Colorectal Cancer While colorectal cancer remains as the second most common cancer in the United States, striking

140,000 people annually, early detection has made it curable in most cases. Predisposing factors for colon cancer are polyps, ulcerative colitis, Crohns disease, previous radiation therapy involving the pelvis (uterine and cervical cancer, seminoma of the testicle), and history of colon cancer in family members. There are two distinctive familial forms of colorectal cancer, one associated with polyps: familial adenomatous polyposis (FAP), and the other one without polyps: hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome types I and type II). In people with these hereditary syndromes the colon cancer has special characteristics. When a hereditary form of colorectal cancer is suspected genetic testing can be done on the patient and first degree relatives. In most cases the exact cause is unknown. What is known is that in populations who consume a diet high in fiber and low in fat, such as Africans, the incidence of colon cancer is extremely low. Industrialization and mass production of foods since the late 1800s has reduced the amount of fiber in the diet through several generations in Western countries. Along with the reduction of fiber, the bulk of stool has been reduced, the bacterial flora has changed and the transit through the colon is slower. Markers eaten with food reach the stomach in seconds, are out of the stomach in 3 hours, travel through the small bowel another 3 hours to reach the colon. The first traces of these markers can be seen in stool in 24 hours and the last of them in 7 days. Therefore, carcinogens produced from bacterial transformation of some chemical ingested with foods have a long time to act on the lining of the colon. The small bowel is protected from these effects because it is devoid of bacteria and transit is quite fast. When colorectal cancer arises from a simple polyp (without the above mentioned risk factors) the progression is quite slow, taking many years to produce symptoms such as blockage or bleeding. This is why surveillance colonoscopy is extremely important to detect polyps before they become cancerous. It is generally recommended to stat having colonoscopies at the age of 50, unless one has predisposing factors which moves the starting age to 40. By the fact that colorectal cancer is a slow growing process surgery is not an emergency. Although the instinctive reaction of most people is to have surgery as soon as the diagnosis is made it is best to take all the necessary time to refine the diagnosis and best prepare for surgery than rush to the operating room. Surgery remains the main therapy for the cure of colorectal cancer. In some cases of rectal cancer chemotherapy and radiation therapy is given before surgery (neoadjuvant therapy) to make the operation more effective and avoid complete removal of the rectum with the anus. In colon cancer chemotherapy may be necessary following surgery (adjuvant therapy) if the staging of the cancer after pathological analysis suggests potential spread of the tumor. Less than 5% of patients with rectal colorectal cancer will need a permanent colostomy, which is the exteriorization of the colon through the abdominal wall to allow for feces to be collected in a plastic pouch. Cure of colorectal cancer is currently achieved in 90% of patients with early stages and 50% of those with advanced disease.

The decision for chemotherapy and radiation is based on staging the cancer. Staging of the cancer is done by the pathologists who analyses the surgical specimen for depth of invasion of the tumor across the wall of the intestine, the presence of tumor cells in lymph nodes and presence of tumor cells at distant organs such as the liver or lung, these are called metastasis. Nowadays pathologist include in the report other factors that define the behavior of the tumor such as the degree of differentiation of the cells (well differentiated are close to normal, poorly differentiated are very abnormal), presence of tumor cells within blood and lymphatic vessels, and genetic markers (oncogenes). Technological advancements have recently made possible to do a staging before surgery in patients with rectal cancer. Because of the accessibility and the fixed location this preoperative staging can be done with either transrectal ultrasound or a special form of MRI (magnetic resonance imaging). Similar to the pathological staging system the depth of penetration of the tumor and the presence of enlarged lymph nodes is what determines the staging of the tumor. If the tumor is at a favorable stage the surgery can be limited to a local excision through the anus (if reachable) or through the abdomen. If the tumor is deemed at an unfavorable stage neoadjuvant therapy is given before surgery. The most common pathological staging system is the TNM (for tumors/nodes/metastases) system. Patients are assigned into a stage according with the American Joint Committee on Cancer (AJCC).

T - The degree of invasion of the intestinal wall Tis- cancer in situ (tumor present, but no invasion) T1 - invasion through submucosa into lamina propria (basement membrane invaded) T2 - invasion into the muscularis propria (i.e. proper muscle of the bowel wall) T3 - invasion through the subserosa T4 - invasion of surrounding structures (e.g. bladder) or with tumor cells on the free external surface of the bowel

N - The degree of lymphatic node involvement N0 - no lymph nodes involved N1 - one to three nodes involved N2 - four or more nodes involved M - The degree of metastasis, i.e., deposits of tumor at distant organs such as the liver M0 - no metastasis M1 - metastasis present Stage Adjuvant Chemotherapy Recommended O Tis N0 M0 100% No I T1 or 2 N0 M0 93% No II A T3 N0 M0 85% Usually not II B T4 N0 M0 72% Usually not III A T3 N1 M0 83% Yes III B T4 N1 M0 64% Yes III C Any T N2 M0 44% Yes IV Any T Any N M1 8% Yes * This figures represent the percentage of survivors at 5 years following surgery and is based on a study of the National Cancer Institute's SEER database, looking at nearly 120,000 people diagnosed with colon cancer between 1991 and 2000. Newer forms of therapy have significantly improved these figures but there is not enough data to build survival tables yet FOLFOX is the most common chemotherapy regimen for treatment of colorectal cancer. It consists of 3 drugs: FOL Folinic acid (leucovorin) F Fluorouracil (5-FU) OX Oxaliplatin (Eloxatin) FOLFOX4: Adjuvant treatment in patients with stage III colon cancer is recommended for 12 cycles, 2 days each cycle, every 2 weeks. Side-effects of oxaliplatin treatment can potentially include: Neuropathy, both an acute, reversible sensitivity to cold and numbness in the hands and feet and a chronic, possibly irreversible foot/leg, hand/arm numbness, often with deficits in proprioception (the sense of the relative position of neighboring parts of the body) fatigue, nausea, vomiting, and/or diarrheal, ototoxicity (hearing loss) In addition, some patients may experience an allergic reaction to platinum-containing drugs. Bevacizumab (Avastin) is new class of drugs used to treat metastatic colorectal cancer, stage IV, called anti-angiogenic agents. These drugs slow down the process of angiogenesis or growth of blood vessels. Tumors derive oxygen and nutrients for their own growth through the growth of these new blood vessels. It is used in combination T N M 5 year survival*

with some of the chemotherapeutic agents mentioned above. In addition to the side effects already mentioned for FOLFOX, Avastin can produce: Bleeding or bruising easily, loss of hair, mouth sores, rash on the hands and feet, tingling or numbness in fingers or toes

Diverticular Disease Diverticuli (plural of diverticulum) are outpouchings of the colon wall. Similar to hernias in the abdominal wall diverticuli develop through weakened points of a muscle layer. In the colon the muscle layer opens gaps for blood vessels to cross and feed the mucosa and return to the body the products of absorption. It is thought that a combination of weakening of the colonic wall and increased pressure inside the colon lead to these outpouchings. The increased pressure is thought to develop from lack of fiber in the diet resulting in less bulk in the colon forcing it to work harder to move the stool column along. The weakening is probably due to loss of collagen fibers in the colonic wall. Each diverticulum becomes a structure very much like the appendix: they can become blocked with stool, infection ensues (diverticulitis) and then can rupture. Ruptures can remain contained in the form of an abscess or can break loose into the peritoneal cavity and produce peritonitis. In very rare instances the abscess smolders for some time and drills a hole into the bladder or the vagina. These patients develop fistulas, colon to bladder (colovesical) result in the passage of gas and stool mixed with urination, and colon to vagina (colovaginal) result in gas and stool passing through the vagina.

Diverticuli are commonly found in either xRays or colonoscopies done for other reasons. It is estimated that 50 percent of Americans by age 60 and nearly all by age 80 have diverticuli in the colon. Eighty percent of these patients never experience any symptoms. Fifteen percent present with recurrent pain and 5% develop the complications already mentioned: abscess, fistula, peritonitis, and bleeding. It has been noted that there are two groups of patients who develop diverticulitis: the patient over the age of sixty who may have sporadic attacks that quickly respond to antibiotic therapy, and at the other extreme, the middle aged patient, late thirties or early forties, who develops severe diverticulitis and quickly escalates to complications. It is easy to see how the elderly can develop both the increased pressure through many years of a diet low in fiber and the weakening of the colon by loss of collagen. Conversely, the more aggressive course in younger patients suggests a different mechanism in the development of diverticuli. Ongoing studies are suggesting some possible genetic differences in collagen metabolism among people that can result in weakening of the colonic wall as well as weakening of the wall of blood vessels leading to aneurysms. The treatment of diverticular disease depends on the type of presentation. In cases of diverticuli producing either no symptoms or just mild pain an increase in the amount of fiber in the diet (fruits, vegetables, grains, and legumes) and other measures to avoid constipation (increased fluid intake, psyllium seeds, stool softeners). Patients who present with more intense pain, especially in the left lower side of the abdomen, fever and malaise have progressed to diverticulitis. Depending on the findings on physical exam, blood work and a CT scan may be in order. Cases of mild diverticulitis may be treated with antibiotics by mouth, e.g., metronidazole and ciprofloxacion. More severe cases require admission to the hospital for intravenous antibiotics and observation. Most patients respond well to antibiotic therapy. A group of patients, however, will have improvement of their symptoms but only temporarily. Depending on the severity and frequency with which diverticulitis recurs surgery becomes the treatment of choice. The other group of patients is that of complicated diverticulitis: abscess, obstruction, fistula, and perforation (bleeding is less common). In this group surgery becomes the only option. Patients with an abscess may benefit from a drain catheter placed in radiology under imaging guidance (ultrasound or CT). This allows for clearing of infection from the abdomen before surgery, which in turn makes reconnection of the bowel safe. In cases of peritonitis, or abscesses than cannot be drained, and in those that cannot receive a proper bowel preparation due to obstruction the best course of action is the removal of the disease colon by surgery and creation of a temporary colostomy. This colostomy is reversed 8 to 12 weeks later once the infection and inflammation has cleared up from the abdomen. Except for the rare case of diverticulitis is localized to the right side of the colon all patients with diverticulitis will require removal of the sigmoid colon (sigmoidectomy or sigmoid resection). Eighty percent of all diverticuli in the colon reside in the sigmoid colon. Even though 20% of diverticuli are left behind the recurrence of diverticulitis is

low because removal of the sigmoid colon facilitates the flow of stool and possibly reduces the increased pressures leading to diverticulitis. Fortunately, most patients who require surgery for diverticulitis nowadays can have a laparoscopic sigmoid resection and reconnection in the same operation, this is known as primary anastomosis as opposed to the staged surgery starting with a Hartmanns procedure and then reversal of the colostomy. Inflammatory Bowel Diseases Under this name we group several diseases that share some similarities but also have very distinctive features. The main two diseases in this group are Crohns disease and ulcerative colitis. In addition to these two there are several other inflammatory processes of the colon called colitides. This includes: collagenous and lymphocitic colitis, colitis cystica profunda, diversion colitis and segmental colitis associated to diverticulitis. The key feature of inflammatory bowel diseases is that there is an abnormal interaction of the immune system of the gut and intestinal bacteria. While these diseases have been called autoimmune diseases they really dont meet the postulates of an autoimmune disease such as rheumatic fever. There is no specific antigen or specific target like in rheumatic fever or lupus. Therefore, the underlying problem is thought to be an improper regulation of the gut immune system overreacting to intestinal bacteria. Inflammatory bowel disease can be induced in animals but if animals are kept in a sterile environment since birth so that the gut never develops a flora the inciting stimuli for inflammatory bowel disease do not work. It is known that inflammatory bowel diseases are more prevalent in some ethnic groups, such Ashkenazi Jews, and that there is a familial tendency to develop these diseases. Over the past few years several gene abnormalities have been implicated in the development of inflammatory bowel disease. However, any of these gene abnormalities is found in only 30% to 40% of patients; therefore, there must be multiple ways of contracting these diseases. Contrary to other illnesses such as cancer where there are records of cases going back many centuries the first cases of inflammatory bowel diseases were described in the early 1900s and in industrialized countries. There have been multiple epidemiological studies linking inflammatory bowel disease to refined sugar, refrigerated food (the cold chain theory), food additives, toothpaste, microorganisms such as the mycobacteria avium paratuberculosis and the measles virus, and the loss of helminthes (parasites) in the bowel. Clearly something has come along with industrialization that has render the bowel to overreact to some type of intestinal bacteria. Although Crohns disease and ulcerative colitis are the two most distinctive forms of inflammatory bowel disease there are multiple subtypes within each of these two diseases. It is very possible that in the near future these two diseases will branch out into many others that will be characterized by genetic markers.

Crohns disease: The main distinctive feature of Crohns disease is that the inflammation in the bowel produces a typical lesion under the microscope called a noncaseating granuloma. This is a granuloma is a nodule consisting of inflammatory and immune cells as well as extracellular matrix. Granulomas form when the immune system attempts to fend off and isolate an antigen. An important distinction of granulomas is whether they are caseating or not. Caseation (literally: turning to cheese) is a form of necrosis at the centre of a granuloma and is a feature of the granulomas of tuberculosis. Crohns disease produces the noncaseating granulomas and these can be found anywhere in the gastrointestinal tract from the mouth to the anus. Along with this inflammatory process of the bowel wall patients experience pain, symptoms of blockage, bleeding, abscesses from perforations of the intestine abnormal communications between hollow viscera and the skin or internally among themselves. In very rare cases patients with Crohns disease develop spontaneous, free perforations with peritonitis. Traditionally, the preferred form of treatment for Crohns disease has been pharmacologic including corticosteroids (prednisone), aminosalicylic acid derivatives, and immune suppressive drugs: methotrexate, azathioprine and 6-mercaptopurine. More recently a new line of drugs has been introduced that are targeted against some mediators of inflammation. The mediator is Tumor Necrosis Factor (TNF), and the drugs are antibodies against TNF produced from either human or mice proteins. Surgery has been reserved for cases where the medications are no longer working or life threatening complications have developed that can only be corrected with surgery. This approach of escalating drug therapy first and reserving surgery as a last resort is called the step up approach. Several markers are been studies to select a specific therapy for an individual patient. This is done because it is recognized that in some patients the step up approach does not work and just delays the inevitable exposing the patient to unnecessary risks. For instance, immune suppression makes surgery more risky in terms of infections and breakdown of wound from poor healing. If we could predict that a patient will need surgery regardless of how many drugs are tried it would make more sense to perform surgery early on and spare the patient from the delay and the risks associated with drug therapy. This approach is called top down and is gaining more acceptance as physicians are becoming more familiar using markers (blood tests) to grade bowel inflammation. Historically, surgery for Crohns disease has been associated with several adverse outcomes. First, patients with Crohns disease seemed to have more complications than patients having similar surgeries for conditions other than Crohns disease. Second, many patients who undergo surgery after many years of Crohns disease begin having more frequent relapses after surgery as if surgery triggers more inflammation. Lastly, surgery leads to more surgery and progressive loss of length of bowel until the patient becomes dependent on parenteral nutrition for survival. While these adverse outcomes are

possible there are usually preventable. Complications after surgery have been linked to two factors: long term use of corticosteroids and presence of infection in the abdomen prior to surgery. This is way prednisone is no longer prescribed for maintenance in Crohns disease. It is only used in short courses when everything else has failed. Intrabdominal infection can be cleared before surgery by placement of drainage catheters in radiology before surgery. The issue of recurrence and need for reoperations goes back to the days when surgery was thought to be curative of Crohns disease. We now recognize that Crohns can be latent anywhere in the gut aside from the segments grossly affected on which surgery is done. Therefore, all patients continue to receive medication after surgery even if the surgeon removes all visible disease. With the introduction of these measures surgery for Crohns disease is as safe and effective as for other diseases: ulcerative colitis or diverticulitis. Ulcerative colitis: The distinctive feature of ulcerative colitis is that it only affects the colon and not the small bowel. Also, it begins from the rectum up without skipping any areas (a pretty common feature of Crohns disease). Finally, ulcerative colitis affect the inner layer of the colon or mucosa where it produces inflanmmation, it is not unusual to look at the bowel from its outside during surgery and think that is quite healthy because the outer layer is not affected. Crohns disease is called transmural because it progresses through all layers of the intestinal wall. The chief symptom of ulcerative colitis is bloody diarrhea. Pain, obstruction and perforation are extremely rare in ulcerative colitis. The inflammation of the rectum also produces a constant urge to defecate not relieved by bowel movements, and incontinence. In severe case the bowel becomes distended and the body can start absorbing toxic substances contained in the colon, this entity is called toxic megacolon and requires immediate surgical intervention. Some patients go on to resolve their symptoms by taking medication. In spite of no longer having symptoms all patients with ulcerative colitis need to have colonoscopies. The likelihood of colon cancer is significantly increased when a patient has had ulcerative colitis and this likelihood is greater in patients who have had ulcerative colitis for more than 20 years and have involvement of the entire colon (pancolitis or universal colitis). Therefore, multiple biopsies are obtained with each colonoscopy and pathologists study them for changes in cellular architecture of the mucosa. From either a normal architecture or a background of chronic inflammation the mucosa may change to dysplasia which is a precancerous condition. Patients with dysplasia are referred for surgery even if they have no signs or symptoms of inflammation.