INTRODUCTION — Despite early diagnosis and treatment, cancers involving the colon or rectum (together referred to as colorectal cancer) can reappear at a later time, even if the cancer was entirely removed during the initial treatment. This reappearance of the cancer is referred to as a recurrence or a relapse.
A colorectal cancer recurrence can be either local (confined to the large intestine or nearby tissues) or at a more distant site. Areas of distant tumor involvement are called metastases. Although most patients with metastatic colorectal cancer develop the tumor recurrence months to years after initial treatment, a small percentage already have metastatic cancer when their cancer is first discovered.
The treatment of patients with colorectal cancer that has spread or metastasized depends upon the extent and location of the tumor involvement. Cure is not possible for most patients with metastatic colorectal cancer, although some patients who have limited involvement (particularly involving the liver) may be cured by further surgery. For others, chemotherapy is the most appropriate option. Chemotherapy does not cure metastatic colorectal cancer, but it can improve symptoms and prolong life.
This topic review will discuss management of patients with metastatic colorectal cancer. Treatment for localized colon cancer and localized rectal cancer is discussed elsewhere (See "Patient information: Treatment of colon cancer" and see "Patient information: Treatment of rectal cancer").
SURGERY FOR RESECTABLE ADVANCED DISEASE — Sometimes surgery can be considered for patients whose colorectal cancer has spread in a limited way outside of the intestine, to an area such as the liver. Up to 30 percent of patients may be cured if the tumor(s) in the liver can be completely removed or resected [1]. In order for this approach to succeed, there must be no cancer outside of the liver.
In some cases, intravenous chemotherapy may be recommended prior to attempted surgical removal of the liver metastases. This approach might permit some patients who have liver metastases that are initially unresectable or borderline resectable (because of size or location) to have successful surgery [2].
It is not clear if additional chemotherapy is beneficial after successful surgical removal of liver metastases. Although several clinical trials have studied this issue, none have shown that survival is better in patients who get chemotherapy after liver surgery compared to those who do not. However, none of the studies used what would be considered to be "modern" chemotherapy regimens. Treatment guidelines suggest that six months of treatment with chemotherapy or observation alone are both reasonable options [3]. Contemporary chemotherapy regimens for metastatic colorectal cancer are described in detail below (See "First-line chemotherapy" below).
At some institutions, the chemotherapy is given directly into the liver (an approach called hepatic intraarterial chemotherapy) with or without additional chemotherapy given into the veins (intravenous chemotherapy) [4]. However, whether this approach is better than intravenous chemotherapy alone is unclear, and the most commonly used approach is intravenous chemotherapy.
CHEMOTHERAPY FOR UNRESECTABLE DISEASE — As noted above, surgery is the only way to cure a patient who has metastatic colorectal cancer. If surgery is not possible, then chemotherapy is generally recommended. Chemotherapy clearly benefits patients by improving symptoms and prolonging survival; it is not intended to cure the cancer.
Conventional chemotherapy — The conventional chemotherapy drugs used to treat metastatic colorectal cancer include: 5-fluorouracil (abbreviated 5-FU), which is usually given into the vein with a second drug called leucovorin, which enhances its activity Orally active 5-FU-like drugs such as capecitabine (Xeloda®) Oxaliplatin (Eloxatin®), which is given intravenously Irinotecan (Camptosar®), also given intravenously
These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment. (See "Chemotherapy side effects" below).
Targeted therapies — Three other drugs that are active in metastatic colorectal cancer, called bevacizumab (Avastin®), cetuximab (Erbitux®), and panitumumab (Vectibix®) work by a different mechanism. All three are referred to as "targeted chemotherapy agents" since they are antibodies (a type of protein) that work to inhibit a protein that is important for the growth and/or survival of colon cancer cells: Avastin binds a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the development of a blood supply within a growing cancer; this blood supply is essential for the tumor to grow and spread. Avastin also enhance the antitumor effect of other chemotherapy drugs. Erbitux targets a different protein, the epidermal growth factor receptor (EGFR), which is found in approximately 80 percent of colorectal cancers. Erbitux is effective even if EGFR is not detected within a person's tumor, possibly because the test is not sensitive in detecting a small number of receptors. Vectibix also targets the EGFR, but in a different way than Erbitux.
Because these drugs do not directly inhibit rapidly dividing cells, they do not have the usual side effects of conventional chemotherapy drugs such as irinotecan, oxaliplatin, and 5-FU. However, they have other unique side effects, which are described in detail below. (See "Chemotherapy side effects" below).
Avastin is not effective when given by itself, without other anticancer drugs. It is used only in combination with 5-FU and irinotecan or oxaliplatin. On the other hand, Erbitux can be used alone or in combination with irinotecan. Ongoing trials are currently evaluating Erbitux and Avastin (both alone and together) with other chemotherapeutic agents in an attempt to find more active combinations.
In the United States, Vectibix is only approved as a "last resort" treatment of metastatic colorectal cancer, after other drugs have failed. Its role in combination with chemotherapy and Avastin is under study.
Assessment during therapy — Regardless of the particular drugs that are chosen, the response to chemotherapy is typically assessed using periodic x-ray studies (such as CT scans), often recommended after every two to three cycles of therapy, and by measuring blood levels of a tumor marker called carcinoembryonic antigen (CEA). CEA levels are typically high in patients who have advanced colorectal cancer, and levels are checked every one to three months during therapy. Persistently rising CEA levels suggest that disease is progressing and that a change in therapy is warranted. However, disease progression should be confirmed with radiographic testing (eg, CT scan) or biopsy before a change in treatment is recommended.
FIRST-LINE CHEMOTHERAPY — Conventional chemotherapy drugs and targeted agents are generally used in combination for patients with newly diagnosed, previously untreated metastatic colorectal cancer. Many different combinations have been developed, and studies are ongoing to determine which combinations and schedules are best. Several different combinations are currently recommended for initial (first-line) treatment.
FOLFOX and FOLFIRI — Two different combination regimens are considered standard approaches for the initial treatment for patients with metastatic colorectal cancer [5,6]. Each of these regimens consists of three drugs, used together in a specific way: Oxaliplatin plus 5-FU and leucovorin (referred to as FOLFOX) Irinotecan plus 5-FU and leucovorin (referred to as FOLFIRI)
In both regimens, the oxaliplatin or irinotecan are typically administered intravenously all at once on the first day of treatment (day 1). The leucovorin and 5-FU are administered on two consecutive days (day 1 and 2) with an initial intravenous bolus (rapidly infused) dose of leucovorin and 5-FU, followed by a continuous infusion of 5-FU administered into the vein over 22 hours. The same doses and schedule of all three drugs are repeated every two weeks. Frequently, the delivery of 5-FU is modified so that the infusion runs for 46 instead of 22 hours, thus eliminating the need for patients to come in for the bolus infusion of 5-FU and leucovorin on day 2.
Both the FOLFOX and FOLFIRI regimens require that patients have a central venous access catheter (often termed a "port") surgically inserted into one of the large blood vessels in the chest and a portable chemotherapy pump at home (referred to as an ambulatory infusion pump). This pump is actually very small, and it fits into a fanny pack that can be worn around the patient's waist.
Both FOLFIRI and FOLFOX have similar outcomes when used as first-line therapy [5,6] and the choice between them is sometimes based upon expected side effects with each regimen (see "Chemotherapy side effects" below). At least in the United States, most patients are offered first-line FOLFOX, and FOLFIRI is reserved for second-line therapy unless there are coexisting medical conditions (such as neuropathy) that might favor the initial use of FOLFIRI.
For patients in whom ambulatory infusion pump therapy is not feasible, the combination of the oral drug Xeloda plus oxaliplatin is an acceptable alternative to the infusional regimens FOLFOX. This regimen is more convenient for the patient, and probably similarly effective for first-line therapy as FOLFOX. However, some side effects (including diarrhea and redness, tenderness, and peeling of the skin of the palms and soles of the feet) may be more pronounced than with FOLFOX.
Combinations of Xeloda with irinotecan may not be as effective and are more toxic than FOLFIRI. As a result, they are usually not recommended.
Benefit of adding Avastin — Encouraging results have been reported when bevacizumab (Avastin®) is combined with 5-FU plus leucovorin and either oxaliplatin or irinotecan (FOLFOX or FOLFIRI). Adding Avastin results in a significantly higher likelihood of a tumor response, and it prolongs survival compared to treatment without Avastin. As long as there are not reasons Avastin should not be used, it is recommended for first-line treatment in persons who receive either FOLFIRI or FOLFOX. Avastin is administered intravenously once every two weeks.
Patients who can't tolerate irinotecan or oxaliplatin — For patients who are not appropriate candidates for an aggressive chemotherapy regimen like FOLFOX or FOLFIRI (for example, because of their age, physical condition or coexisting medical problems), intravenous 5-FU plus leucovorin with or without Avastin may be a reasonable, less toxic alternative. In this regimen, both agents are administered as a short injection weekly for six of every eight weeks.
Another alternative is Xeloda alone, which is taken in pill form twice daily for 14 of every 21 days. Xeloda has about the same level of effectiveness as intravenous 5-FU plus leucovorin. These regimens are slightly less effective than oxaliplatin or irinotecan-containing chemotherapy regimens (FOLFOX or FOLFIRI), but in general, they have fewer side effects and do not require a central venous access catheter or ambulatory infusion pump.
SECOND-LINE THERAPY — If the cancer continues to grow despite chemotherapy, or it begins to enlarge again after an initial response to the first-line chemotherapy regimen, a different chemotherapy combination may be tried (if the patient is well enough to tolerate additional therapy). Because survival can be prolonged by second-line (as well as third-line) therapy, exposure to all of the most active medications at some point in the treatment (ie, 5-FU, oxaliplatin, irinotecan, Avastin, Erbitux, Vectibix) is thought to be more important than the specific sequence or order of drug administration.
The choice of second-line treatment typically depends on what was given originally. Two different approaches may be considered, but it is unknown whether either approach is superior to the other: If FOLFOX (or Xeloda plus oxaliplatin) plus Avastin was the first-line regimen, patients are typically switched to FOLFIRI with or without Avastin. If FOLFIRI plus Avastin was given as the first-line therapy, the patient is usually switched to FOLFOX or Xeloda plus oxaliplatin with or without Avastin.
Whether or not Avastin should be continued with the second-line regimen is a very controversial area, and should be discussed with a physician.
Erbitux — Adding Erbitux to irinotecan can shrink tumors in patients who stop responding to irinotecan-containing chemotherapy combinations (such as FOLFIRI or even irinotecan alone). Most often, the combination of Erbitux plus irinotecan is used for third-line therapy after failure of both FOLFOX and FOLFIRI. However, it is also sometimes used as second line therapy if there is progression on FOLFIRI plus Avastin.
Erbitux is also approved for use as a single agent to treat metastatic colorectal cancer in patients who cannot tolerate irinotecan-based chemotherapy.
Vectibix — In the United States, panitumamab (Vectibix®) is approved as a "last resort" treatment of metastatic CRC, after other drugs have failed. In one trial, patients receiving panitumumab after failing irinotecan and oxaliplatin-containing chemotherapy were significantly more likely to be alive and disease-free 8 weeks after treatment, than were those who had supportive care only without further chemotherapy (49 versus 30 percent). Combinations of panitumumab with conventional chemotherapy and bevacizumab are currently being studied.
CHEMOTHERAPY SIDE EFFECTS — The side effects of chemotherapy depend upon the type, combination, and schedule of drugs that are administered. The most common side effects of each agent are listed below, but is important to review all of the potential side effects of any therapy with the healthcare team.
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 are more likely when 5-FU and leucovorin are given five days in a row (rather than weekly), especially in older patients. For this reason, most oncologists prefer the weekly regimen. Hair loss is less common with 5-FU plus leucovorin than with combinations of irinotecan or oxaliplatin plus 5-FU/leucovorin.
Xeloda — The most common side effect of Xeloda is hand-foot syndrome, a condition that causes soreness, redness and peeling of the skin of the palms and soles of the feet. Otherwise, oral 5-FU-like drugs such as Xeloda have the same side effects as intravenous 5-FU, although diarrhea and mucositis are somewhat less common.
Irinotecan — Irinotecan usually causes more diarrhea, lower blood counts, more fatigue, and more hair loss compared to 5-FU. When irinotecan is combined with 5-FU and leucovorin (FOLFIRI), the most common side effect is diarrhea. Patients should call their healthcare provider immediately if severe diarrhea develops.
Oxaliplatin — Oxaliplatin can cause numbness and tingling of the hands and feet, and this is more likely with longer durations of therapy. This drug can also cause an unusual sensitivity to cold temperatures. This can result in painful spasms of the throat while inhaling cold air or ingesting cold liquids. Patients should not drink cold fluids in the several days surrounding their oxaliplatin infusions, avoid inhaling cold air, and avoid exposing the hands and feet to cold when possible.
Avastin — Avastin can rarely cause an allergic reaction. If the reaction is severe, the drug may need to be stopped. Because there is a small risk that Avastin can impair wound healing, surgery should be avoided for at least four weeks before and after Avastin (if possible) to avoid this potential side effect.
Avastin may also cause bleeding or, uncommonly, perforation of the bowel during treatment. It can also increase blood pressure or cause protein in the urine. Close monitoring is necessary to detect these problems early so that they can be effectively treated.
There is an increased risk of blood clots for patients using Avastin in combination with 5-FU. Approximately 5 percent of patients have serious events such as strokes and heart attacks during therapy. The risk appears to be highest in patients with prior heart problems, and in those over the age of 65.
Erbitux — Erbitux can cause allergic reactions slightly more frequently than Avastin. If severe, treatment with Erbitux may be stopped. Patients will be closely monitored for allergic reactions during and after their infusion.
Other side effects include a skin rash that resembles acne, and low blood levels of magnesium. Low magnesium levels can cause weakness, heart rhythm abnormalities, and lead to low levels of other components of the blood, such as potassium and calcium.
Vectibix — Vectibix can also cause allergic reactions which, if severe, may require that drug treatment be stopped. Other side effects are similar to those with Erbitux, including skin rash, which may be severe and accompanied by infection, and low blood levels of magnesium.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. 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/
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. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(http://www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The American Gastroenterological Association
(www.gastro.org)
The American College of Gastroenterology
(www.acg.gi.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Goldberg, RM, Fleming, TR, Tangen, CM, et al. Surgery for recurrent colon cancer: Strategies for identifying resectable recurrence and success rates after resection. Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group. Ann Intern Med 1998; 129:27.
2. Adam, R, Delvart, V, Pascal, G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004; 240:644.
3. National Comprehensive Cancer Network (NCCN) guidelines available online at www.nccn.org/patients/patient_gls.asp.
4. Kemeny, N, Huang, Y, Cohen, AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999; 341:2039.
5. 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 2004; 22:23.
6. 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 2004; 22:229.
Friday, October 12, 2007
Treatment of metastatic colorectal cancer
INTRODUCTION — Despite early diagnosis and treatment, cancers involving the colon or rectum (together referred to as colorectal cancer) can reappear at a later time, even if the cancer was entirely removed during the initial treatment. This reappearance of the cancer is referred to as a recurrence or a relapse.
A colorectal cancer recurrence can be either local (confined to the large intestine or nearby tissues) or at a more distant site. Areas of distant tumor involvement are called metastases. Although most patients with metastatic colorectal cancer develop the tumor recurrence months to years after initial treatment, a small percentage already have metastatic cancer when their cancer is first discovered.
The treatment of patients with colorectal cancer that has spread or metastasized depends upon the extent and location of the tumor involvement. Cure is not possible for most patients with metastatic colorectal cancer, although some patients who have limited involvement (particularly involving the liver) may be cured by further surgery. For others, chemotherapy is the most appropriate option. Chemotherapy does not cure metastatic colorectal cancer, but it can improve symptoms and prolong life.
This topic review will discuss management of patients with metastatic colorectal cancer. Treatment for localized colon cancer and localized rectal cancer is discussed elsewhere (See "Patient information: Treatment of colon cancer" and see "Patient information: Treatment of rectal cancer").
SURGERY FOR RESECTABLE ADVANCED DISEASE — Sometimes surgery can be considered for patients whose colorectal cancer has spread in a limited way outside of the intestine, to an area such as the liver. Up to 30 percent of patients may be cured if the tumor(s) in the liver can be completely removed or resected [1]. In order for this approach to succeed, there must be no cancer outside of the liver.
In some cases, intravenous chemotherapy may be recommended prior to attempted surgical removal of the liver metastases. This approach might permit some patients who have liver metastases that are initially unresectable or borderline resectable (because of size or location) to have successful surgery [2].
It is not clear if additional chemotherapy is beneficial after successful surgical removal of liver metastases. Although several clinical trials have studied this issue, none have shown that survival is better in patients who get chemotherapy after liver surgery compared to those who do not. However, none of the studies used what would be considered to be "modern" chemotherapy regimens. Treatment guidelines suggest that six months of treatment with chemotherapy or observation alone are both reasonable options [3]. Contemporary chemotherapy regimens for metastatic colorectal cancer are described in detail below (See "First-line chemotherapy" below).
At some institutions, the chemotherapy is given directly into the liver (an approach called hepatic intraarterial chemotherapy) with or without additional chemotherapy given into the veins (intravenous chemotherapy) [4]. However, whether this approach is better than intravenous chemotherapy alone is unclear, and the most commonly used approach is intravenous chemotherapy.
CHEMOTHERAPY FOR UNRESECTABLE DISEASE — As noted above, surgery is the only way to cure a patient who has metastatic colorectal cancer. If surgery is not possible, then chemotherapy is generally recommended. Chemotherapy clearly benefits patients by improving symptoms and prolonging survival; it is not intended to cure the cancer.
Conventional chemotherapy — The conventional chemotherapy drugs used to treat metastatic colorectal cancer include: 5-fluorouracil (abbreviated 5-FU), which is usually given into the vein with a second drug called leucovorin, which enhances its activity Orally active 5-FU-like drugs such as capecitabine (Xeloda®) Oxaliplatin (Eloxatin®), which is given intravenously Irinotecan (Camptosar®), also given intravenously
These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment. (See "Chemotherapy side effects" below).
Targeted therapies — Three other drugs that are active in metastatic colorectal cancer, called bevacizumab (Avastin®), cetuximab (Erbitux®), and panitumumab (Vectibix®) work by a different mechanism. All three are referred to as "targeted chemotherapy agents" since they are antibodies (a type of protein) that work to inhibit a protein that is important for the growth and/or survival of colon cancer cells: Avastin binds a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the development of a blood supply within a growing cancer; this blood supply is essential for the tumor to grow and spread. Avastin also enhance the antitumor effect of other chemotherapy drugs. Erbitux targets a different protein, the epidermal growth factor receptor (EGFR), which is found in approximately 80 percent of colorectal cancers. Erbitux is effective even if EGFR is not detected within a person's tumor, possibly because the test is not sensitive in detecting a small number of receptors. Vectibix also targets the EGFR, but in a different way than Erbitux.
Because these drugs do not directly inhibit rapidly dividing cells, they do not have the usual side effects of conventional chemotherapy drugs such as irinotecan, oxaliplatin, and 5-FU. However, they have other unique side effects, which are described in detail below. (See "Chemotherapy side effects" below).
Avastin is not effective when given by itself, without other anticancer drugs. It is used only in combination with 5-FU and irinotecan or oxaliplatin. On the other hand, Erbitux can be used alone or in combination with irinotecan. Ongoing trials are currently evaluating Erbitux and Avastin (both alone and together) with other chemotherapeutic agents in an attempt to find more active combinations.
In the United States, Vectibix is only approved as a "last resort" treatment of metastatic colorectal cancer, after other drugs have failed. Its role in combination with chemotherapy and Avastin is under study.
Assessment during therapy — Regardless of the particular drugs that are chosen, the response to chemotherapy is typically assessed using periodic x-ray studies (such as CT scans), often recommended after every two to three cycles of therapy, and by measuring blood levels of a tumor marker called carcinoembryonic antigen (CEA). CEA levels are typically high in patients who have advanced colorectal cancer, and levels are checked every one to three months during therapy. Persistently rising CEA levels suggest that disease is progressing and that a change in therapy is warranted. However, disease progression should be confirmed with radiographic testing (eg, CT scan) or biopsy before a change in treatment is recommended.
FIRST-LINE CHEMOTHERAPY — Conventional chemotherapy drugs and targeted agents are generally used in combination for patients with newly diagnosed, previously untreated metastatic colorectal cancer. Many different combinations have been developed, and studies are ongoing to determine which combinations and schedules are best. Several different combinations are currently recommended for initial (first-line) treatment.
FOLFOX and FOLFIRI — Two different combination regimens are considered standard approaches for the initial treatment for patients with metastatic colorectal cancer [5,6]. Each of these regimens consists of three drugs, used together in a specific way: Oxaliplatin plus 5-FU and leucovorin (referred to as FOLFOX) Irinotecan plus 5-FU and leucovorin (referred to as FOLFIRI)
In both regimens, the oxaliplatin or irinotecan are typically administered intravenously all at once on the first day of treatment (day 1). The leucovorin and 5-FU are administered on two consecutive days (day 1 and 2) with an initial intravenous bolus (rapidly infused) dose of leucovorin and 5-FU, followed by a continuous infusion of 5-FU administered into the vein over 22 hours. The same doses and schedule of all three drugs are repeated every two weeks. Frequently, the delivery of 5-FU is modified so that the infusion runs for 46 instead of 22 hours, thus eliminating the need for patients to come in for the bolus infusion of 5-FU and leucovorin on day 2.
Both the FOLFOX and FOLFIRI regimens require that patients have a central venous access catheter (often termed a "port") surgically inserted into one of the large blood vessels in the chest and a portable chemotherapy pump at home (referred to as an ambulatory infusion pump). This pump is actually very small, and it fits into a fanny pack that can be worn around the patient's waist.
Both FOLFIRI and FOLFOX have similar outcomes when used as first-line therapy [5,6] and the choice between them is sometimes based upon expected side effects with each regimen (see "Chemotherapy side effects" below). At least in the United States, most patients are offered first-line FOLFOX, and FOLFIRI is reserved for second-line therapy unless there are coexisting medical conditions (such as neuropathy) that might favor the initial use of FOLFIRI.
For patients in whom ambulatory infusion pump therapy is not feasible, the combination of the oral drug Xeloda plus oxaliplatin is an acceptable alternative to the infusional regimens FOLFOX. This regimen is more convenient for the patient, and probably similarly effective for first-line therapy as FOLFOX. However, some side effects (including diarrhea and redness, tenderness, and peeling of the skin of the palms and soles of the feet) may be more pronounced than with FOLFOX.
Combinations of Xeloda with irinotecan may not be as effective and are more toxic than FOLFIRI. As a result, they are usually not recommended.
Benefit of adding Avastin — Encouraging results have been reported when bevacizumab (Avastin®) is combined with 5-FU plus leucovorin and either oxaliplatin or irinotecan (FOLFOX or FOLFIRI). Adding Avastin results in a significantly higher likelihood of a tumor response, and it prolongs survival compared to treatment without Avastin. As long as there are not reasons Avastin should not be used, it is recommended for first-line treatment in persons who receive either FOLFIRI or FOLFOX. Avastin is administered intravenously once every two weeks.
Patients who can't tolerate irinotecan or oxaliplatin — For patients who are not appropriate candidates for an aggressive chemotherapy regimen like FOLFOX or FOLFIRI (for example, because of their age, physical condition or coexisting medical problems), intravenous 5-FU plus leucovorin with or without Avastin may be a reasonable, less toxic alternative. In this regimen, both agents are administered as a short injection weekly for six of every eight weeks.
Another alternative is Xeloda alone, which is taken in pill form twice daily for 14 of every 21 days. Xeloda has about the same level of effectiveness as intravenous 5-FU plus leucovorin. These regimens are slightly less effective than oxaliplatin or irinotecan-containing chemotherapy regimens (FOLFOX or FOLFIRI), but in general, they have fewer side effects and do not require a central venous access catheter or ambulatory infusion pump.
SECOND-LINE THERAPY — If the cancer continues to grow despite chemotherapy, or it begins to enlarge again after an initial response to the first-line chemotherapy regimen, a different chemotherapy combination may be tried (if the patient is well enough to tolerate additional therapy). Because survival can be prolonged by second-line (as well as third-line) therapy, exposure to all of the most active medications at some point in the treatment (ie, 5-FU, oxaliplatin, irinotecan, Avastin, Erbitux, Vectibix) is thought to be more important than the specific sequence or order of drug administration.
The choice of second-line treatment typically depends on what was given originally. Two different approaches may be considered, but it is unknown whether either approach is superior to the other: If FOLFOX (or Xeloda plus oxaliplatin) plus Avastin was the first-line regimen, patients are typically switched to FOLFIRI with or without Avastin. If FOLFIRI plus Avastin was given as the first-line therapy, the patient is usually switched to FOLFOX or Xeloda plus oxaliplatin with or without Avastin.
Whether or not Avastin should be continued with the second-line regimen is a very controversial area, and should be discussed with a physician.
Erbitux — Adding Erbitux to irinotecan can shrink tumors in patients who stop responding to irinotecan-containing chemotherapy combinations (such as FOLFIRI or even irinotecan alone). Most often, the combination of Erbitux plus irinotecan is used for third-line therapy after failure of both FOLFOX and FOLFIRI. However, it is also sometimes used as second line therapy if there is progression on FOLFIRI plus Avastin.
Erbitux is also approved for use as a single agent to treat metastatic colorectal cancer in patients who cannot tolerate irinotecan-based chemotherapy.
Vectibix — In the United States, panitumamab (Vectibix®) is approved as a "last resort" treatment of metastatic CRC, after other drugs have failed. In one trial, patients receiving panitumumab after failing irinotecan and oxaliplatin-containing chemotherapy were significantly more likely to be alive and disease-free 8 weeks after treatment, than were those who had supportive care only without further chemotherapy (49 versus 30 percent). Combinations of panitumumab with conventional chemotherapy and bevacizumab are currently being studied.
CHEMOTHERAPY SIDE EFFECTS — The side effects of chemotherapy depend upon the type, combination, and schedule of drugs that are administered. The most common side effects of each agent are listed below, but is important to review all of the potential side effects of any therapy with the healthcare team.
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 are more likely when 5-FU and leucovorin are given five days in a row (rather than weekly), especially in older patients. For this reason, most oncologists prefer the weekly regimen. Hair loss is less common with 5-FU plus leucovorin than with combinations of irinotecan or oxaliplatin plus 5-FU/leucovorin.
Xeloda — The most common side effect of Xeloda is hand-foot syndrome, a condition that causes soreness, redness and peeling of the skin of the palms and soles of the feet. Otherwise, oral 5-FU-like drugs such as Xeloda have the same side effects as intravenous 5-FU, although diarrhea and mucositis are somewhat less common.
Irinotecan — Irinotecan usually causes more diarrhea, lower blood counts, more fatigue, and more hair loss compared to 5-FU. When irinotecan is combined with 5-FU and leucovorin (FOLFIRI), the most common side effect is diarrhea. Patients should call their healthcare provider immediately if severe diarrhea develops.
Oxaliplatin — Oxaliplatin can cause numbness and tingling of the hands and feet, and this is more likely with longer durations of therapy. This drug can also cause an unusual sensitivity to cold temperatures. This can result in painful spasms of the throat while inhaling cold air or ingesting cold liquids. Patients should not drink cold fluids in the several days surrounding their oxaliplatin infusions, avoid inhaling cold air, and avoid exposing the hands and feet to cold when possible.
Avastin — Avastin can rarely cause an allergic reaction. If the reaction is severe, the drug may need to be stopped. Because there is a small risk that Avastin can impair wound healing, surgery should be avoided for at least four weeks before and after Avastin (if possible) to avoid this potential side effect.
Avastin may also cause bleeding or, uncommonly, perforation of the bowel during treatment. It can also increase blood pressure or cause protein in the urine. Close monitoring is necessary to detect these problems early so that they can be effectively treated.
There is an increased risk of blood clots for patients using Avastin in combination with 5-FU. Approximately 5 percent of patients have serious events such as strokes and heart attacks during therapy. The risk appears to be highest in patients with prior heart problems, and in those over the age of 65.
Erbitux — Erbitux can cause allergic reactions slightly more frequently than Avastin. If severe, treatment with Erbitux may be stopped. Patients will be closely monitored for allergic reactions during and after their infusion.
Other side effects include a skin rash that resembles acne, and low blood levels of magnesium. Low magnesium levels can cause weakness, heart rhythm abnormalities, and lead to low levels of other components of the blood, such as potassium and calcium.
Vectibix — Vectibix can also cause allergic reactions which, if severe, may require that drug treatment be stopped. Other side effects are similar to those with Erbitux, including skin rash, which may be severe and accompanied by infection, and low blood levels of magnesium.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. 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/
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. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(http://www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The American Gastroenterological Association
(www.gastro.org)
The American College of Gastroenterology
(www.acg.gi.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Goldberg, RM, Fleming, TR, Tangen, CM, et al. Surgery for recurrent colon cancer: Strategies for identifying resectable recurrence and success rates after resection. Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group. Ann Intern Med 1998; 129:27.
2. Adam, R, Delvart, V, Pascal, G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004; 240:644.
3. National Comprehensive Cancer Network (NCCN) guidelines available online at www.nccn.org/patients/patient_gls.asp.
4. Kemeny, N, Huang, Y, Cohen, AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999; 341:2039.
5. 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 2004; 22:23.
6. 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 2004; 22:229.
A colorectal cancer recurrence can be either local (confined to the large intestine or nearby tissues) or at a more distant site. Areas of distant tumor involvement are called metastases. Although most patients with metastatic colorectal cancer develop the tumor recurrence months to years after initial treatment, a small percentage already have metastatic cancer when their cancer is first discovered.
The treatment of patients with colorectal cancer that has spread or metastasized depends upon the extent and location of the tumor involvement. Cure is not possible for most patients with metastatic colorectal cancer, although some patients who have limited involvement (particularly involving the liver) may be cured by further surgery. For others, chemotherapy is the most appropriate option. Chemotherapy does not cure metastatic colorectal cancer, but it can improve symptoms and prolong life.
This topic review will discuss management of patients with metastatic colorectal cancer. Treatment for localized colon cancer and localized rectal cancer is discussed elsewhere (See "Patient information: Treatment of colon cancer" and see "Patient information: Treatment of rectal cancer").
SURGERY FOR RESECTABLE ADVANCED DISEASE — Sometimes surgery can be considered for patients whose colorectal cancer has spread in a limited way outside of the intestine, to an area such as the liver. Up to 30 percent of patients may be cured if the tumor(s) in the liver can be completely removed or resected [1]. In order for this approach to succeed, there must be no cancer outside of the liver.
In some cases, intravenous chemotherapy may be recommended prior to attempted surgical removal of the liver metastases. This approach might permit some patients who have liver metastases that are initially unresectable or borderline resectable (because of size or location) to have successful surgery [2].
It is not clear if additional chemotherapy is beneficial after successful surgical removal of liver metastases. Although several clinical trials have studied this issue, none have shown that survival is better in patients who get chemotherapy after liver surgery compared to those who do not. However, none of the studies used what would be considered to be "modern" chemotherapy regimens. Treatment guidelines suggest that six months of treatment with chemotherapy or observation alone are both reasonable options [3]. Contemporary chemotherapy regimens for metastatic colorectal cancer are described in detail below (See "First-line chemotherapy" below).
At some institutions, the chemotherapy is given directly into the liver (an approach called hepatic intraarterial chemotherapy) with or without additional chemotherapy given into the veins (intravenous chemotherapy) [4]. However, whether this approach is better than intravenous chemotherapy alone is unclear, and the most commonly used approach is intravenous chemotherapy.
CHEMOTHERAPY FOR UNRESECTABLE DISEASE — As noted above, surgery is the only way to cure a patient who has metastatic colorectal cancer. If surgery is not possible, then chemotherapy is generally recommended. Chemotherapy clearly benefits patients by improving symptoms and prolonging survival; it is not intended to cure the cancer.
Conventional chemotherapy — The conventional chemotherapy drugs used to treat metastatic colorectal cancer include: 5-fluorouracil (abbreviated 5-FU), which is usually given into the vein with a second drug called leucovorin, which enhances its activity Orally active 5-FU-like drugs such as capecitabine (Xeloda®) Oxaliplatin (Eloxatin®), which is given intravenously Irinotecan (Camptosar®), also given intravenously
These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment. (See "Chemotherapy side effects" below).
Targeted therapies — Three other drugs that are active in metastatic colorectal cancer, called bevacizumab (Avastin®), cetuximab (Erbitux®), and panitumumab (Vectibix®) work by a different mechanism. All three are referred to as "targeted chemotherapy agents" since they are antibodies (a type of protein) that work to inhibit a protein that is important for the growth and/or survival of colon cancer cells: Avastin binds a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the development of a blood supply within a growing cancer; this blood supply is essential for the tumor to grow and spread. Avastin also enhance the antitumor effect of other chemotherapy drugs. Erbitux targets a different protein, the epidermal growth factor receptor (EGFR), which is found in approximately 80 percent of colorectal cancers. Erbitux is effective even if EGFR is not detected within a person's tumor, possibly because the test is not sensitive in detecting a small number of receptors. Vectibix also targets the EGFR, but in a different way than Erbitux.
Because these drugs do not directly inhibit rapidly dividing cells, they do not have the usual side effects of conventional chemotherapy drugs such as irinotecan, oxaliplatin, and 5-FU. However, they have other unique side effects, which are described in detail below. (See "Chemotherapy side effects" below).
Avastin is not effective when given by itself, without other anticancer drugs. It is used only in combination with 5-FU and irinotecan or oxaliplatin. On the other hand, Erbitux can be used alone or in combination with irinotecan. Ongoing trials are currently evaluating Erbitux and Avastin (both alone and together) with other chemotherapeutic agents in an attempt to find more active combinations.
In the United States, Vectibix is only approved as a "last resort" treatment of metastatic colorectal cancer, after other drugs have failed. Its role in combination with chemotherapy and Avastin is under study.
Assessment during therapy — Regardless of the particular drugs that are chosen, the response to chemotherapy is typically assessed using periodic x-ray studies (such as CT scans), often recommended after every two to three cycles of therapy, and by measuring blood levels of a tumor marker called carcinoembryonic antigen (CEA). CEA levels are typically high in patients who have advanced colorectal cancer, and levels are checked every one to three months during therapy. Persistently rising CEA levels suggest that disease is progressing and that a change in therapy is warranted. However, disease progression should be confirmed with radiographic testing (eg, CT scan) or biopsy before a change in treatment is recommended.
FIRST-LINE CHEMOTHERAPY — Conventional chemotherapy drugs and targeted agents are generally used in combination for patients with newly diagnosed, previously untreated metastatic colorectal cancer. Many different combinations have been developed, and studies are ongoing to determine which combinations and schedules are best. Several different combinations are currently recommended for initial (first-line) treatment.
FOLFOX and FOLFIRI — Two different combination regimens are considered standard approaches for the initial treatment for patients with metastatic colorectal cancer [5,6]. Each of these regimens consists of three drugs, used together in a specific way: Oxaliplatin plus 5-FU and leucovorin (referred to as FOLFOX) Irinotecan plus 5-FU and leucovorin (referred to as FOLFIRI)
In both regimens, the oxaliplatin or irinotecan are typically administered intravenously all at once on the first day of treatment (day 1). The leucovorin and 5-FU are administered on two consecutive days (day 1 and 2) with an initial intravenous bolus (rapidly infused) dose of leucovorin and 5-FU, followed by a continuous infusion of 5-FU administered into the vein over 22 hours. The same doses and schedule of all three drugs are repeated every two weeks. Frequently, the delivery of 5-FU is modified so that the infusion runs for 46 instead of 22 hours, thus eliminating the need for patients to come in for the bolus infusion of 5-FU and leucovorin on day 2.
Both the FOLFOX and FOLFIRI regimens require that patients have a central venous access catheter (often termed a "port") surgically inserted into one of the large blood vessels in the chest and a portable chemotherapy pump at home (referred to as an ambulatory infusion pump). This pump is actually very small, and it fits into a fanny pack that can be worn around the patient's waist.
Both FOLFIRI and FOLFOX have similar outcomes when used as first-line therapy [5,6] and the choice between them is sometimes based upon expected side effects with each regimen (see "Chemotherapy side effects" below). At least in the United States, most patients are offered first-line FOLFOX, and FOLFIRI is reserved for second-line therapy unless there are coexisting medical conditions (such as neuropathy) that might favor the initial use of FOLFIRI.
For patients in whom ambulatory infusion pump therapy is not feasible, the combination of the oral drug Xeloda plus oxaliplatin is an acceptable alternative to the infusional regimens FOLFOX. This regimen is more convenient for the patient, and probably similarly effective for first-line therapy as FOLFOX. However, some side effects (including diarrhea and redness, tenderness, and peeling of the skin of the palms and soles of the feet) may be more pronounced than with FOLFOX.
Combinations of Xeloda with irinotecan may not be as effective and are more toxic than FOLFIRI. As a result, they are usually not recommended.
Benefit of adding Avastin — Encouraging results have been reported when bevacizumab (Avastin®) is combined with 5-FU plus leucovorin and either oxaliplatin or irinotecan (FOLFOX or FOLFIRI). Adding Avastin results in a significantly higher likelihood of a tumor response, and it prolongs survival compared to treatment without Avastin. As long as there are not reasons Avastin should not be used, it is recommended for first-line treatment in persons who receive either FOLFIRI or FOLFOX. Avastin is administered intravenously once every two weeks.
Patients who can't tolerate irinotecan or oxaliplatin — For patients who are not appropriate candidates for an aggressive chemotherapy regimen like FOLFOX or FOLFIRI (for example, because of their age, physical condition or coexisting medical problems), intravenous 5-FU plus leucovorin with or without Avastin may be a reasonable, less toxic alternative. In this regimen, both agents are administered as a short injection weekly for six of every eight weeks.
Another alternative is Xeloda alone, which is taken in pill form twice daily for 14 of every 21 days. Xeloda has about the same level of effectiveness as intravenous 5-FU plus leucovorin. These regimens are slightly less effective than oxaliplatin or irinotecan-containing chemotherapy regimens (FOLFOX or FOLFIRI), but in general, they have fewer side effects and do not require a central venous access catheter or ambulatory infusion pump.
SECOND-LINE THERAPY — If the cancer continues to grow despite chemotherapy, or it begins to enlarge again after an initial response to the first-line chemotherapy regimen, a different chemotherapy combination may be tried (if the patient is well enough to tolerate additional therapy). Because survival can be prolonged by second-line (as well as third-line) therapy, exposure to all of the most active medications at some point in the treatment (ie, 5-FU, oxaliplatin, irinotecan, Avastin, Erbitux, Vectibix) is thought to be more important than the specific sequence or order of drug administration.
The choice of second-line treatment typically depends on what was given originally. Two different approaches may be considered, but it is unknown whether either approach is superior to the other: If FOLFOX (or Xeloda plus oxaliplatin) plus Avastin was the first-line regimen, patients are typically switched to FOLFIRI with or without Avastin. If FOLFIRI plus Avastin was given as the first-line therapy, the patient is usually switched to FOLFOX or Xeloda plus oxaliplatin with or without Avastin.
Whether or not Avastin should be continued with the second-line regimen is a very controversial area, and should be discussed with a physician.
Erbitux — Adding Erbitux to irinotecan can shrink tumors in patients who stop responding to irinotecan-containing chemotherapy combinations (such as FOLFIRI or even irinotecan alone). Most often, the combination of Erbitux plus irinotecan is used for third-line therapy after failure of both FOLFOX and FOLFIRI. However, it is also sometimes used as second line therapy if there is progression on FOLFIRI plus Avastin.
Erbitux is also approved for use as a single agent to treat metastatic colorectal cancer in patients who cannot tolerate irinotecan-based chemotherapy.
Vectibix — In the United States, panitumamab (Vectibix®) is approved as a "last resort" treatment of metastatic CRC, after other drugs have failed. In one trial, patients receiving panitumumab after failing irinotecan and oxaliplatin-containing chemotherapy were significantly more likely to be alive and disease-free 8 weeks after treatment, than were those who had supportive care only without further chemotherapy (49 versus 30 percent). Combinations of panitumumab with conventional chemotherapy and bevacizumab are currently being studied.
CHEMOTHERAPY SIDE EFFECTS — The side effects of chemotherapy depend upon the type, combination, and schedule of drugs that are administered. The most common side effects of each agent are listed below, but is important to review all of the potential side effects of any therapy with the healthcare team.
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 are more likely when 5-FU and leucovorin are given five days in a row (rather than weekly), especially in older patients. For this reason, most oncologists prefer the weekly regimen. Hair loss is less common with 5-FU plus leucovorin than with combinations of irinotecan or oxaliplatin plus 5-FU/leucovorin.
Xeloda — The most common side effect of Xeloda is hand-foot syndrome, a condition that causes soreness, redness and peeling of the skin of the palms and soles of the feet. Otherwise, oral 5-FU-like drugs such as Xeloda have the same side effects as intravenous 5-FU, although diarrhea and mucositis are somewhat less common.
Irinotecan — Irinotecan usually causes more diarrhea, lower blood counts, more fatigue, and more hair loss compared to 5-FU. When irinotecan is combined with 5-FU and leucovorin (FOLFIRI), the most common side effect is diarrhea. Patients should call their healthcare provider immediately if severe diarrhea develops.
Oxaliplatin — Oxaliplatin can cause numbness and tingling of the hands and feet, and this is more likely with longer durations of therapy. This drug can also cause an unusual sensitivity to cold temperatures. This can result in painful spasms of the throat while inhaling cold air or ingesting cold liquids. Patients should not drink cold fluids in the several days surrounding their oxaliplatin infusions, avoid inhaling cold air, and avoid exposing the hands and feet to cold when possible.
Avastin — Avastin can rarely cause an allergic reaction. If the reaction is severe, the drug may need to be stopped. Because there is a small risk that Avastin can impair wound healing, surgery should be avoided for at least four weeks before and after Avastin (if possible) to avoid this potential side effect.
Avastin may also cause bleeding or, uncommonly, perforation of the bowel during treatment. It can also increase blood pressure or cause protein in the urine. Close monitoring is necessary to detect these problems early so that they can be effectively treated.
There is an increased risk of blood clots for patients using Avastin in combination with 5-FU. Approximately 5 percent of patients have serious events such as strokes and heart attacks during therapy. The risk appears to be highest in patients with prior heart problems, and in those over the age of 65.
Erbitux — Erbitux can cause allergic reactions slightly more frequently than Avastin. If severe, treatment with Erbitux may be stopped. Patients will be closely monitored for allergic reactions during and after their infusion.
Other side effects include a skin rash that resembles acne, and low blood levels of magnesium. Low magnesium levels can cause weakness, heart rhythm abnormalities, and lead to low levels of other components of the blood, such as potassium and calcium.
Vectibix — Vectibix can also cause allergic reactions which, if severe, may require that drug treatment be stopped. Other side effects are similar to those with Erbitux, including skin rash, which may be severe and accompanied by infection, and low blood levels of magnesium.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. 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/
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. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(http://www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The American Gastroenterological Association
(www.gastro.org)
The American College of Gastroenterology
(www.acg.gi.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Goldberg, RM, Fleming, TR, Tangen, CM, et al. Surgery for recurrent colon cancer: Strategies for identifying resectable recurrence and success rates after resection. Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group. Ann Intern Med 1998; 129:27.
2. Adam, R, Delvart, V, Pascal, G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004; 240:644.
3. National Comprehensive Cancer Network (NCCN) guidelines available online at www.nccn.org/patients/patient_gls.asp.
4. Kemeny, N, Huang, Y, Cohen, AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999; 341:2039.
5. 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 2004; 22:23.
6. 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 2004; 22:229.
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)
[1-6]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. A Comparison of Laparoscopically Assisted and Open Colectomy for Colon Cancer. N Engl J Med 2004; 350:2050.
2. Andre, T, Boni, C, Mounedji-Boudiaf, L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350:2343.
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.
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)
[1-6]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. A Comparison of Laparoscopically Assisted and Open Colectomy for Colon Cancer. N Engl J Med 2004; 350:2050.
2. Andre, T, Boni, C, Mounedji-Boudiaf, L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350:2343.
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.
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)
[1-6]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. A Comparison of Laparoscopically Assisted and Open Colectomy for Colon Cancer. N Engl J Med 2004; 350:2050.
2. Andre, T, Boni, C, Mounedji-Boudiaf, L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350:2343.
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.
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)
[1-6]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. A Comparison of Laparoscopically Assisted and Open Colectomy for Colon Cancer. N Engl J Med 2004; 350:2050.
2. Andre, T, Boni, C, Mounedji-Boudiaf, L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350:2343.
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.
Screening for colon cancer
INTRODUCTION — Colorectal cancer (cancer of the large portion of the bowel [colon] or rectum) is a common, preventable disease. Approximately one-third of people who develop it die of the disease, making it the second leading cause of cancer death. However, screening tests now make it possible to detect existing cancers at an early, treatable stage and even to prevent the development of colorectal cancer.
There is general agreement by experts that all adults should undergo screening beginning at age 50, or earlier for people who are at high risk for colorectal cancer. Several different tests are currently available, and new tests are being developed; all of these have advantages and disadvantages. The optimal screening test depends upon a person's preferences and their risk of colon cancer. It is important to review each test's effectiveness, safety, convenience, and costs.
EFFECTIVENESS OF SCREENING — Most colorectal cancers develop gradually over many years. They begin as small, benign tumors called adenomatous polyps. These polyps grow, develop precancerous changes, eventually become cancerous, and later spread and become incurable. This progression takes at least 10 years in most people.
The screening tests described below all work by detecting pre-cancers at the polyp stage before they become cancerous or by detecting cancers themselves while they are still curable. Regular screening for and removal of polyps can reduce a person's risk of developing colorectal cancer by up to 90 percent. In addition, early detection of cancers that are already present in the colon often allows for successful treatment.
WHO SHOULD BE SCREENED? — Several factors increase an individual's risk of developing colorectal cancer. The presence of these factors will determine the age at which screening should begin, the frequency of screening, and the screening tests that are most appropriate.
Small increases in risk — Several characteristics increase the risk of colorectal cancer two to several fold. While each is of some importance individually, risk can be substantially increased if several are present together. Family history of colorectal cancer — The occurrence of colorectal cancer in a family member increases the risk of getting the cancer, especially if it is a first degree relative (a parent, brother or sister, or child), several family members are affected, or if the cancers have occurred at an early age (eg, before age 55 years). Prior colorectal cancer or polyps — People who have previously had colorectal cancer have an increased risk of developing a new colorectal cancer. People who have had adenomatous polyps before the age of 60 years are also at increased risk for colorectal cancer. (See "Patient information: Colon polyps"). Increasing age — Although the average person has a 5 percent lifetime risk of developing colorectal cancer, 90 percent of these cancers occur in people older than 50 years of age. Risk increases throughout life. Race — Black Americans have a higher risk of dying from colorectal cancer than white Americans. This risk is also high in native Alaskans and low in American Indians. Lifestyle factors — Several lifestyle factors have been linked to the risk of colorectal cancer. Factors that appear to increase risk include: A diet high in fat and red meat and low in fiber A sedentary lifestyle Cigarette smoking
Factors that may decrease risk include: Folic acid supplements Calcium supplements Aspirin, ibuprofen, and related drugs (the evidence for these is not yet strong enough to recommend taking them for this purpose)
Large increase in risk — Some conditions are associated with very high rates of colorectal cancer. Familial adenomatous polyposis — Familial adenomatous polyposis (FAP) is an uncommon inherited condition associated with an increased risk of colorectal cancer. Nearly 100 percent of people with this condition will develop colorectal cancer during their lifetime, and most of these cancers occur before the age of 50 years. FAP causes hundreds of polyps to develop throughout the colon. Hereditary nonpolyposis colon cancer — Hereditary nonpolyposis colon cancer (HNPCC) is another inherited condition associated with an increased risk of colorectal cancer. It is slightly more common than FAP, but is still uncommon. About 70 percent of people with HNPCC will experience colorectal cancer by the age of 65. Cancer also tends to occur at younger ages and in the part of the colon on the right side of the body (the ascending colon).
HNPCC is suspected in those with a strong family history of colon cancer; several family members from different generations may have been affected, some of whom developed the cancer relatively early in life. Persons with HNPCC are also at risk for other types of cancer, including endometrial (uterine), stomach, bladder, renal (kidney) and ovarian cancer. Inflammatory bowel disease — The risk of colorectal cancer is increased in people with Crohn's disease of the colon or ulcerative colitis. The risk increases as the amount of inflamed colon increases and as the duration of disease increases; pancolitis (inflammation of the entire colon) and colitis of 10 years' duration or longer are associated with the greatest risk for colorectal cancer. Risk is not increased in irritable bowel disease.
SCREENING TESTS — Four tests are currently recommended for colorectal cancer screening: the fecal occult blood test, sigmoidoscopy, barium enema, and colonoscopy.
Fecal occult blood test — Colorectal cancers (and, more rarely, polyps) often bleed, releasing microscopic amounts of blood into the stool. The blood is frequently not visible to the naked eye, requiring specialized tests for detection. The fecal occult blood test can be used to detect blood in the stool. Procedure — This simple test is performed by putting small amounts of stool on chemically coated cards. Usually, two samples from three consecutive stools are applied to the cards at home and returned to the clinician. The sample on the card is then treated with a solution that changes color when blood is present.
Some simple dietary restrictions for two days prior to testing can improve the accuracy of the test. These include: Eliminate red meat, turnips, and horseradishes Avoid drugs that may irritate the stomach lining (such as aspirin, ibuprofen-like drugs) Do not take vitamin C Eat high-fiber foods Effectiveness — The fecal occult blood test, when performed once every year, has been shown to reduce the risk of dying from colorectal cancer by up to one-third [1]. Risks and disadvantages — Because polyps seldom bleed, the fecal occult blood test is less likely to detect polyps than other screening tests (see below). In addition, only 2 to 5 percent of people with a positive test actually have colorectal cancer; thus, for every patient with cancer, 50 patients are unnecessarily distressed and undergo tests that eventually reveal no cancer. Following the dietary restrictions above reduces the chance of a false-positive test. Additional testing — If a fecal occult blood test has a positive result, the entire colon should be examined, usually with colonoscopy.
Sigmoidoscopy — Sigmoidoscopy allows direct viewing of the lining of the rectum and the lower part of the colon (the descending colon, show figure 1). This area accounts for about one-half of the total area of the rectum and colon, where half of the cancers occur. (See "Patient information: Flexible sigmoidoscopy"). Procedure — Sigmoidoscopy requires that the patient prepare by cleaning out the bowel. This usually involves consuming a clear liquid diet, laxatives, and using an enema shortly before the examination. During the procedure, a thin, lighted tube is advanced into the rectum and the left side of the colon to check for polyps and cancer. Biopsies (small samples of tissue) can be removed during sigmoidoscopy. Sigmoidoscopy may be performed in a doctor's office. The procedure may cause mild cramping; most people do not need sedative drugs and are able to return to work or other activities the same day. Effectiveness — Physicians who perform sigmoidoscopy can identify polyps and cancers in the descending colon and rectum with a high degree of accuracy. Studies suggest that sigmoidoscopy, performed as infrequently as every 5 to 10 years, reduces death from cancers in the lower half of the colon and rectum (the area directly examined) by 66 percent [2]. Risks and disadvantages — The risks of sigmoidoscopy are small. The procedure can create a small tear in the intestinal wall in about 2 per every 10,000 people; death from this complication is rare. A major disadvantage of sigmoidoscopy is that it cannot detect polyps or cancers located in the right side of the colon. Additional testing — Certain changes in the left-sided colon increase the likelihood of polyps or cancer in the remaining part of the colon. Thus, if sigmoidoscopy reveals suspicious findings in the left-sided colon, such as many small polyps or polyps with certain microscopic features, colonoscopy may be recommended to view the entire length of the colon.
Fecal occult blood test and sigmoidoscopy — Combined screening with a fecal occult blood test and sigmoidoscopy is a common practice and may be more effective than screening with either test alone [3].
Colonoscopy — Colonoscopy allows direct viewing of the lining of the rectum and the entire colon (show figure 1). (See "Patient information: Colonoscopy"). Procedure — During colonoscopy, a thin, lighted tube is used to directly view the lining of the rectum and the entire colon. This test can therefore detect polyps and cancers that are beyond the reach of the sigmoidoscope. People are usually given a mild sedative drug during the procedure. Effectiveness — Colonoscopy detects most small polyps and almost all large polyps and cancers [4]. Polyps and some cancers can be removed during this procedure. Risks and disadvantages — The risks of colonoscopy are greater than those of other screening tests. Colonoscopy leads to serious bleeding or a tear of the intestinal wall in about 1 in 1,000 people. Because the procedure requires sedation, most people must be accompanied home after the procedure and are unable to return to work or other activities on the same day.
Barium enema test — A barium enema test provides a detailed x-ray picture of the rectum and the entire colon (show figure 1). A double-contrast barium enema is usually recommended. Procedure — During a barium enema test, liquid barium is used to coat the inside of the colon. The barium outlines the profile of the colon on x-rays and can reveal structural abnormalities such as polyps and cancers. Preparation for a barium enema entails cleansing the colon with a saline laxative. Some people experience mild cramping during the procedure, but sedative drugs are usually not necessary, and most people can return to work or other activities on the same day. Effectiveness — The barium enema test detects about one-half of large polyps and about 40 percent of all polyps in the colon and rectum [5]. Most experts feel that screening with barium enema reduces the risk of dying from colorectal cancer, but this has not been definitively proven. Risks and disadvantages — The barium enema test is relatively safe compared with other screening tests for colorectal cancer. Additional testing — If a barium enema test reveals an abnormality, a colonoscopy may be recommended.
New tests — Several new screening tests for colorectal cancer are being developed and evaluated. These tests include improved fecal occult blood tests, fecal tests for genetic abnormalities linked to colorectal cancer, and a type of computed tomography (CT) scan called a virtual colonoscopy. These tests are still being studied, and they are not yet recommended for routine screening.
Virtual colonoscopy, in particular, is being performed more commonly. The major advantages of virtual colonoscopy compared with optical colonoscopy are that the procedure is safe, and there is no need for sedation. However, if a worrisome polyp is found on virtual colonoscopy, a traditional colonoscopy will be needed for confirmation and biopsy. Additionally, the accuracy of virtual colonoscopy depends upon how it is performed; the test that is currently available may not be accurate enough for use as a screening test.
SCREENING PLANS — The screening plan that is recommended depends upon a person's risk of colorectal cancer.
Average risk of colorectal cancer — People with an average risk of colorectal cancer should begin screening at age 50. The tests differ in features (effectiveness in preventing cancer, comfort, safety, cost, and convenience). No single screening test has been identified as the best test. The available options should be discussed with a clinician to develop a screening plan that can be followed.
Some clinicians recommend a fecal occult blood test once per year and a sigmoidoscopy once every five years; a combination of these screening tests may also be recommended. Alternative screening plans include a barium enema test once every five years or colonoscopy once every 10 years. If the results of one or more of these tests is abnormal, more frequent examinations with colonoscopy may be recommended.
Increased risk of colorectal cancer — Screening plans for people with an increased risk may entail screening at a younger age, more frequent screening, and the use of more sensitive screening tests (like colonoscopy). The optimal screening plan depends upon the reason for increased risk.
Family history of colorectal cancer
- 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 five years.
- 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, or two or more second degree relatives (grandparent, aunt, uncle) with colorectal cancer 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 are considered to have an average risk of colorectal cancer (See "Average risk of colorectal cancer" above).
Familial adenomatous polyposis — People with a family history of familial adenomatous polyposis (FAP) should consider genetic counseling and genetic testing to determine if they carry the affected gene. People who carry the gene or do not know if they carry the gene should begin screening with sigmoidoscopy once every year, beginning at puberty. If this screening reveals many polyps, plans for colectomy (surgical removal of the colon) should be considered; this surgery is the only way to prevent colorectal cancer in people with FAP.
Hereditary nonpolyposis colon cancer — People with a family history of hereditary nonpolyposis colon cancer (HNPCC) should consider genetic counseling and genetic testing to determine if they carry the affected gene. People who carry the gene or who do not know if they carry the gene should be screened with colonoscopy or barium enema because HNPCC is associated with cancers of the right-sided colon. This screening should be done once every one to two years between age 20 and 30 years, and once every year after age 40. Because polyps can progress more rapidly to cancer in people with HNPCC, more frequent screening may also be recommended.
Inflammatory bowel disease — In people with ulcerative colitis or Crohn's disease of the colon, the optimal screening plan depends upon the amount of colon affected and the duration of the disease. Screening usually entails colonoscopy once every one to two years beginning after eight years of pancolitis (inflammation of the entire colon) or after 15 years of colitis of the left-sided colon. (See "Patient information: Crohn's disease" and see "Patient information: Ulcerative colitis").
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/healthtopics.html)
The American Gastroenterological Association
(www.gastro.org)
The American College of Gastroenterology
(www.acg.gi.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Mandel, JS, Bond, JH, Church, TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993; 328:1365.
2. Selby, JV, Friedman, GD, Quesenberry, CP Jr, Weiss, NS. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992; 326:653.
3. Winawer, SJ, Flehinger, BJ, Schottenfeld, D, Miller, DG. Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 1993; 85:1311.
4. Rex, DK, Cutler, CS, Lemmel, GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997; 112:24.
5. Winawer, SJ, Stewart, ET, Zauber, AG, et al. A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. National Polyp Study Work Group. N Engl J Med 2000; 342:1766.
There is general agreement by experts that all adults should undergo screening beginning at age 50, or earlier for people who are at high risk for colorectal cancer. Several different tests are currently available, and new tests are being developed; all of these have advantages and disadvantages. The optimal screening test depends upon a person's preferences and their risk of colon cancer. It is important to review each test's effectiveness, safety, convenience, and costs.
EFFECTIVENESS OF SCREENING — Most colorectal cancers develop gradually over many years. They begin as small, benign tumors called adenomatous polyps. These polyps grow, develop precancerous changes, eventually become cancerous, and later spread and become incurable. This progression takes at least 10 years in most people.
The screening tests described below all work by detecting pre-cancers at the polyp stage before they become cancerous or by detecting cancers themselves while they are still curable. Regular screening for and removal of polyps can reduce a person's risk of developing colorectal cancer by up to 90 percent. In addition, early detection of cancers that are already present in the colon often allows for successful treatment.
WHO SHOULD BE SCREENED? — Several factors increase an individual's risk of developing colorectal cancer. The presence of these factors will determine the age at which screening should begin, the frequency of screening, and the screening tests that are most appropriate.
Small increases in risk — Several characteristics increase the risk of colorectal cancer two to several fold. While each is of some importance individually, risk can be substantially increased if several are present together. Family history of colorectal cancer — The occurrence of colorectal cancer in a family member increases the risk of getting the cancer, especially if it is a first degree relative (a parent, brother or sister, or child), several family members are affected, or if the cancers have occurred at an early age (eg, before age 55 years). Prior colorectal cancer or polyps — People who have previously had colorectal cancer have an increased risk of developing a new colorectal cancer. People who have had adenomatous polyps before the age of 60 years are also at increased risk for colorectal cancer. (See "Patient information: Colon polyps"). Increasing age — Although the average person has a 5 percent lifetime risk of developing colorectal cancer, 90 percent of these cancers occur in people older than 50 years of age. Risk increases throughout life. Race — Black Americans have a higher risk of dying from colorectal cancer than white Americans. This risk is also high in native Alaskans and low in American Indians. Lifestyle factors — Several lifestyle factors have been linked to the risk of colorectal cancer. Factors that appear to increase risk include: A diet high in fat and red meat and low in fiber A sedentary lifestyle Cigarette smoking
Factors that may decrease risk include: Folic acid supplements Calcium supplements Aspirin, ibuprofen, and related drugs (the evidence for these is not yet strong enough to recommend taking them for this purpose)
Large increase in risk — Some conditions are associated with very high rates of colorectal cancer. Familial adenomatous polyposis — Familial adenomatous polyposis (FAP) is an uncommon inherited condition associated with an increased risk of colorectal cancer. Nearly 100 percent of people with this condition will develop colorectal cancer during their lifetime, and most of these cancers occur before the age of 50 years. FAP causes hundreds of polyps to develop throughout the colon. Hereditary nonpolyposis colon cancer — Hereditary nonpolyposis colon cancer (HNPCC) is another inherited condition associated with an increased risk of colorectal cancer. It is slightly more common than FAP, but is still uncommon. About 70 percent of people with HNPCC will experience colorectal cancer by the age of 65. Cancer also tends to occur at younger ages and in the part of the colon on the right side of the body (the ascending colon).
HNPCC is suspected in those with a strong family history of colon cancer; several family members from different generations may have been affected, some of whom developed the cancer relatively early in life. Persons with HNPCC are also at risk for other types of cancer, including endometrial (uterine), stomach, bladder, renal (kidney) and ovarian cancer. Inflammatory bowel disease — The risk of colorectal cancer is increased in people with Crohn's disease of the colon or ulcerative colitis. The risk increases as the amount of inflamed colon increases and as the duration of disease increases; pancolitis (inflammation of the entire colon) and colitis of 10 years' duration or longer are associated with the greatest risk for colorectal cancer. Risk is not increased in irritable bowel disease.
SCREENING TESTS — Four tests are currently recommended for colorectal cancer screening: the fecal occult blood test, sigmoidoscopy, barium enema, and colonoscopy.
Fecal occult blood test — Colorectal cancers (and, more rarely, polyps) often bleed, releasing microscopic amounts of blood into the stool. The blood is frequently not visible to the naked eye, requiring specialized tests for detection. The fecal occult blood test can be used to detect blood in the stool. Procedure — This simple test is performed by putting small amounts of stool on chemically coated cards. Usually, two samples from three consecutive stools are applied to the cards at home and returned to the clinician. The sample on the card is then treated with a solution that changes color when blood is present.
Some simple dietary restrictions for two days prior to testing can improve the accuracy of the test. These include: Eliminate red meat, turnips, and horseradishes Avoid drugs that may irritate the stomach lining (such as aspirin, ibuprofen-like drugs) Do not take vitamin C Eat high-fiber foods Effectiveness — The fecal occult blood test, when performed once every year, has been shown to reduce the risk of dying from colorectal cancer by up to one-third [1]. Risks and disadvantages — Because polyps seldom bleed, the fecal occult blood test is less likely to detect polyps than other screening tests (see below). In addition, only 2 to 5 percent of people with a positive test actually have colorectal cancer; thus, for every patient with cancer, 50 patients are unnecessarily distressed and undergo tests that eventually reveal no cancer. Following the dietary restrictions above reduces the chance of a false-positive test. Additional testing — If a fecal occult blood test has a positive result, the entire colon should be examined, usually with colonoscopy.
Sigmoidoscopy — Sigmoidoscopy allows direct viewing of the lining of the rectum and the lower part of the colon (the descending colon, show figure 1). This area accounts for about one-half of the total area of the rectum and colon, where half of the cancers occur. (See "Patient information: Flexible sigmoidoscopy"). Procedure — Sigmoidoscopy requires that the patient prepare by cleaning out the bowel. This usually involves consuming a clear liquid diet, laxatives, and using an enema shortly before the examination. During the procedure, a thin, lighted tube is advanced into the rectum and the left side of the colon to check for polyps and cancer. Biopsies (small samples of tissue) can be removed during sigmoidoscopy. Sigmoidoscopy may be performed in a doctor's office. The procedure may cause mild cramping; most people do not need sedative drugs and are able to return to work or other activities the same day. Effectiveness — Physicians who perform sigmoidoscopy can identify polyps and cancers in the descending colon and rectum with a high degree of accuracy. Studies suggest that sigmoidoscopy, performed as infrequently as every 5 to 10 years, reduces death from cancers in the lower half of the colon and rectum (the area directly examined) by 66 percent [2]. Risks and disadvantages — The risks of sigmoidoscopy are small. The procedure can create a small tear in the intestinal wall in about 2 per every 10,000 people; death from this complication is rare. A major disadvantage of sigmoidoscopy is that it cannot detect polyps or cancers located in the right side of the colon. Additional testing — Certain changes in the left-sided colon increase the likelihood of polyps or cancer in the remaining part of the colon. Thus, if sigmoidoscopy reveals suspicious findings in the left-sided colon, such as many small polyps or polyps with certain microscopic features, colonoscopy may be recommended to view the entire length of the colon.
Fecal occult blood test and sigmoidoscopy — Combined screening with a fecal occult blood test and sigmoidoscopy is a common practice and may be more effective than screening with either test alone [3].
Colonoscopy — Colonoscopy allows direct viewing of the lining of the rectum and the entire colon (show figure 1). (See "Patient information: Colonoscopy"). Procedure — During colonoscopy, a thin, lighted tube is used to directly view the lining of the rectum and the entire colon. This test can therefore detect polyps and cancers that are beyond the reach of the sigmoidoscope. People are usually given a mild sedative drug during the procedure. Effectiveness — Colonoscopy detects most small polyps and almost all large polyps and cancers [4]. Polyps and some cancers can be removed during this procedure. Risks and disadvantages — The risks of colonoscopy are greater than those of other screening tests. Colonoscopy leads to serious bleeding or a tear of the intestinal wall in about 1 in 1,000 people. Because the procedure requires sedation, most people must be accompanied home after the procedure and are unable to return to work or other activities on the same day.
Barium enema test — A barium enema test provides a detailed x-ray picture of the rectum and the entire colon (show figure 1). A double-contrast barium enema is usually recommended. Procedure — During a barium enema test, liquid barium is used to coat the inside of the colon. The barium outlines the profile of the colon on x-rays and can reveal structural abnormalities such as polyps and cancers. Preparation for a barium enema entails cleansing the colon with a saline laxative. Some people experience mild cramping during the procedure, but sedative drugs are usually not necessary, and most people can return to work or other activities on the same day. Effectiveness — The barium enema test detects about one-half of large polyps and about 40 percent of all polyps in the colon and rectum [5]. Most experts feel that screening with barium enema reduces the risk of dying from colorectal cancer, but this has not been definitively proven. Risks and disadvantages — The barium enema test is relatively safe compared with other screening tests for colorectal cancer. Additional testing — If a barium enema test reveals an abnormality, a colonoscopy may be recommended.
New tests — Several new screening tests for colorectal cancer are being developed and evaluated. These tests include improved fecal occult blood tests, fecal tests for genetic abnormalities linked to colorectal cancer, and a type of computed tomography (CT) scan called a virtual colonoscopy. These tests are still being studied, and they are not yet recommended for routine screening.
Virtual colonoscopy, in particular, is being performed more commonly. The major advantages of virtual colonoscopy compared with optical colonoscopy are that the procedure is safe, and there is no need for sedation. However, if a worrisome polyp is found on virtual colonoscopy, a traditional colonoscopy will be needed for confirmation and biopsy. Additionally, the accuracy of virtual colonoscopy depends upon how it is performed; the test that is currently available may not be accurate enough for use as a screening test.
SCREENING PLANS — The screening plan that is recommended depends upon a person's risk of colorectal cancer.
Average risk of colorectal cancer — People with an average risk of colorectal cancer should begin screening at age 50. The tests differ in features (effectiveness in preventing cancer, comfort, safety, cost, and convenience). No single screening test has been identified as the best test. The available options should be discussed with a clinician to develop a screening plan that can be followed.
Some clinicians recommend a fecal occult blood test once per year and a sigmoidoscopy once every five years; a combination of these screening tests may also be recommended. Alternative screening plans include a barium enema test once every five years or colonoscopy once every 10 years. If the results of one or more of these tests is abnormal, more frequent examinations with colonoscopy may be recommended.
Increased risk of colorectal cancer — Screening plans for people with an increased risk may entail screening at a younger age, more frequent screening, and the use of more sensitive screening tests (like colonoscopy). The optimal screening plan depends upon the reason for increased risk.
Family history of colorectal cancer
- 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 five years.
- 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, or two or more second degree relatives (grandparent, aunt, uncle) with colorectal cancer 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 are considered to have an average risk of colorectal cancer (See "Average risk of colorectal cancer" above).
Familial adenomatous polyposis — People with a family history of familial adenomatous polyposis (FAP) should consider genetic counseling and genetic testing to determine if they carry the affected gene. People who carry the gene or do not know if they carry the gene should begin screening with sigmoidoscopy once every year, beginning at puberty. If this screening reveals many polyps, plans for colectomy (surgical removal of the colon) should be considered; this surgery is the only way to prevent colorectal cancer in people with FAP.
Hereditary nonpolyposis colon cancer — People with a family history of hereditary nonpolyposis colon cancer (HNPCC) should consider genetic counseling and genetic testing to determine if they carry the affected gene. People who carry the gene or who do not know if they carry the gene should be screened with colonoscopy or barium enema because HNPCC is associated with cancers of the right-sided colon. This screening should be done once every one to two years between age 20 and 30 years, and once every year after age 40. Because polyps can progress more rapidly to cancer in people with HNPCC, more frequent screening may also be recommended.
Inflammatory bowel disease — In people with ulcerative colitis or Crohn's disease of the colon, the optimal screening plan depends upon the amount of colon affected and the duration of the disease. Screening usually entails colonoscopy once every one to two years beginning after eight years of pancolitis (inflammation of the entire colon) or after 15 years of colitis of the left-sided colon. (See "Patient information: Crohn's disease" and see "Patient information: Ulcerative colitis").
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/healthtopics.html)
The American Gastroenterological Association
(www.gastro.org)
The American College of Gastroenterology
(www.acg.gi.org)
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Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Mandel, JS, Bond, JH, Church, TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993; 328:1365.
2. Selby, JV, Friedman, GD, Quesenberry, CP Jr, Weiss, NS. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992; 326:653.
3. Winawer, SJ, Flehinger, BJ, Schottenfeld, D, Miller, DG. Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 1993; 85:1311.
4. Rex, DK, Cutler, CS, Lemmel, GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997; 112:24.
5. Winawer, SJ, Stewart, ET, Zauber, AG, et al. A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. National Polyp Study Work Group. N Engl J Med 2000; 342:1766.
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