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ColonCancer,Adenocarcinoma
Tomislav Dragovich, MD, PhD, Associate Professor of Medicine and Director of Clinical Gastrointestinal Cancer Program, Arizona Cancer Center, University of Arizona College of Medicine Vassiliki L Tsikitis, MD, Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona Medical Center Updated: Sep 28, 2010

Introduction
Background
Invasive colorectal cancer is a preventable disease. Early detection through widely applied screening programs is the most important factor in the recent decline of colorectal cancer in developed countries (see Deterrence/Prevention). Full implementation of the [1 ] screening guidelines can cut mortality rate from colorectal cancer in the United States by an estimated additional 50%; even greater reductions are estimated for countries where screening tests may not be widely available at present. New and more comprehensive screening strategies are also needed. Fundamental advances in understanding the biology and genetics of colorectal cancer are taking place. This knowledge is slowly making its way into the clinic and being employed to better stratify individual risks of developing colorectal cancer, discover better screening methodologies, allow for better prognostication, and improve ones ability to predict benefit from new anticancer therapies. In the past 10 years, an unprecedented advance in systemic therapy for colorectal cancer has dramatically improved outcome for patients with metastatic disease. Until the mid 1990s, the only approved agent for colorectal cancer was 5-fluorouracil. New agents [2 ] that became available in the past 10 years include cytotoxic agents such as irinotecan and oxaliplatin, oral fluoropyrimidines [3 ] (capecitabine and tegafur), and biologic agents such as bevacizumab, cetuximab, and panitumumab. Though surgery remains the definitive treatment modality, these new agents will likely translate into improved cure rates for patients with early stage disease (stage II and III) and prolonged survival for those with stage IV disease. Further advances are likely to come from the development of new targeted agents and integration of those agents with other modalities such as surgery, radiation therapy, and liver-directed therapies. An image depicting standard colectomies for adenocarcinoma of the colon can be seen below.

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Standard colectomies for adenocarcinoma of the colon.

Pathophysiology
Genetically, colorectal cancer represents a complex disease, and genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Sequence of molecular and genetic events leading to transformation from [4 ] adenomatous polyps to overt malignancy has been characterized by Vogelstein and Fearon. The early event is a mutation of APC (adenomatous polyposis gene), which was first discovered in individuals with familial adenomatous polyposis (FAP). The protein encoded by APC is important in activation of oncogene c-myc and cyclin D1, which drives the progression to malignant phenotype. Although FAP is a rare hereditary syndrome accounting for only about 1% of cases of colon cancer, APC mutations are very frequent in sporadic colorectal cancers. In addition to mutations, epigenetic events such as abnormal DNA methylation can also cause silencing of tumor suppressor genes or activation of oncogenes, compromising the genetic balance and ultimately leading to malignant transformation. Other important genes in colon carcinogenesis include KRAS oncogene , chromosome 18 loss of heterozygosity (LOH) leading to inactivation of SMAD4 (DPC4), and DCC (deleted in colon cancer) tumor suppression genes. Chromosome arm 17p deletion and mutations affecting p53 tumor suppressor gene confer resistance to programmed cell death (apoptosis) and are thought to be late events in colon carcinogenesis. A subset of colorectal cancers is characterized with deficient DNA mismatch repair. This phenotype has been linked to mutations of genes such as MSH2, MLH1, and PMS2. These mutations result in so-called high frequency microsatellite instability (H-MSI), which can be detected with an immunocytochemistry assay. H-MSI is a hallmark of hereditary nonpolyposis colon cancer syndrome (HNPCC, Lynch syndrome), which accounts for about 6% of all colon cancers. H-MSI is also found in about 20% of sporadic colon cancers.

Frequency
United States

The American Cancer Society estimated that 148,810 individuals would be diagnosed with colorectal cancer and 49,960 would die from [5 ] this disease in the United States in 2008.

International

In 2003, the World Health Organization estimated that approximately 940,000 individuals were be diagnosed with colorectal cancer worldwide and 492,000 died from it that year.

Mortality/Morbidity
Colorectal cancer is a major health burden worldwide. The incidence and mortality from colon cancer has been on a slow decline over the past 20 years in the United States; however, colon cancer remained the third most common cause of cancer-related mortality in 2008. A multitude of risk factors have been linked to colorectal cancer, including heredity, environmental exposures, and inflammatory syndromes affecting gastrointestinal tract.

Race
Recent trends in the United States suggest a disproportionally higher incidence and death from colon cancer in African Americans than in whites. Hispanic persons have the lowest incidence and mortality from colorectal cancer.

Sex
The incidence of colorectal cancer is about equal for males and females.

Age
Age is a well-known risk factor for colorectal cancer, as it is for many other solid tumors. The timeline for progression from early premalignant lesion to malignant cancer ranges from 10-20 years. The incidence of colorectal cancer peaks at about age 65 years.

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Clinical
History
Due to increased emphasis on screening practices, colon cancer is now often detected during screening procedures. Other common clinical presentations include iron-deficiency anemia, rectal bleeding, abdominal pain, change in bowel habits, and intestinal obstruction or perforation. Right-sided lesions are more likely to bleed and cause diarrhea, while left-sided tumors are usually detected later and could present with bowel obstruction.

Physical
Physical findings could be very nonspecific (fatigue, weight loss) or absent early in the disease course. In more advanced cases, abdominal tenderness, macroscopic rectal bleeding, palpable abdominal mass, hepatomegaly, and ascites could be present on physical examination.

Causes
Colorectal cancer is a multifactorial disease process, with etiology transcending genetic factors, environmental exposures (including diet), and inflammatory conditions of digestive tract. Though much about colorectal cancer genetics remains unknown, current research indicates that genetic factors have the greatest correlation to colorectal cancer. Hereditary mutation of the APC gene is the cause of familial adenomatous polyposis (FAP), where affected individuals carry an almost 100% risk of developing colon cancer by age 40 years. Hereditary nonpolyposis colon cancer syndrome (HNPCC, Lynch syndrome) carries about 40% lifetime risk of developing colorectal cancer; individuals with this syndrome are also at increased risk for urothelial cancer, endometrial cancer, and other less common cancers. Lynch syndrome is characterized by deficient mismatch repair (dMMR) due to inherited mutation in one of the mismatch repair genes, such as hMLH1, hMSH2, hMSH6, hPMS1, hPMS2, and possibly other undiscovered genes. HNPCC is a cause of about 6% of all colon cancers. Although the use of aspirin may reduce the risk of colorectal neoplasia in some populations, a study by Burn et al found no effect on the incidence of colorectal cancer among carriers of Lynch syndrome with use of aspirin, resistant starch, or [6 ] both. Dietary factors are the subject of intense and ongoing investigations. Epidemiological studies have linked increased risk of colorectal cancer with a diet high in red meat and animal fat, low-fiber diet, and low overall intake of fruits and vegetables. Factors associated with lower risk include folate intake, calcium intake, and estrogen replacement therapy. However, most of these studies were retrospective epidemiological studies and have yet to be validated in prospective, placebo-controlled, interventional trials. Lifestyle choices such as alcohol and tobacco consumption, obesity, and sedentary habits have also been associated with increased risk for colorectal cancer. Association between body mass index (BMI) and risk of colorectal adenomas and cancer has been reported, but few studies have had adequate sample size for conducting stratified analyses. Jacobs et al pooled data from 8,213 participants in 7 prospective studies of metachronous colorectal adenomas to assess whether the association between BMI and metachronous neoplasia varied by sex, family history, colorectal subsite, or features of metachronous lesions. Exploratory analyses indicated that BMI was significantly related to most histologic characteristics of metachronous adenomas among men but not among women. The researchers concluded that body [8 ] size may affect colorectal carcinogenesis at comparatively early stages, particularly among men. Inflammatory bowel diseases such as ulcerative colitis and Crohns disease also carry an increased risk of developing colorectal adenocarcinoma. The risk for developing colorectal malignancy increases with the duration of inflammatory bowel disease and the greater extent of colon involvement.
[7 ]

Differential Diagnoses
Arteriovenous malformation (AVM) Carcinoid/Neuroendocrine Tumors and Rare Tumors of GI Tract Crohn Disease Diverticulosis, Small Intestinal Ileus Ischemic bowel Small Intestinal Carcinomas Ulcerative Colitis

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Gastrointestinal Lymphoma

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Workup
Laboratory Studies
Laboratory studies are done with a goal of assessing patients organ function (liver, kidneys) in anticipation of diagnostic and therapeutic procedures (imaging, biopsy, surgery, chemotherapy) and also to estimate tumor burden (CEA level).

Complete blood cell count Chemistries and liver function tests Serum carcinoembryonic antigen (CEA) should be obtained preoperatively as it carries prognostic value and when highly elevated may indicate more advanced, disseminated disease.

Imaging Studies
Adequate imaging of the chest and abdomen should be obtained for staging purposes, ideally preoperatively. Chest radiograph or chest CT scan Abdominal barium study to better delineate primary lesion preoperatively Abdominal/pelvic computerized tomography (CT scan), contrast ultrasound of the abdomen/liver, and abdominal/pelvic MRI are appropriate for imaging abdomen and liver, for the purpose of staging. Positron emission tomography (PET) scans are emerging as a very useful modality for staging and assessment of colorectal cancers. The newest addition, a fusion PET-CT scan, allows for detection of metastatic deposits and has added tissue-based resolution of CT scan. Of note, some histologies, especially a mucinous signet-ring cell variant of colorectal cancer, may not be well visualized on a PET scan.

Procedures
A suspicion of colorectal cancer diagnosis warrants rectal examination and colonoscopy with a biopsy of suspicious lesion. Colonoscopy Sigmoidoscopy Double contrast barium enema After tissue diagnosis is confirmed, further workup is driven by the clinical setting (eg, profuse bleeding and obstruction may require an emergent surgery), patient status and comorbidities, and presenting symptoms.

Histologic Findings
The microscopic appearance of colon 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.

Staging
The TNM staging system has become the international standard for staging of colorectal cancer. It uses 3 descriptors: T for primary tumor, N for lymph nodal involvement, and M for metastasis. In turn, these are divided into the following categories: Tumor categories Tx:No description of the tumor's extent is possible because of incomplete information. Tis: In situ carcinoma; the tumor involves only the muscularis mucosa

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T1: The cancer has grown through the muscularis mucosa and extends into the submucosa T2:The cancer has grown through the submucosa and extends into the muscularis propria T3: The cancer has grown through the muscularis propria and into the outermost layers of the colon but not through them; it has not reached any nearby organs or tissues T4a: The cancer has grown through the serosa (visceral peritoneum) T4b: The cancer has grown through the wall of the colon and is attached to or invades nearby tissues or organs Node categories Nx:No description of lymph node involvement is possible because of incomplete information N0:No cancer in nearby lymph nodes N1a:Cancer cells found in 1 nearby lymph node N1b:Cancer cells found in 2 to 3 nearby lymph nodes N1c:Small deposits of cancer cells found in areas of fat near lymph nodes, but not in the lymph nodes themselves. N2a:Cancer cells found in 4 to 6 nearby lymph nodes N2b: Cancer cells found in 7 or more nearby lymph nodes Metastasis categories M0:No distant spread seen M1a: The cancer has spread to 1 distant organ or set of distant lymph nodes M1b:The cancer has spread to more than 1 distant organ or set of distant lymph nodes, or has spread to distant parts of the peritoneum

Table 1. TNM Staging System for Colon Cancer

Stage Stage 0

Primary Tumor (T) Carcinoma in situ (Tis) Tumor may invade submucosa (T1) or muscularis propria (T2) Tumor invades muscularis (T3) or adjacent organs or structures (T4) T3 T4a T4b T1-4

Regional Lymph Node (N) N0

Remote Metastasis (M) M0

Stage I

N0

M0

Stage II Stage IIA Stage IIB Stage IIC Stage IIIA

N0 N0 N0 N0 N1-2

M0 M0 M0 M0 M0

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Stage IIIB Stage IIIC Stage IVA Stage IVB

T1-4 T3-4 T1-4 T1-4

N1-2 N1-2 N1-3 N1-3

M0 M0 M1a M1b

Prognostic factors associated with staging Patient prognosis is a function of clinical and histopathologic stage of colon cancer at diagnosis. In addition to the well-established significance of standard pathological features such as depth of bowel wall penetration (T), number of locoregional lymph nodes involved (N), and presence of extra-colonic metastases (M), several other factors have been proven to be of importance (see list below). These include number of harvested and processed lymph nodes, histologic grade, and evidence of lymphovascular and perineural invasion. Bowel obstruction at diagnosis, ulcerative growth pattern, perforation, and elevated preoperative CEA level have all been shown to be [9 ] associated with worse prognosis. Molecular prognostic factors such as p53, loss of heterozygosity for 18q, mutations of deleted in colon cancer gene (DCC), EGFR amplification, and KRAS mutations have all been investigated but are not currently used as prognostic factors in standard clinical practice. Deficient mismatch repair (dMMR), which is associated with high frequency microsatellite instability (H-MSI), has been recently shown to be associated with better clinical outcome for patients with resectable colon cancer; this was based on a retrospective analysis of [10,11 ] In addition, it appears that patients with dMMR (H-MSI) did several large randomized trials of adjuvant therapy for colon cancer. [12 ] not benefit from fluorouracil-based adjuvant therapy. This may become a useful test for prognosis and treatment planning in patients with resectable colon cancer. Selected prognostic factors and 5-year relapse-free survival in patients with colorectal cancer, based on the Mayo Clinic calculator (http://www.mayoclinic.com/calcs) for population of patients aged 60-69 years (data regarding numbers of lymph nodes analyzed is [13 ] from Le Voyer el al, 2003 ) are as follows (prognostic factor, 5-year relapse-free survival): T3N0 (11-20) nodes analyzed 79% T3N0 low grade 73% T3N0 ( 10 lymph nodes examined) 72% T3N0 high grade 65% T4N0 low grade 60% T4N0 high grade 51% T3N1 49% T3N2 15% A review of Surveillance, Epidemiology, and End Results (SEER) population-based data on colon cancer by the AJCC Hindgut Taskforce found that that T1-2N2 cancers have a better prognosis than T3-4N2,T4bN1 have a similar prognosis to T4N2, T1-2N1 have a similar prognosis to T2N0/T3N0, and T1-2N2a have similar prognosis to T2N0/T3N0 (T1N2a) or T4aN0 (T2N2a); in addition, prognosis for T4a lesions is better than T4b by N category. The number of positive nodes affects prognosis. The Taskforce proposed [14 ] the following revisions of the TN categorization for colon cancer : Shift T1-2N2 lesions from IIIC to IIIA/IIIB Shift T4bN1 from IIIB to IIIC

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Subdivide T4/N1/N2 Revise substaging of stages II/III.

Treatment
Medical Care
Systemic chemotherapy 5-Fluorouracil remains the backbone of chemotherapy regimens for colon cancer, both in the adjuvant and metastatic setting. In the past 10 years, it was established that combination regimens provide improved efficacy and prolonged progression-free survival in patients with metastatic colon cancer. In addition to 5-fluorouracil, oral fluoropyrimidines such as capecitabine (Xeloda) and tegafur are increasingly used as monotherapy or in combination with oxaliplatin (Eloxatin) and irinotecan (Camptosar). Some of the standard [15 ] combination regimens employ prolonged continuous infusion of fluorouracil (FOLFIRI, FOLFOX) or capecitabine (CAPOX, XELOX, XELIRI). Availability of new classes of active drugs and biologics for colorectal cancer pushed the expected survival for patients with metastatic disease from 12 months 2 decades ago to about 22 months currently. A meta-analysis of 6 randomized phase II and II trials examined the efficacy of capecitabine with oxaliplatin (CAP/OX) compared with fluorouracil with oxaliplatin (FU/OX) in metastatic colorectal cancer. CAP/OX resulted in a lower response rate but overall progression-free survival and overall survival were not affected and were similar in both treatment regimens. Characteristic toxicity [16 ] occurred in the FU schedules and thrombocytopenia and hand-foot syndrome were more prominent in the CAP regimens. In a phase III multicenter trial, Kim et al compared overall survival of second-line therapy for patients with advanced colorectal carcinoma refractory to fluorouracil. Fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) (n=246) versus irinotecan (n=245) was compared (crossover to the other treatment was mandated if disease progression occurred). Overall survival did not significantly differ between FOLFOX4 and irinotecan; however, FOLFOX 4 improved response rate (RR) and time to progression (TTP) compared with [17 ] irinotecan (P=0.0009 for each RR and TTP). FOLFOX4 was associated with more neutropenia and paresthesias. Key clinical questions relate to the most advantageous selection of drug combination and the sequence of different treatment options in individual patients with colorectal cancer. This information is to be derived from information on tumor biology, patient performance status, organ function, and pharmacogenomics testing. Adjuvant (postoperative) chemotherapy The standard therapy for patients with stage III and some patients with stage II colon cancer for the last 2 decades consisted of [18,19,20 ] This approach has been tested in several large fluorouracil in combination with adjuncts such as levamisole and leucovorin. randomized trials and has been shown to reduce individual 5-year risk of cancer recurrence and death by about 30%. Two recent large randomized trials (MOSAIC and NASBP-C06) investigated the addition of oxaliplatin to fluorouracil (FOLFOX4 and FLOX, respectively) and demonstrated a significant improvement in 3-year disease-free survival for patients with stage III colon cancer. The addition of irinotecan to fluorouracil in the same patient population provided no benefit based on the results from two large randomized trials (CALGB 89803 and PETACC 3). Another randomized study, XACT, demonstrated noninferiority of capecitabine (Xeloda) compared to 5-FU/leucovorin as adjuvant therapy for patients with stage III colon cancer. A large trial comparing capecitabine plus oxaliplatin (XELOX) versus FOLFOX has completed accrual, but survival data have not yet been reported. The role of adjuvant chemotherapy for stage II colon cancer is controversial. A large European trial (QUASAR) demonstrated small but significant benefit (3.6%) in terms of absolute 5-year survival rate for those patients who received 5-fluorouracil/leucovorin versus those in the control group. Ongoing adjuvant trials are investigating additional risk stratification of stage II colon cancer based on clinicopathological and molecular markers (ECOG 5202 trial). Though information on results of adjuvant therapy in stage II and III colon cancer is limited, a data set assembled by the Adjuvant Colon Cancer Endpoints group with fluorouracil-based adjuvant therapy was recently analyzed. The authors concluded that adjuvant chemotherapy provides significant disease-free survival benefit because it reduces the recurrence rate particularly within the first 2 [21 ] years of adjuvant therapy but with some benefit in years 3-4. Biologic agents

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Bevacizumab (Avastin) was the first anti-angiogenesis drug to be approved in clinical practice and the first indication was for metastatic colorectal cancer. This is a humanized monoclonal antibody to vascular endothelial growth factor (VEGF) and a pivotal trial demonstrated improved progression-free and overall survival when bevacizumab was added to chemotherapy (IFL, fluorouracil plus irinotecan). A pooled analysis of cohorts of older patients (aged 65 years or older) from 2 randomized clinical trials examined the benefit of bevacizumab plus fluorouracil-based chemotherapy in first-line treatment of metastatic colorectal cancer. The study concluded that adding bevacizumab to fluorouracil-based chemotherapy improved overall survival and progression-free survival in older patients as it [22 ] does in younger patients, without increased risks of treatment in the older age group. Two other biologic agents approved for colorectal cancer are epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies. Cetuximab (Erbitux) is a chimeric monoclonal antibody approved as monotherapy or in combination with irinotecan (Camptosar) in [23 ] patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin therapy. Panitumumab (Vectibix) is fully human monoclonal antibody and the current indication as a monotherapy for patients with colorectal cancer in whom combination chemotherapy failed or was not tolerated. A recent trial by Hecht et al evaluated panitumumab added to bevacizumab and chemotherapy (oxaliplatin- and irinotecan-based) as first-line treatment of metastatic colorectal cancer and concluded [24 ] that the addition of panitumumab resulted in increased toxicity and decreased progression-free survival. Intratumoral KRAS gene mutation can predict sensitivity to anti-EGFR antibodies. Investigators from a large international trial exploring the benefit of adding cetuximab to first-line chemotherapy with FOLFIRI (CRYSTAL Trial) reported that only patients with wild-type KRAS derived clinical benefit from cetuximab. Patients with mutant KRAS had no clinical benefit from adding cetuximab to chemotherapy and experienced only unnecessary toxicity. KRAS mutations are present in about 40% of colon adenocarcinomas. Based on these results, testing for KRAS mutation has been already added to cetuximab indication by European regulatory agency (EMEA) and is expected to be added to United States indication by the FDA as well. Bokemeyer et al examined the overall response rate when combining cetuximab with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4), as opposed to the regimen without cetuximab, for first-line treatment of metastatic colorectal cancer in a randomized study. They also examined the influence of the KRAS mutation status. They concluded that the overall response rate for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone though a statistically significant increase in odds for a response with the addition of cetuximab could not be established, except in patients with KRAS wild-type tumors, for whom the addition of cetuximab [26 ] increased chance of response and lowered risk of disease progression. Other mutations that involve some of the kinases downstream from KRAS (such as BRAF and PI3K) are being investigated and may result in even more selective methods to identify patients that may benefit from EGFR inhibition. Radiation therapy While radiation therapy remains a standard modality for patients with rectal cancer, the role of radiation therapy is limited in colon cancer. It does not have a role in the adjuvant setting, and in metastatic settings, it is limited to palliative therapy for selected metastatic sites such as bone or brain metastases. Newer, more selective ways of administering radiation therapy such as stereotactic radiotherapy (CyberKnife) and tomotherapy are currently being investigated and may extend indications for radiotherapy in the management of colon cancer in the future.
[25 ]

A prospective, multicenter, randomized phase III study by Hendlisz et al compared the addition of yttrium-90 resin to a treatment 2 regimen of fluorouracil 300 mg/m IV infusion (days 1-14 q8wk) with fluorouracil IV alone. Yytrium-90 was injected intra-arterially into the hepatic artery. Findings showed that the addition of radioembolization with yytrium-90 significantly improved time to liver [27 ] progression and median time to tumor progression.

Surgical Care
Surgery is the only curative modality for localized colon cancer (stage I-III) and potentially provides the only curative option for patients with limited metastatic disease in liver and/or lung (stage IV disease). The general principles for all operations include removal of the primary tumor with adequate margins including areas of lymphatic drainage.

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For lesions in the cecum and right colon, a right hemicolectomy is indicated. During a right hemicolectomy, the ileocolic, right colic, and right branch of the middle colic vessels are divided and removed. Care must be taken to identify the right ureter, the ovarian or testicular vessels, and the duodenum. If the omentum is attached to the tumor, it should be removed en bloc with the specimen. For lesions in the proximal or middle transverse colon, an extended right hemicolectomy can be performed where the ileocolic, right colic, and middle colic vessels are divided and the specimen is removed with its mesentery. For lesions in the splenic flexure and left colon, a left hemicolectomy is indicated. The left branch of the middle colic vessels, the inferior mesenteric vein, and the left colic vessels along with their mesenteries are included with the specimen. For sigmoid colon lesions, a sigmoid colectomy is appropriate. The inferior mesenteric artery is divided at its origin, and dissection proceeds toward the pelvis until adequate margins are obtained. Care must be taken during dissection to identify the left ureter and the left ovarian or testicular vessels. Total abdominal colectomy with ileorectal anastomosis may be required for patients who have been diagnosed with HNPCC, attenuated familial adenomatous polyposis, and metachronous cancers in separate colon segments or at times in acute malignant colon obstructions with unknown status of the proximal bowel. The advent of laparoscopy has revolutionized the surgical approach of colonic resections for cancers. The same oncologic principles are respected. Large prospective randomized trials have demonstrated that there are no significant differences with regard to intraoperative or postoperative complications, perioperative mortality rates, readmission or reoperation rates, or rate of surgical wound recurrence. At a median follow-up of 7 years, no significant differences existed in the 5-year disease-free survival rate (69% versus 68% in the laparoscopy-assisted colectomy [LAC] and open colectomy groups, respectively) or overall survival (76% versus 75%). Overall laparoscopic colectomy provides comparable oncologic outcomes (cause-specific survival, disease recurrence, number of [28,29,30,31,32,33 ] lymph nodes harvested) to those achieved with an open approach. Standard management of patients with metastatic disease is systemic chemotherapy. The proper use of elective colon/rectal resections in nonobstructed patients with stage IV disease is a source of continuing debate. Medical oncologists properly note the major drawbacks to palliative resection, such as loss of performance status and risks of surgical complications that potentially lead to delay in chemotherapy. However, surgeons understand that elective operations have lower morbidity than emergent operations on patients who are receiving chemotherapy. Only randomized prospective data could eventually demonstrate the survival benefit of palliative resection for patients with stage IV colon cancer. Data presented at the American Society of Clinical Oncology 45th Annual Meeting in 2009 indicated that patients with asymptomatic surgically incurable colorectal cancer do not require immediate surgery for [34 ] primary tumor removal. During the past decade, colonic stents have introduced an effective method of palliation for obstruction in patients with unresectable liver metastasis. Curative intent resections of liver metastases have significantly improved long-term survival with acceptable postoperative morbidity. A multivariate analysis of 1001 patients who underwent potentially curative resection of liver metastases identified 5 factors as independent predictors of worse outcome: size greater than 5 cm, disease-free interval of less than a year, more than one tumor, [35 ] primary lymph-node positivity, and CEA greater than 200 ng/mL. Although resection is the only potentially curative treatment for patients with colon metastases, other therapeutic options, for those who are not surgical candidates, include thermal ablation techniques. Cryotherapy uses probes to freeze tumors and surrounding hepatic parenchyma. It requires laparotomy and can potentially have significant morbidity including liver cracking, thrombocytopenia, and disseminated intravascular coagulation (DIC). Radiofrequency ablation (RFA) uses probes that heat liver tumors and the surrounding margin of tissue to create coagulation necrosis. RFA can be performed percutaneously, laparoscopically, or through an open approach. Although RFA has minimal morbidity, local recurrence is a significant problem and is correlated with tumor size. Hepatic arterial infusion (HAI) of chemotherapeutic agents such as FUDR is a consideration following partial hepatectomy. Standard colectomies for adenocarcinoma of the colon are depicted in the image below.

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Standard colectomies for adenocarcinoma of the colon.

Consultations
Surgical consultation Colorectal cancer, especially early stage disease, can be cured surgically. Following diagnosis and staging, obtaining surgical consultation for the possibility of resection may be appropriate. After surgery, the stage of the tumor may be advanced depending on the 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 possible resection. In some cases, resection of previously unresectable liver metastases may become feasible after cytoreduction with neoadjuvant chemotherapy. Therefore, ongoing involvement of the surgical oncologist is very important in patient care, even if the tumor is not considered resectable at the time of diagnosis. In advanced disease, surgical intervention may be helpful in palliative care of bleeding or obstruction. Gastroenterology consultation Gastroenterology consultation is critical 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 examination. A colonoscopy or sigmoidoscopy 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. Recent advent of colorectal stents allows a nonsurgical management of impending obstruction in patients who present with unresectable, metastatic disease. GI consultation is necessary in the follow-up of patients after surgical resection and adjuvant chemotherapy. Patients must be screened for recurrent disease in the colon by colonoscopic examination at 1 year after surgery and then every 3 years.

Diet
Abundant epidemiological literature suggests association of risk for developing colorectal cancer with dietary habits, environmental exposures, and level of physical activity. Less is known about effect of diet and physical activity on the recurrence of colon cancer. A prospective observational study involving patients from the CALGB 89803 adjuvant trial demonstrated adverse effect with regards to risk for recurrence and increased mortality for patients following a "Western" diet (high intake of red meat, refined grains, fat, and sweets) compared to patients with a "prudent" diet (high intake of fruits and vegetables, poultry, and fish). In another observational study from the same cohort of patients, patients were prospectively monitored and physical activity was recorded. The study concluded that physical activity reduces the risk of recurrence and mortality in patients with resected stage III colon cancer. These interesting and important observations pave the way for future interventional studies involving diet and physical activity in patients with stage II and III colon cancer.

Activity
See Diet.

Medication
Commonly used combination regimens Adjuvant therapy 5-Fluorouracil + leucovorin (weekly schedule, low dose leucovorin) 5-Fluorouracil: 500 mg/m IV weekly for 6 weeks Leucovorin: 20 mg/m IV weekly for 6 weeks, administered before 5-fluorouracil Repeat cycle every 8 weeks for a total of 24 weeks.
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LV5FU2 (de Gramont regimen) 5-Fluorouracil: 400 mg/m IV bolus, followed by 600 mg/m IV continuous infusion for 22 hours on days 1 and 2 Leucovorin: 200 mg/m IV on days 1 and 2 as a 2-hour infusion before 5-fluorouracil Repeat cycle every 2 weeks for a total of 12 cycles. Oxaliplatin + 5-fluorouracil + leucovorin (FOLFOX4) Oxaliplatin: 85 mg/m IV on day 1 5-Fluorouracil: 400 mg/m IV bolus, followed by 600 mg/m IV continuous infusion for 22 hours on days 1 and 2 Leucovorin: 200 mg/m IV on days 1 and 2 as a 2-hour infusion before 5-fluorouracil Repeat cycle every 2 weeks for a total of 12 cycles. Metastatic disease Irinotecan + 5-fluorouracil + leucovorin (FOLFIRI regimen) Irinotecan: 180 mg/m IV on day 1 5-Fluorouracil: 400 mg/m IV bolus on day 1, followed by 2400 mg/m IV continuous infusion for 46 hours Leucovorin: 400 mg/m IV on day 1 as a 2-hour infusion, prior to 5-fluorouracil Repeat cycle every 2 weeks. Oxaliplatin + 5-fluorouracil + leucovorin (FOLFOX6) Oxaliplatin: 100 mg/m IV on day 1 5-Fluorouracil: 400 mg/m IV bolus on day 1, followed by 2400 mg/m IV continuous infusion for 46 hours Leucovorin: 400 mg/m IV on day 1 as a 2-hour infusion, before 5-fluorouracil Repeat cycle every 2 weeks. Oxaliplatin + 5-fluorouracil + leucovorin (mFOLFOX7) Oxaliplatin: 100 mg/m IV on day 1 5-Fluorouracil: 3000 mg/m IV continuous infusion on day 1 for 46 hours Leucovorin: 400 mg/m IV on day 1 as a 2-hour infusion, before 5-fluorouracil Repeat cycle every 2 weeks. Capecitabine + oxaliplatin (XELOX) Capecitabine: 850-1000 mg/m PO bid on days 1-14 Oxaliplatin: 100-130 mg/m IV on day 1 Repeat cycle every 21 days. FOLFOX4 + bevacizumab Oxaliplatin: 85 mg/m IV on day 1 5-Fluorouracil: 400 mg/m IV bolus, followed by 600 mg/m IV continuous infusion on days 1 and 2 Leucovorin: 200 mg/m IV on days 1 and 2 as a 2-hour infusion before 5-fluorouracil Bevacizumab: 10 mg/kg IV every 2 weeks Repeat cycle every 2 weeks.
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

Antineoplastic Agent, Antimetabolite (pyrimidine)

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5-Fluorouracil (5-FU, Adrucil, Efudex)

Fluoropyrimidine analog. Cell cycle-specific with activity in the S-phase as single agent and has for many years been combined with biochemical modulator leucovorin. Mainstay of medical chemotherapy for colorectal cancer for patients for more than 40 y. Has activity as single agent that inhibits DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. Shown to be effective in adjuvant setting. Classic antimetabolite anticancer drug with chemical structure similar to endogenous intermediates or building blocks of DNA or RNA synthesis. 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), which leads to accumulation of dUMP, which then gets misincorporated into the DNA in the form of 5-FdUTP resulting in inhibition of DNA synthesis and function with cytotoxic DNA strandbreaks. 5-FUTP is incorporated into RNA and interferes with RNA processing. Current standard adjuvant therapy for colon cancer involves combination 5-FU/LV chemotherapy. Saltz regimen (5-FU/LV/CPT11) now standard first-line therapy for metastatic colon cancer. Because of 2 2 toxicity, maximum of 400 mg/m of 5-FU and 100 mg/m of CPT11 can be used as starting dose. Levamisole is no longer an appropriate component of adjuvant therapy.
Dosing
Adult

Bolus schedule: 425600 mg/m2 weekly, with or without leucovorin Protracted (pump) infusion: 200-300 mg/m2/24 h continuously 46 hour infusion (pump): 24003000 mg/m2/46 h, repeat every 14 days Standard therapy: 500 mg/m2 IV weekly for 4 wk q6wk Adjuvant therapy Mayo Clinic regimen: 425 mg/m2/d IV bolus on days 1-5 after LV for 5 d every 4 wk; 6 mo of therapy is current practice Roswell Park regimen: Continuous infusion weekly for 6 wk; 2 wk off
Pediatric

Not established
Interactions

Increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents
Contraindications

Documented hypersensitivity, bone marrow suppression, serious infection, topical administration contraindicated in pregnancy
Precautions
Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Nausea, oral and GI ulcers, depression of immune system, and hemopoiesis failure (bone marrow suppression) may occur; adjust dosage in renal impairment Toxic effects include diarrhea, mucositis, myelosuppression, hand-foot syndrome (palmar-plantar erythrodysesthesia), dry skin, hyperpigmentation, neurological toxicity (cerebellar ataxia), cardiac toxicity

Capecitabine (Xeloda)

Fluoropyrimidine carbamate prodrug from of 5-fluorouracil (5-FU). Capecitabine itself is inactive. Undergoes hydrolysis in liver and tissues to form the active moiety (fluorouracil), inhibiting thymidylate synthetase, which in turn blocks methylation of deoxyuridylic acid to thymidylic acid. This step interferes with DNA and to a lesser degree with RNA synthesis.
Dosing
Adult

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1250 mg/m PO q12h pc for 2 wk followed by 1 wk of rest period; administer as 3-wk cycle
Pediatric

Not established
Interactions

Aluminum/magnesium hydroxide antacids or meals increase drug absorption; increased risk of bleeding with anticoagulants (monitor INR and PT frequently), NSAIDs, platelet inhibitors, thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents; coadministration with leucovorin may cause diarrhea, dehydration, and death from severe enterocolitis; may increase phenytoin levels
Contraindications

Documented hypersensitivity to drug or related products; severe renal impairment (CrCl <30 mL/min); dihydropyrimidine dihydrogenase (DPD) deficiency
Precautions
Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Adjust dose in moderate renal impairment (CrCl 30-50 mL/min); discontinue drug if intractable diarrhea, bone marrow suppression, myocardial ischemia, or stomatitis develop; caution in patients that have received extensive pelvic radiation or alkylating therapy; hand and foot syndrome characterized by numbness, dysesthesia/paresthesia, tingling, erythema, blistering, severe pain, desquamation, and painless or painful swelling may occur Toxic effects include diarrhea, hand-foot syndrome, nausea and vomiting, elevations in bilirubin and transaminases, myelosuppression, neurologic syndrome (cerebellar ataxia), cardiac toxicity

Antidote, Folic Acid Antagonist

Leucovorin (Folinic acid, Citrovorum Factor)

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. Binds to and stabilizes ternary complex of FdUTP (intracellular active metabolite of fluoropyrimidines) and thymidylate synthetase (TS), augmenting cytotoxic effects of 5-fluorouracil. Used as an adjunct to fluorouracil.
Dosing
Adult
2

20-400 mg/m IV in combination with 5-fluorouracil 2 Standard therapy: 20 mg/m IV every wk for 4 wk q6wk 2 Adjuvant therapy: 20 mg/m IV before 5-FU on days 1-5 for 5 d q4wk (Mayo Clinic regimen); 6 mo of therapy is current practice
Pediatric

Not established
Interactions

Decreases effect of methotrexate, phenytoin, phenobarbital, sulfamethoxazole and trimethoprim combinations; increases toxicity of fluorouracil
Contraindications

Documented hypersensitivity; pernicious anemia or vitamin deficient megaloblastic anemias

Precautions

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Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Do not administer intrathecally or intraventricularly Toxic effects include skin rash, pruritus, facial flushing, and nausea and vomiting

Antineoplastic Agent, Miscellaneous

Irinotecan is a topoisomerase I inhibitor.

Irinotecan (Camptosar, CPT-11)

Semisynthetic derivative of camptothecin, an alkaloid extract from the Camptotheca acuminate tree. Inactive in its parent form. Converted by the carboxylesterase enzyme to its active metabolite from, SN-38. SN-38 binds to and stabilizes the topoisomerase I-DNA complex and prevents the relegation of DNA after it has been cleaved by 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.
Dosing
Adult

Monotherapy: 2 125 mg/m IV over 90 min weekly for 4 wk, followed by a 2-wk rest; schedule can be modified to 2 wk followed by a 1-wk rest 2 300-350 mg/m IV on an every-3-wk schedule 2 180 mg/m IV as monotherapy or in combination with infusional 5-FU/LV on an every-2-wk schedule
Pediatric

Not established
Interactions

Concomitant administration with other antineoplastics may result in prolonged neutropenia and thrombocytopenia in addition to increased morbidity/mortality
Contraindications

Documented hypersensitivity, severe diarrhea, febrile neutropenia, unresponsive or progressive adenocarcinoma, and pregnancy
Precautions
Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Adverse effects include myelosuppression, alopecia, nausea, vomiting, and diarrhea (early and late), and elevations in transaminases and bilirubin; monitor bone marrow function

Antineoplastic Agent, Alkylating Agent

Oxaliplatin is a platinum analog.

Oxaliplatin (Eloxatin, Diaminocyclohexane platinum, DACH-platinum)

Third-generation platinum-based antineoplastic agent used in combination with an infusion of 5-fluorouracil (5-FU) and leucovorin for treatment of metastatic colorectal cancer in patients with recurrence or progression following initial treatment with irinotecan, 5-FU, and

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leucovorin. Also indicated for previously untreated advanced colorectal cancer in combination with 5-FU and leucovorin. Covalently binds to DNA with preferential binding to the N-7 position of guanine and adenine. DNA mismatch repair enzymes are unable to recognize oxaliplatin-DNA adducts in contrast with other platinum-DNA adducts as a result of their bulkier size. Forms interstrand and intrastrand Pt-DNA crosslinks that inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific with activity in all phases of the cell cycle.
Dosing
Adult
2 2 2

Day 1: 85 mg/m IV over 2 h; administer simultaneously with leucovorin 200 mg/m ; followed by 5-FU 400 mg/m IV bolus over 2-4 2 min, then 5-FU 600 mg/m IV continuous infusion in 500 mL D5W over 22 h 2 2 2 Day 2: Leucovorin 200 mg/m IV over 2 h, followed by 5-FU 400 mg/m IV bolus over 2-4 min, then 5-FU 600 mg/m IV as a continuous infusion in 500 mL D5W over 22 h 2 Oxaliplatin can also be administered at 130 mg/m IV on a q3wk schedule
Pediatric

Not established
Interactions

May increase 5-FU serum concentration by approximately 20%

Contraindications

Documented hypersensitivity to oxaliplatin or other platinum compounds (allergic reactions may present with facial flushing and rash, pneumonitis)
Precautions
Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Anaphylaxis may occur within minutes of administration; may cause neurotoxicity with acute and chronic forms (acute toxicity seen in 80-85% of all patients and is characterized by a peripheral sensory neuropathy with distal paresthesias, visual and voice changes, often triggered or exacerbated by exposure to cold), pulmonary fibrosis, bone marrow suppression, GI tract symptoms (eg, nausea, vomiting, diarrhea, stomatitis), renal or hepatic toxicity (decrease dose), or thromboembolism, myelosuppression; dilute IV only in dextrose-containing solution

Antineoplastic Agent, Monoclonal Antibody

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 EGF receptor inhibits activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased production of matrix metalloproteinase and vascular endothelial growth factor. 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.
Dosing
Adult
2

First dose: 400 mg/m IV infused over 2 h 2 Weekly maintenance doses: 250 mg/m IV infused over 1 h Not to exceed infusion rate of 10 mg/min (ie, 5 mL/min); must administer with low-proteinbinding 0.22 m in-line filter; premedication with an H1 antagonist (eg, diphenhydramine 50 mg IV) recommended

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Pediatric

Not established
Interactions

Limited data exist; none reported

Contraindications

None for metastatic colorectal carcinoma

Precautions
Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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 reactions; common adverse effects include acnelike rash, dry skin, pruritus, tiredness or weakness, fever, diarrhea, constipation, abdominal pain, hypomagnesemia, infusion reaction, paronychia, hypertrichia; may rarely cause interstitial lung disease; do not shake or dilute solution; sunlight can exacerbate any skin reactions

Bevacizumab (Avastin)

Indicated in combination with a fluoropyrimidine-based chemotherapy as a first-line or second-line treatment for metastatic colorectal cancer. Murine derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting vascular endothelial growth factor (VEGF). Inhibiting new blood vessel formation denies blood, oxygen, and other nutrients needed for tumor growth. Used in combination with standard chemotherapy.
Dosing
Adult

5-10 mg/kg IV over 60 min q2wk until disease progression detected

Pediatric

Not established
Interactions

Coadministration with 5-fluorouracil increases incidence (2-fold) of serious and fatal arterial thromboembolic events (ie, CVA, MI, TIAs, angina)
Contraindications

Documented hypersensitivity
Precautions
Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Common adverse effects include hypertension, epistaxis, fatigue, thrombosis, increased risk of bleeding, diarrhea, leukopenia, proteinuria, nephritic syndrome, 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), reversible posterior leukoencephalopathy syndrome (RPLS), nasal septum perforation, and internal bleeding; increases risk of serious and fatal

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arterial thrombotic events with 5-fluorouracil Do not initiate treatment for at least 28 days 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

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.
Dosing
Adult

6 mg/kg IV infused over 60 min q2wk

Pediatric

Not established
Interactions

Data limited; none reported

Contraindications

None known
Precautions
Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Common adverse effects include rash (acneiform), paronychia, hypomagnesemia, fatigue, abdominal pain, nausea, and diarrhea, pneumonitis; 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-proteinbinding filter

Follow-up
Further Outpatient Care
Pooled analysis form several large adjuvant trials reported that 85% of colon cancer recurrences occur within 3 years from after resection of primary tumor. Therefore, patients with resected colon cancer (stage II and III) should undergo regular surveillance for at least 5 years following resection. An update of American Society of Clinical Oncology (2005) recommends physical examinations every 3-6 months for the first 3 years, every 6 months during years 4 and 5, and subsequently at the discretion of physician and based on individual risk assessment. Serum CEA level should be checked every 3 months in patients with stage II or III disease for at least 3 years and every 6 months in years 4 and 5. Computerized tomography (CT) of the chest and abdomen should be performed annually for at least 3 years after resection of primary tumor. All patients with colon cancer should have preoperative or postoperative colonoscopy to document absence of additional primary colon tumors or polyps. In the absence of high-risk pathology on the first colonoscopy or increased susceptibility for colon cancer, follow-up colonoscopy should be performed at 3 years after surgery and then, if normal, once every 5 years thereafter.

Deterrence/Prevention
Colorectal cancer prevention strategies are based on our understanding of colorectal carcinogenesis and availability of pharmacologic agents that are effective yet minimally toxic. The efficacy of these agents is usually first tested in high-risk populations. Celecoxib (Celebrex), a selective cyclooxygenase-2 inhibitor was first tested in patients with familial adenomatous polyposis (FAP).

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Celecoxib was effective in decreasing the number and size of polyps on serial colonoscopies, which was the primary surrogate endpoint for this trial. The drug was approved for FAP patients, although it remains to be seen if this intervention translates to reduced cancer incidence and prolonged survival. Other NSAIDs, such as sulindac and nonselective cyclooxygenase inhibitors were tested in lower risk populations. Enthusiasm for cyclooxygenase-2 inhibitors as chemopreventive agents has dampened because of a high incidence of cardiovascular toxicity (rofecoxib) in trial patients. An aspirin prevention trial suggested a benefit in terms of polyp prevention with low-dose (81 mg) aspirin. Some recent trials focused on combined inhibition of polyamine production and cyclooxygenase inhibition. A recent report from a large randomized trial of a combination of sulindac and dimethylformamine (DMFO), an inhibitor of ornithine decarboxylase (ODC), described a dramatic effect of this combination in reducing polyp recurrence in patients with prior history of colon polyps. Confirmatory trials are [36 ] ongoing. Screening The goal of colorectal cancer screening is to decrease mortality through diagnosis and treatment of precancerous lesions (adenomatous colon polyps) and early curable cancerous lesions. The evidence for the importance of early detection and removal of colorectal polyps in preventing development of invasive cancer is mostly indirect but has been corroborated by data from many trials. In the United States, a Joint Guideline was developed by the American Cancer Society, US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. The Guideline lists appropriate screening procedures and their indications and frequency based on projected individual risks of developing colorectal cancer. Their testing options for the early detection of colorectal cancer and adenomatous polyps for asymptomatic adults aged 50 years and older can be summarized as follows: Tests that detect adenomatous polyps and cancer Flexible sigmoidoscopy every 5 years, or Colonoscopy every 10 years, or Double-contrast barium enema every 5 years, or computed tomographic colonography every 5 years Tests that primarily detect cancer Annual guaiac-based fecal occult blood test with high test sensitivity for cancer, or Annual fecal immunochemical test with high test sensitivity for cancer, or Stool DNA test with high sensitivity for cancer, interval uncertain For individuals who carry an increased or high risk of developing colorectal cancer such as persons with prior history of polyps, prior history of colorectal cancer, family history of colon cancer, or history of inflammatory bowel diseases screening should start at an earlier age and be more frequent and more stringent. Those genetically diagnosed or suspected of having hereditary familial syndromes such as HNPCC or FAP should be treated as having high risk of developing colon and rectal cancer and should adhere to a more [37 ] intense surveillance protocol.

Prognosis
The approximate 5-year survival rate for colorectal cancer patients in the United States (all stages included) is 65%. Survival is inversely related to stage; patients with stage I have a 95% 5-year survival rate, and those with stage III have only a 60% survival rate. For patients with metastatic, stage IV disease, the 5-year survival rate is estimated at approximately 10% (see Staging).

Multimedia

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Media file 1: Standard colectomies for adenocarcinoma of the colon.

References
1. [Guideline] Desch CE, Benson AB 3rd, Somerfield MR, et al. Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. Nov 20 2005;23(33):8512-9. [Medline]. 2. Sanoff HK, Sargent DJ, Campbell ME, et al. Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741. J Clin Oncol. Dec 10 2008;26(35):5721-7. [Medline]. 3. Chu, E and DeVita VT. Physicians' cancer chemotherapy drug manual. Jones and Bartlett publishers. 2008. 4. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. Sep 1 1988;319(9):525-32. [Medline]. 5. Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2008. CA Cancer J Clin 2008; 58:71-96; originally published online; DOI: 10.3322/CA2007.0010. Feb 20, 2008;[Medline]. 6. [Best Evidence] Burn J, Bishop DT, Mecklin JP, Macrae F, et al. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med. Dec 11 2008;359(24):2567-78. [Medline]. 7. Meyerhardt JA, Niedzwiecki D, Hollis D, et al. Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. JAMA. Aug 15 2007;298(7):754-64. [Medline]. 8. [Best Evidence] Jacobs ET, Ahnen DJ, Ashbeck EL, Baron JA, Greenberg ER, Lance P, et al. Association between body mass index and colorectal neoplasia at follow-up colonoscopy: a pooling study. Am J Epidemiol. Mar 15 2009;169(6):657-66. [Medline]. 9. Ogino S, Kawasaki T, Kirkner GJ, Ohnishi M, Fuchs CS. 18q loss of heterozygosity in microsatellite stable colorectal cancer is correlated with CpG island methylator phenotype-negative (CIMP-0) and inversely with CIMP-low and CIMP-high. BMC Cancer. May 2 2007;7:72. [Medline]. 10. [Best Evidence] Quasar Collaborative Group, Gray R, Barnwell J, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. Dec 15 2007;370(9604):2020-9. [Medline]. 11. Saltz LB, Kelsen DP. Adjuvant treatment of colorectal cancer. Annu Rev Med. 1997;48:191-202. [Medline]. 12. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. Jul 17 2003;349(3):247-57. [Medline]. 13. Le Voyer TE, Sigurdson ER, Hanlon AL, et al. Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol. Aug 1 2003;21(15):2912-9. [Medline]. 14. [Best Evidence] Gunderson LL, Jessup JM, Sargent DJ, Greene FL, Stewart AK. Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol. Jan 10 2010;28(2):264-71. [Medline]. 15. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. Jan 15 2004;22(2):229-37. [Medline]. 16. [Best Evidence] Arkenau HT, Arnold D, Cassidy J, Diaz-Rubio E, Douillard JY, Hochster H, et al. Efficacy of oxaliplatin plus capecitabine or infusional fluorouracil/leucovorin in patients with metastatic colorectal cancer: a pooled analysis of randomized trials. J Clin Oncol. Dec 20 2008;26(36):5910-7. [Medline]. 17. [Best Evidence] Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, et al. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. Jun 10 2009;27(17):2848-54. [Medline]. 18. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. Jan

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1 2004;22(1):23-30. [Medline].

http://emedicine.medscape.com/article/277496-print

19. Haller DG, Catalano PJ, Macdonald JS, O'Rourke MA, Frontiera MS, Jackson DV. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. Dec 1 2005;23(34):8671-8. [Medline]. 20. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. Jun 3 2004;350(23):2335-42. [Medline]. 21. [Best Evidence] Sargent D, Sobrero A, Grothey A, O'Connell MJ, Buyse M, Andre T, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. Feb 20 2009;27(6):872-7. [Medline]. 22. [Best Evidence] Kabbinavar FF, Hurwitz HI, Yi J, Sarkar S, Rosen O. Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. J Clin Oncol. Jan 10 2009;27(2):199-205. [Medline]. 23. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. Jul 22 2004;351(4):337-45. [Medline]. 24. [Best Evidence] Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. Feb 10 2009;27(5):672-80. [Medline]. 25. Jimeno A, Messersmith WA, Hirsch FR, Franklin WA, Eckhardt SG. KRAS Mutations and Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer: Practical Application of Patient Selection. J Clin Oncol. Jan 5 2009;[Medline]. 26. [Best Evidence] Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. Feb 10 2009;27(5):663-71. [Medline]. 27. [Best Evidence] Hendlisz A, Van den Eynde M, Peeters M, Maleux G, Lambert B, Vannoote J, et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. Aug 10 2010;28(23):3687-94. [Medline]. 28. Boller AM, Nelson H. Colon and rectal cancer: laparoscopic or open?. Clin Cancer Res. Nov 15 2007;13(22 Pt 2):6894s-6s. [Medline]. 29. Fleshman J, Sargent DJ, Green E, Anvari M, Stryker SJ, Beart RW Jr. Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial. Ann Surg. Oct 2007;246(4):655-62; discussion 662-4. [Medline]. 30. Jayne DG, Guillou PJ, Thorpe H, et al. Randomized trial of laparoscopic-assisted resection of colorectal carcinoma: 3-year results of the UK MRC CLASICC Trial Group. J Clin Oncol. Jul 20 2007;25(21):3061-8. [Medline]. 31. Kuhry E, Schwenk WF, Gaupset R, Romild U, Bonjer HJ. Long-term results of laparoscopic colorectal cancer resection. Cochrane Database Syst Rev. Apr 16 2008;CD003432. [Medline]. 32. [Best Evidence] Lacy AM, Delgado S, Castells A, et al. The long-term results of a randomized clinical trial of laparoscopyassisted versus open surgery for colon cancer. Ann Surg. Jul 2008;248(1):1-7. [Medline]. 33. Veldkamp R, Kuhry E, Hop WC, et al. Laparoscopic surgery versus open surgery for colon cancer: short-term outcomes of a randomised trial. Lancet Oncol. Jul 2005;6(7):477-84. [Medline]. 34. Poultsides GA, Servais EL, Saltz LB, Patil S, Kemeny NE, Guillem JG. Outcome of Primary Tumor in Patients With Synchronous Stage IV Colorectal Cancer Receiving Combination Chemotherapy Without Surgery As Initial Treatment. J Clin Oncol. Jun 1 2009;[Medline]. 35. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for

23 de 25

07/10/10 09:07

Colon Cancer, Adenocarcinoma: [Print] - eMedicin...

http://emedicine.medscape.com/article/277496-print

metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. Sep 1999;230(3):309-18; discussion 318-21. [Medline]. 36. Meyskens FL Jr, McLaren CE, Pelot D, Fujikawa-Brooks S, Carpenter PM, Hawk E, et al. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res (Phila Pa). Jun 2008;1(1):32-8. [Medline]. 37. [Guideline] Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. May-Jun 2008;58(3):130-60. [Medline]. 38. Greene FL, Page DL, Fleming ID, et al. Cancer staging manual. 6 ed. New York: Springer; 2002. 39. [Guideline] National Comprehensive Cancer Network. Clinical practice guidelines in oncology-V.4.. 2005. 40. Venook A. Critical evaluation of current treatments in metastatic colorectal cancer. Oncologist. Apr 2005;10(4):250-61. [Medline].
th

Keywords
colon cancer, colorectal cancer, adenocarcinoma, gastrointestinal cancer, colorectal malignancy, colon cancer prevention, colon cancer treatment, colon cancer medications, colon cancer detection, colon cancer screening

Contributor Information and Disclosures

Author

Tomislav Dragovich, MD, PhD, Associate Professor of Medicine and Director of Clinical Gastrointestinal Cancer Program, Arizona Cancer Center, University of Arizona College of Medicine Tomislav Dragovich, MD, PhD is a member of the following medical societies: American Association for Cancer Research and American Society of Clinical Oncology Disclosure: Nothing to disclose.
Coauthor(s)

Vassiliki L Tsikitis, MD, Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona Medical Center Vassiliki L Tsikitis, MD is a member of the following medical societies: American College of Surgeons, American Society of Colon and Rectal Surgeons, and Association of Women Surgeons Disclosure: Nothing to disclose.
Medical Editor

Philip Schulman, MD, Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center; Clinical Professor, Department of Medicine, New York University School of Medicine Philip Schulman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, and Medical Society of the State of New York Disclosure: celgene Honoraria Speaking and teaching; Amgen Honoraria Speaking and teaching; genetech/idec Honoraria Speaking and teaching
Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine Disclosure: eMedicine Salary Employment
CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

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Disclosure: Nothing to disclose.
Chief Editor

http://emedicine.medscape.com/article/277496-print

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine; Consulting Staff, Arizona Cancer Center Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research Disclosure: GlobeImmune Salary Consulting
Further Reading Related eMedicine topic Colon, Adenocarcinoma (Radiology) Clinical studies Fluorouracil and Leucovorin Plus Either Irinotecan or Oxaliplatin With or Without Cetuximab in Treating Patients With Previously Untreated Metastatic Adenocarcinoma of the Colon or Rectum Celecoxib Combined With Fluorouracil and Leucovorin in Treating Patients With Resected Stage III Adenocarcinoma (Cancer) of the Colon Trial for Microarray Analysis of Colon Cancer Outcome-A (MACCO-A) 1994-2010 by Medscape. All Rights Reserved (http://www.medscape.com/public/copyright)

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