Colon Cancer: A Review

1. General Background 2. General Anatomy 3. Epidemiology/Etiology 4. Relevant Physiology 5. Diagnosis 6. Surgical Management 7. Medical Therapy 8. Screening 9. Prognosis and Complications 10. Conclusion 11. References

1. General Background
Colorectal cancer (CRC) is unfortunately an all-too common lethal disease and is a major health concern that affects men and women equally. Worldwide it accounts for approximately 1 million new cancers and one-half million deaths, equating 10 percent of all cancer deaths annually(1). Although both colon and rectal cancer are similar in many respects, there are significant differences due, in part, to there anatomic locations. This review focuses on colon cancer; please refer to a subsequent review for more details on rectal cancer.

2. General Anatomy
The colon is a muscular organ of approximately 150 cm in length. It extends from the cecum and terminal ileal junction at the ileocecal valve to the rectosigmoid junction. From inside out the bowel layers include mucosa, submucosa, muscularis propria (longitudinal externally and circular internally), and serosa. The organ is divided into four parts: the ascending, transverse, descending and sigmoid regions. The ascending colon lies in the retroperitoneum, on average 15 cm in length. It is continuous with the cecum, a blind-ending loop, considered the beginning of the colon but smaller in diameter, and ends at the hepatic flexure. The transverse colon is the longest segment, about 45cm, and stretches from the hepatic to the splenic flexure. Its course is convex and is located intraperitoneally based on a long mesentery. At its superior aspect the transverse colon is adherent to the greater omentum, while along the inferior border lies its blood supply via the transverse mesocolon extending upward from the retroperitoneum adjacent to the pancreas. The descending colon is 25cm in length and runs from the splenic flexure, where it is attached to the 11th rib by the phrenocolic ligament, and ends at the sigmoid junction. While the descending colon, like the ascending, is secondarily retroperitonealized, the sigmoid colon, akin to the transverse colon lies intraperitoneal. The sigmoid colon forms a loop of about 30-40cm within the hypogastrium and ends at rectum. Nearby, the iliac vessels, ureter, and sacral plexus lie posteriorly, while the bladder (and in females, the uterus) are adjacent anteriorly.

Arterial supply comes from the superior (SMA) and inferior (IMA) mesenteric arteries, with the superior supplying up to the distal one third of the transverse colon and the inferior supplying distal portion, including the proximal rectum. A marginal artery connects the two and forms an arcade along the mesenteric border, also named the artery of Drummond. Named branches include the ileocolic (supplying the ileum, cecum and appendix), the right colic (supplying the ascending and proximal transverse colon), the middle colic (supplying the transverse colon), the left colic (supplying the distal transverse and descending colon) and the sigmoid artery (supplying the sigmoid colon and proximal rectum). A direct connection between the SMA and IMA is often seen known as the arc of Riolan or meandering mesenteric artery. An increased diameter of this arc suggests obstruction of one of the major vessels. Anatomical variations are not uncommon. Although collateral circulation is significant, inconsistent watershed areas do occur at the splenic and hepatic flexures, along with the rectosigmoid junction. The venous drainage mirrors the arterial supply with the inferior mesenteric vein emptying into the splenic vein and then forming the portal vein together with the superior mesenteric vein.

Lymphatic drainage also follows the arterial anatomy. Epicolic nodes lie adjacent to the colon, draining proximally into the paracolic nodes, and subsequently into intermediate nodes located along the above named vessels. Ultimately lymph drainage reaches the primary nodes located at the SMA and IMA level before going into the para-aortic nodal chain.

Innervation of the colon comes from both sympathetic and parasympathetic systems. The sympathetic nerves arise from the sympathetic plexuses of spinal levels T1 to L3 located at pre-aortic ganglia and mesenteric vessels. The parasympathetic nerves arise from the vagus, supplying the colon up to the splenic flexure, and sacral nerves S2-S4 which supply the descending colon and rectum.In broad terms, the main functions of the colon include concentrating the fecal fluid by absorption, storing fecal material, and minimal digestion of nutrients. The absorption of these nutrients depends mostly on their digestion by microflora. They include but are not limited to starches and nonstarch polysaccharides, bile acids not absorbed by the terminal ileum and short chain fatty acids (SCFA). These SCFA are the primary substrate for colonocytes, especially butyrate, but also include acetate and proprionate. Fecal fluid absorption and concentration is mostly done in the ascending colon, while the descending and sigmoid are responsible for storage.

3. Epidemiology/Etiology
The incidence of CRC varies tremendously worldwide with the highest rates occurring in North America and Western Europe. Developing countries like Africa and Asia despite having a lower incidence (2) unfortunately also have lower five-year survival rates. In the United States, the incidence of colorectal carcinoma in whites has been steadily decreasing, while the rates in blacks continue to rise. There has also been a gradual shift toward right-sided or proximal colon cancers observed worldwide,(3) which may, in part, be due to increased screening rates with colonoscopy, thus identifying these lesions more often.

Several different mechanisms have been identified to explain the development of CRC. The most common involves the initial growth and subsequent transformation of adenomatous polyps, which are abnormal cells located in intramural glands. These adenomas grow over time and invade locally to become adenocarcinomas--although the overall conversion rate remains relatively low. The risk does increase with polyp size and the percentage of villous component within the adenomas (4). In addition, other risk factors have been linked to the development of CRC from an epidemiological stand-point. These include age, diet, certain diseases like inflammatory bowel disease and, and a genetic predisposition. Gender, though controversial, does not appear to be a risk factor. Age remains a major one, with a rare diagnosis before the age of 40 outside of a familial genetic predisposition. The age-specific incidence of adenomatous polyps and CRC is 1 in 5000 for 40 to 50 year olds and 1 in 250 for individuals greater than 80 years of age (5). Diet has been suggested as a risk factor, with a diet low in fiber and high in fat as a suggestive cause, although exceptions have been noted. For example, Eskimos have a low incidence of CRC, despite partaking in a diet low in fiber and high in animal fat. While some authors suggest a diet high in fiber may decrease the contact time between carcinogens in the bowel lumen with the mucosa, other studies demonstrate that fiber supplementation has no significant protective effect (6). The majority of studies, however, suggest that fiber in the diet has a protective effect by decreasing the time it takes for fecal matter to transit through the bowel and by binding carcinogens through increasing stool bulk (7). Other hypotheses regarding changes in diet and the development of CRC involve alterations in stool bacterial flora leading to increased bile salts which are a known risk factor (8). This is the groundwork behind the research and use of pro and pre-biotics (9). Other dietary components that have been proposed as protective factor include vitamin B6, calcium, and folate (10) (11) (12). Medications that have been proposed to decrease the risk include NSAIDS, hormone replacement therapies in women, and statins (13) (14) (15), although the degree to which these are protective has not been completely elucidated. Diseases that are associated with an increased rate of development of CRC include inflammatory bowel disease with ulcerative colitis, for example, having a 30% risk after 25 years if pancolitis is present (16) and previous diagnosis of other cancers--especially breast, uterine, ovarian, and other gastrointestinal tract cancers. Finally, other risk factors include smoking, obesity, exposure to certain viruses, alcohol, and some studies even suggesting diabetes to be a risk factor (17).

Family history is also important, with the risk of colon cancer increasing 3-fold with CRC occurring in a first-degree relative. The majority, however, are sporadic rather than familial, which only account for 5% of cases (18). All of the familial syndromes are inherited in autosomal fashion and can broadly be divided into familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). FAP, accounting for approximately 1% of all CRC, is a syndrome where hundreds to thousands of polyps develop in the colon and other parts of the GI tract early in life. Individuals have a close to 100% risk of developing colorectal cancer by the age or 40 if untreated (19). Associated syndromes are Gardner’s and Turcot’s syndrome, which are include osteomas/desmoids and central nervous system tumors, respectively. HNPCC, accounting for ~4-6% of all CRC, is associated with a 75% chance of having cancer by the age of 65. Patients have fewer polyps than FAP, that are often located in the ascending colon and sessile in nature (20). The syndrome can be subdivided into Lynch I and II, with Lynch I being sited specific to the colon and Lynch II associated with adenocarcinomas in the uterus, ovary, stomach and pancreas. The Amsterdam Criteria is used to help diagnose patients with HNPCC. To fulfill these criteria, patients must have 3 or more relatives with colorectal cancer, one of whom is a first degree relative of the other two, two or more generations need to be affected, and at least one of the relatives diagnosed before the age of 50. Since then these criteria have been modified to include HNPCC-associated tumors (Amsterdam II), and the Bethesda and revised Bethesda criteria were developed with even broader inclusion criteria including some characteristics regarding the tumor or adenomas themselves (21).

4. Relevant Physiology
As stated above, over 70% of colorectal cancers, regardless of etiology, arise from adenomatous polyps. A polyp is a mass that arises from the intestinal mucosa and often projects into the lumen of the bowel. Recent evidence also suggests that depressed polyps carry an increased risk of malignancy as well. Unfortunately, most are asymptomatic, highlighting the need for adequate screening and surveillance. They can be classified as hamartomas (juvenile polyps), hyperplastic polyps and adenomatous polyps. Although only adenomatous polyps are felt to be premalignant, large or extensive polyps of the other varieties have been associated with an increase risk of cancer (22). Despite this, only a minority of these lesions eventually develop into cancer. Adenomatous polyps are classified by gross appearance (pedunculated or sessile), histological appearance (tubular, villous or tubulovillous), size and degree of cellular atypia (23). Hereditary and somatic molecular changes have been noted in adenomatous polyps, which are thought to lead via a multistep process into invasive carcinoma (24). The mutations that occur can be divided into three categories: mutations of tumor suppressor genes, oncogenes, or DNA repair genes (25). Tumor suppressor genes normally suppress or control cell growth, thus when this function is lost, cell growth becomes uncontrolled. As this works via an autosomal recessive trait, both alleles need to be damaged to lose control. On the other hand, oncogenes are mutated proto-oncogenes and stimulate cell growth, and require only one allele to be mutated to cause dysfunction. DNA repair genes correct DNA errors that occur either during replication or mutational change. Dysfunction of these genes leads to the overall accumulation of mutations and increased possibility of uncontrolled growth.

This adenoma-carcinoma sequence takes place over 10 to 15 years. It includes characteristic changes like point mutations in the K-ras proto-oncogene; hypomethylation of DNA, leading to gene activation; loss of tumor-suppressor gene (the adenomatous polyposis coli (APC) gene on 5q21 and colorectal cancer (DCC) gene on 18q) and mutations in the p53 tumor-suppressor gene. These alterations then result in mucosal proliferation forming a polyp and finally carcinoma. Since the discovery of the APC mutation, it is seen as the major etiology of FAP (26). APC mutations are also very common in sporadic colorectal cancers. Mutations associated with the cause of HNPCC include MLH1 and MSH2 germline mutations (27). All these changes have been associated with increased risk of recurrence following surgery. Although molecular markers are being investigated (28), the most important prognostic factor remains surgical pathologic staging of the resected primary tumor, which is discussed later in this review.
Although most patients harboring a malignancy will have an isolated lesion on presentation, approximately 3-10% of patients will present with cancer in multiple locations. In addition, the presence of multiple adenomas has been shown to significantly increase the risk of both subsequent colorectal adenomas and carcinomas (29). Thus it is imperative to ensure an evaluation of the entire colon is performed to exclude more proximal or distant disease. Local and distant metastases, when present, occur following tumor cell migration through lymphatic channels to mesenteric or para-aortic lymph nodes and hematogenous spread to distant organs such as the liver, lung, and brain.

Lastly the degree of local invasion is critically important to accurate staging, management, and prognosis. Once an invasive component is present, lymph node metastasis and local recurrence are increased and often a more extensive resection than just polypectomy is required. Haggitt and colleagues proposed a classification system according to the depth of invasion seen on pathology following a polypectomy: Level 0 (no invasion muscularis mucosa), Level 1 (invasion through muscularis mucosa limited to head of polyp), Level 2 (invasion through muscularis mucosa limited to neck of polyp), Level 3 (invasion through muscularis mucosa in any part of the stalk), and Level 4 (invasion into the submucosa of the bowel wall below the polyp). These levels correlate with degree of lymph node metastases with level 0-3 being associated with less than 5% risk and level 4 has a 10-25% risk of associated metastases (30).

5. Diagnosis
Colon cancer often causes no symptoms until it reaches an advanced stage, especially with right sided lesions in a capacious cecum. Screening is therefore the primary modality of diagnosis (31). Symptoms may be present, but difficult to elucidate, as they are often very general and not very specific. Thus in addition to hematochezia, melena, abdominal pain, and change in bowel habits, patients should be questioned regarding fatigue and weakness that may be due to iron deficiency anemia seen especially with right-sided cancers. Iron deficiency is also seen more commonly in developing countries due increased prevalence of parasitic infections. Weight loss may be present, but most commonly seen in more advanced stages and metastatic disease. The abdominal pain can be secondary to a number of conditions, including obstruction, peritoneal dissemination, or perforation. A change in bowel habits is mostly seen in left-sided cancers as right-sided cancers tend to grow outwards and, as such, very rarely cause obstruction outside of obstructing the ileocecal valve. Tenesmus can be associated with colon cancer, although again mostly with rectal cancer. Importantly, symptomatic patients tend to have a worse prognosis as they often present in later stages (32).

The initial diagnostic workup for patients either symptomatic or in need of screening is similar with the exception of regular computed tomography (CT) scanning which has no role in screening. A digital rectal exam (DRE) is needed to evaluate the rectum and sphincter tone. It only detects tumors low enough to be felt in the distal part of the rectum but is useful as an initial screening test. Fecal occult blood testing (FOBT) is used to test for blood in the stool. It has the advantage of being inexpensive, and having good compliance. A major disadvantage is that most colon cancers do not bleed till later stages and many false positives are found. Yet in many large scale series, annual or biennial testing with fecal occult blood has been shown to significantly reduce the incidence of colorectal cancer. This is especially important in those areas where other screening methods are limited. Sigmoidoscopy can be used for evaluation of the rectum and distal part of the colon up to 60cm. The procedure can be performed in the office without sedation. It is inexpensive and cost-effective; however, it can only evaluate the colon to approximately the splenic flexure and, as such, could miss more proximal lesions: up to 40% of cancers are proximal to the splenic flexure. In general, colonoscopy is favored as it not only can biopsy or remove a lesion as with sigmoidoscopy; it can also evaluate the entire colon Double contrast barium enema (DCBE) can be used if scopes are unavailable, but can miss sessile polyps. Accuracy of DCBE and colonoscopy are 67% and 94%, respectively (33). The sensitivity of DCBE for adenomas less than 0.5 cm is 32%; for adenomas of 0.6-1cm is 53%; and larger than 1cm is 48% (34). With this procedure an enema of barium sulfate is administered. Air is then insufflated into the colon, distending it, resulting in a thin layer of barium over the inner mucosal lining. Plain film is used for evaluation. For scopes and DCBE the colon needs to be prepped with bowel preparations including polyetheleneglycol (PEG) and Magnesium Citrate. If these preparations are not available, a clear liquid diet for 1-2 days may be used. Although still only available in select institutions, virtual colonoscopy in which a CT scan is used to reconstruct a three-dimensional image of the inner surface of the colon, has been recently added as a recommended screening tool (54). Here the CT replaces the plain film used in DCBE. Polyps found, however, still need to be removed by standard colonoscopy. Standard abdominopelvic and chest CT, while not used in routine screening, is essential in pre-surgical evaluation. It can demonstrate regional tumor extension, lymphatic and distant metastases, and potential complications like perforation and fistula formation. Other modalities include plain chest radiograph for lung metastases and intra-operative ultrasound for hepatic metastases.

Positron emission tomography (PET) is a 3-dimensional scanning technology in which a radioactive sugar is injected intravenously and collects in tissues with high metabolic activity, including cancer cells. Areas with high emission are suggestive of malignancy and this test can be useful in localizing metastases or recurrence. Currently it is not used for screening or for routine workup.

Other pre-operative tests that are suggested include a cell blood count (CBC), chemistry panel, carcinoembryonic antigen (CEA), CA19-9, and liver function tests (LFTs). One needs to be aware that CEA can be related to tumor load, but is not very reliable as it is also elevated in pancreatic and hepatobiliary disease (35). Its levels are often used for monitoring response to medical treatment, especially in treatment of recurrence. A more recent approach uses radioactively labeled antibodies directed against CEA (36). Regarding LFTs, they can be normal even with hepatic metastases and are thus not a reliable marker for liver involvement, but allow some evaluation of liver synthetic function, and when abnormal may lead to further evaluation for disease. Lastly genetic counseling and DNA testing should be performed if available, especially in those patients with a known genetic disposition or familial syndrome.

The most common colon cancer cell type is adenocarcinoma arising from the glandular columnar epithelium, accounting for 95% of cases. Other types of malignancy include lymphoma, sarcoma, melenoma and squamous cell carcinoma. The differential diagnoses remains large and includes diverticulitis, colitis, inflammatory bowel disease, ischemia, or foreign bodies.

As stated, accurate staging leads to both proper management and prognostic significance for the patient. Therefore, depth of tumor penetration, presence of lymph node involvement and distant metastases guide the preoperative clinical and postoperative pathological staging process. Although radiographic and endoscopic findings can be used to assign a clinical stage, surgical assessment and histopathologic examination are often necessary outside of the end stage patient (37). Currently two staging classification systems are used: Dukes (38) and TNM (39) (Tumor, lymph Node and Metastases) (Tables 1 and 2).

Table 1: TNM Staging

Table 2: AJCC and Duke Staging

Approximately 15 to 20 percent of patients have distant metastatic disease at the time of presentation. Spread occurs to regional lymph nodes or to the liver via the portal venous circulation. The liver represents the most frequent visceral site of metastatic spread with one third of recurrent disease being associated with hepatic lesions. Rarely CRC metastasizes to the lungs, supraclavicular lymph nodes, bone, or brain without a liver lesion being present through systemic hematogenous spread. The median survival after the detection of such distant metastases is 6 to 9 months.

Most recurrences after a surgical resection occur within the first 4 years with one third to one half occurring in the first 2 years. For this reason the 5-year survival rate remains important for prognosis and predicting local and distant recurrence. (See below)

6. Surgical Management
Surgery is the only potentially curative modality for localized colon cancer. In addition, it is often required for diagnosis, staging or palliation of tumor-related obstruction or bleeding. Goals for surgery are exploration of abdomen, resection of involved segment, and wide lymphadenectomy—all with minimal complications. Total colectomy is necessary in patients with familial syndromes, multiple lesions, or those at high risk for further development of a malignancy. Pre-operative bowel prep is often recommended to reduce microbial load (40) although the utility of bowel preparation in elective surgery has been questioned, with some evidence suggesting it actually increases postoperative complications (41).

The vast majority of polyps can be removed at the time of diagnosis via the endoscope. Solitary tubular adenomas can be removed by either ligation or snaring of the pedicle for those pedunculated lesions or piecemeal polypectomy. Sessile lesions may need removal by submucosal dissection, but depending on size location (i.e., >4cm or right sided in the thin-walled cecum) surgical excision is often indicated. Complete excision is always desirable for good pathologic assessment. If carcinoma is discovered in the polyp without invasion of the line of resection, no further workup is necessary. If it is, surgery is indicated. As discussed previously, level of invasion is important in risk of lymphatic metastases and plan of surgery. Criteria needed for endoscopic management include: Haggitt level 1, 2 and 3; polyp is complete at pathologic examination and can completely be evaluated; no vascular or lymphatic invasion is present; no poor histological differentiation; and the margin of excision is not involved (46).

After resection, the remaining colon segments are primarily anastomosed to create a functioning colon, if possible. If this is not possible or in those patients with distal lesions and poor sphincter control a stoma is created. The extent of resection should include at least a 5 cm segment of normal bowel on either side (42). Excision of accompanying vascular arcades and associated mesentery is needed to completely excise the associated lymphatics. Recommendations are that at least 12 lymph nodes should be assessed for accurate staging and prognosis (43). Sentinel node biopsy at the time of colon resection can be used and is under investigation (44). A no touch technique has been advocated by some authors with the goal of avoiding intraoperative tumor manipulation to decrease shedding of tumor cells (45). This involves early division and ligation of the vascular supply, and occlusion of the proximal and distal bowel lumen around the area of the tumor prior to resection of the tumor bearing colon.

Patient positioning can be either supine or low lithotomy position. Before the skin incision patients should have preoperative antibiotics and deep venous thrombosis prophylaxis. Although not mandatory, ureteral catheters can be considered for help in ureteral identification during surgery. Skin incision can be midline or lower transverse. Resection of right-sided colon cancer is done via a right hemicolectomy. Overall care must be taken to visualize and protect the duodenum, right ureter, and right gonadal vessels as the right colon is mobilized. Visualization of these structures is mandatory to prevent injury. Mobilization begins at the ileocecal junction and continues along the lateral peritoneal attachments up to the hepatic flexure. This allows medial mobility of the colon away from the retroperitoneal tissue to give exposure to the ureter, spermatic vein and ovary if present. Some surgeons prefer a medial approach in which the ileocolic artery is initially divided and dissection proceeds in a medial to lateral fashion between the retroperitoneum and mesentery. With either method, when local invasion is present, multivisceral enbloc resection is necessary to obtain negative margins (47). Tissue planes between tumor and invaded organ should never be disrupted as this may decrease the cure rate by more than 50 percent (48). In general, the right colon is resected up to the right of the middle colic vessels with ligation and resection of the right branch of the middle colic artery. Lesions located at the hepatic flexure may require an extended right hemicolectomy with division of the middle colic artery at its base and extended resection of the associated bowel and mesentery. During this procedure, the lesser sac is entered via detachment of the omentum from the greater curvature of the stomach. If the cecum is involved, the specimen should include approximately 30cm of the terminal ileum in the resection. Control the ileocolic and right colic vessels as they are encountered during dissection can be performed with clamps or tissue sealant devices. In general dividing vessels about 1cm from the branch divisions is often preferred to prevent narrowing of the remaining vessels, though major branches should be taken proximally to ensure adequate lymph node retrieval. After ligation of all necessary vessels and mesentery, the specimen can be transected and delivered. Once adequate hemostasis and integrity of remaining structures such as the ureter has been confirmed, the bowel anastomosis can be performed with a one or two layer suture closure or stapling technique. Rotation of the ileum may be necessary and closure of exposed mesentery may be performed.

Left colon cancers require a left hemicolectomy with associated draining lymphatics or a sigmoid colectomy (49). After thorough abdominal exploration, the inferior mesenteric artery is identified and ligated after the takeoff of the left colic branch for more distal lesions or just at the takeoff of the left colic branch for a standard left hemicolectomy. Although high ligation near the aorta has been advocated by some authors, others have failed to demonstrate any survival advantage from this practice, even in those with stage III lymph node positive disease. The inferior mesenteric vein is ligated at the point of the duodenojejunal recess. Mobilization begins with the colon by dividing the arcade vessels and peritoneum at the left colic gutter from the base of the peritoneal reflection from the rectum to the splenic flexure. The mobilization proceeds again with lateral to medial or medial to lateral fashion and again identification of the ureter should take place early. The rectum may be mobilized for a small distance by separating the mesentery from the sacrum and ligating the mesenteric vessels at the rectosigmoid colon, although these planes should normally be relatively preserved with colon cancers. For an extended left hemicolectomy, full splenic flexure mobilization should be performed with division of the splenocolic ligament prior to mobilizing the transverse colon to the base of the middle colic artery. This vessel is dividing either near its base at the pancreas or division of the left branch for a standard left hemicolectomy. Once the remainder of the colon is mobilized, it is divided at the proximal and distal ends, and an anastomosis is performed. Additional length can be obtained by further mobilization of the rectum or more proximal mobilization (including ligation of the middle colic near its base if that was not performed). Excess tension should be avoided at all costs to avoid an ischemic anastomosis. Care must be taken to not damage the left ureter, left gonadal vessels, and tail of the pancreas during resection. Also small tears might occur in the spleen by excessive retraction and should be avoided.

Tumors in the transverse colon are usually resected from the hepatic flexure to the splenic flexure, extended right hemicolectomy (the authors’ preference) or extended left hemicolectomy, with removal of the contiguous mesentery of the middle colic vessels and techniques described above. If a total colectomy is indicated, for example with FAP, primary anastomosis is still possible with an ileorectal anastomosis.

In general, metastases are associated with poor prognosis. However colon resection is indicated unless there is carcinomatosis to prevent local complications of obstruction and perforation. Patients with isolated liver or pulmonary metastases may be resectable for cure. Resectability of a liver metastasis is determined using preoperative imaging, intraoperative ultrasound, and by direct palpation and visualization during resection. Lesions in the right lobe are amenable to right hepatectomy while small lesions of the central or left liver lobe can be resected through anatomic "segments.” Lesions that initially are not amenable to surgical resection may become so after preoperative chemotherapy or immunotherapy regimens. Lesions that are still not amenable to surgical resection can be treated with modalities including radio-frequency ablation, cryoablation, and chemoembolization.

Unresectable or metastatic disease can benefit from palliative surgery for relief of obstruction or control of bleeding via resection, stoma construction, or, in severe cases, side-to-side bypass. Ostomies can be divided into loop colostomy or end colostomy with or without creation of a mucous fistula. With the first method stool is diverted through the ostomy. A mucous fistula serves to decompress the secretions from the distal bowel. End colostomy without mucous fistula diverts the stool with the distal bowel ending in a blind loop, also referred to as a Hartmann’s pouch.

Colorectal cancer is the most common reason for colonic obstruction in the United States, whereas volvulus is the more common cause in developed countries. In general management of malignant obstruction should be considered for immediate resection if possible as it is a surgical emergency. Distention due to gas buildup from swallowed air and bacterial fermentation and accumulation of stool and liquid occurs rapidly. Also vascular compromise is a risk due to increased intramural pressure and can result in ischemic necrosis. A closed loop obstruction occurs when both the proximal and distal ends of the colon are occluded. Obstruction due to cancer in the rectum is often relieved by colostomy followed by neoadjuvant chemoradiation with later resection. Colon cancer on the other hand can be surgically treated with primary anastomosis if healthy ends of resection are present, or by colostomy if deemed necessary (60). Where available, colonic stenting is an option for resolution of the obstruction itself without treatment of the cancer. Always keep in mind that pseudo-obstruction or Ogilvie’s Syndrome needs to be ruled out before committing to mechanical obstruction.

Lastly, laparoscopic approaches have been increasingly applied and are evolving. Though the technology is often not available in developing countries, or rural areas, it is gaining foothold as a preferred approach in many centers. Yet, technical experience is required to ensure adequate and equivalent outcomes as its open predecessor. Several series have demonstrated advantages including reduced postoperative pain, earlier recovery of bowel function, and shorter length of hospital stay (50). A unique complication is tumor spread in port sites, though this has not been borne out in larger studies apart from the initial reports following the early use of this modality. Overall, the laparoscopic approach provides oncologic outcomes that are comparable to those achieved using open approaches (51).

7. Medical Therapy
Although an extensive review of the medical therapy for colon cancer is beyond the scope of this article, a few generalizations should be noted. Adjuvant therapies for colon cancers are very distinct from those for rectal cancers. Whereas in rectal cancer, chemoradiation therapy is extensively used, often in an upfront role, in colon cancer, chemotherapy remains the principal adjuvant treatment, with the addition of radiotherapy not showing improved outcome (52). In this setting chemotherapy is used to reduce the likelihood of metastasis developing, shrink tumor size, or slow tumor growth. Chemotherapy is often applied after surgery for cure (adjuvant) or as the primary therapy if surgery is not indicated (palliative). Very rarely with colon cancer will chemotherapy be used in a neoadjuvant (initial) setting. In general, adjuvant treatment should be started within 6-7 weeks of surgery, following healing of the surgical wounds. Although this has been well established in stage III disease, use in stage II disease is less clearly defined (53).

Regimens include the combination of 5-fluorouracil, leucovorin, and oxaliplatin. Irinotecan has also been used with more recently bevacizumab, a monoclonal antibody to VEG-F, being used in the recurrent and resistant disease. It is often given IV over a 4-6 week time frame on a weekly basis. Intrahepatic lesions if not treated with surgery can be treated with chemotherapy as well, either systemically with the above regimens or intraarterial with Floxuridine. If progression of disease occurs during adjuvant therapy, options are limited. Repeat surgical resection may necessary or other second line chemotherapeutic agents could be used.

Other therapies are being investigated like Bacillus Calmette-Guérin (BCG) as an adjuvant mixed with autologous tumor cells in immunotherapy (54) and introduction of exogenous genes. All these hold enormous potential, although considerable practical difficulties remain.

8. Screening
The rationale for colorectal cancer screening programs lies both in the fact that the earlier detection of localized, superficial cancers in asymptomatic individuals will increase the surgical cure rate and that the detection and resection of polyps prior to cancerous development decreases the incidence of CRC (55). Screening is recommend for CRC in average-risk people older than 50 years as well as in people 40 years old and older that have a family history of CRC. Modalities are discussed above. Guidelines include fecal occult blood testing every year combined with flexible sigmoidoscopy every 5 years, double-contrast barium enema every 5-10 years, colonoscopy every 10 years and recently virtual colonoscopy every 5 years has been added (56).

9. Prognosis and Complications
The overall 5-year survival rate from colon cancer for all-comers in all stages is 60%. In the United States nearly 60,000 patients die of the disease each year, making it the second leading cause of death. Accurate staging allows the physician to provide prognostic information to the patient. As a part of this, determining depth of invasion, number of involved lymph nodes (one to four lymph nodes versus five or more lymph nodes) (57) and presence of distant disease is imperative. The survival rate depends on the stage at the time of diagnosis. Approximate 5-year survival rates are: stage I 90%,; stage IIA 85%; IIB 72%; IIIA 83%, IIIB 64%, stage IIIC 44% and stage IV 8%.

After an apparently curative resection, diagnostic concern should focus on the early recognition of recurrence and the detection of metachronous carcinomas and adenomas. In 30-50% of patients recurrent disease develops despite undergoing an initial apparently curative resection, with the majority of these manifesting within the first 2 years. Local recurrence alone accounts for approximately one third of recurrences, distant metastases alone (mostly hepatic) are found in approximately 45%, and in the remainder multiple locations are involved (58). Once recurrent disease is discovered, the average survival time is usually less than a year, although improvements in adjuvant therapy have improved this dismal outcome.

Surgery may be necessary to obtain diagnostic tissue in patients with recurrent disease. These patients may warrant reexploration for diagnosis and possible resection. Although a minority of such patients may still have the potential for cure through a combination of surgery and chemotherapy, extensive evaluation to fully elucidate the extent of disease is imperative to ensure useful and not futile exploration.

Operative mortality in most centers is less than 5%, but increases with complicated cases like perforation and small hospital volume of cases. The number one cause for morbidity and mortality following surgery is cardiorespiratory complications such as myocardial infarction and pneumonia, as most cancers occur in the elderly population. Although anastomotic leaks following resection are a major morbidity and potential source of mortality, these occur in only ~3-10% following colonic resection. When small, they can be self-limiting and treated with antibiotics and/or drainage. Larger leaks may need drainage by insertion of drains, although often re-operation and proximal diversion are required.

Other nonfatal complications include wound infection, wound dehiscence, hernia, fistulas, hematomas, genitourinary dysfunction like urinary retention and impotence, adhesions and adjacent organ injury (59).

Adverse effects from adjuvant therapy are common and include diarrhea, mucositis, neutropenia, hair loss, skin hypersensitivity and sclerosing cholangitis. They can also result in secondary complications such as dehydration with renal failure and metabolic disorders following severe diarrhea or infectious risks due to neutropenia. To try to prevent the likelihood of such adverse effects, initial adjuvant doses can be lowered and increased over the next 2-3 doses.

10. Conclusion
Colon cancer is a health issue worldwide. Yet it is a potentially preventable disease, highlighting the need for adequate mass-scale screening by whatever means available. Primary prevention involves behavior modification and elimination of risk factors, such as increasing physical activity, decreasing alcohol consumption and tobacco use, and eating more fiber and other elements like calcium and folate. Secondary prevention involves early tumor detection by screening and evaluation. Tertiary prevention includes decreasing mortality in those patients with established tumors by proper surgical and medical management. Colon cancer is a disease that requires multidisciplinary teamwork from the general practitioner to the gastroenterologist, general surgeon, medical and occasionally radiation oncologist. A well defined guideline for screening, biopsies, surgical and medical management for both primary and recurrent disease is important to not only screen appropriate patients and reduce its incidence, but also care for those affected by this disease.

Lionel R. Brounts, MD*, Robert Zulu, MD+, Scott R. Steele, MD*

*Department of Surgery, Madigan Army Medical Center, Tacoma, Washington. +Department of Surgery, School of Medicine, Lusaka, Zambia

Corresponding author:
Scott R. Steele, MD
Department of Surgery
Madigan Army Medical Center
Fort Lewis, WA 98431
Phone: (253) 968-2200
Fax: (253) 968-0232; 968-5900
Email: harkersteele@mac.com

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