Colon Cancer, Adenocarcinoma

Synonyms and related keywords: colon cancer, colo-rectal cancer, colorectal cancer, rectal cancer, Dukes stage A colon cancer, Dukes stage B colon cancer, Dukes stage C colon cancer, Dukes stage D colon cancer, adenocarcinomas, adenomatous polyps, inflammatory bowel disease, ulcerative colitis, hereditary polyposis, nonpolyposis syndromes, adenomatous polyposis coli gene, APC gene, familial polyposis,familial adenomatous polyposis, FAP, beta-catenin mutations, DNA methylation changes, DPC4 gene, DCC gene, hereditary nonpolyposis colon cancer, ras gene mutations, occult bleeding, intestinal obstruction, ascites, rectal mass, rectal bleeding, colonic polyps, APC tumor suppressor gene, alcohol consumption, Ki-ras oncogene, intestinal polyps, obesity, azoxymethane, polymyositis, occult blood, carcinoembryonic antigen, CEA


INTRODUCTION

Background: Colorectal cancer is the third most common cancer in both men and women in the United States. Risk factors include age, a diet rich in fat and cholesterol, inflammatory bowel disease (especially ulcerative colitis), and genetic predisposition, including hereditary polyposis and nonpolyposis syndromes.

If detected early, colorectal cancer is curable by surgery. Adjuvant chemotherapy can prolong survival in disease that has reached the lymph nodes. Both systemic and locoregional chemotherapy (eg, intrahepatic intraarterial chemotherapy for liver metastases) have a role in patients with metastatic colon cancer. Radiotherapy is used in cases of rectal cancer to reduce the risk of local recurrence.

Long-term survival correlates with stage of disease in colorectal cancer. Progress has been made in understanding the molecular basis of colorectal cancer predisposition and progression. Efforts are underway to develop better screening strategies, chemopreventive approaches, and novel therapies to improve patient survival rates and to minimize toxicity. Despite all efforts, colorectal cancer remains the third leading cause of death from cancer in the United States.

Recent advances have included the development of orally available forms of 5-fluorouracil (5-FU) and the demonstration that anti-vascular endothelial growth factor (VEGF) therapy with bevacizumab prolongs survival in advanced colorectal cancer when combined with irinotecan, 5-FU, and leucovorin.

Pathophysiology: The vast majority of colorectal cancers are adenocarcinomas, which arise from preexisting adenomatous polyps that develop in the normal colonic mucosa. This adenoma-carcinoma sequence is a well-characterized clinical and histopathologic series of events with which discrete molecular genetic alterations have been associated.

Pioneering work by Bert Vogelstein and colleagues over the last 20 years has identified a number of critically important genetic alterations that contribute, through their multiplicity over many years, to the eventual development of colorectal cancer. The earliest event appears to involve the APC (adenomatous polyposis coli) gene, which is mutated in individuals affected by familial adenomatous polyposis (FAP). The protein encoded by the APC gene targets the degradation of beta-catenin, a protein component of a transcriptional complex that activates growth-promoting oncogenes, such as cyclin D1 or c-myc. APC mutations are very common in sporadic colorectal cancer, and beta-catenin mutations have also been identified.

DNA methylation changes are a relatively early event and have been detected at the polyp stage. Colorectal cancers and polyps have an imbalance in genomic DNA methylation, with global hypomethylation and regional hypermethylation. Hypomethylation can lead to oncogene activation, whereas hypermethylation can lead to silencing of tumor suppressor genes. ras gene mutations are observed commonly in larger polyps but not smaller polyps, suggesting a role for this oncogene in polyp growth.

Chromosome arm 18q deletions are a later event associated with cancer development. These deletions likely involve the targets DPC4 (a gene deleted in pancreatic cancer and involved in the transforming growth factor [TGF]-beta growth-inhibitory signaling pathway) and DCC (a gene frequently deleted in colon cancer). Chromosome arm 17p losses and tumor suppressor p53 mutations are common late events in colon cancer. Bcl2 overexpression leading to inhibition of cell death signaling has been observed as a relatively early event in colorectal cancer development. 18q deletions detected in Dukes stage B colon cancers have been associated with an increased risk of recurrence following surgery, and studies are in progress to determine whether patients with 18q deletions might benefit from more aggressive adjuvant chemotherapy.

Another predisposing condition is hereditary nonpolyposis colon cancer, in which affected individuals inherit a mutation in one of several genes involved in DNA mismatch repair, including MSH2, MLH1, and PMS2. ras gene mutations have been detected in the stool of patients with colorectal cancer and may in the future be useful in early diagnosis.

Although the use of nonsteroidal anti-inflammatory agents, such as sulindac, have been shown to affect the number of polyps, this has not translated to a clinical impact on cancer prevention.

Frequency:

• In the US: The American Cancer Society estimates that about 104,950 new cases of colon cancer and 40,340 new cases of rectal cancer will be reported in 2005 in the United States. Combined, the 2 cancer types will cause about 56,290 deaths.

• Internationally: According to the World Health Organization's April 2003 report on global cancer rates more than 940,000 new cases of colorectal cancer and nearly 500,000 deaths are reported worldwide each year.

Mortality/Morbidity: The overall 5-year survival rate from colon cancer is approximately 60%, and nearly 60,000 people die of the disease each year in the United States. The 5-year survival rate is different for each stage (see Staging); the staging classification for colon cancer can predict prognosis well. For Dukes stage A tumors involving only the mucosa, the 5-year survival rate exceeds 90%, whereas for metastatic colon cancer, the 5-year survival rate is about 5%. For Dukes stage B colon cancers, the 5-year survival rate is greater than 70% and can be greater than 80% if the tumor does not penetrate the muscularis mucosa. Once the tumor has spread to the lymph nodes (ie, Dukes stage C), the 5-year survival rate usually is less than 60%.

Race: Recent data demonstrate a decrease in incidence rates of colorectal carcinoma in whites since the mid 1980s, particularly for the distal colon and rectum. Proximal colon carcinoma rates in blacks are considerably higher than in whites and continue to increase, whereas rates in whites show signs of decline.

Sex: The frequency of colon cancer is essentially the same among men and women.

Age: Age is a well-known risk factor for colon cancer, and risk begins to rise in people older than 40 years. Age is a risk factor because a number of rare genetic alterations are believed to occur within the somatic cells of the colonic epithelium over years, ultimately leading to the development of colon cancer in older individuals. Individuals affected by one of the well-known familial predispositions to colon cancer are much more likely to develop cancer at a young age. For example, individuals with familial adenomatous polyposis have a 100% chance of developing colon cancer unless their colon is removed surgically, usually when they are aged 20-30 years.

CLINICAL

History: Colon cancer often is found by screening and may be completely asymptomatic. Approximately 50% of patients present with abdominal pain, 35% with altered bowel habits, 30% with occult bleeding, and 15% with intestinal obstruction. Right-sided colon cancers tend to be larger and more likely to bleed, whereas left-sided tumors tend to be smaller and more likely to be obstructing. Obtain a family history of colon cancer, familial polyposis, or ulcerative colitis. Consider the possibility of cancer of the colon in patients with a fever of unknown origin and in patients with polymyositis.

Physical: The physical examination findings may be completely normal, especially in early stage colorectal cancer, or general or specific findings due to progression of the disease may be present. These may include weight loss, cachexia, abdominal discomfort or tenderness, liver mass, abdominal distention, ascites, rectal mass, rectal bleeding, or occult blood on rectal examination.

Causes: A number of risk factors have been associated with colon cancer. Colonic polyps, which occur with increasing age, represent a risk for colon cancer development. A study considering the clinical evidence for the adenoma-carcinoma sequence recently concluded that adenomas probably are precursors of carcinomas, but the ultimate effect of removing polyps on reducing cancer incidence in the population remains unknown.

Genetics is a very important risk factor for development of colorectal cancer. Familial polyposis, in which patients inherit a mutant copy of the APC tumor suppressor gene, is rare but confers very high risk. Familial nonpolyposis colon cancer, which accounts for 1-5% of colon cancers, develops because of inherited mutations in DNA mismatch repair genes.

Alcohol consumption is a risk factor for gastrointestinal cancer, including colon cancer. Increasing age and a lower intake of total folate have been associated with mutations of the Ki-ras oncogene, which are found commonly in colorectal cancer. Diet, and in particular fat content of diet, has been associated with increased risk of colon cancer. Animal studies have found that dietary beef induces and dietary rye bran prevents formation of intestinal polyps. Several studies have suggested that red meat and processed meats, through the action of heme, predispose to colon cancer by enhancing formation of N-nitrosocompounds, which result in DNA damage. One study suggested that obesity, rather than fat intake per se, predisposed to colon cancers induced in animals by exposure to the carcinogen azoxymethane.

The evidence is weak that soy food or isoflavones in the diet protect a person from colon cancer. Exercise is believed to reduce the risk of colon cancer. The risk of colon cancer may be decreased among women who recently used postmenopausal hormone replacement therapy. Women who are postmenopausal and who have never used hormone replacement therapy have a higher risk of colon, but not rectal, cancer than do women who are premenopausal and of the same age, sociocultural class, and dietary habits. Apparently, no association exists between frequency of bowel movement or laxative use and risk of colon cancer. Some data associate calcium intake and risk of colon cancer. A statistically significant association exists between Helicobacter exposure and colonic polyps.

Tobacco smoking is associated with a higher risk of colon cancer, which appears to be mediated by induction of 5-lipoxygenase–associated angiogenic pathways.

DIFFERENTIALS

Crohn Disease
Diverticulitis
Diverticulosis, Small Intestinal
Fecal Incontinence
Ileus
Inflammatory Bowel Disease
Kaposi Sarcoma
Peritonitis and Abdominal Sepsis
Ulcerative Colitis
Uremia

Other Problems to be Considered:

In patients who present with lower GI bleeding, the differential diagnosis includes colorectal cancer, inflammatory bowel disease (ulcerative colitis or Crohn disease), diverticular disease, uremia, Rendu-Osler-Weber syndrome, foreign bodies, polyps, metastatic disease, intestinal lymphomas, or Kaposi sarcoma involving the gut.

Causes of intestinal obstruction other than cancer include adhesions, peritonitis, inflammatory bowel disease, fecal impaction, strangulated bowels, and ileus. Obstruction is less common for right-sided lesions because the ascending colon is wider than the distal colon and the fecal content is fluid.

WORKUP

Lab Studies:

• Carcinoembryonic antigen

• Obtaining a preoperative carcinoembryonic antigen (CEA) level can be helpful in the clinical management of colorectal cancer. CEA is much less likely to be elevated in poorly differentiated colon or rectal carcinomas.

• If CEA level is elevated preoperatively, it can be monitored for evidence of recurrence. Remember the following 2 things: (1) CEA may be elevated for reasons other than colon cancer, such as pancreatic or hepatobiliary disease, and elevation does not always reflect cancer or disease recurrence; (2) recurrence remains a possibility when CEA is not elevated, even if CEA was elevated preoperatively. Findings of other tests, such as CT scans and colonoscopy, must be incorporated in detection of recurrence.

• If the CEA is elevated in recurrent or metastatic colorectal cancer, the CEA level may be helpful to monitor response. A rising CEA would not be expected if the tumor were responding to therapy, and a falling CEA would not be expected if the tumor were not responding to therapy. The real value of monitoring CEA after initial resection is that it can allow early identification of patients who may benefit from additional surgery with curative intent.

• Cancer antigen 19-9: Other tumor markers, such as cancer antigen 19-9 (CA 19-9) may also be helpful, if initially elevated. Some studies have suggested that the expression of multiple tissue cancer antigens is associated with a greater incidence of recurrence and shorter disease-free survival rates.

• Other blood lab tests include standard complete blood cell counts and electrolyte and chemistry panels. Liver function testing should be performed, but results can be normal despite the presence of metastatic disease.

• Urinalysis

Imaging Studies:

• Chest radiography: This is part of the routine evaluation and staging workup. It may reveal metastatic spread to the lungs.

• Computed tomographic scanning

• Abdominal/pelvic CT scans can be useful in diagnosis of colon cancer that has metastasized to lymph nodes and liver. Multiple metastases in the liver render colon cancer incurable by surgery and chemotherapy.

• Metastatic colon cancer does not, however, preclude surgery as an option for palliation, eg, in cases with bleeding or obstruction. A subset of patients with solitary or few surgically resectable hepatic metastases may be candidates for aggressive surgery with curative intent. A German study reported a 5-year tumor-free survival rate of 34% and an actuarial 10-year survival rate of 21% in such patients (Scheele, 1996).

• Chest CT scans can be helpful to identify lung metastases. Prognosis is poor in patients with liver and lung metastases.

• CT scans also are very helpful in the follow-up of patients with resected, as well as metastatic, disease. Imaging can diagnose recurrent disease and can document response to chemotherapy.

• PET imaging (FDG-PET) may be useful for staging colorectal cancer and may be very useful in detecting recurrent disease.

• A study reported in December of 2004 concluded that PET/CT and contrast-enhanced CT (ceCT) provided similar information regarding hepatic metastases of colorectal cancer, whereas PET/CT was superior to ceCT for the detection of recurrent intrahepatic tumors after hepatectomy, extrahepatic metastases, and local recurrence at the site of the initial colorectal surgery. Based on the results, Selzner et al routinely perform PET/CT on all patients who are evaluated for liver resection for metastatic colorectal cancer (Selzner, 2004).

Procedures:

• Although not perfect, colonoscopy allows examination of the entire colon, and can be used to obtain a biopsy of suggestive lesions or to remove polyps.

• Adequate bowel cleansing is necessary prior to many procedures. Several preparations are marketed for bowel cleansing (eg, polyethylene glycol 3350 [GoLYTELY, NuLYTELY], magnesium citrate [Citroma], senna [X-Prep]) in preparing patients for surgery or gastrointestinal procedures such as endoscopy, colonoscopy, and barium x-ray studies.
• Bowel cleansing preparations may be used with various dietary preparations (eg, clear liquid diet 1-2 d before surgery or procedure) and are convenient to administer on an outpatient basis.

• Colonoscopy can be performed safely in older individuals; other factors must be considered in the decision whether to use this procedure. One recent study suggested that, in a clinical setting, the decision to perform colonoscopy should consider proximal lesions of clinical interest, life expectancy of the patient, costs, and risks associated with the procedure.

• Recent data suggest that periodic colonoscopy may be the most effective and cost-effective screening method.

• Double-contrast barium enemas are an option for screening for colorectal cancer and can aid in establishing the diagnosis of colon cancer.

• This procedure has limitations and can miss lesions in the region of the ileocecal valve or the distal rectum or in patients with severe diverticulosis.

• In patients who have undergone colonoscopic polypectomy, colonoscopic examination is a more effective method of surveillance than double-contrast barium enema.

• In a recent study of the use of barium enema in Norway, the correct diagnosis was made in 90.9% of cases, and the investigators concluded that barium enema examination is valuable in the diagnosis of colon cancer, comparing favorably with colonoscopy. The primary reason for missed radiologic diagnosis was failure to observe important lesions visible on the radiographs.

• Flexible sigmoidoscopy is a screening tool that can detect polyps or cancers as far as 60 cm from the anus. If polyps are found in the distal colon, others may be in the proximal colon and can be detected by colonoscopy. However, a recent important finding indicates that proximal lesions that are missed by flexible sigmoidoscopy are not associated with the presence of distal lesions in 50% of cases.

Histologic Findings: The microscopic appearance of colonic adenocarcinomas may be that of well-differentiated or poorly differentiated glandular structures. Normal topological architecture of colonic epithelium in terms of a crypt-villous axis is lost. Anorectal lesions have a squamous morphology.

The treating physician must review the histologic findings in order to confirm the diagnosis and establish the specific disease that is being treated. In medical oncology, this is a basic principle that directs appropriate therapy.

Staging: Two classifications have been of use: the TNM ([primary] tumor, [regional lymph] node, [remote] metastasis) staging and the Dukes classification.

Table 1. TNM Staging System for Colon Cancer

Stage	Primary Tumor (T)	Regional Lymph Node (N)	Remote Metastasis (M)
Stage 0	Carcinoma in situ	N0	M0
Stage I	Tumor may invade submucosa (T1) or muscularis (T2).	N0	M0
Stage II	Tumor invades muscularis (T3) or perirectal tissues (T4).	N0	M0
Stage IIIA	T1-4	N1	M0
Stage IIIB	T1-4	N2-3	M0
Stage IV	T1-4	N1-3	M1

Table 2. Dukes Classification

Stage	Characteristics
Dukes stage A	Carcinoma in situ limited to mucosa or submucosa (T1, N0, M0)
Dukes stage B	Cancer that extends into the muscularis (B1), into or through the serosa (B2)
Dukes stage C	Cancer that extends to regional lymph nodes (T1-4, N1, M0)
Dukes stage D	Modified classification; cancer that has metastasized to distant sites (T1-4, N1-3, M1)

An excellent correlation exists between stage and 5-year survival rate in patients with colon cancer. For stage I or Dukes stage A, the 5-year survival rate following surgical resection exceeds 90%. For stage II or Dukes stage B, 5-year survival rate is 70-85% following resection, with or without adjuvant therapy. For stage III or Dukes stage C, 5-year survival rate is 30-60% following resection and adjuvant chemotherapy. For stage IV or Dukes stage D, 5-year survival rate is poor (approximately 5%).

TREATMENT

Medical Care: Important advances have been made regarding the first-line standard therapy of metastatic colorectal cancer. Both a European trial and a US trial found that the rate of response to the combination of 5-FU, leucovorin (LV), and irinotecan (CPT11) was higher than that to 5-FU/leucovorin or CPT11 alone. In addition, the higher response rate translated to a greater median survival duration (about 14 mo) with the combination regimen. Similarly, a phase III European study demonstrated significantly improved response rates with the addition of oxaliplatin to the 5-FU/leucovorin regimen, while another study reported significantly prolonged progression-free survival with this combination. Studies to confirm improvement in overall survival are ongoing.

In 2004, anti-VEGF therapy with bevacizumab (Avastin) was shown to increase survival in patients receiving Avastin in combination with irinotecan, 5-FU, and leucovorin. Colorectal cancer was the first cancer type to be shown to respond to antiangiogenic therapy as demonstrated by the clinical trials performed by Herb Hurwirtz and colleagues at Duke University. Based on the evidence for improved median survival rates, the FDA approved Avastin for use in combination therapy in advanced colorectal cancer.

• Standard therapy for metastatic colon cancer is CPT11 plus 5-FU/leucovorin, also known as the Saltz regimen. In 2005, the standard therapy for metastatic colorectal cancer is IFL plus bevacizumab (irinotecan, 5-FU, leucovorin, Avastin).

• Each of the agents in the Saltz regimen is administered by IV injection weekly for 4 weeks every 6 weeks.
• Diarrhea is the most commonly encountered adverse effect with this regimen. Other adverse effects include mucositis, neutropenia, hair loss, and skin hypersensitivity reactions. The combination of 5-FU/leucovorin/CPT11 has the potential for severe toxicity, mainly diarrhea leading to dehydration and vascular collapse, in some patients. Many clinicians start therapy with an approximately 25% decrease in doses of CPT11 (100 mg/m² rather than 125 mg/m²) and 5-FU (400 mg/m² rather than 500 mg/m²) and escalate to full doses only if the initial cycle of treatment is well tolerated.

• Other agents are active. Interestingly, cetuximab (Erbitux), which targets the EGF receptor, has activity in colon cancer, whereas gefitinib (Iressa), which is a small molecule inhibitor of the tyrosine kinase activity of epidermal growth factor receptor (EGFR), is not active. EGFR is frequently overexpressed in colon cancer, but mutations have not been reported.
• Intrahepatic chemotherapy for colon cancer with liver metastasis is intraarterial floxuridine (FUDR).

• Following resection of the primary colon cancer and lymph nodes, 2 options for chemotherapy exist: systemic chemotherapy with a standard regimen such as 5-FU/leucovorin/CPT11 or intrahepatic (intraarterial) chemotherapy with FUDR.
• The second option is worth considering for patients with large or multiple liver lesions because this route results in delivery of a higher dose of chemotherapy to the liver metastases. The underlying principle is that liver metastases derive their blood supply primarily through the hepatic arterial circulation, whereas normal liver derives most of its blood supply through the portal vein.
• The major adverse effect of intraarterial FUDR is sclerosing cholangitis, which may be quite severe and may necessitate discontinuation of therapy.

• Adjuvant therapy for colon cancer is 5-FU/leucovorin. However, in 2004, the results of the phase III MOSAIC adjuvant chemotherapy trial evaluating 2246 patients with stage II and III (Dukes B and C) colon cancer demonstrated that adding oxaliplatin to 5-FU/leucovorin resulted in a reduction in relapse rates and a modest increase in 3-year disease-free survival. Should these findings result in improved overall survival upon longer follow-up of the data, then this regimen would represent a significant change to the standard of adjuvant care. Studies evaluating the efficacy of bevacizumab in the adjuvant setting are also underway.

• 5-FU/levamisole is no longer an appropriate component of adjuvant therapy for colon cancer.
• Studies have demonstrated a survival advantage for patients with Dukes stage C colon cancer who receive adjuvant chemotherapy. The 5-FU–based therapy has been administered in the past according to several schedules, including continuous infusion daily for 5 days every 4 weeks (Mayo Clinic regimen) and weekly for 6 weeks with 2 weeks off (Roswell Park regimen).
• In terms of patient survival, no study has demonstrated the superiority of daily therapy for 5 days every 4 weeks over weekly therapy for 6 weeks or any other schedule. Thus, at present, the regimens that can be administered on an outpatient basis (weekly for 6 wk with 2 wk off or daily for 5 d q4wk) are the most popular and are widely considered to be essentially equivalent as per the International Multicentre Pooled Analysis of Colon Trials (IMPACT).
• Adjuvant chemotherapy for stage II (Dukes B) remains controversial, although the National Surgical Adjuvant Breast and Bowel Project (NSABP) meta-analysis of 4 prior adjuvant NSABP studies demonstrated a 30% reduction in mortality with adjuvant chemotherapy. In addition, the latest QUASAR (a randomized study of adjuvant chemotherapy versus observation including 3238 colorectal patients) data update demonstrated a small (3%) absolute survival benefit in such patients. Therefore, patients with Dukes B disease and any adverse risk factor (large primary tumor [T4], pathologic T3 level of invasion >15 mm, left-sided tumor location, obstructing or perforating tumors, less than 12 lymph nodes removed, poorly differentiated tumors, perineural invasion, venous invasion, elevated tumor markers, tumor budding, tumor nodules) should be considered for adjuvant therapy.

Surgical Care: The classic surgical procedure for colon cancer is anterior resection that involves a "no touch" isolation technique. The abdomen is explored to determine whether the tumor is resectable, and resection is performed segmentally (eg, right or left hemicolectomy) with end-to-end anastomosis. A resection margin of 10 cm of grossly normal bowel on both sides of the tumor along with associated lymph nodes is recommended. Total colonic resection is performed for patients with familial polyposis and multiple colonic polyps.

The role of lymphatic mapping (LM) and sentinel lymphadenectomy (SL) is undergoing investigation, although preliminary results appear conflicting. However, identification of micrometastatic nodal disease resulted in upstaging of disease in 5-50% of patients.

• Laparoscopic colon resection: The technology exists to use laparoscopic techniques to achieve colon resection. A recent study reported favorable results with 5 years of follow-up.

• Sphincter replacement by electrically stimulated skeletal muscle neosphincter and artificial anal sphincter provide a continence option for patients with end-stage fecal incontinence and those requiring abdominoperineal resection. A multicenter prospective study is underway at Memorial Sloan Kettering Cancer Center in New York to evaluate the safety and effectiveness of an artificial bowel sphincter (ABS) prosthesis. The objective of this study is to demonstrate that the ABS prosthesis can be implanted surgically without serious adverse sequelae and can provide an acceptable level of continence, determined through the use of a fecal incontinence scoring system patient questionnaire.

• Partial hepatectomy for colorectal cancer metastases limited to the liver is a therapeutic option for a subset of patients with recurrent colorectal cancer that appears to be confined to the liver. Some studies have reported an increased median survival duration in highly selected patients. Predictors of a better outcome include a single metastasis, longer disease-free interval from resection of the primary tumor to presentation with metastasis, CEA level less than 200 ng/mL, tumors less than 5 cm in diameter, unilobar disease, and negative margins after resection. Early detection of recurrent colorectal cancer includes imaging by CT or MRI. PET scanning appears to be more accurate than CT and has become increasingly used to identify recurrent disease, but it can miss small foci of the disease. CEA levels also may be useful to detect recurrence, although false-positives and false-negatives occur.

• Other therapeutic options for liver metastases include cryoablation (a technique currently performed during abdominal surgery) and hepatic arterial infusion (HAI) of chemotherapeutic agents such as FUDR. Adjuvant HAI FUDR is a consideration following partial hepatectomy. An effort is underway to investigate the role of chemotherapy in converting unresectable into resectable disease.

Consultations:

• Surgical consultation

• Colorectal cancer, especially early stage disease, can be cured surgically. Thus, following diagnosis and staging, obtaining surgical consultation for the possibility of resection may be appropriate. Following surgery, the stage of the tumor may be advanced depending on operative findings (eg, lymph node involvement, palpable liver masses, peritoneal spread).
• In the care of patients with colorectal cancer and isolated liver metastases, consider surgical consultation for resection, if possible, and as an option to introduce intrahepatic intra-arterial chemotherapy through an implantable pump. However, improved survival has been demonstrated only for HAI combined with systemic chemotherapy following resection (Barber, 2004).
• In advanced disease, surgical intervention may be very helpful in palliative care of bleeding or obstruction.

• Gastroenterology consultation

• GI consultation is very important for screening of high-risk individuals (ie, people with family history of colorectal cancer or polyposis syndromes) and those individuals who are found to be inappropriately iron deficient or to have occult blood on screening fecal exam. A GI consultation is necessary to visualize the colon endoscopically, to obtain biopsies, or to resect polyps. GI consultation may be necessary in the management of advanced disease.
• GI consultation is necessary in the follow-up of patients with colorectal cancer subsequent to resection and adjuvant chemotherapy. Patients must be screened for recurrent disease in the colon by periodic colonoscopic examination. Because colonic neoplasms (ie, adenocarcinoma) are slow growing, initially this colonoscopic follow-up is performed once a year for 2-3 years and subsequently every 2-3 years.

• Radiation oncology

• Patients with rectal cancer must be referred for radiation oncology consultation. Radiation has been demonstrated to reduce the risk of local recurrence of rectal cancer following surgical resection. Thus, in the adjuvant setting, the therapy for rectal cancer includes combination of radiation and chemotherapy. This is a basic difference between the therapy of colon cancer and rectal cancer.
• Radiation may be useful in palliative care (eg, to reduce tumor growth in specific locations following metastasis of colorectal cancer). Such therapy may improve the quality of life (eg, by helping to control pain or spinal cord compression or superior vena cava [SVC] syndrome).
• Consultation with interventional radiology may be appropriate for patients with colorectal cancer and liver metastases in order to discuss potential benefits of palliative chemoembolization.

Diet: Diet is regular.

Activity: Activity may be performed as tolerated.

MEDICATION

Current medical therapy for metastatic colon cancer involves the use of antimetabolites and cytotoxic agents (ie, 5-FU and CPT11). Standard therapy for metastatic colon cancer is CPT11 plus 5-FU/leucovorin (LV). Standard adjuvant therapy for resected colon cancer is 5-FU/LV. An intergroup study comparing 5-FU/LV and the Saltz regimen (5-FU/LV/CPT11) as adjuvant therapy has completed accrual and is in the follow-up phase. The MOSAIC trial (5-FU/LV vs 5-FU/LV/oxaliplatin) reported 3-year follow-up data, and is awaiting data maturation. The use of capecitabine, an oral agent, is under evaluation as a potential replacement for 5-FU/LV, and has been combined with irinotecan and oxaliplatin.

If disease progression occurs despite adjuvant therapy, options are limited, and the responses are poor. For patients with recurrent disease, prior therapy determines available treatment options. Selected patients should undergo repeat colonoscopy and surgical resection if a second intraluminal tumor is identified. If previous treatment involved irinotecan, second-line treatment would often entail the use of oxaliplatin-based regimens, which may include novel agents in a clinical trial setting.

FDA approval has been given for the use of cetuximab alone or with irinotecan in irinotecan-refractory metastatic cancer. If oxaliplatin is used adjuvantly, then irinotecan, in combination with other novel agents would be considered in the context of clinical trials. Anti-EGFR strategies, including cetuximab and other thymidine kinase (TK) inhibitors, such as gefitinib, in combination with various chemotherapy agents, are in clinical trials. Antiangiogenesis approaches continue to be explored.

The 5-FU–based therapy has been administered in the past using several schedules, including continuous infusion daily for 5 days every 4 weeks (Mayo Clinic regimen) and continuous infusion weekly for 6 weeks with 2 weeks off (Roswell Park regimen).

Intrahepatic chemotherapy for colon cancer with liver metastasis is intraarterial FUDR following resection of the primary colon cancer and lymph nodes. Consider this therapeutic option for patients with multiple liver lesions, because this route results in delivery of a higher dose of chemotherapy to the liver metastases. Intraarterial FUDR therapy usually is delivered through an implanted subcutaneous pump, which is refilled periodically. The major adverse effect of intraarterial FUDR is sclerosing cholangitis, which may be quite severe and may necessitate discontinuation of therapy.

Drug Category: Antineoplastic agents -- Current standard therapy for colon cancer involves combination chemotherapy. Diarrhea is the most commonly encountered adverse effect with this regimen. Other adverse effects include mucositis, neutropenia, hair loss, and skin hypersensitivity reactions. Bowel perforation or GI bleeding can rarely occur.

Drug Name	Fluorouracil (Adrucil) -- Mainstay of medical chemotherapy for colorectal cancer for patients for more than 40 y. Has activity as single agent and has for many years been combined with biochemical modulator leucovorin (folinic acid). Shown to be effective in adjuvant setting and in patients with metastatic disease, in whom regression can occur (in less than 20%). Classic antimetabolite (ie, anticancer drug with chemical structure similar to endogenous intermediates or building blocks of DNA or RNA synthesis). In 1950s, tumor cells were observed to incorporate this base into their DNA preferentially compared to normal colonic epithelia. 5-FU inhibits tumor cell growth through at least 3 different mechanisms that ultimately disrupt DNA synthesis or cellular viability. These effects depend on intracellular conversion of 5-FU into 5-FdUMP, 5-FUTP, and 5-FdUTP. 5-FdUMP inhibits thymidylate synthase (key enzyme in DNA synthesis). 5-FUTP is incorporated into RNA and interferes with RNA processing, and 5-FdUTP is incorporated into DNA, leading to cytotoxic DNA strand breakage. Current standard adjuvant therapy for colon cancer involves combination 5-FU/LV chemotherapy (see Standard Therapy). Saltz regimen (5-FU/LV/CPT11) now standard first-line therapy for metastatic colon cancer. Because of toxicity, maximum of 400 mg/m2 of 5-FU and 100 mg/m2 of CPT11 can be used as starting dose. Recent clinical trial data have demonstrated equivalence of efficacy between 6 mo of 5-FU/LV and oral prodrug capecitabine; therefore, it is being used increasingly in the adjuvant setting.
Adult Dose	Standard therapy: 500 mg/m2 1 h after leucovorin 20 mg/m2 IV, dose weekly for 4 wk q6wk Adjuvant therapy Mayo Clinic regimen: 425 mg/m2/d IV bolus on days 1-5 1 h after LV 20 mg/m2 for 5 d q4wk; 6 mo of therapy is current practice Roswell Park regimen: 500 mg/m2 1 h after 2-h infusion of LV 500 mg/m2 for 6 wk; 2 wk off
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bone marrow suppression; serious infection; unresponsive or progressive adenocarcinoma; pregnancy
Interactions	Increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents; leucovorin is a reduced folate, which, when combined with 5-FU, more effectively blocks thymidylate synthase (leads to improved response rates in therapy)
Pregnancy	D - Unsafe in pregnancy
Precautions	Nausea, oral and GI ulcers, depression of immune system, and hematopoiesis failure (ie, bone marrow suppression) may occur; adjust dosage in renal impairment

Drug Name	Irinotecan (Camptosar) -- Inhibits topoisomerase I, inhibiting DNA replication. Effective in treatment of colorectal cancer. Current standard therapy for metastatic colon cancer involves combination of 5-FU/LV/CPT11 chemotherapy (see Standard Therapy). Because of toxicity problems associated with Saltz regimen (5-FU/LV/CPT11), now standard first-line therapy for metastatic colon cancer, maximum of 400 mg/m2 of 5-FU and 100 mg/m2 of CPT11 can be used as starting dose.
Adult Dose	125 mg/m2 IV over 90 min qwk for 4 wk q6wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe diarrhea; febrile neutropenia; unresponsive or progressive adenocarcinoma
Interactions	Concomitant administration with other antineoplastics may result in prolonged neutropenia and thrombocytopenia in addition to increased morbidity/mortality risk
Pregnancy	D - Unsafe in pregnancy
Precautions	Adverse effects include myelosuppression, alopecia, nausea, vomiting, and diarrhea; monitor bone marrow function

Drug Name	Leucovorin (Wellcovorin) -- Reduced form of folic acid that does not require enzymatic reduction reaction for activation. Allows for purine and pyrimidine synthesis, both of which are needed for normal erythropoiesis. Current standard therapy for colon cancer involves combination chemotherapy.
Adult Dose	Standard therapy: 20 mg/m2 IV every wk for 4 wk every 6 wk Adjuvant therapy: 20 mg/m2 IV before 5-FU on days 1-5 for 5 d every 4 wk (Mayo Clinic regimen); 6 mo of therapy is current practice
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; pernicious anemia; vitamin-deficient megaloblastic anemias
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not to administer intrathecally or intraventricularly

Drug Name	Oxaliplatin (Eloxatin) -- A platinum-based antineoplastic agent used in combination with an infusion of 5-fluorouracil (5-FU) and leucovorin in the adjuvant setting, or for the treatment of metastatic colorectal cancer in patients with recurrence or progression following initial treatment with irinotecan, 5-FU, and leucovorin. It forms interstrand and intrastrand Pt-DNA crosslinks that inhibit DNA replication and transcription. The cytotoxicity is cell-cycle nonspecific.
Adult Dose	Day 1: 85 mg/m2 IV over 2 h; administer simultaneously with leucovorin 200 mg/m2; followed by 5-FU 400 mg/m2 IV bolus over 2-4 min, then 5-FU 600 mg/m2 IV continuous infusion in 500 mL D5W over 22 h Day 2: Leucovorin 200 mg/m2 IV over 2 h, followed by 5-FU 400 mg/m2 IV bolus over 2-4 min, then 5-FU 600 mg/m2 IV as a continuous infusion in 500 mL D5W over 22 h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to oxaliplatin or other platinum compounds
Interactions	May increase 5-FU serum concentration by approximately 20%
Pregnancy	D - Unsafe in pregnancy
Precautions	Anaphylaxis may occur within minutes of administration; may cause neuropathy, pulmonary fibrosis, bone marrow suppression, GI tract symptoms (eg, nausea, vomiting, stomatitis), renal or hepatic toxicity (decrease dose), or thromboembolism; dilute IV only in dextrose-containing solution

Drug Name	Cetuximab (Erbitux) -- Recombinant human/mouse chimeric monoclonal antibody that specifically binds to the extracellular domain of human epidermal growth factor receptors (EGFR, HER1, c-ErbB-1). Cetuximab-bound EGFR inhibits activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased production of matrix metalloproteinase and VEGF. Indicated for treating irinotecan-refractory, EGFR-expressed, metastatic colorectal carcinoma. Treatment is preferably combined with irinotecan. May be administered as monotherapy if irinotecan is not tolerated.
Adult Dose	First dose: 400 mg/m2 IV infused over 2 h Weekly maintenance doses: 250 mg/m2 IV infused over 1 h Not to exceed infusion rate of 10 mg/min (ie, 5 mL/min); must administer with low-protein–binding 0.22 mm in-line filter; premedication with an H1 antagonist (eg, diphenhydramine 50 mg IV) recommended
Pediatric Dose	Not established
Contraindications	None for metastatic colorectal carcinoma
Interactions	Limited data exist; none reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution with documented hypersensitivity, including allergy to murine proteins; may cause infusion-related hypotension and airway distress (eg, bronchospasm, stridor, hoarseness), particularly with the first infusion (90%); premedicate with diphenhydramine 50 mg IV; decrease dose with mild or moderate (grade 1 or 2) infusion reaction and immediately and permanently discontinue with severe (grade 3 or 4) infusion reaction; common adverse effects include acnelike rash, dry skin, tiredness or weakness, fever, constipation, and abdominal pain; may rarely cause interstitial lung disease; do not shake or dilute solution; sunlight can exacerbate any skin reactions

Drug Name	Bevacizumab (Avastin) -- Indicated as a first-line treatment for metastatic colorectal cancer. Murine-derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting VEGF. Inhibiting new blood vessel formation denies blood, oxygen, and other nutrients needed for tumor growth. Used in combination with standard chemotherapy.
Adult Dose	5 mg/kg IV q2wk until disease progression detected
Pediatric Dose	Not established
Contraindications	None reported
Interactions	Coadministration with 5-FU increases incidence (2-fold) of serious and fatal arterial thromboembolic events (ie, CVA, MI, TIAs, angina)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Angiogenesis is critical to fetal development and use of bevacizumab during pregnancy would likely result in adverse fetal effects; common adverse effects include hypertension, fatigue, thrombosis, diarrhea, leukopenia, proteinuria, headache, anorexia, and stomatitis; may cause serious or fatal but rare events, including gastrointestinal perforation, intra-abdominal infections, impaired wound healing, hemoptysis (particularly with lung cancers), and internal bleeding; increases risk of serious and fatal arterial thrombotic events with 5-FU; do not initiate treatment for at least 28 d following major surgery; the surgical incision should be fully healed; breastfeeding should be discontinued during and for at least 20 d following treatment with bevacizumab

Drug Name	Panitumumab (Vectibix) -- Recombinant human IgG2 kappa monoclonal antibody that binds to human epidermal growth factor receptor (EGFR). Indicated to treat colorectal cancer that has metastasized following standard chemotherapy.
Adult Dose	6 mg/kg IV infused over 60 min q2wk
Pediatric Dose	Not established
Contraindications	None known
Interactions	Data limited; none reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Common adverse effects include rash, fatigue, abdominal pain, nausea, and diarrhea; serious adverse effects include pulmonary fibrosis, severe rash complicated by infections, infusion reactions (for grade I or II reaction, reduce infusion rate by 50%; for grade III or IV reaction, immediately discontinue permanently), ocular toxicity, abdominal pain, vomiting, and constipation; administer using low-protein–binding filter

FOLLOW-UP

Further Inpatient Care:

• Conduct inpatient care as needed.

Further Outpatient Care:

• Follow-up is very important for patients with colorectal cancer in order to detect recurrence and initiate appropriate therapy.

• For patients with metastatic disease who receive 5-FU–based therapy, the therapy is continued until adverse effects limit the therapy or evidence of disease progression occurs. During active therapy for metastatic disease, obtaining follow-up CT scans of the abdomen and chest every 2 months is customary.

• The clinician should consider obtaining FGD-PET imaging, which may be useful in detecting recurrent disease.

• For patients with progressive disease, options for further therapy must be discussed, including discontinuing therapy, intrahepatic chemotherapy (if appropriate), and experimental (ie, phase I) therapy. For patients who receive adjuvant chemotherapy, follow-up is necessary to rule out recurrence.

Deterrence/Prevention:

• Fecal occult blood screening

• The effect of either annual or biennial fecal occult blood screening on the incidence of colorectal cancer was evaluated recently in a large prospective randomized case-controlled study of 46,551 individuals in Minnesota. In this study, in the group of patients that was screened by stool guaiac testing, 1 of 6 was positive; these patients underwent further diagnostic evaluation, including barium enema, proctosigmoidoscopy, upper GI series, and colonoscopy. Although sigmoidoscopy and upper GI series were discontinued part way through the 18-year study, colonoscopy was performed throughout and led to the diagnosis of polyps and cancers.

• The incidence of colorectal cancer was found to be significantly reduced in both the annually and biennially screened groups compared to the control group. Colorectal cancer was detected in 417 of the annually screened group and 435 of the biennially screened group, while 507 cases were detected in the controls (80% and 83% incidence compared to control group, respectively). The authors concluded that identification and removal of colorectal cancer precursor lesions (ie, adenomatous polyps) led to reduced incidence of colorectal cancer in the screened groups.

• Eighteen years of follow-up was required to be able to demonstrate the reduction in incidence of colorectal cancer using fecal occult blood screening.

• Currently, debate exists about when fecal occult blood screening should begin in the general population, as well as about the best screening method. Clearly, more efforts directed at screening are needed because this not only reduces morbidity and mortality rates but also the incidence of colorectal cancer.

Prognosis:

• Prognosis depends on stage (see Staging).

Patient Education:

• Refer patients with early onset colorectal cancer for genetic counseling. Such counseling may lead to awareness and/or testing of family members at risk.

• For excellent patient education resources, visit eMedicine's Cancer Center; Esophagus, Stomach, and Intestine Center; and Cholesterol Center. Also, see eMedicine's patient education articles Colon Cancer, Diverticulosis and Diverticulitis, High Cholesterol, and Cholesterol FAQs.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Accurate timely diagnosis of colorectal cancer is important for optimal care.

• Discontinuation of ineffective therapy is important to avoid further toxicity and to maximize quality of life.

• Appropriate management of complications, including neutropenic fevers and mucositis, is important.

• Management of bowel perforation or GI bleeding may be necessary in rare cases.

• Follow-up care, including screening for recurrence and reinitiation of therapy, is necessary.

• Use of PET imaging in addition to CT scanning may be useful in diagnosing recurrence.