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ArcMesa Educators
A Subsidiary of Arc Communications Inc.
Ralph M Myerson is a board-certified internist with over 50 years experience in patient care, teaching, and clinical research. He is a graduateof Tufts College School of Medicine and received his post-graduate trainingat the Boston City Hospital. Following three years of duty as an ArmyMedical Officer in North Africa and Italy during World War II, he joined theVeterans Administration, serving at the Wilmington and Philadelphia VAHospitals as Chief of Medicine and Chief of Staff. He served as GroupDirector and consultant in gastroenterology at Smith, Kline & FrenchLaboratories and, during his tenure there from 1975 to 1985, wasinstrumental in the post-marketing medical aspects of Tagamet®.
During his professional career, Dr Myerson has been very active in medical writing and has authored over 150 publications, including eight textbooks and numeroustextbook chapters. Since 1985 he has confined most of his activities to medical writing, serving as aconsultant to many pharmaceutical companies. He has been active as a contributor to lay periodicalsand in the dissemination of educational material to lay audiences.
Dr Myerson is a member of Phi Beta Kappa, Alpha Omega Alpha, and numerous medical and civic organizations. He has held the faculty position of Professor or Clinical Professor of Medicine at the MedicalCollege of Pennsylvania (now part of the Allegheny University Health Sciences Center) since 1957, and wasformerly Adjunct Professor of Medicine at the University of Pennsylvania School of Medicine.
The objectives of this course are to acquaint the participant with the following: The demography and epidemiology of colorectal cancer The risk factors operating in the pathogenesis of colorectal cancer a. The role of geneticsb. The polypoid syndromes predisposing to colorectal cancerc. The risk factors and protection afforded by diet, micronutrients, antioxidants and other ingestants, including NSAIDs, cox-2 inhibitors The influence of lifestyle on the pathogenesis of colorectal cancer a. physical activity and body massb. reproduction and exogenous hormone usec. smoking and alcohol Colorectal cancer screening and surveillance, e.g., guidelines for patient selection andtechniques employed.
The patient with advanced colorectal cancer 2000 – ArcMesa Educators/Ralph M. Myerson or any part thereof, may not be duplicated or reproduced without the permission of the author.
By reviewing the course content and completing the post test at the end of this continuing medical educationactivity, you are entitled to receive two credit hours if you achieve a score of 70% or greater. Estimated time tocomplete this activity is two hours.
ArcMesa Educators is accredited by the Accreditation Council for Continuing Medical Education to sponsorcontinuing medical education for physicians. ArcMesa designates this activity for two (2) credits in Category I towards the AMA Physician’s Recognition Award.
Each physician should only claim those hours of credit that he/she actually spent in the educational activity.
Authors are expected to disclose any real or apparent conflict(s) of interest regarding the content or subject matterof this activity. Ralph Myerson has indicated he has nothing to disclose relative to this activity. Medium used: Home Study Booklet
COURSE INSTRUCTIONS
FOR INTERNET AND HOME STUDY PARTICIPANTS! 1. Read the course material carefully. Internet participants may study online or print a copy of the course for off-line study. Start when you are fresh and take your time.
2. This course has an "open book" exam; review the text at any time as a learning aid or as a check on your responses prior to completing the exam.
3. Be sure to answer each exam question; blanks are counted as incorrect answers. A minimum
score of 70% is required for successful completion of this course.
4. Following the exam is a brief "course evaluation form" that we encourage you to complete. We value your evaluation responses and suggestions so that we can upgrade our procedures andcourse materials to serve you even better in the future.
5. The processing fee for this course entitles only one person to receive certification of completion. All course completions and certifications will be on file and maintained byArcMesa for six years.
6. After successful completion of the course exam, Internet users can return to their "Member History" page and print their own Certificate of Completion. Home study exams are
processed the day they are received by ArcMesa and certificates are posted for return by 1st
Class mail the next day.
7. If you fail the exam you may retest for $10.00 by calling ArcMesa and requesting another examination and/or home study booklet for re-testing. Note: Re-testing on the Internet will
incur the full course charge again!
If you have any questions about your examination or your Certificate of Completion, please call
ArcMesa at: 1-800-597-6372
Your Certificate of Completion will reflect the following data: Date of completion, name, profession/occupation, license number (if provided), course title,CE/CME hours awarded, provider name and approval number (if applicable). Home studycertificates will show the exam score and questions missed; Internet users receive an online gradereport.
Thank you for choosing ArcMesa Educators!
Cancer of the colon and rectum is second only to lung cancer as the leading cause of cancer-related deaths in this country.1 Approximately 131,000 new cases were diagnosed in the US in 1997 and approximately 55,000 patients died of the disease.1 The average lifetime risk is about 6%, with an almost equal occurrence in men and women, and 93% of the cases occur after the age of 50. Each victim who dies loses an average of 13 years of life. The 5-year survival is 50% to 55%, of whom 92% have localized disease and 7% have metastatic disease. Mortality is even higher in African-American men and women who have a 50% greater probability of dying from colon cancer than do white men There are large differences in the incidence of colorectal carcinoma between the developed countries of the Western World and Asia, South America and Africa. The evidence is that colorectal cancer is highly sensitive to changes in the environment. Among immigrants and their descendants, incidence rates rapidly reach those of the host country, sometimes within the migrating generation. For example, Japanese immigrants to Hawaii who have a low native rate of colorectal cancer, have acquired the highest rates of colorectal cancer in the world. Similar changes have been noticed among Israeli Jews who migrated from low-risk areas such as Yemen or North Africa.1,2 This type of data lends strong support to the role of diet as an important risk factor in colorectal cancer.3 There are, however, other accepted and well-recognized risk factors such as a family history of colorectal cancer, hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, and ulcerative colitis. Table 1 lists the incidence of colorectal cancer by risk category.
Table 1: Incidence of Colorectal Cancer by Risk Category5
Average risk (sporadic, no identifiable risk factor). 75% Family history of colorectal cancer.15 to 20% Hereditary nonpolyposis colorectal cancer.(HNPCC).3 to 8% As indicated in Table 1, most persons who develop colorectal cancer have no identifiable risk factors. Persons considered to be at "average" risk for colorectal cancer do not fit any of the higher risk categories, having no personal history of colorectal cancer or adenomatous polyps, no family history of colorectal neoplasia, no inflammatory bowel disease and no unexplained anemia. As previously indicated, there is presumptive evidence of an environmental risk factor and suspicion has been directed at diet and nutrition. Other possible factors in the pathogenesis of colorectal cancer include physical activity and body mass, reproductive activity, exogenous hormone use, the use of nonsteroidal anti-inflammatory agents (NSAIDs), smoking, and alcohol.4 Knowledge of the genetics of colorectal cancer has accumulated rapidly during the last decade. The genes responsible for the inherited syndromes of familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) have been identified and genetic testing is commercially available.5 The genes involved in the pathogenesis of the rare hamartomatous polyposis syndromes have also been identified.6-8 The inherited syndromes of colon cancer and colonic polyposis are listed in Table 2.
Table 2: Inherited Syndromes of Colon Cancer and Colonic Polyps
Hereditary nonpolyposis colorectal cancer; Lynch syndromes I and II (HNPCC) Familial adenomatous polyposis (FAP) FAP is an autosomal dominantly inherited condition characterized by the development of hundreds to thousands of colonic adenomatous polyps and a near 100% risk for cancer of the colon if the colon is not removed. Polyps begin to emerge at an average age of 16 years and, if left untreated, one or more of the polyps will progress to cancer by the average age of 44 years. Several variants of FAP include the Gardner syndrome, which is characterized by extracolonic manifestations of osteomas, skin fibromas and epidermoid cysts. In the Turcot syndrome there are accompanying CNS malignancies, notably medulloblastoma. A recently described variant of FAP is attenuated adenomatous polyposis coli in which affected persons exhibit about 30 colonic adenomas and have an approximately 10-year delay in cancer occurrence.
FAP and its variants arise from inherited mutations of the adenomatous polyposis coli (APC) gene.
This results in unregulated proliferation of cells and decreased apoptosis (programmed cell death).
One allele of the APC gene is inherited in a mutated form and mutation of the other allele occurs later. The gene has been mapped on chromosome 5q and has been cloned and sequenced. The precise location of the mutation within the gene is responsible for the disease characteristics of FAP.
Hereditary nonpolyposis colorectal cancer (HNPCC) HNPCC is an inherited autosomal dominant syndrome with a tendency for earlier onset than FAP but with the presence of only one or a few polyps. It is associated with a pattern of other cancers, particularly those involving the endometrium, urinary tract, stomach, or biliary system. Most authorities use the so-called Amsterdam criteria for the diagnosis of HNPCC: (1) three first-degree relatives with one of the relevant cancers; (2) cancer involving 2 generations; and (3) one cancer diagnosed under the age of 50 years. Others feel that the Amsterdam criteria are too restrictive for Each of these conditions is inherited in an autosomal dominant fashion with high penetrance. A complex array of genetic abnormalities has been identified for each entity. Contrary to early belief, it is now known that these syndromes exhibit a significant risk for colon cancer and other Peutz-Jeghers disease is characterized by melanin pigment spots that occur around the lips, but also on the buccal mucosa and other areas. Histologically, characteristic polyps are found in the small bowel and sometimes throughout the G-I tract. Symptoms often begin during the second decade of life and arise from complications of the polyps such as bleeding, abdominal pain and intussusception.
After age 40, malignancy is the major cause of morbidity. Colon, small bowel and upper G-I tract cancers all occur, but represent only a 2 to 12% risk of malignancy. There is a 50% risk of malignancy overall, however, with breast, pancreas, and ovarian cancer being most common. The gene for the Peutz-Jeghers syndrome9-11 has been identified as occurring on chromosome 19.9-11 Juvenile polyposis (JP) is defined as the presence of more than 10 juvenile polyps, most often found in the colon, but also occurring throughout the small bowel. Symptoms from benign polyps often occur during the first decade of life. There is an apparent substantial risk of colon cancer later in life, with some studies reporting up to a 50% lifetime risk of this malignancy.
The most consistent feature of Cowden syndrome (CS) is the presence of tirchilemmoma (hair tumors), most commonly observed on the skin over the bridge of the nose, but also on the gingiva and tongue. Hamartomatous polyps are also common and may occur anywhere in the G-I tract. They are usually juvenile polyps, although neurofibromas, lipomas and other hamartomatous polyps are also seen. There is a 3% to 10% risk of thyroid cancer, a 25% to 50% chance of breast cancer and an increased risk for ovarian and uterine cancer in this disease. An increase risk of G-I cancer, however, THE ROLE OF DIET AND NUTRITION IN THE EPIDEMIOLOGY OFCOLORECTAL CANCER Potter and his coworkers have recently conducted a comprehensive review of the literature on this subject, and have classified the reported studies by food categories.1 They, as well as other investigators, have emphasized the multifactorial pathogenesis of colorectal cancer and have stressed the important interrelationships that exist between genetic factors and changes in environment both at the level of the individual and at the level of ethnic, racial and geographic origin.1 Vegetables, Food, Fiber and Micronutrients Modest (and not entirely consistent) findings of lower risk have been reported in association with higher consumption of vegetables and fruit. One study on rectal cancer in Seventh-Day Adventists showed a small but significant reduction in risk with higher consumption of green salad. The most recent study from the same group noted a somewhat lower risk of colorectal cancer with a higher intake of a variety of plant foods, but was statistically significant only for legumes. One study reported a decrease in the incidence of adenomatous polyps in men with a higher intake of In addition, Potter et al reported that 17 of 21 case-control studies reported some degree of reduced risk with higher consumption of at least one category of fruit or vegetable.1 Particular consistency was noted for raw, green, and cruciferous vegetables.12 A meta-analysis of six case-control studies of vegetables and colon cancer reported a combined odds relation of 0.48 with a 95% confidence level of 0.41 to 0.57 for highest versus lowest quintiles of vegetable consumption. Of 10 case-control studies of rectal cancer reporting on statistical significance, 8 reported a significant inverse association of intake with colon cancer for at least one vegetable or fruit category with most consistent results for cruciferous vegetables. Studies on fruit consumption are less impressive than The mechanisms whereby vegetables and fruits are protective against colorectal cancer may be related to their content of potential anticarcinogens, such as carotenoids, folate and the antioxidant vitamins which may exert scavenger activity on free oxygen radicals, thereby preventing their deleterious effects on DNA. Dietary constituents may also possess antimutagenic and anticarcinogenic substances such as phenols, flavonoids, isothiocyanates, and indoles which act at various points in the carcinogenic process, including induction of detoxifying enzymes, inhibition of nitrosamines, antioxidation and provision of substrates for antineoplastic agents, detoxifying enzymes, and inhibitors. Some have attributed the reduced risk of colorectal cancer in association with consumption of vegetables as due to micronutrients in food such as carotenoids, ascorbate, and folate, but the data are inconsistent and, as yet, unconvincing.
The high folate content of fruits and vegetables may be a factor in their protective role in colorectal cancer. Hypomethylation of DNA had been implicated as an early step in colon carcinogenesis.
Folate may be important in providing the availability of sources of methylation to prevent this and allowing DNA to enhance its integrity and that of the nucleotide pool.14 Fiber as a protective against gastrointestinal cancer has received considerable notice. No association was found between colorectal cancer in either a recent cohort study or a prospective study. However, a combined analysis of 13 case-control studies report a reduction in colorectal cancer risk with increasing intake of dietary fiber and similar findings have been reported in a meta-analysis of 16 case-control studies.12 Fiber from vegetables and cereal has been associated with a more than halving of risk for adenomatous polyps in men. The heterogeneous nature of dietary fiber and the measurements of intake, have posed some difficulty in the interpretation of the results. Fiber is a variable mixture of cellulose, hemicellulose, pectins, and lignin. Its protective effect may be related to increased stool volume, which leads to decreased transit time and dilution of potential carcinogens while minimizing their contact with the colonic mucosa, Conversely an increase in the incidence of colorectal carcinoma has been noted in patients who suffer from chronic constipation although this theory has been recently challenged by the Nurses Health Study.
The World Cancer Research Fund (WCRF) concluded that "evidence that diets high in vegetables protect against cancers of the colon and rectum is convincing," that "diets high in fiber possibly decrease the risk of colon cancer," but "the data on fruit are more limited and inconsistent; no A number of cohort and case-control studies have been performed studying meat consumption as a risk factor in colorectal carcinoma.1 In its review of the data,10 the WCRF found that of the 16 cohort trials studying the problem, 8 were consistent with a statistically significant increased risk of colorectal cancer associated with high meat consumption. Seven were equivalent and only 1 demonstrated a decrease in risk. Similarly, of 26 case-control studies of colorectal neoplasms (23 of cancer and 3 of adenomatous polyps), the WCRF showed that 16 reported a significantly increased risk associated with meat consumption compared to 7 studies that were equivalent.13 Of the 83 estimates of risk associated with these studies, 47 were statistically significantly greater than 1, while 31 were equivocal, and only 5 were negative.
Attempts have been made to correlate the increased risk of meat consumption with dietary fat.
Howe et al15 reported on a combined analysis of 13 case-control studies of colorectal cancer involving 5287 case patients and 10,478 control subjects from various populations with different cancer risks and diets. They found no evidence of any increased risk associated with total dietary fat. However, several studies have reported a significant relationship between colorectal cancer and saturated or animal fat. Of 19 cohort and case-control studies, 11 showed some evidence of an elevated risk associated with higher intakes of saturated/animal fat, 2 showed weak inverse association, and 6 showed no association. Thus, while the evidence is consistent with a higher risk with animal/saturated fat than with total fat, the data are not entirely convincing, leading to the conclusion that the association with red meat consumption does not appear to be mediated by its lipid content.13 Evidence for involvement of protein or iron appears even weaker.13 It has been demonstrated in animals that specific heterocyclic amines present in cooked meat have been shown to be carcinogenic and capable of producing mutations in the APC gene.
The Public Health recommendation for both heart disease and cancer is "if eaten at all, limit intake of red meat to less than three ounces daily.13 "Free" oxygen radicals or "excited" oxygen molecules are the byproducts of many normal metabolic processes in the human body. Both animal and human studies have demonstrated that these oxygen molecules are not passive, but are reactive and may be potentially harmful. Their potentially deleterious effects include denaturization of proteins and damage to nucleic acids and DNA leading Nutrient chemopreventives such as the retinoids (vitamin A), carotenoids (β-carotene, provitamin A), tocopherols (vitamin E), and ascorbic acid derivatives (vitamin C) have been widely promoted as antioxidant agents, which act as free radical scavengers preventing the potential damage of the free radicals. It has become increasing apparent, however, that the development of a beneficial or a detrimental cellular response by a nutrient depends on the net balance of the nutrient's antioxidant and prooxidant characteristics. This in turn is dependent on the redox potential of the individual molecule and the inorganic chemistry of the cell. When antioxidant activity of the nutrient predominates, beneficial scavenger activity results; on the other hand, when inappropriate prooxidant activity develops in normal cells, reactive oxygen metabolites are generated that are capable of damaging DNA and cellular membranes. To predict whether a specific nutrient will have a beneficial or detrimental effect on a particular tissue or cell, it is important to identify markers that will characterize the biologic activities of each nutrient and elucidate a possible mechanism of action for that nutrient. This objective has yet to be realized, and much of the evidence concerning the potential value of the chemopreventive nutrients has been extrapolated from animal or in vitro studies or derived from studies based on an observational approach. There is evidence that most free radical injury is iron-related and promoted by iron.
Experiments in animals have shown that high-dose supplemental β-carotene protects against ultraviolet light and chemically induced cancers, blocks cancer progression, stimulates immune responses and is anticarcinogenic. Vitamin C may be useful in the prevention by its influence on carcinogenesis including its antioxidant effect, blocking of formation of nitrosamines and fecal mutagens, enhancement of immune response, and detoxification of liver enzymes. Similar mechanisms, especially its stimulant action on the immune system, have been evoked for the role of vitamin E in the prevention of carcinogenesis.
An extrapolation of these findings to the human situation has led to the consensus opinion that five servings of fruits and vegetables containing the above nutrients would reduce the incidence of various cancers. Antioxidants may be responsible, at least in part, for the findings, previously reported, that fruits and vegetables have a beneficial effect in the prevention of colorectal carcinoma.
The complexities involved in the multitude of compounds included among the nutrient chemopreventives are considerable. Knowledge concerning the chemical and biologic activities of these compounds is limited, and, more importantly, the redox potential of each of these derivatives Despite these basic limitations in knowledge, approximately 200 epidemiological studies have appeared in the literature with remarkably consistent results. For all cancer sites, a statistically significant protective effect of fruit and vegetable consumption was found in 128 of 156 dietary studies in which results were expressed in terms of relative risk. Included in the group were 38 studies of cancers of the colon and bladder. Of these, 23 resulted in a significant reduction in risk. An inverse relationship between vitamin C intake and a decreased risk of colorectal cancer has been reported.17 The association between a higher intake of calcium and colorectal neoplasms has been explored in both cohort and case-control studies.13 Most of the evidence suggests a reduced risk or no association.
There are intervention studies showing that calcium reduces proliferation in the upper part of the colonic crypt and observational studies that calcium reduces the likelihood of metachronous adenomas.18 Most recently, a double-blind, placebo-controlled intervention trial showed a statistically significant 15% to 20% reduction in the incidence of metachronous colorectal adenomas.19 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) NSAIDs, including aspirin, have been consistently associated with a reduced risk of colorectal cancer. At least seven case-control studies and four cohort studies have reported a lower risk of colorectal cancer in association with NSAID intake.20 An inverse relationship between adenomatous polyps was also seen with regular aspiring use. Two studies, a cohort study and a low-dose aspirin intervention study reported null results.21 More recent evidence involves the effective use of cyclooxygenase-2 (cox-2) inhibitors in not only preventing carcinogenesis, but also in halting the growth and progression of polyps, a progression that usually culminates in full-bloom colorectal carcinoma.22,23 The evidence suggests that familial adenomatous polyposis (FAP) is linked to over-expression of cyclooxygenase-2. In a recent study,24 celecoxib was found to significantly reduce the number of colorectal polyps in patients with FAP.
Seventy-seven patients with FAP were randomly assigned 6 months of 100 mg or 400 mg of celecoxib daily, or to placebo. The patients who received the 400 mg bid dosage had a 28% reduction in the mean number of colorectal polyps (p=0.003 in comparison with placebo, and a 30.7% reduction in the polyp burden (the sum of polyp diameters) with a p=0.001 compared to placebo. Celecoxib has received FDA approval for use in FAP.
Animal studies have shown that cox-2 inhibition produces effects on epithelial proliferation, apoptosis and angiogenesis.25,26 There is also evidence that the NSAIDs (including aspirin) suppress the HNPCC-associated mutator phenotype in favor of a more stable subset of cells.27 Any clinical benefits of this observation await clinical studies.
THE ROLE OF LIFE STYLE IN THE PATHOGENESIS OF COLORECTAL CANCER There is abundant evidence that certain parameters of lifestyle play significant roles as risk factors in the pathogenesis of colorectal cancer. In the vast majority of instances, these risk factors interact with genetic and environmental risk factors in a complex fashion that makes it difficult to assign specific and precise roles to individual risk factors.
The inverse relationship between physical activity and risk of colon cancer has been a consistent finding.13 Of 9 cohort studies, only 2 reported no substantial association, and of 11 case-control studies, 10 showed an inverse relationship between a high total physical activity and the risk of colon cancer. Individuals with high levels of activity throughout their lives had the lowest risk. There is little evidence that physical activity modifies the risk of rectal cancer.
One hypothesis for the role of physical activity is that by stimulating colonic peristalsis, physical activity decreases the time of contact between the colon contents and the colonic epithelium, thereby decreasing the risk of carcinogenic influences on the epithelium. Exercise has also been shown to have a favorable effect on the immune system and on acute and chronic hormonal effects as well. Insulin, glucose, and triacylglycerol levels are lowered by physical activity. These factors may result in a less favorable local environment for development of colon cancer.
Four cohort studies and 8 case-control studies have demonstrated that men who are in the highest quintile for body size and classified as obese, have as much as a twofold increase in the risk of colon cancer.15 Using the body mass index (BMI = weight in kg/height in meters squared), 5 studies in men showed no relationship between BMI and risk of colon cancer. Data in women have been generally negative. However, the Iowa Women’s Health Study showed that subjects who were in the highest quintile of BMI had a statistically significant 40% higher risk for colon cancer than those who were in the lowest quintile. A large US multi-center case-control study involving 2000 case patients and 2400 controls found no association between BMI and increased risk of colon cancer at high levels of long-term vigorous physical activity. However, risk appeared to be related to total energy intake and to BMI at lower levels of such activity in men with little such association in women.28 Waist to hip ratio was associated with increased risk in men but not in women. Obesity does not appear to influence the risk of rectal cancer.
Early studies had reported a higher risk of colon cancer in nulliparous women. More than 20 studies have reported on reproduction and colon cancer. Cohort studies have generally reported no association between age at first birth or parity and colon cancer. The findings on the association of hormone replacement therapy and the risk of colon cancer have been inconsistent. Of 12 studies investigating this association, 7 showed a statistically significant lower risk of colon cancer with hormonal replacement therapy (HRT); two studies showed trends toward a lower risk; two studies reported null findings; and 1 showed an elevated risk among HRT users. An approximate halving of the risk with recent HRT has been reported, a degree of risk that was maintained for about 10 years after cessation of HRT.29 A similar pattern of association exists between HRT and the risk of adenomatous polyps of the colon and rectum.30 Several studies have reported a higher risk of colon cancer among cigar, pipe, and cigarette smokers, especially among those with long smoking histories.30 An elevated risk of adenomatous polyps associated with cigarette smoking has been a consistent finding.31 Tobacco smoke is a major source of carcinogens including heterocyclic amines, polycyclic hydrocarbons and nitrosamines. There is incomplete evidence concerning any role played by these substances in colonic carcinogenesis. The problem is similar to that concerning the carcinogens in meat.
Over half of the cohort and case-control studies on the effect of alcohol on colon and rectal cancer have reported an increased risk associated with alcohol consumption. The risk has been consistently higher in men than in women perhaps because of the lower consumption of alcohol in women. No one source of alcohol (e.g., beer) has been found to have a greater risk than others. The risk seems proportional to the amount of intake.
A local solvent or cytotoxic alcohol has been proposed as a possible mechanism, but would be more relevant to the upper gastrointestinal tract. It may also exert its effect through associated deficiencies in nutrients, especially folate. Additionally, alcohol is known to inhibit DNA repair.1 The importance of detecting and removal of polyps and early colorectal cancers has lead to the development of colorectal cancer screening. Actually, in clinical practice, there are three types of Screening is defined as the use of any detection method in a patient who has no symptoms
and no personal history of colon polyps or cancer.
Surveillance usually involves colonoscopy and includes examinations in those with previous
neoplasia (polyps or colon cancer), a family history of colon cancer or an inherited polyposis
syndrome, and individuals with long-standing ulcerative colitis and Crohn's disease.
Diagnostic examinations are those undertaken in symptomatic persons or in persons with a
positive fecal occult blood test.
Recent federal legislation has provided for Medicare reimbursement for colorectal cancer screening and surveillance, and the state of Virginia has introduced legislation making it mandatory that all health care providers, including private providers, include a colorectal cancer screening benefit.
Guidelines have been established concerning the screening procedures.33 It should be emphasized that those individuals who have risk factors, such as a strong family history of colonic cancer or polyp disease, a personal history of polyps, previous colon cancer or ulcerative colitis, require much more vigorous surveillance than does the patient without those risk factors. Several methods of colon cancer screening are available and guidelines have been recommended for their use. It is generally agreed that all individuals over the age of 50 should undergo colorectal cancer screening.
Table 3 lists the screening procedures recommended by the Agency for Healthcare Policy and Research (AHCPR) and the American Cancer Society (ACS) for the average risk individual.
Table 3: Options for Screening Average Risk Persons
AHCPR and ACS Guidelines
Annual FOBT and flexible sigmoidoscopy every 5 years Double contrast barium enema every 5 to 10 years ACS guidelines do not include FOBT by itself Fecal occult blood (FOBT). This is a simple procedure that can be done by the patient (kits areavailable at pharmacies and elsewhere) or by the physician. If positive for blood, it should berepeated and, if still positive, further diagnostic studies such as listed below should be done.
A positive FOBT does not help in deciding the source of bleeding and if tests of the largebowel are negative for a source, the upper gastrointestinal tract should be investigated.34There is convincing evidence showing that colorectal mortality rates can be reduced by 15%to 35% by screening with FOBTs.35 Flexible sigmoidoscopy (FS) every 5 years. This allows the physician to directly visualize therectum and lower portion of the colon. Polyps may be removed and biopsies done throughthe sigmoidoscope. If large (> 1 cm) polyps are found, colonoscopy is recommended. Polyps< 1 cm should be biopsied and if adenoma or cancer is found, colonoscopy is recommended.
Flexible sigmoidoscopy does not allow for visualization of the upper two-thirds of the colon.
However, about 50% to 60% of colorectal cancers and adenomas are detected with FS.
Medicare reimburses for a flexible sigmoidoscopy every 4 years.
Colonoscopy. This is the "gold standard" for colorectal cancer screening, allowing thephysician to visualize the entire colon and to remove polyps and take tissue samples.
Medicare reimburses high-risk patients for colonoscopy every 2 years. Those with "average"risk should have colonoscopy every 10 years, but there are those who favor a 5-year interval.
Barium enema. This x-ray procedure may be substituted for the flexible sigmoidoscopy at thediscretion of the physician. It has the advantage of allowing x-ray visualization of the entirecolon, but does not allow for polyp or tissue removal. Additionally, the barium enema maymiss the detection of small polyps.
A number of innovative techniques for early detection of colorectal cancer are under investigation.
Detection of biomarkers in stool specimens. A number of biomarkers of neoplastictransformation, have been detected in fecal colonocytes, and studies are underway onimmunochemical assays and fecal DNA, but as yet nothing has been shown to be sufficientlysensitive to be considered as screening tools for colorectal cancer. A pattern of markers mayeventually identify individuals who should be screened because their risk of adenomas orcancer is high.36 "Virtual colonoscopy" with spital computed tomography or MRI. To date, most experiencehas been with computed tomographic colonography (CTC). After air insufflation (via therectum) creates a pneumocolon, helical or spiral CT scanners are employed. The diagnosticinterpretations are done on the virtual image obtained rather than on the patient. Theamount of radiation required is less than that of a conventional CT scan. The data can beprocessed by advanced computer software. Preliminary results, particularly in the detectionof small polyps, are encouraging.36 The evidence to date shows that screening for colorectal cancer is a cost-effective intervention.37 THE PATIENT WITH ADVANCED COLORECTAL CANCER The signs and symptoms of colon cancer depend to a large degree on the site of the lesion. A change in bowel habits, especially of a progressive nature, is common to lesions in all segments of the colon. The right half of the colon, the absorptive portion, produces a group of symptoms revolving around disturbances of physiologic functions of the colon and often gives rise to dyspeptic symptoms that may be mistaken for functional dyspepsia, gall bladder disease, or the irritable colon syndrome. Abdominal discomfort is frequently present and may be accompanied by local tenderness especially if the growth has progressed to the serosal surface. If unattended this may lead to overt perforation with signs of peritonitis or local abscess formation. An accompanying anemia without gross evidence of blood loss is frequently a telltale sign suggestive of a right-sided colonic lesion.
The left colon is more likely to produce symptoms of obstruction and gross bleeding is more common especially when there is rectal involvement. Pain is usually the result of the obstructive process and tends to be crampy in nature. Left-sided perforation may occur but is less common than that associated with right-sided lesions. The usual accompanying signs of malignant disease such as weight loss, anorexia, and weakness may be present especially when metastases have occurred.
Physical examination may be completely negative although on occasions the mass lesion may be palpated. The diagnosis is established by endoscopy and/or barium enema but the true extent of the lesion may not be ascertained until surgical exploration. Metastases to the liver are the most manifestation of distant spread, although lung metastases visible on chest x-ray are not uncommon.
The management of the patient with an established diagnosis of colorectal cancer is based on the findings present in that particular case. Each patient’s case is unique and should be handled as such.
Radical surgical extirpation is without question the procedure of choice from the standpoint of curability. When the lesion has progressed to such an extent that this is not possible, some palliative procedure for shunting the fecal current is often useful. In the case of cancer of the rectum there are advocates for preoperative radiotherapy. Different surgical procedures are applicable to lesions in different parts of the colon and they may be performed in single or multiple stages depending on the general condition of the patient and the situation found at exploration.
There has been recent renewed enthusiasm concerning the use of chemotherapy in colon cancer, particularly in those cases with liver metastases. Intense research continues in this area, and several new agents have been introduced as well as a number of combination therapies. The Mayo Clinic regimen of 5-fluorouracil (5-FU) in combination with leucovorin continues to hold the spotlight as the baseline standard. However, some investigators claim that the Mayo's regimen of a daily x 5 regimen is overly toxic, citing a necessity to lower dosage in 45% of cases.38 There have been optimistic reports on a regimen employing hepatic artery infusion (HAI) of floxuridine (FUDR) in combination with systemic irinotecan (CPT-11). Using this regimen, investigators at Memorial Sloan Kettering observed high levels of tumor regression with a response rate of 72%.39 Oxaliptan represents a new active agent that has been reported to show promise in combination with 5-FU40,41 and with CPT-1142 both in the US and in France. Sensory neuropathy has been a frequent side effect of oxaliptan, but is reversible.
In June 2000, the FDA approved a new indication for irinotecan hydrochloride injection (Camptosar®, Pharmacia) as first-line therapy in combination with a 5-flourouracil and leucovorin to treat metastatic colorectal carcinoma.43 The approval was based on two multi-center, randomized controlled trials in patients with metastatic cancer of the colon or rectum.
One study was conducted in Europe with 385 patients randomized to receive 5-FU and leucovorin with or without irinotecan. The study demonstrated statistically significant improvement in survival in the irinotecan group (median 17.4 months vs 14.1 months p<0.05). The second study was conducted in the US and randomly assigned 683 patients to 1 of 3 arms: 1) single-agent irinotecan, weekly for 4 weeks every 6 weeks; 2) irinotecan, 125 mg/m2, leucovorin 20 mg/m2, and 5-FU 500 mg/m2 weekly for 4 weeks every 6 weeks, and 3) leucovorin, 20 mg/m2, followed by 5 F-U, 500 mg/m2, daily for 5 days every 4 weeks. The primary analysis was a comparison of the combination irinotecan arm with the arm without irinotecan. This study also demonstrated improvement in survival in patients treated with all three drugs (median 14.8 vs 12.6 months, p<0.05).
In the European study, neutropenia, neutropenic fever, late-onset diarrhea, and treatment discontinuation due to toxic effects were more common in patients whose regimen included irinotecan; but nausea, vomiting, and diarrhea were more common in those receiving all three drugs.
Unfortunately, most US colorectal cancer patients have been diagnosed when they have already developed symptoms such as rectal bleeding, a change in bowel habits, or abdominal pain. Under these circumstances, more than half of these patients have disease that has already spread to the lymph nodes and/or liver and their chances of survival have been significantly reduced.
It has become increasingly apparent that the effective control of colorectal cancer lies in early detection. This objective has been successfully accomplished by the combination of scientific advances and enlightened social, political, and economic forces. The identification of genetic, environmental, and social factors that place an individual at high risk for colorectal cancer have been identified. The definition of these risk factors has made possible the identification of individuals at an increased risk of colorectal cancer.
The clarification of the value of the various screening techniques and their refinement has enabled the application of these screening techniques not only to the high risk individual but to the "average" risk individual as well. The liberalization of reimbursement for colorectal screening has provided ready access to the process—so much so that colorectal cancer screening is now recommended for all Finally, the emphatic endorsement of this policy by medical, social and media agencies has resulted in an increased awareness of its importance with an unquestioned benefit to those participating in 1. Potter JD. Colorectal cancer; molecules and populations. J Natl Cancer Inst 1999;91:916-32.
2. Bedine MS. Colorectal carcinomas: etiology, diagnosis and screening. Comp Ther 1999;25:163-8.
3. Singh PN, Fraser GE. Dietary risk factors for colon cancer in a low risk population. Am J 4. Read TF, Rodner IJ. Colorectal cancer risk factors and recommendations for early detection. Amer 5. Terdiman JP, Conrad PG, Sleisinger MH. Genetic testing in hereditary colorectal carcinoma; indications and procedures. Gastroenterol 1999:94:2344-50 6. Burt RW. Genetics of colon cancer. Prac Gastroenterol 2000;24:64-77.
7. Lynch HT, Shaw TG, Lynch JF. The genetics of colorectal cancer. reprinted from Primary Care 8. Burt RW, Jacoby RF. Polyposis syndromes. In Yamada T (ed.) Textbook of Gastroenterology, 3rd edition, Philadelphia, JB Lippincott, 1999. chap 86, pp 1995-2002 9. Hamminski A, Markie d, Tomlinson I, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 1998;391:184-7.
10. Jenne DE, Reimann H, Negu J, et al. Peutz-Jeghers syndrome is caused by mutation in a novel serine/threonine kinase. Nat Genet 1998;18:18-43.
11. Dong SM, Kim KM, Kim SY, et al. Frequent somatic mutation in serine/threonine kinase 11/Peutz-Jeghers syndrome gene in left-sided colon cancer. Cancer Res 1998;58:3787-90.
12. Fuchs CS, Giovannucci EL, Colditz GQ, et al. Dietary fiber and risk of colorectal cancer and adenoma in women. N Engl J Med 1999;340:169-76.
13. World Cancer Research Fund (WCRF) Panel (Potter, JD, Chair). Diet, nutrition and the prevalence of cancer: a global perspective. Washington, DC, WCRF/American Institute ofCancer research, 1997.
14. Lengauer C, Kinzler KW, Vogelstein B. DNA methylation and genetic instability in colorectal cancer cells. Proc Natl Acad Sci USA 1997;94:2545-50.
15. Howe GR, Aronson KJ, Benito E, et al. The relationship between dietary fat intake and risk of colorectal cancer: evidence from the combined analysis of 13 case-control studies. Cancer CausesControl 1997;8:215-28.
16. Giovanucci E, Goldin B. The role of fat, fatty acids, and total energy intake in the etiology of human colonic cancer. Am J Clin Nutr 1997;66 (6 Suppl):S1564-S1571.
17. Hercberg S, Galan P, Preziosi P, et al. The potential role of antioxidant vitamins in preventing cardiovascular diseases and cancers. 1998; Nutrition 14:413-20.
18. Hyman J, Baron JA, Dain BJ, et al. Dietary and supplemental calcium and the recurrence of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 1998;7:291-5.
19. Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas: Calcium Polyp Prevention Study Group. N Engl J Med 1999;340:101-7.
20. Rosenberg L, Loruk C, Shapiro S. Nonsteroidal anti-inflammatory drug use and reduced risk of large bowel cancer. Cancer 1998;72:2326-33.
21. Sturmer T, Glynn RJ, Lee IM, et al. Aspirin use and colorectal cancer: post-trial follow-up from the Physicians Heart Study. Ann Intern Med 1998;128:713-20.
22. Kawamori T, Rao CV, Seibert F, et al. Chemopreventive action of celecoxib, a specific cyclooxygenase-2 inhibitor against colonic carcinogenesis. Cancer Res 1998;58:409-12.
23. Kalgutkar AS, Crews BC, Rowlinson SW, et al. Aspirin-like molecules that covalently inactivate cyclooxygenase-2. Science 1998;280:1268-70.
24. Steinbach G, Lynch PM, Phillips, RKS, et al. The effect of celcoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342:1946-52.
25. Barnes CJ, Cameron H, Harman WE, et al. Non-steroidal anti-inflammatory drug effect on crypt cell proliferation and apoptosis during initiation of rat colon carcinogenesis. Br J Cancer 1998;77:573-80.
26. 1.Tsujii M, Kawano S, Tsuji S, et al. Cyclooxygenase regulates angiogenesis induced by colon 27. Ruschoff J, Wallinger S, Dietmaier W, et al. Aspirin inhibits the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection. Proc Natl Acad Sci1998;95:11301-6.
28. Slattery ML, Potter J, Caan B, et al. Energy balance and colon cancer – beyond physical activity.
29. Kampman E, Potter J, Slattery ML, et al. Hormone replacement therapy, reproduction history and colonic cancer: a multi-center, case control study in the United States. Cancer Causes Control1997;8:146-58.
30. Fernandez E, La Vecchia C, Braga C, et al. Hormone replacement therapy and risk of colon and rectal cancer. Cancer epidemiol Biomarkers Prev 1998;7:329-33.
31. Kneki P, Hakama M, Jarvinen R, et al. Smoking and risk of colorectal cancer. Br J Cancer 32. Potter JD, Biglin J, Fosdick L, et al. Colorectal adenomatous and hyperplastic polyps: smoking and N-acetyltransferase polymorphism. Cancer Epidemiol Biomarker Prev 1999;8:69-75.
33. Rex, DK. Current recommendations for colorectal cancer screening. Reprinted from Primary 34. Rockey DC, Koch J, Cello JP, et al. Frequency of upper gastrointestinal and colonic lesions in patients with positive fecal occult blood tests. N Engl J Med 1998;339:153-9.
35. American College of Physician Guidelines for fecal occult blood testing. Ann Intern Med 36. Ahlquist DA, Johnson CD. Innovative techniques for colorectal cancer screening.
The < Reprinted from Primary Care and Cancer 1999;19:10-14.
37. Brown ML, Knopf KB. Is colorectal cancer screening really cost effective ? Reprinted from 38. Vincent M, Whiston F, Tomiak A. Mini-meta-analysis of toxicity of full-dose Mayo regimen (FUFA) from two randomized control trials (RTCs). A concern about dose. Abstract 930;American Society of Clinical Oncology, Atlanta, May 15, 1999.
39. Ron IG, Kemeny NE, Tong B, et al. Phase I/II study of escalating doses of systemic irinotecan (CPT-11) with hepatic arterial infusion of floxuridine (FUDR) and dexamethasone (D) with orwithout cryosurgery for patients with unresectable hepatic metastases from colorectal cancer.
Abstract 908, American Society of Clinical Oncology, Atlanta, May 15, 1999.
40. Bleiberg H, Brienza S, Gerard B, et al. Oxaliplatin combined with high dose 24-hour continuous 5-FU infusion and folinic acid based regimen in patients with advanced colorectal cancer (CRC).
Abstract 925. American Society of Clinical Oncology, Atlanta, May 15, 1999.
41. Zori Comba A, Blajman C, Richardet E, et al. Bimonthly oxaliplatin (L-OHP) with (A) or without (B) fluorouracil and leucovorin (FA). Proven evidence of synergism in a phase II randomizedtrial. Abstract 953. American Society of Clinical Oncology, Atlanta, May 15, 1999.
42. Kretschmer A, Mezger J, Thuss-Patience PC, et al. Oxaliplatin (Ox) after irinotecan (Iri).
Antitumor activity and clinical benefit of 3rd and higher-line chemotherapy with Ox forpatients with metastatic colorectal cancer (MCC) after failure of Iri). Abstract 995. AmericanSociety of Clinical Oncology, Atlanta, May 15, 1999.
43. Henney JE. New first-line therapy for colorectal cancer. JAMA 2000:284:33.
Please select "True" or "False" for questions 1-14 and the most appropriate answer for question 15. Mark your selections on the Answer Sheet for return to ArcMesa or on the Internet electronic test form.
Unanswered questions are counted as incorrect and it takes at least 70% correct responses for a passing score.
The incidence of colon cancer in men is about twice that in women.
In most cases of colorectal cancer, there is no identifiable risk factor.
Familial adenomatous polyposis (FAP) poses a near 100% risk for the development of colon cancer.
The Peutz-Jeghers syndrome is not a precursor of cancer.
There is evidence that a diet high in vegetable content acts to prevent colon cancer.
Fiber is a variable mixture of cellulose, hemicellulose, pectins, and lignin.
Free oxygen radicals have been incriminated in denaturalization of proteins and damage to nucleic acids and DNA.
The cycoooxygenase-2 (cox-2) inhibitor, celecoxib, appears to disrupt the growth of polyps in familial adenomatous polyposis.
No relationship between physical activity and colon cancer has been found.
10. Legislation allowing Medicare reimbursement for colon cancer screening has recently been 11. An increased risk of adenomatous polyps has been associated with cigarette smoking.
12. Screening for colon cancer with fecal occult blood testing has been shown to be of no significant value.
13. Colorectal cancer screening is now recommended for all "average risk" individuals over the age of 50.
14. Flexible sigmoidoscopy is capable of detecting 50% to 60% of colorectal cancers or adenomas.
An increased incidence of colon cancer has been attributed to which one of the following: A. raw fruit
B. saturated animal fat
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