Treatment of colon cancer

INTRODUCTION — The colon is the long section of the gastrointestinal system that connects the small intestine to the rectum. Often called the large intestine or large bowel, the colon consists of four segments, named for their position and shape (show figure 1). The ascending colon begins at the small intestine and extends up on the right side of the abdomen. The transverse colon goes across the abdomen to the left side, where it joins the descending colon, which extends down to the sigmoid colon, named for its S-shape. The sigmoid colon connects to the rectum, which in turn joins to the anus, the opening where waste (fecal) matter passes out of the body. Colon cancer can start in any of the four sections of the colon. Approximately 106,000 new cases of colon cancer are diagnosed each year in the United States.

STAGING — Treatment and prognosis depend upon the stage of the cancer. Colon cancer staging is based upon how far the cancer has penetrated into the lining of the colon, whether the cancer involves lymph nodes adjacent to the colon, and whether the cancer has spread to other organs. Initial staging usually involves a colonoscopy (a test in which a flexible tube with a camera is guided through the colon), abdominal and pelvic CT scan (specialized x-rays), and a chest x-ray. (See "Patient information: Colonoscopy" and see "Patient information: Flexible sigmoidoscopy").

The final staging of a colon cancer frequently depends upon the findings during surgery, which is the most accurate way to determine how far the tumor has spread. The two most commonly used staging systems are the: Astler - Coller modification of the Dukes system (show table 1) TNM system ("Tumor, nodes, metastases") (show table 2)

In general, the extent of a colon cancer can be considered as either localized (stage I to III) or advanced (stage IV). The process of staging colon cancer is evolving as scientists gain a greater understanding about the biologic behavior of colon cancer. As an example, it is becoming increasingly apparent that specific genetic features of a colon cancer can help to determine how aggressive it is. A better understanding of these features may help to further refine colon cancer staging and to guide treatment.

A blood test for carcinoembryonic antigen (CEA, a substance produced by most colon cancers that circulates in the blood) should be obtained before a patient has his or her initial surgery. An elevated CEA level that does not return to a normal after surgery may be a sign of persistent disease and requires further evaluation.

SURGERY — Regardless of the extent of the cancer, surgery has the most important role in treating colon cancer for the following reasons: The cancerous part of the colon and the associated lymph nodes can be removed, providing a cure for those with early stage disease. It provides the opportunity to examine the abdominal area for signs of cancer spread. It can prevent complications from the tumor such as obstruction (blockage) of the colon and bleeding.

In patients with cancer limited to the colon, the type of surgery depends upon the location and stage of the tumor. As a general rule, the part of the bowel that contains the tumor is removed along with its draining lymph glands (also called nodes). The colon is then reconnected allowing for normal bowel function. In some cases, a temporary colostomy (an opening between the colon and the skin made to collect waste from the intestine) may be necessary to allow healing of the intestine before the reconnection can be accomplished safely.

Laparoscopic versus open surgery — Although the majority of patients undergo surgery for colon cancer using a conventional or open operation (in which the surgeon makes a large incision over the front of the abdominal wall, and removes the tumor and associated lymph nodes under direct vision), newer studies suggest that a less invasive approach called laparoscopy may be just as effective, and associated with a faster recovery from surgery, as long as it is performed by surgeons who are experienced and comfortable with this approach.

For laparoscopic surgery, a video-endoscope is introduced into the abdomen through four or five very small incisions, through which the surgeon can visualize and remove the colon cancer. Like an open resection, the procedure is performed under general anesthesia, but the recovery time is generally faster because the incisions are much smaller and cut very little, if at all, into muscle. However, because the field of vision is very small, this approach is more complex and demanding for the surgeon.

Multiple clinical studies have shown similar results with the open and laparoscopic approach to colon cancer surgery. In one of the largest of these, the COST (Clinical Outcomes of Surgical Therapy) trial, 872 patients with colon cancer were randomly assigned to open or laparoscopic surgery [1]. At three years after surgery, the number of patients whose cancers recurred was similar in both groups, as was their survival.

Operating time was significantly longer in the laparoscopy treated group (150 versus 95 minutes), and in one-fifth of the laparoscopic cases, the surgeon had to switch to an open procedure during the operation. The duration of hospital stay was one day shorter in the group treated laparoscopically (five versus six days) and they required intravenous pain killers for one less day (three versus four days). There were no significant differences in the complications from surgery between the groups.

Although laparoscopic resection is an acceptable approach to surgery for colon cancer, a surgeon's expertise and experience are critically important to the success of this approach.

CHEMOTHERAPY — Adjuvant (meaning "additional") chemotherapy is usually recommended for patients in whom it is suspected that residual cancer remains in the body after the primary tumor has been removed. Even if the tumor has been completely removed, tiny cancer cells may remain in the body and grow, causing relapse after surgery. This is most likely in patients who have positive lymph nodes (stage III disease). In such patients, chemotherapy can prevent relapse and prolong survival.

The best treatment for patients who are at high risk for relapse following surgery is an area of intense ongoing research. At the present time, the best approach appears to involve chemotherapy. Several options are available for adjuvant chemotherapy in patients with resected colon cancer.

Intravenous 5-FU and leucovorin — One option includes two medications: 5-fluorouracil (5-FU) and leucovorin, given in cycles over a period of six to eight months. Both drugs are typically given by vein in one of two schedules: Weekly treatment for six out of every eight weeks, for four cycles (eight months) Five days in a row, every four or five weeks, for a total of six cycles (six to seven months)

Either way of administering these drugs is effective, although the side effects may be more severe when chemotherapy is given five days in a row every four to five weeks.

Use of FOLFOX — Another option is to add a third drug (oxaliplatin) to 5-FU and leucovorin. In a research study that compared this regimen (termed FOLFOX) to 5-FU and leucovorin in patients with node-positive colon cancer, patients receiving FOLFOX had a 7 percent higher chance of being relapse-free at three years (78 versus 73 percent) [2].

However, administration of the FOLFOX regimen is more complicated than that of 5-FU and leucovorin, and there is no evidence that survival is superior. In the FOLFOX regimen, the leucovorin and 5-FU must be administered on two consecutive days using a continuous infusion of 5-FU administered into the vein over 22 hours. This method of administration of the 5-FU requires that patients be managed either with a portable chemotherapy pump at home, or be admitted to the hospital once every two weeks in order to receive the long infusions of 5-FU.

Some experts suggest that the more toxic FOLFOX regimen be preferentially used in patients with high-risk stage III disease (ie, more than three involved lymph nodes, or a T4 primary tumor [show table 2]).

Orally active drugs — A third acceptable option for adjuvant therapy of colon cancer is to use a pill form of the drug 5-FU, of which two are available: Xeloda (capecitabine) and UFT.

In the United States, the available pill form of 5-FU is Xeloda (capecitabine). It is usually given twice a day for 14 of every 21 days for six months. The similar benefit of Xeloda as compared to bolus 5-FU and leucovorin in patients with node-positive colon cancer was shown in a trial called the X-ACT study [3]. In this study, Xeloda was at least as effective as 5-FU and LV, and there were fewer side effects, including a condition called hand-foot syndrome. In this condition, patients develop temporary soreness and redness of the palms and soles of the feet, which may be followed by peeling of the skin.

Similarly, a second study showed comparable outcomes when intravenous 5-FU and leucovorin was compared to the oral 5-FU derivative UFT (which was given daily for 28 of every 35 days, for five courses). UFT is available in Europe and in Asian countries, but not in the United States.

Benefits — As mentioned above, the benefit of chemotherapy depends upon the stage of the tumor and other individual patient factors.

Stage III colon cancer — In patients with stage III (node-positive) colon cancer, the administration of an appropriate course of chemotherapy following surgery reduces the risk of dying of cancer by about 30 percent. This magnitude of benefit is relative large, and as a result, adjuvant chemotherapy with any of the following regimens described above is considered standard of care throughout the world.

Acceptable treatment includes a 6 month course of one of the following regimens: Intravenous leucovorin-modulated 5-FU An oral 5-FU derivative such as Xeloda (capecitabine) or UFT Oxaliplatin (Eloxatin®) plus 5-FU and leucovorin (abbreviated FOLFOX).

Stage II colon cancer — In contrast to the situation with stage III colon cancer, the use of chemotherapy for patients with tumors that have grown through the bowel wall but with negative lymph nodes (stage II disease) is controversial. Chemotherapy is not routinely recommended for treating such patients, but may be recommended if particular risks are present, such as with a tumor that has obstructed or perforated the colon wall.

If there is a benefit for adjuvant chemotherapy in patients with negative lymph nodes (ie, stage II disease), it is small, 5 percent or less. In one report, the five-year survival rate for patients with stage II colon cancer who did and did not receive adjuvant chemotherapy was 81 versus 76 percent [4].

The American Society of Clinical Oncology recommends against routine administration of 5-FU-based chemotherapy for patients with resected stage II colon cancer [5]. However, they suggest that adjuvant therapy be considered for medically fit patients in certain circumstances, such as patients who have fewer than six lymph nodes in the surgical specimen, T4 tumors (show table 2), or perforation of the tumor through the bowel wall. In such patients, the risk of cancer spread or recurrence is relatively high. This is a situation in which you should discuss the benefits and risks of chemotherapy with your doctor.

If chemotherapy is administered to patients with stage II colon cancer, acceptable options include: Intravenous leucovorin-modulated 5-FU An oral 5-FU derivative such as Xeloda® (capecitabine) or UFT

Side effects — The side effects of chemotherapy depend upon the drugs that are administered, and their administration schedule.

Intravenous 5-FU and leucovorin — The most common side effects are diarrhea, mucositis (soreness in the mouth), and temporary low blood counts. In general, diarrhea and mucositis may be more likely when 5-FU and leucovorin are given five days in a row, especially in older patients. Alopecia (loss of hair) is unlikely with 5-FU.

Oral 5-FU — Oral types of 5-FU (Capecitabine [Xeloda®] in the United States, UFT in Europe and Asia) shares the same side effects as intravenous 5-FU; however the likelihood of diarrhea and mucositis is lower. The most common side effect of capecitabine is "hand-foot syndrome," a condition of soreness, redness, and peeling of the skin of the palms and soles of the feet. Supplemental vitamin B6 (also called pyridoxine) may provide benefit in this condition.

Oxaliplatin — Oxaliplatin can be associated with numbness and tingling of the hands and feet, the likelihood of which is increased with longer durations of therapy. This drug is also associated with an unusual sensitivity to cold temperatures, which manifests itself as painful spasms of the throat that are induced by either inhaling cold air or ingesting cold liquids. Patients should not drink cold fluids in the several days surrounding their oxaliplatin infusions, and should avoid inhaling cold air as much as possible.

RADIATION THERAPY — Although helpful in the treatment of rectal cancer, radiation treatment is not typically used to treat colon cancer in its early stages. Like chemotherapy, radiation therapy may be helpful for patients who are at high risk of recurrence, such as those in whom cancer has perforated the wall of the colon or spread to adjoining organs. It may also be used in treating advanced stages of the disease and in treating some metastases, particularly if they are painful.

PROGNOSIS — Each patient is different, and it is impossible to predict for any individual exactly what to expect in the future. Both before and after cancer treatment, ongoing management, lifestyle changes, and future treatment options will be discussed with a healthcare provider.

Prognosis generally depends on the stage of cancer at the time that it is removed. Cancer that is identified and treated early has the best prognosis. The following are average five-year survival rates for patients with various stages of cancer according to the most commonly used TNM staging system (show table 2): Stage 0 - 100 percent Stage I: T1 - 97 percent; T2 - 90 percent Stage II: T3 - 78 percent; T4 - 63 percent Stage III:

Any T; N1 = 1-3 positive regional lymph nodes; M0 - 66 percent
Any T; N2 = 4 or more positive regional nodes; M0 - 37 percent
Stage IV: Any M1 = presence of distant metastases - 4 percent

Other factors that affect prognosis include tumor location, type of the cancer cells, and the patterns of molecular or genetic abnormalities that cause the cancer. However, none of these is used routinely to predict outcome after treatment.

FOLLOW-UP TREATMENT — The term surveillance refers to follow-up testing to detect either a recurrence of the cancer or a new colorectal cancer after surgery for colon cancer. Aggressive surveillance other than colonoscopy is not warranted in patients with stage I colorectal cancer since over 95 percent are cured of their disease by surgery alone. The following recommendations are for patients with stage II or III colorectal cancer. These recommendations are consistent with guidelines issued by the American Society of Clinical Oncology (show table 3) [6]: Patients should see their doctor every three to six months for the first three years and then yearly thereafter. A medical history should be done at each visit, with the goal of highlighting symptoms that could suggest cancer recurrence. The physical examination should include a rectal examination for those patients who have undergone low anterior resections (a type of operation done for patients with rectal cancer). A blood test for carcinoembryonic antigen (CEA, a substance produced by most colon cancers that circulates in the blood) should be obtained every one to three months in patients with stage II and III disease for at least the first two years after the initial operation. An increase in the serum CEA may be the first sign of a recurrence of the cancer. This is true even if preoperative CEA levels were normal. This test is mainly valuable if it detects recurrence of the cancer that may then be cured by further surgery. Thus, periodic CEA levels may not be necessary in patients who would not be able to undergo further surgery for a recurrent cancer. (See "Patient information: Treatment of metastatic colorectal cancer"). All patients with colorectal cancer should undergo a complete colonoscopy either before surgical resection or within a few months after resection. This is to make certain that polyps and other cancers are not present in other areas of the colon. Colonoscopy should be repeated one year after the above colonoscopy to evaluate for additional polyps or new cancers. If none are detected, the next surveillance colonoscopy should be performed three years later. Any symptoms or laboratory values that suggest recurrence should prompt colonoscopy prior to the third year after surgery. If this test is normal, surveillance colonoscopy should be performed every five years.

The following tests are not necessary for routine surveillance: Fecal occult blood testing (ie, testing for microscopic amounts of blood in the stool) Liver function tests (a panel of blood tests) Complete blood count (a blood test)

Yearly chest x-rays are unlikely to be of any benefit for individuals who have no symptoms. A chest x-ray is indicated to look for lung metastases (areas of cancer spread) if the CEA is elevated.

Yearly CT scanning also is unlikely to be of any benefit for individuals who have no symptoms. Abdominal CT is indicated to look for intraabdominal metastases if CEA elevations are discovered or the patient develops symptoms that arise from the abdomen.

CLINICAL TRIALS — Researchers are continually conducting clinical trials of cancer treatments to find better ways of treating diseases like colon cancer. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/


IMPLICATIONS FOR FAMILY — A diagnosis of colon cancer can be devastating, not only for the patient, but also for their family. The best way to cope with a diagnosis of colon cancer varies from person to person and among families. Do not underestimate the importance of good support; it is something that you should discuss with your doctor.

Another important issue is that close relatives (siblings, parents, or children) of a person who has had colorectal cancer or specific types of polyps (adenomatous polyps) have a higher risk of developing polyps and colon cancer themselves.

Relatives should understand the following information: People who have one first-degree relative (parent, brother, sister, or child) who has experienced colorectal cancer or adenomatous polyps at a young age (before the age of 60 years), or two first-degree relatives diagnosed at any age, should begin screening earlier, typically at age 40, or 10 years younger than the earliest diagnosis in their family, whichever comes first, and screening should be repeated every 5 years. (See "Patient information: Screening for colon cancer" and see "Patient information: Colonoscopy"). People who have one first-degree relative (parent, brother, sister, or child) who has experienced colorectal cancer or adenomatous polyps at age 60 or later should begin screening at age 40, and screening should be repeated as for average risk people. People with a second-degree relative (grandparent, aunt, or uncle) or third-degree relative (great-grandparent or cousin) with colorectal cancer may be screened as average risk people.

Some conditions (such as hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis) are associated with an even higher risk of colonic polyps or cancer in family members, warranting a more aggressive approach to screening family members. These issues should be discussed with a healthcare provider who is experienced in these areas.

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute

1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
National Library of Medicine

(www.nlm.nih.gov/medlineplus)
The American Gastroenterological Association

(www.gastro.org)
The American College of Gastroenterology

(www.acg.gi.org)


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3. Twelves, C, Wong, A, Nowacki, MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005; 352:2696.
4. Gill, S, Loprinzi, CL, Sargent, DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?. J Clin Oncol 2004; 22:1797.
5. Benson AB, 3rd, Schrag, D, Somerfield, MR, et al. American Society of Clinical Oncology Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer. J Clin Oncol 2004; 22:3408.
6. Desch, CE, Benson, AB III, Smith, TJ, et al. Recommended colorectal cancer surveillance guidelines by the American Society of Clinical Oncology. J Clin Oncol 1999; 17:1312.