cells are hypomethylated, growth factors that are repressed when cells are done growing maybe turned on again when the previously methylated areas of the genome are activated again. There are three genes affected by mutations, //KRAS, NRAS,// and //BRAF,// which are results of uncontrolled epidermal growth factor receptor (EGFR). When EGFR is activated by a ligand, a small molecule that activates a particular pathway, the EGFR signals the cell to survive, migrate, and undergo angiogenesis and proliferation. All of these pathways are hallmarks of cancer with apoptosis, metastasis, angiogenesis, and proliferation. The doctors explained how cetuximab and panitumumab are EGFR-targeted antibodies that help treat colon cancer. They work by binding to the EGFR instead of the ligand, which will stop the activation of the //KRAS, NRAS,// and //BRAF// genes from keeping the cell from reaching apoptosis [ ]. Colon cancer develops slowly and over time. The normal epithelium will become a small adenoma, which is a result of mismatched repair mutation and methylation of the MLH1 gene, which is related to mismatch repair. The small adenoma will become a large adenoma when the //KRAS// and //BRAF// genes fail to turn off due to constant use of EGFR leading to further abnormal growth of the cell. The large adenoma will become cancerous when the //PIK3CA// and //PTEN// genes are activated. The cancer will eventually metastasize and be problematic throughout the entire body [ ]. Irwin’s doctor explained the importance of the 5-fluorouracil (5-FU) chemotherapy and how the drug works. Chemotherapy, particularly 5-FU, is important because it attacks the DNA, RNA, and inhibits a nucleotide synthetic enzyme called thymidylate synthase (TS). 5-FU breaks into three metabolites: fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP), and fluorouridine triphosphate (FUTP). FdUMP inhibits DNA synthesis, FdUTP leads to apotosis via DNA damage, and FUTP leads to apotosis via RNA damage [ ]. Although the 5-FU attacks all cells, the doctor explained that because cancer cells are growing faster than regular cells, and if doctors can kill the growing cancer faster than the regular cells, then the treatment is on the right path. The diagnosis initially shocked Irwin and his family, but the doctor explained the possible treatments for the stage IIB colon cancer. The doctor said there were several treatment courses. They quickly explained that stage I cancer was easily removable via surgery, but stage II was where it got tricky. Hopefully surgery would fully remove the tumor, but because of its shape, the tumor could not be fully removed. Because the edges of the cancer were not smooth, the doctors were unable to cleanly remove the tumor, and they had to rely on other methods to attempt to get rid of the cancer. [ ] The doctor then explained to Irwin that he needed to undergo chemotherapy to remove the remaining cancer. Unfortunately this was to slow, and the cancer eventually grew to stage IV and metastasized. After finding out the cancer had metastasized, the doctor gave Irwin some treatment options. The doctor told Irwin about: surgery, radiofrequency ablation, cryosurgery, chemotherapy, radiation therapy, targeted therapy, and clinical trials. [ ] The doctor told Irwin about the possibilities of surgery. The cancer grew too large for a local excision, which is just the doctor inserting a cutting instrument into the rectum and finding the localized tumor. The two remaining options were a resection of colon via anastomosis or colostomy. The difference, explained by the doctor, is an anastomosis is when a portion of the colon is removed, and the healthy ends of the colon are sewn together. Colostomies on the other hand, are where the doctor cannot sew the ends together and a hole in the stoma is made for waste to pass through. Radiofrequency ablation is when an electrode is inserted through either the rectum or a small slit in the abdomen and used to burn the cancer. Cryosurgery is the exact opposite as radiofrequency where doctors freeze the cancerous site. There are two types of chemotherapy, regional and systemic. Chemotherapy is a cocktail of drugs that kill cells, particularly cancer, and stop the growth. Regional chemotherapy is when the doctors are able to localize cancer and direct the drug to the specified area. This kind of chemotherapy would be used for a stage II cancer where the tumor is still contained in one area. Systemic chemotherapy is when the chemo drugs are given to the whole system and most commonly used when cancer has metastasized to multiple organs. Radiation therapy is where high-energy rays are either focused externally or internally. External radiation therapy is when doctors use a machine outside the body to send radiation to the targeted tumor. External radiation is used for later stages of cancer, as it will radiate more area. Internal radiation is when radioactive substances are inside objects are surgically placed by the cancer directly radiating that region. Internal radiation is used for more localized tumors. Targeted therapy is when doctors use particular drugs to attack cancer cells and not normal cells like chemotherapy. The doctor explained the two types of targeted therapies for colon cancer are monoclonal antibodies and angiogenesis inhibitors. Monoclonal antibodies identify cancer cells and inhibit their growth and the ability to spread. Angiogenesis inhibitors are when cancerous blood vessels are inhibited. [ ] As it turns out, the colon was to be sewn together, and Irwin got an anastomosis. The tissue around the cancerous region of his colon was healthy enough to sew back together. After surgery, Irwin received a combination of regional chemotherapy and radiation in his colon. The doctor gave Irwin 5-FU (fluorouracil) chemotherapy, a common drug used to treat colorectal cancer. He would go one week of treatment, then rest for another week, and go through several intervals of this therapy. Irwin unfortunately suffered from some of the side effects of chemotherapy such as nausea, vomiting and diarrhea. [ ] These side effects occur because the chemo drugs not only kill cancer cells, but the normal cells in Irwin’s digestive tract, and because the doctors originally targeted Irwin’s colon, it makes sense that he was vomiting and having diarrhea. However, since the cancer had spread throughout Irwin’s body, all the doctor could do was give him chemo and radiation treatments to prolong his life a few months, and prescribe morphine for the pain and let Irwin live the last months of his life. The doctor’s treatment of the cancer was not the best possible course of treatment. Doctors should have used regional chemotherapy to target the colon cancer while it was still in its stage II phase. Once the cancer had metastasized, they could have used systemic chemotherapy to treat the cancer throughout Irwin’s body. Furthermore, the doctors should have used targeted therapies as well as the chemo and radiation. While in stage II, monoclonal antibodies would have been the preferred treatment because the antibodies will slow the growth of the colon cancer and help prevent the cancer from spreading. Once the cancer had reached stage IV, angiogenesis inhibitors should have been used to limit the spread of cancer to further blood cells. The doctor should have initially used cetuximab and panitumumab to hopefully shrink the tumor immediately after the diagnosis and before surgery to prevent the cancer from growing any further, but they never took that action. However, they made the right choice to use 5-FU as the chemotherapy drug because it is most effective on colon and breast cancers [ ]. Irwin’s colon cancer eventually spread to his bladder, and after removing one of his cancerous bladders, the doctors had hoped they removed all the cancer. However, they must have missed some of the cancer during surgery, and the cancer had spread throughout his lymphatic system. From here, Irwin spent as much time with his family as possible, surviving one and a half years after the cancer had spread throughout his lymphatic system. Irwin is survived by his wife Elaine, his two children Laurie and Dean, and four grandchildren.

I love you Grandpa.