BackgroundColorectal cancer is the third most common cancer in both men and women in the United States. Risk factors include age, a diet rich in fat and cholesterol, inflammatory bowel disease (especially ulcerative colitis), and genetic predisposition, including hereditary polyposis and nonpolyposis syndromes.
If detected early, colorectal cancer is curable by surgery. Adjuvant chemotherapy can prolong survival in disease that has reached the lymph nodes. Both systemic and locoregional chemotherapy (eg, intrahepatic intraarterial chemotherapy for liver metastases) have a role in patients with metastatic colon cancer. Radiotherapy is used in cases of rectal cancer to reduce the risk of local recurrence.
Long-term survival correlates with stage of disease in colorectal cancer. Progress has been made in understanding the molecular basis of colorectal cancer predisposition and progression. Efforts are underway to develop better screening strategies, chemopreventive approaches, and novel therapies to improve patient survival rates and to minimize toxicity. Despite all efforts, colorectal cancer remains the third leading cause of death from cancer in the United States.
Recent advances have included the development of orally available forms of 5-fluorouracil (5-FU) and the demonstration that anti-vascular endothelial growth factor (VEGF) therapy with bevacizumab prolongs survival in advanced colorectal cancer when combined with irinotecan, 5-FU, and leucovorin.
Pathophysiology
The vast majority of colorectal cancers are adenocarcinomas, which arise from preexisting adenomatous polyps that develop in the normal colonic mucosa. This adenoma-carcinoma sequence is a well-characterized clinical and histopathologic series of events with which discrete molecular genetic alterations have been associated.
Pioneering work by Bert Vogelstein and colleagues over the last 20 years has identified a number of critically important genetic alterations that contribute, through their multiplicity over many years, to the eventual development of colorectal cancer. The earliest event appears to involve the APC (adenomatous polyposis coli) gene, which is mutated in individuals affected by familial adenomatous polyposis (FAP). The protein encoded by the APC gene targets the degradation of beta-catenin, a protein component of a transcriptional complex that activates growth-promoting oncogenes, such as cyclin D1 or c-myc. APC mutations are very common in sporadic colorectal cancer, and beta-catenin mutations have also been identified.
DNA methylation changes are a relatively early event and have been detected at the polyp stage. Colorectal cancers and polyps have an imbalance in genomic DNA methylation, with global hypomethylation and regional hypermethylation. Hypomethylation can lead to oncogene activation, whereas hypermethylation can lead to silencing of tumor suppressor genes. ras gene mutations are observed commonly in larger polyps but not smaller polyps, suggesting a role for this oncogene in polyp growth.
Chromosome arm 18q deletions are a later event associated with cancer development. These deletions likely involve the targets DPC4 (a gene deleted in pancreatic cancer and involved in the transforming growth factor [TGF]-beta growth-inhibitory signaling pathway) and DCC (a gene frequently deleted in colon cancer). Chromosome arm 17p losses and tumor suppressor p53 mutations are common late events in colon cancer. Bcl2 overexpression leading to inhibition of cell death signaling has been observed as a relatively early event in colorectal cancer development. 18q deletions detected in Dukes stage B colon cancers have been associated with an increased risk of recurrence following surgery, and studies are in progress to determine whether patients with 18q deletions might benefit from more aggressive adjuvant chemotherapy.
Another predisposing condition is hereditary nonpolyposis colon cancer, in which affected individuals inherit a mutation in one of several genes involved in DNA mismatch repair, including MSH2, MLH1, and PMS2. ras gene mutations have been detected in the stool of patients with colorectal cancer and may in the future be useful in early diagnosis.
Although the use of nonsteroidal anti-inflammatory agents, such as sulindac, have been shown to affect the number of polyps, this has not translated to a clinical impact on cancer prevention.
FrequencyUnited States
The American Cancer Society estimates that about 104,950 new cases of colon cancer and 40,340 new cases of rectal cancer will be reported in 2005 in the United States. Combined, the 2 cancer types will cause about 56,290 deaths.
International
According to the World Health Organization's April 2003 report on global cancer rates more than 940,000 new cases of colorectal cancer and nearly 500,000 deaths are reported worldwide each year.
Mortality/MorbidityThe overall 5-year survival rate from colon cancer is approximately 60%, and nearly 60,000 people die of the disease each year in the United States. The 5-year survival rate is different for each stage (see
Staging); the staging classification for colon cancer can predict prognosis well. For Dukes stage A tumors involving only the mucosa, the 5-year survival rate exceeds 90%, whereas for metastatic colon cancer, the 5-year survival rate is about 5%. For Dukes stage B colon cancers, the 5-year survival rate is greater than 70% and can be greater than 80% if the tumor does not penetrate the muscularis mucosa. Once the tumor has spread to the lymph nodes (ie, Dukes stage C), the 5-year survival rate usually is less than 60%.
Race
Recent data demonstrate a decrease in incidence rates of colorectal carcinoma in whites since the mid 1980s, particularly for the distal colon and rectum. Proximal colon carcinoma rates in blacks are considerably higher than in whites and continue to increase, whereas rates in whites show signs of decline.
SexThe frequency of colon cancer is essentially the same among men and women.
Age
Age is a well-known risk factor for colon cancer, and risk begins to rise in people older than 40 years. Age is a risk factor because a number of rare genetic alterations are believed to occur within the somatic cells of the colonic epithelium over years, ultimately leading to the development of colon cancer in older individuals. Individuals affected by one of the well-known familial predispositions to colon cancer are much more likely to develop cancer at a young age. For example, individuals with familial adenomatous polyposis have a 100% chance of developing colon cancer unless their colon is removed surgically, usually when they are aged 20-30 years.
HistoryColon cancer often is found by screening and may be completely asymptomatic. Approximately 50% of patients present with abdominal pain, 35% with altered bowel habits, 30% with occult bleeding, and 15% with intestinal obstruction. Right-sided colon cancers tend to be larger and more likely to bleed, whereas left-sided tumors tend to be smaller and more likely to be obstructing. Obtain a family history of colon cancer, familial polyposis, or ulcerative colitis. Consider the possibility of cancer of the colon in patients with a fever of unknown origin and in patients with polymyositis.
Physical
The physical examination findings may be completely normal, especially in early stage colorectal cancer, or general or specific findings due to progression of the disease may be present. These may include weight loss, cachexia, abdominal discomfort or tenderness, liver mass, abdominal distention, ascites, rectal mass, rectal bleeding, or occult blood on rectal examination.
CausesA number of risk factors have been associated with colon cancer. Colonic polyps, which occur with increasing age, represent a risk for colon cancer development. A study considering the clinical evidence for the adenoma-carcinoma sequence recently concluded that adenomas probably are precursors of carcinomas, but the ultimate effect of removing polyps on reducing cancer incidence in the population remains unknown.
Genetics is a very important risk factor for development of colorectal cancer. Familial polyposis, in which patients inherit a mutant copy of the APC tumor suppressor gene, is rare but confers very high risk. Familial nonpolyposis colon cancer, which accounts for 1-5% of colon cancers, develops because of inherited mutations in DNA mismatch repair genes.
Alcohol consumption is a risk factor for gastrointestinal cancer, including colon cancer. Increasing age and a lower intake of total folate have been associated with mutations of the Ki-ras oncogene, which are found commonly in colorectal cancer. Diet, and in particular fat content of diet, has been associated with increased risk of colon cancer. Animal studies have found that dietary beef induces and dietary rye bran prevents formation of intestinal polyps. Several studies have suggested that red meat and processed meats, through the action of heme, predispose to colon cancer by enhancing formation of N-nitrosocompounds, which result in DNA damage. One study suggested that obesity, rather than fat intake per se, predisposed to colon cancers induced in animals by exposure to the carcinogen azoxymethane.
The evidence is weak that soy food or isoflavones in the diet protect a person from colon cancer. Exercise is believed to reduce the risk of colon cancer. The risk of colon cancer may be decreased among women who recently used postmenopausal hormone replacement therapy. Women who are postmenopausal and who have never used hormone replacement therapy have a higher risk of colon, but not rectal, cancer than do women who are premenopausal and of the same age, sociocultural class, and dietary habits. Apparently, no association exists between frequency of bowel movement or laxative use and risk of colon cancer. Some data associate calcium intake and risk of colon cancer. A statistically significant association exists between Helicobacter exposure and colonic polyps.
Tobacco smoking is associated with a higher risk of colon cancer, which appears to be mediated by induction of 5-lipoxygenase–associated angiogenic pathways.
Author: Wafik S El-Deiry, MD, PhD, Professor of Medicine, Department of Hematology/Oncology; Co-Program Leader, Radiation Biology Program, Abramson Comprehensive Cancer Center, University of Pennsylvania School of MedicineWafik S El-Deiry is a member of the following medical societies:
American Association for Cancer Research,
American Society for Clinical Investigation,
American Society of Clinical Oncology, and
American Society of Gene TherapyEditors: Philip Schulman, MD, Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center; Clinical Professor, Department of Medicine, New York University School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems; John S Macdonald, MD, Professor of Medicine, New York Medical College; Chief, Division of Medical Oncology, St Vincent's Hospital and Medical Center; Medical Director, Saint Vincent's Comprehensive Cancer Center
