Colon Cancer

WHAT IS COLON CANCER?

Colon cancer is a disease in which malignant (cancer) cells form in the tissues of the colon.

The colon is part of the body’s digestive system. The digestive system removes and processes nutrients (vitamins, minerals, carbohydrates, fats, proteins, and water) from foods and helps pass waste material out of the body. The digestive system is made up of the esophagus, stomach, and the small and large intestines. The first 6 feet of the large intestine are called the large bowel or colon. The last 6 inches are the rectum and the anal canal. The anal canal ends at the anus (the opening of the large intestine to the outside of the body).



WHAT ARE RISK FACTORS OF COLON CANCER?

Age and health history can affect the risk of developing colon cancer.

Up to 70% of patients with colorectal cancer have no identifiable risk factors. Possible factors are as:

History of colorectal cancer or adenomas is risk factors to development of cancer, especially villus adenomas has highest risk.
Smoking: About 2.5-fold increased risk of adenomas in tobacco users.
Dietary factors: Low-fiber, high-caloric-intake, and high-animal fat diets may increase risk.
Calcium deficiency: Daily intake of 1.25-2.0 g of calcium is associated with a reduced risk of recurrent adenomas in a randomized placebo-controlled trial.
Inflammatory bowel disease: Ulcerative colitis and Crohn disease increase risk of colorectal cancer by 7- to 11-fold and twofold, respectively.
Family history: In the general population, one first-degree relative with cancer results in an increased relative risk of 1.7, if two relatives are affected, relative risk increases to 2.75;also increased risk if first-degree relative develops an adenomatous polyp before age of 60 years. True hereditary forms of cancer account for only 6% of colorectal cancer.
HOW TO DETECT COLON CANCER?

Possible signs of colon cancer include a change in bowel habits or blood in the stool.

These and other symptoms may be caused by colon cancer or by other conditions. A doctor should be consulted if any of the following problems occur:

A change in bowel habits.
Blood (either bright red or very dark) in the stool.
Diarrhea, constipation, or feeling that the bowel does not empty completely.
Stools that are narrower than usual.
General abdominal discomfort (frequent gas pains, bloating, fullness, or cramps).
Weight loss with no known reason.
Constant tiredness.
Vomiting.
Tests that examine the rectum, rectal tissue, and blood are used to detect (find) and diagnose colon cancer.

The following tests and procedures may be used:

Physical examand history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
Fecal occult blood test: A test to check stool (solid waste) for blood that can only be seen with a microscope. Small samples of stool are placed on special cards and returned to the doctor or laboratory for testing.
Digital rectal exam: An exam of the rectum. The doctor or nurse inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas.
Barium enema: A series of x-rays of the lower gastrointestinal tract. A liquid that contains barium (a silver-white metallic compound) is put into the rectum. The barium coats the lower gastrointestinal tract and x-rays are taken. This procedure is also called a lower GI series.
Sigmoidoscopy: A procedure to look inside the rectum and sigmoid (lower) colon for polyps, abnormal areas, or cancer. A sigmoidoscope (a thin, lighted tube) is inserted through the rectum into the sigmoid colon. Polyps or tissue samples may be taken for biopsy.
Colonoscopy: A procedure to look inside the rectum and colon for polyps, abnormal areas, or cancer. A colonoscope (a thin, lighted tube) is inserted through the rectum into the colon. Polyps or tissue samples may be taken for biopsy.



Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer.





Virtual colonoscopy: A procedure that uses a series of x-rays called computed tomography to make a series of pictures of the colon. A computer puts the pictures together to create detailed images that may show polyps and anything else that seems unusual on the inside surface of the colon. This test is also called colonography or CT colonography.


HOW TO TREAT COLON CANCER?

Stage 0 Colon Cancer

Stage 0 colon cancer is the most superficial of all the lesions and is limited to the mucosa without invasion of the lamina propria.

Treatment options:

Local excision or simple polypectomy with clear margins.
Colon resection for larger lesions not amenable to local excision.
Stage I Colon Cancer

Because of its localized nature, stage I has a high cure rate.

Treatment options:

Wide surgical resection and anastomosis. The role of laparoscopic techniques in the treatment of colon cancer is under evaluation in a multicenter prospective randomized trial comparing laparoscopic-assisted colectomy (LAC) to open colectomy. The quality-of-life component of this trial has been published and reported minimal short-term quality-of-life benefits with LAC.

Stage II Colon Cancer

Treatment options:

Wide surgical resection and anastomosis. The role of laparoscopic techniques in the treatment of colon cancer is under evaluation in a multicenter prospective randomized trial comparing laparoscopic-assisted colectomy (LAC) to open colectomy.
Following surgery, patients should be considered for entry into carefully-controlled clinical trials evaluating the use of systemic or regional chemotherapy, radiation therapy, or biologic therapy.
Adjuvant therapy

The potential value of adjuvant therapy for patients with stage II (Dukes’ B or MAC B2 or B3) colon cancer also remains controversial. Although subgroups of patients with stage II colon cancer may be at higher-than-average risk for recurrence (including those with anatomic features such as tumor adherence to adjacent structures, perforation, complete obstruction, or with biologic characteristics such as aneuploidy, high S-phase analysis, or deletion of 18q), evidence is inconsistent that adjuvant 5-fluorouracil (5-FU)-based chemotherapy is associated with an overall improved survival compared with surgery alone. Investigators from the National Surgical Adjuvant Breast and Bowel Project have indicated that the reduction in risk of recurrence by adjuvant therapy in patients with stage II disease is of similar magnitude to the benefit seen in patients with stage III disease treated with adjuvant therapy, although an overall survival advantage has not been established. A randomized trial of postoperative fluorouracil plus levamisole compared to surgery alone showed no survival advantage to postoperative adjuvant chemotherapy. A meta-analysis of 1,000 stage II patients whose experience was amalgamated from a series of trials indicates a 2% advantage in disease-free survival at 5 years when adjuvant therapy-treated patients treated with 5-FU-leucovorin are compared to untreated controls. Patients with stage II colon cancer remain candidates for clinical trials in which either surgery alone or 5-FU-leucovorin represent standard therapy.

Stage III Colon Cancer

Stage III colon cancer denotes lymph node involvement. Studies have indicated that the number of lymph nodes involved affects prognosis; patients with 1 to 3 involved nodes have a significantly better survival than those with 4 or more involved nodes.

Treatment options:

Wide surgical resection and anastomosis. The role of laparoscopic techniques in the treatment of colon cancer is under evaluation in a multicenter prospective randomized trial comparing laparoscopic-assisted colectomy (LAC) to open colectomy. The quality-of-life component of this trial has been published and reported minimal short-term quality-of-life benefits with LAC.
For patients who are not candidates for clinical trials, postoperative chemotherapy with fluorouracil (5-FU)-leucovorin for 6 months. Based on preliminary results from the MOSAIC trial presented at the American Society of Clinical Oncology meeting in 2003, adjuvant FOLFOX4 (oxaliplatin, leucovorin, 5-FU) demonstrated prolonged 3-year survival but did not demonstrate an overall survival advantage.

Eligible patients should be considered for entry into carefully-controlled clinical trials comparing various postoperative chemotherapy regimens which are now also including oxaliplatin-based and irinotecan-based chemotherapy with new targeted agents, postoperative radiation therapy, or biological therapy, alone or in combination.
Adjuvant therapy

Improved outcomes with postoperative radiation therapy have been suggested in single-institution retrospective reviews for certain high-risk subsets of colon cancer patients (T3 or T4, tumor location in immobile sites, local perforation, obstruction, residual disease postresection). A phase III randomized Intergroup trial designed to test the benefit of adding radiation therapy to surgery and 5-FU-levamisole chemotherapy for selected high-risk colon cancer patients (T4; or T3, N1-N2 ascending/descending colon) was closed early secondary to inadequate patient accrual, and preliminary analysis of 222 patients demonstrated no relapse or overall survival benefit for the group receiving radiation therapy.

In the late 1980s, a passive immunotherapy approach to adjuvant treatment of stage III colorectal cancer demonstrated encouraging results in a single randomized trial. This trial compared postoperative administration of a murine monoclonal antibody to 17-1A antigen (MOAB 17-1A), a cell surface glycoprotein of uncertain function expressed on both normal and malignant epithelial cells, to surgery alone. Treated patients appeared to have a survival benefit comparable to that seen in adjuvant chemotherapy trials, with a relative reduction in mortality of 32% (95% confidence interval (CI), 8-51). The small size of this trial, however, was associated with a wide CI for the observed benefit and the result remains to be confirmed. Other adjuvant immunotherapeutic approaches, including autologous tumor vaccines, are also under clinical evaluation.

Stage IV and Recurrent Colon Cancer

Stage IV colon cancer denotes distant metastatic disease. Treatment of recurrent colon cancer depends on the sites of recurrent disease demonstrable by physical examination and/or radiographic studies. In addition to standard radiographic procedures, radioimmunoscintography may add clinical information which may affect management.

Treatment options:

Surgical resection of locally recurrent cancer.
Surgical resection/anastomosis or bypass of obstructing or bleeding primary lesions in selected metastatic cases.
Resection of liver metastases in selected metastatic patients (5-year cure rate for resection of solitary or combination metastases exceeds 20%) or ablation in selected patients.
Resection of isolated pulmonary or ovarian metastases in selected patients.
Palliative radiation therapy.
Palliative chemotherapy.
Surgical resection of isolated metastases (liver, lung, ovaries).
Clinical trials evaluating new drugs and biological therapy.
Clinical trials comparing various chemotherapy regimens or biological therapy, alone or in combination.
Locally recurrent colon cancer

Locally recurrent colon cancer, such as a suture line recurrence, may be resectable.

Liver metastasis

Approximately 50% of colon cancer patients will be diagnosed with hepatic metastases, either at the time of initial presentation or as a result of disease recurrence. Although only a small proportion of patients with hepatic metastases are candidates for surgical resection, advances in tumor ablation techniques and in both regional and systemic chemotherapy administration provide for a number of treatment options.

For patients with hepatic metastasis considered to be resectable (based on limited number of lesions, intrahepatic locations of lesions, lack of major vascular involvement, absent or limited extrahepatic disease, and sufficient functional hepatic reserve), a negative margin resection has resulted in 5-year survival rates of 25% to 40% in mostly nonrandomized studies. Improved surgical techniques and advances in preoperative imaging have allowed for better patient selection for resection.

For patients with hepatic metastases deemed unresectable, radiofrequency ablation has emerged as a safe technique (2% major morbidity, <1% mortality rate) that may provide for long-term tumor control. Cryosurgical ablation remains an option for patients with certain tumors not amenable to resection.

Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy. Patients with limited pulmonary metastases, and patients with both pulmonary and hepatic metastases, may also be considered for surgical resection, with 5-year survival possible in highly-selected patients.

The role of adjuvant chemotherapy after potentially-curative resection of liver metastases is uncertain. A trial of hepatic arterial floxuridine plus systemic fluorouracil (5-FU) plus leucovorin was shown to result in improved 2-year disease-free and overall survival (86% versus 72%, P=.03), but did not show a significant statistical difference in median survival, compared with systemic 5-FU therapy alone. A second trial preoperatively randomized 109 patients who had 1 to 3 potentially resectable colorectal hepatic metastases to either no further therapy or postoperative hepatic arterial floxuridine plus systemic 5-FU. Of those randomized, 27% were deemed ineligible at the time of surgery, leaving only 75 patients evaluable for recurrence and survival. While liver recurrence was decreased, median or 4-year survival was not significantly different. Further studies are required to evaluate this treatment approach and to determine whether more effective systemic combination chemotherapy alone may provide similar results compared with hepatic intra-arterial therapy plus systemic treatment.

Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no consistent improvement in survival when compared with systemic chemotherapy. Controversy regarding the efficacy of regional chemotherapy has led to initiation of a large multicenter phase III trial (CLB-9481) of hepatic arterial infusion versus systemic chemotherapy. The use of the combination of intra-arterial chemotherapy with hepatic irradiation, especially employing focal radiation of metastatic lesions, is under evaluation. Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.

Other drug combinations described in this section:

AIO regimen (folic acid, 5-FU, irinotecan):
Irinotecan (100 mg/m2) as a 2-hour infusion day 1; leucovorin (500 mg/m2) as a 2-hour infusion day 1; followed by 5-FU (2,000 mg/m2) intravenous (IV) bolus via ambulatory pump over 24 hours weekly x 4 every 52 weeks.
Douillard regimen (folic acid, 5-FU, irinotecan):
Irinotecan (180 mg/m2) as a 2-hour infusion day 1; leucovorin (200 mg/m2) as a 2-hour infusion days 1 and 2; followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) via ambulatory pump over 22 hours days 1 and 2 every 2 weeks.
FOLFOX4 regimen (oxaliplatin, leucovorin, 5-FU):
Oxaliplatin (85 mg/m2) as a 2-hour infusion day 1; leucovorin (200 mg/m2) as a 2-hour infusion days 1 and 2; followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) via ambulatory pump over 22 hours days 1 and 2 every 2 weeks.
FOLFOX6 regimen (oxaliplatin, leucovorin, 5-FU):
Oxaliplatin (85-100 mg/m2) as a 2-hour infusion day 1; leucovorin (400 mg/m2) as a 2-hour infusion day 1; followed by a loading dose of 5-FU (400 mg/m2) IV bolus on day 1, then 5-FU (2,400-3,000 mg/m2) via ambulatory pump over 46 hours every 2 weeks.
FOLFIRI regimen (folic acid, 5-FU, irinotecan):
Irinotecan (180 mg/m2) as a 2-hour infusion day 1; leucovorin (400 mg/m2) as a 2-hour infusion day 1; followed by a loading dose of 5-FU (400 mg/m2) IV bolus on day 1, then 5-FU (2,400-3,000 mg/m2) via ambulatory pump over 46 hours every 2 weeks.
IFL (or Saltz) regimen (irinotecan, 5-FU, leucovorin):
Irinotecan (125 mg/m2), 5-FU (500 mg/m2) IV bolus, and leucovorin (20 mg/m2) IV bolus weekly for 4 out of 6 weeks.
First-line chemotherapy treatment

In stage IV and recurrent colon cancer, chemotherapy has been used for palliation. Combinations of 5-FU and leucovorin with irinotecan (FOLFIRI, AIO, IFL) or oxaliplatin (FOLFOX4, FOLFOX6) are considered to be standard.

Based on recent data, recommended first-line regimens for patients with advanced colorectal cancer include FOLFOX4, FOLFOX6, FOLFIRI, Douillard, and AIO.

Second-line chemotherapy treatment

Treatment of patients who progress after first-line chemotherapy is guided by which treatment was used for first-line treatment. Patients who were treated with a FOLFOX-based regimen should be treated with an irinotecan-based regimen and patients who already received an irinotecan-based regimen should be treated with a FOLFOX-based regimen.

For patients who are clinically unlikely to tolerate aggressive combination chemotherapy, or who have unacceptable pre-existing comorbid disease, an infusional single-agent 5-FU-based regimen without either oxaliplatin or irinotecan remains a reasonable treatment option. A phase III trial (GERCOR C96.1) demonstrated that infusional 5-FU-leucovorin administered on the same schedule as that used in the Douillard regimen was less toxic and more active in terms of response rate and progression-free survival than low-dose bolus daily times 5 days 5-FU-leucovorin in patients with advanced or metastatic colorectal cancer.

NOVAL THERAPIES

IFL-bevacizumab( monoclonal antibody):The American Society of Clinical Oncology 2003 meeting, the results of 2 randomized trials incorporating novel therapies in patients with colorectal cancer were presented. The results of a randomized trial were presented that compared IFL-placebo with IFL-bevacizumab, a monoclonal antibody, against the vascular endothelial growth factor receptor in 925 patients with advanced colorectal cancer. Bevacizumab was administered at a dose of 5 mg/kg every other week. The median progression-free survival of patients treated with IFL plus bevacizumab was 10.6, versus 6.2 months (P=.00001) for patients treated with IFL and placebo, and the median overall survival was 20.3 versus 15.6 months (P=.00003), respectively. Overall response rates were also superior for the bevacizumab-containing regimen (44.9 versus 34.7%, P=.029). Patients treated with bevacizumab and IFL had a higher overall incidence of grade 3 to 4 toxic effects (85% versus 74%, P<.01).
Cetuximab: A study compared cetuximab, a monoclonal antibody, against epidermal growth factor receptor, alone or in combination with irinotecan in 329 patients with irinotecan-refractory colorectal cancer. Patients treated with the combination regimen had a significantly higher response rate of 22.9% compared to 10.8% for patients treated with cetuximab alone (P=.0074) and a longer time to treatment failure (4.1 months versus 1.5 months, P<.0001), but there was no significant improvement in median survival between arms.
Irnotecan/CPT11: The medicine is a topoisomerase-targeting agent with activity in patients with advanced colorectal cancer who have previously been treated with 5-FU. Response rates range from 15% to 25%.Irinotecan can be given at 125 mg/m2 infused over 90 minuts weekly for 4 weeks followed by 2 weeks rest, or at 350mg/m2 over 90 minutes every 3 weeks. Delayed-onset diarrhea is the main adverse effect and must be managed by administrating high-dose loperamide,4mg initially and then 2mg for at least 12 hours.
Combination of irnotecan and 5-FU and LV:A significantly improved overall response rate(33%) was showed for the combination which wasconsisted of Irnotecan,125mg/m2,and weekly 5-FU,500mg/m2,and LV,20mg/m2, in patients with untreated colorectal cancer. If confirmed,the data would support the use of irinotecan and 5-FU combination as a initial therapy in newly diagnosed patients with advanced disease.
Hepatic artery chemotherapy (HAI): The liver is the most common site for metastasis of colorectal cancer, with one third involving the liver only, and median survival less than 1 year with 13% 3-year survival; two thirds of patients dying of colon cancer have liver involvement. The rationale for use of HAI is that metastatic tumors like HCC obtain most of their blood from the hepatic artery. Optimal agents for this regional treatment would be drugs extracted by the liver during the first pass, thereby reducing systemic drug levels and toxicity. It was demonstrated that hepatic extraction of floxuridine (FUDR) was fourfold higher after hepatic arterial injection compared with systemic injection. The ability to administer a higher dose locally exposes tumors to a higher drug concentration than can be achieved with systemic therapy. The indications for HAI are patients with diffuse unresectable liver metastases, but no extrahepatic disease, who have failed systemic chemotherapy. From 1980 to 1990 five randomized studies were done comparing HAI to systemic chemotherapy for unresectable colorectal hepatic metastases, with response rate of 42% to 62% versus 10% to 21%,and 1-year survival of 60% to 85% versus 42% to 60%,and 2-year survival of 18% to 44% versus 16% to 30%.Overall,these trials showed a significantly better response rate with HAI compared with systemic chemotherapy. However, survival between two groups was similar. More recently, it has been shown that combination of FUDR or 5-FU and leucovorin, which is a potent modulator of FUDR and 5-FU,can achieve response rate of 70% with low toxicity and with 33% to 40% 2-year survival rates, comparable to survival of patients who givensurgical resection (30% of 5-year survival).
Photodynamic therapy: It may be used in patients with obstructiverectal cancer who can’t be resected, and results in palliation of symptoms.
Radiofrequency ablation (RFA): Two recent studies have demonstrated that RFA is a safe and effective treatment for unresectable colorectal metastases .RFA-related mortality ranged from 0% to 4% and complications occurred in 2.4% to 8%.When a short follow-up, local recurrence at the RFA site was only 1.8% to 18%.Longer follow-up is needed, but it appears that RFA is an effective treatment for unresectable colorectal metastases confined to the liver. The only limitation of RFA is the small size of lesions that can be treated –generally less than 4 cm.
Cryoablation: There has been a more extensive experience with cryosurgery for liver metastases from colorectal cancer than for HCC. The development of vacuum-insulated cryoprobes and high-quality ultrasound has allowed for precise, rapid, controlled freezing of liver tumors. Several studies have shown that cryosurgery is safe, with operative mortality from 0% to 4% and complication rates of 8% to 15%.In a small group of treated patients, 62% of patients were alive,28% without evidence of recurrence at the end of a median follow-up of 2 years. Comparing with RFA, which is only effective for small size of colorectal metastases, cryoablation is eligible for larger metastases.
HOW TO DETECT PROGNOSIS OF COLON CANCER?

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) depends on the following:

The stage of the cancer (whether the cancer is in the inner lining of the colon only, involves the whole colon, or has spread to other places in the body).
Whether the cancer has blocked or created a hole in the colon.
The blood levels of carcinoembryonic antigen (CEA; a substance in the blood that may be increased when cancer is present) before treatment begins.
Whether the cancer has recurred.
The patient’s general health.
Treatment options depend on the following:

The stage of the cancer.
Whether the cancer has recurred.
The patient’s general health.
Cancer of the colon is a highly treatable and often curable disease when localized to the bowel. Surgery is the primary form of treatment and results in cure in approximately 50% of patients. Recurrence following surgery is a major problem and is often the ultimate cause of death.

Prognostic factors

The prognosis of patients with colon cancer is clearly related to the degree of penetration of the tumor through the bowel wall, the presence or absence of nodal involvement, and the presence or absence of distant metastases. These 3 characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance.

Many other prognostic markers have been evaluated retrospectively for patients with colon cancer, although most, including allelic loss of chromosome 18q or thymidylate synthase expression, have not been prospectively validated. Microsatellite instability, also associated with hereditary nonpolyposis colon cancer (HNPCC), has been shown to be associated with improved survival independent of tumor stage in a population-based series of 607 patients younger than 50 years with colorectal cancer. Treatment decisions depend on factors such as physician and patient preferences and the stage of the disease rather than the age of the patient. Racial differences in overall survival after adjuvant therapy have been observed, without differences in disease-free survival, suggesting that comorbid conditions play a role in survival outcome in different patient populations.

Follow-up



Following treatment of colon cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease. The impact of such monitoring on overall mortality of patients with recurrent colon cancer, however, is limited by the relatively small proportion of patients in whom localized, potentially curable metastases are found. To date, no large-scale randomized trials have documented the efficacy of a standard, postoperative monitoring program. CEA is a serum glycoprotein frequently used in the management of patients with colon cancer. A review of the use of this tumor marker suggests the following:

A CEA level is not a valuable screening test for
colorectal cancer due to the large numbers of
false-positive and false-negative reports.
Postoperative CEA testing should be restricted
to patients who would be candidates for
resection of liver or lung metastases.
Routine use of CEA levels alone for
monitoring response to treatment should
not be recommended.
The optimal regimen and frequency of follow-up examinations are not well defined, however, because the impact on patient survival is not clear and the quality of data is poor. New surveillance methods, including CEA immunoscintigraphy and positron emission tomography, are under clinical evaluation.