Colorectal Cancer
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The incidence and mortality rates of colorectal cancer in both women and men have declined modestly or remained the same over the past decade. It is estimated that 74,700 women in the United States will be diagnosed with cancer of the colon or rectum in 2003 and an estimated 28,800 women will die of the disease by the end of the year, making colorectal cancer the third leading cause of cancer death among women in the United States. Native Alaskan women have the highest incidence and mortality rates due to colorectal cancer, followed by African American women, while Native Americans of New Mexico have the lowest rates. It is estimated that deaths due to colorectal cancer could be reduced as much as 50 percent if current screening techniques were implemented as recommended.
In April 2000, NCI released the Report of the Colorectal Cancer Progress Review Group. The national agenda identified an expansion of the current fundamentals through cooperation, collaboration, and new technologies as vital to advancement. NCI will be preparing and issuing a progress report on the implementation of the PRG's recommendations in 2004.
Biology
There is evidence that the addition of methyl groups to stretches of DNA where the C and G nucleotide pairing is repeated can lead to inactivation of genes involved in DNA repair and tumor initiation and progression. Additional research has discovered a connection between gene methylation and MSI, which may elucidate pathways for colorectal cancer development.
Risk Factors
A number of studies are currently investigating risk factors associated with colorectal cancer, including the role of IGF-1 and its binding proteins; insulin; diet; nutrient levels, such as folate, vitamin D, and antioxidants; postmenopausal hormones; smoking behaviors; BMI, physical activity, and energy fibers.
Obesity. Reports have shown that men with a high BMI are at increased risk for colon cancer. The relationship between BMI and colon cancer in women is more complex. Obesity is associated with increased risk of colon cancer in premenopausal women, but not in postmenopausal women. Risk may be modified by high levels of physical activity and is opposite to the relationship found in obesity and breast cancer where post-menopausal obesity increases risk.
Diet and Exercise. The roles of diet, energy balance, and physical activity in the etiology of colorectal cancer remain unclear. In animal studies, both saturated and polyunsaturated fatty acids from vegetable sources increased cancer risk, while diets lower in calories and high in dietary fiber, fruits, and vegetables reduce risk. The most consistent epidemiological findings for lowering risk are maintenance of a healthy body weight, exercise, and vegetable consumption. Increased colon cancer risks are seen in those with low intakes of folate, calcium, and vitamin D. Investigators in the recently completed Polyp Prevention Trial found no evidence after 4 years of follow up, that adopting a low-fat, high-fiber, fruit and vegetable-enriched eating plan reduced the recurrence of colorectal polyps, frequently a precursor of colorectal cancer. Continued follow-up of these patients may lead to further understanding of the long-term impact of diet on neoplasia. Alcohol consumption and a sedentary lifestyle have been associated in some, but not all, studies with an increased risk of colorectal cancer.
Polyp Biomarkers Study. In collaboration with the Veterans Administration (VA), NCI is establishing a biological specimen bank within an ongoing VA Cooperative Study, to examine characteristics of and risk factors for the presence of large and small polyps.
Colon Cancer Family Registries (CFRs). NCI currently supports six primary registries of familial colon cancer located throughout the world. These registries, established in 1997, assemble and maintain comprehensive lists of families with histories of colon cancer, including those resulting from familial adenomatous polyposis (FAP) syndromes and HNPCC. The registries bank blood samples and tumor biopsies for research purposes and include information on race and ethnicity, diet, and lifestyle information.
CGN, SEER, Colon CFRS. Eight hundred pairs of siblings or close relatives, where one individual has been diagnosed with colon cancer, are being recruited to identify genetic loci significant to the disease. The investigations will be conducted in individuals where there is no known HNPCC or FAP in hope of identifying cancer susceptibility regions.
Early Detection, Diagnosis, and Prognosis
Cancer-Screening Practices. New efforts are under way to increase awareness of screening benefits and treatment for colon cancer, including the CDC led, broad based educational campaign AScreen for Life.@ NCI has launched a study to understand how screening for colorectal cancer is being conducted in the United States and to help identify barriers to screening and appropriate follow up. Investigators from NCI, CDC, and HCFA are collaborating on a study designed to obtain nationally representative data on the physician and health system factors that may affect the use of screening and diagnostic follow up related to early detection of colorectal cancer in community practice. NCI also has a formal working relationship with the CDC on colorectal cancer-screening awareness programs.
Disparity issues for colorectal cancer exist, in part, because of low screening rates among low-income and minority populations. NCI is funding numerous studies related to increasing detection and diagnosis in racial and ethnic minorities and in those historically underscreened by making health communications culturally friendly and studying community-based primary care for future intervention approaches.
Noninvasive diagnosis, detection, and screening methods for colorectal cancer are being developed and tested. A team of NCI supported investigators have been testing for tumor-associated alterations in cancer cells shed in stool samples. Studies are under way to determine the specificity of these markers in symptomless patients.
PLCO Trial. Flexible sigmoidoscopy for colorectal cancer screening and follow-up will continue for 14 years following enrollment in PLCO. The study results will help to determine whether screening tests will reduce the number of deaths from colorectal, lung, prostate, and ovarian cancers. An etiologic component of the trial will collect biospecimens from a subset of participants to identify risk factors for colorectal adenoma and cancers.
Prognostic Indicators. Current prognostic indicator assessment relies on diagnostic pathology methods. Recent research on molecular markers has identified allelic imbalance, when chromosome pairs are different from one another, as a potential prognostic marker. Digital single nucleotide polymorphism analysis, a technology developed in SPOREs, has been able to accurately and reliably identify allelic imbalance in the two colorectal cancer relevant chromosomes, 8 and 18. This technology has shown that 42 percent of patients with allelic imbalance in both chromosomes had recurrence within 5 years while 26 percent of patients with allelic imbalance in one chromosome had recurrence within 5 years. Gene expression profiles studies in the Director's Challenge program are under way to determine profiles that discern those cancers that will recur after surgery, when metastasis will occur, and response to chemotherapy. Results so far indicate that the expression of gene clusters predict cancer cell behavior.
Prevention
NSAIDs. Nonsteroidal anti-inflammatory drugs block the COX-1 enzyme, required for healthy mucosal lining, and the COX-2 enzyme, which is produced in response to inflammation and precancerous tissue, such as polyps. Celecoxib (Celebrex), a selective COX-2 inhibitor, has been approved by the FDA for the treatment of osteoarthritis and adult rheumatoid arthritis. NSAID studies noted lower incidences of colorectal polyps, colorectal cancer, and death by colorectal cancer, which spurred further investigation and sponsorship of celecoxib studies by NCI. Ongoing clinical trials are investigating efficacy of celecoxib in reducing polyp occurrence, as well as its effect on cellular and molecular biomarkers in rectal mucosa. Other studies are in progress to identify biological markers for cancer progression for noncancerous polyps. NCI studies have found that in persons with surgically removed precancerous polyps, a baby aspirin (80 mg of aspirin) can reduce the risk of recurrence by 19 percent, and by 40 percent in persons with advanced adenomas. Larger doses did not show significant changes in either polyps or advanced adenomas.
Diet. NCI is supporting studies in women of Shanghai, looking at potential protective effects of low fat diet against colorectal cancer. Investigators using data from the Nurses= Health Study, the Health Professional Follow-up Study, and the Physician's Health Study have found strong evidence that consuming about 700 mg of calcium per day can reduce the risk of developing colon cancer in both men and women. Other results have shown that multivitamins with folate, diets rich in both folate and methionine, and alcohol consumption lower than moderate to heavy, may decrease colon cancer risk in women with family histories of the disease.
Treatment
FOLFOX4. Oxaliplatin is an investigational drug, used in conjunction with two routine cancer drugs in an experimental regimen, FOLFOX4. In a large, randomized clinical trial, patients on FOLFOX4 showed significant improvement outcomes, including longer life span, longer time to tumor progression, better response rate and fewer severe side effects.
Gleevec. Originally approved in May 2001 for the treatment of chronic myelogenous leukemia, NCI has launched clinical trials for the safety and efficacy of this monoclonal antibody for the treatment of gastrointestinal stromal tumors (GIST) since researchers found evidence of its success in treating this rare form of cancer. Results showed dramatic reduction of tumor size in 53 percent of patients and decreased growth rates in another 28 percent of patients. Despite development of drug resistance, 88 percent of patients were living 1 year after treatment initiation.
Quality of Life
Laparoscopic surgery for colon cancer resulted in slightly shorter hospital stays and less postoperative pain medication while in the hospital compared to standard surgery patients. However, quality of life measures and symptom management within the first 2 months after surgery are similar for both procedures. These studies were conducted in 428 men and women with colon cancer already enrolled in the Clinical Outcomes of Surgical Therapy trial, which is being conducted in 37 centers in the United States and Canada.
