COLORECTAL CANCER OVERVIEW
Colon and rectal cancer are cancers that involve the lowest part of the digestive system: the large intestine and the rectum (figure 1). Despite early diagnosis and treatment, cancers involving the colon or rectum (colorectal cancer) can reappear at a later time, even if the cancer was entirely removed during the initial treatment. (See "Patient information: Colon and rectal cancer (Beyond the Basics)".)
Reappearance of the colorectal cancer after initial curative therapy 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 distant site. When the recurrence develops at a site away from the colon or rectum, it is called a metastasis.
In other cases, a colorectal cancer will have already spread to distant sites by the time it is diagnosed. This is also referred to as metastatic (stage IV) colorectal cancer.
Cure is not possible for most patients with metastatic colorectal cancer, although some patients who have limited involvement (particularly restricted to the liver or lung) can be cured with 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 article will discuss management of patients with metastatic colorectal cancer. Treatment for localized colon cancer and localized rectal cancer is discussed elsewhere. (See "Patient information: Colon and rectal cancer (Beyond the Basics)".)
TREATMENT FOR RESECTABLE METASTATIC COLORECTAL CANCER
Sometimes surgery is an option for a person 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 people may be cured if metastases in the liver can be completely removed (the medical term for this is "resected") . In order for surgery to be considered, there must be no evidence of cancer outside of the liver, and there must be an adequate amount of normal liver left behind after the resection to sustain life.
There is controversy and variability about what is considered "resectable" versus "nonresectable" metastatic disease in the liver. If at all possible, patients should request a consultation with an experienced liver surgeon or surgical oncologist (a surgeon with expertise in the treatment of cancer) before deciding upon a treatment plan.
Chemotherapy may be recommended before surgery in some cases, even if the metastatic disease appears confined to the liver. This approach may help a person who is a borderline candidate for surgery (because of the size or location of the tumors) to have successful surgery after the colorectal cancer metastases have been reduced in size by the chemotherapy .
If surgical removal of the liver metastases is successful, additional chemotherapy is often recommended after surgery . (See 'First-line chemotherapy for metastatic colorectal cancer' 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) . However, it is unclear if this approach is better than intravenous chemotherapy alone; the most commonly used approach is intravenous chemotherapy.
Surgical treatment may also be considered for a patient with a limited amount of metastatic disease in the lung.
CHEMOTHERAPY FOR UNRESECTABLE COLORECTAL CANCER
As noted above, surgery is the only way to cure metastatic colorectal cancer. In most cases, surgery is not possible, and chemotherapy is recommended to reduce symptoms and prolong survival. Although chemotherapy provides meaningful improvements in survival, it is not possible to cure metastatic colorectal cancer with chemotherapy alone.
Continuum of care concept — With most types of incurable cancer (other than metastatic colorectal cancer), individual chemotherapy drugs or regimens are given continuously until the cancer stops responding to that drug or regimen, and then an entirely new regimen (termed "second-line therapy") may be tried.
The situation is different with metastatic colorectal cancer because there are many active drugs that can be combined in a number of ways. In addition, treatment-related side effects may be lessened by limiting the number of doses of certain drugs. Thus, instead of giving the first-line regimen until the tumor progresses, treatment is often individualized.
- Specific chemotherapy drugs may be given, stopped, and then restarted at a later time, sometimes in combination with other chemotherapy drugs.
- Periods of aggressive chemotherapy may be interspersed with periods of "maintenance" chemotherapy, allowing the patient to have the greatest possible quality of life while minimizing side effects.
This has been referred to as the "continuum of care" approach to treatment of metastatic colorectal cancer.
Conventional chemotherapy — The conventional chemotherapy drugs used to treat metastatic colorectal cancer include:
- 5-fluorouracil (abbreviated FU), which is usually given into the vein with a second drug called leucovorin, which enhances its activity
- Orally active 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 'Colorectal cancer chemotherapy side effects' below.)
Targeted chemotherapy — Three other drugs that are active against metastatic colorectal cancer work by a different mechanism. These are referred to as "targeted chemotherapy agents" since they are antibodies (a type of protein) that work to inhibit a specific protein that is important for the growth and/or survival of colon cancer cells.
Because targeted chemotherapy does not directly interfere with rapidly dividing cells, they do not have the usual side effects of conventional chemotherapy. However, targeted chemotherapy has other unique side effects, which are described in detail below. (See 'Colorectal cancer chemotherapy side effects' below.)
Currently available targeted chemotherapy includes:
Bevacizumab (Avastin) — Bevacizumab binds to 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. Bevacizumab enhances the antitumor effect of other chemotherapy drugs. Bevacizumab is not effective when given by itself, but is generally given in combination with other drugs, such as oxaliplatin and irinotecan (see below).
Aflibercept (Zaltrap) — Intravenous aflibercept represents another method of interfering with a tumor’s blood supply; it is a fusion protein that acts by “trapping” VEGF and preventing it from activating its receptors on the tumor cells. In the United States, aflibercept is approved, in combination with irinotecan-based chemotherapy, for patients whose tumors have progressed while receiving an oxaliplatin-containing chemotherapy regimen, with or without bevacizumab.
Regorafenib (Stivarga) — Regorafenib is a pill form of a drug that blocks several VEGF receptors as well as other proteins referred to as kinases. In the United States, regorafenib is approved as a single agent for the treatment of patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens as well as other targeted therapies.
Cetuximab (Erbitux) — Cetuximab targets a different protein, the epidermal growth factor receptor (EGFR), which is found in about 80 percent of colorectal cancers. Erbitux® is effective even if EGFR is not found in an individual tumor.
Cetuximab does not work for all patients. It depends on whether or not the tumor has a specific abnormality (a mutation in a gene called K-ras).
- If the tumor has a K-ras mutation, cetuximab does not work.
- If the tumor does not have a K-ras mutation, cetuximab does work (ie, it is effective).
Unlike bevacizumab, cetuximab is active when given alone or in combination with other drugs, like irinotecan.
Panitumumab (Vectibix) — Like cetuximab, panitumumab also targets the EGFR. Like cetuximab, it is effective only for tumors that do not have a specific mutation in the K-ras gene.
Monitoring during treatment — A person's response to chemotherapy is monitored with periodic X-ray studies (such as CT scans) every six to eight weeks during therapy. In addition, blood levels of a tumor marker called carcinoembryonic antigen (CEA) are generally measured every one to three months during therapy. CEA levels are typically high in people with advanced colorectal cancer; persistently rising CEA levels suggest that disease is progressing and a change in therapy is warranted.
However, a rising CEA alone is not sufficient evidence to prompt a change in treatment. Disease progression should be confirmed with radiographic testing (eg, CT scan) or a biopsy before changing treatment.
FIRST-LINE CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER
Conventional chemotherapy drugs and targeted agents are generally used in combination for people with newly diagnosed, previously untreated metastatic colorectal cancer. Many different combinations have been developed and may be recommended for initial (first-line) treatment. The following sections will review the choices for the chemotherapy "backbone". Following this is a discussion of adding targeted chemotherapy agents, such as bevacizumab, to this backbone.
FOLFOX, FOLFIRI, and XELOX — Several combination chemotherapy regimens may be considered for the initial treatment of metastatic colorectal cancer [5,6]. Each of these regimens consists of two or three drugs, used together in a specific way:
- Oxaliplatin plus FU and leucovorin (referred to as FOLFOX)
- Irinotecan plus FU and leucovorin (referred to as FOLFIRI)
- Oxaliplatin plus capecitabine (referred to as XELOX or CAPOX)
With FOLFOX and FOLFIRI, the oxaliplatin or irinotecan are typically given into a vein (intravenously) all at once on the first day of treatment (day 1). The leucovorin and 5-FU are given IV on two consecutive days (days 1 and 2). Both regimens require that patients have a central venous access catheter (often termed a "port"), which is surgically inserted into one of the large blood vessels in the chest, and a portable chemotherapy pump at home (referred to as a home infusion pump). This pump is actually very small, and it fits into a pack that can be worn around the waist.
Both FOLFIRI and FOLFOX result in similar outcomes when used as first-line therapy [5,6]; the choice between them is often based upon expected side effects (see 'Colorectal cancer chemotherapy side effects' below). In the United States, patients are typically offered FOLFOX as the first-line regimen, with FOLFIRI reserved as a second-line treatment unless there are coexisting medical conditions (such as burning pain in the hands/feet, called neuropathy) that might favor the initial use of FOLFIRI.
With XELOX, the oral drug capecitabine (Xeloda®) is given, along with intravenous oxaliplatin. This regimen is more convenient for the patient because it does not require a home infusion pump. The oxaliplatin is usually administered through a central venous line because it causes pain when administered into an arm vein.
XELOX is probably as effective as FOLFOX for first-line treatment. However, some side effects (including diarrhea and hand-foot syndrome [redness, tenderness, and peeling of the skin of the palms and soles of the feet]) may be more pronounced with XELOX.
How long is the first-line regimen recommended? — The optimal duration of initial FOLFOX or XELOX is controversial.
- If a person is responding well and has no severe or bothersome side effects, it is reasonable to continue the regimen until the tumor progresses.
- Another acceptable approach is to give three or four months of FOLFOX or XELOX, and then switch to "maintenance chemotherapy" with FU plus leucovorin or capecitabine. The oxaliplatin would be restarted at the time of disease progression. This regimen may delay the development of oxaliplatin-related neuropathy.
- If a patient develops a severe neuropathy during treatment with FOLFOX or XELOX, oxaliplatin may need to be withdrawn, at least temporarily, to allow the neuropathy to resolve. During this time, maintenance chemotherapy with 5-FU and leucovorin or capecitabine alone may be substituted, or a different chemotherapy regimen (eg, FOLFIRI) could be considered. (See 'Second-line treatment of metastatic colorectal cancer' below.) The risk associated with a complete break in chemotherapy in this setting is also addressed below. (See 'Can I take a break from chemotherapy?' below.)
The optimal duration of treatment with FOLFIRI is not clear. Patients who initially take FOLFIRI usually require a change in treatment because of disease progression, rather than side effects.
Can I take a break from chemotherapy? — As noted above, a temporary discontinuation of oxaliplatin could be considered after three to four months of FOLFOX or XELOX therapy if the colorectal cancer has responded to treatment, there are no cancer-related symptoms, and tumor growth is not interfering with the function of other organs (eg, liver failure, bowel obstruction). However, a full break in therapy is usually not recommended because of the possibility that survival may be shortened. In most cases, continuation of at least some chemotherapy with 5-FU and leucovorin will be advised.
If chemotherapy is stopped completely because of side effects or patient preference, close monitoring is recommended; this generally includes a CT scan every two months. If the colorectal cancer begins to progress, chemotherapy is generally restarted as soon as possible.
There is less information about the potential harm of a complete treatment break with FOLFIRI. At least one study suggested that intermittent, rather than continuous, chemotherapy did not adversely impact survival.
Bevacizumab — Adding bevacizumab to FOLFOX, XELOX, or FOLFIRI significantly increases the likelihood that the tumor will respond and prolongs survival compared with treatment without bevacizumab.
In most cases, bevacizumab is recommended as a component of the first-line treatment of metastatic colorectal cancer, along with FOLFIRI, FOLFOX, or XELOX. However, the benefits of adding bevacizumab to these chemotherapy regimens must be balanced against the potentially serious side effects that can occur with this drug (eg, bleeding, blood clots). (See 'Bevacizumab (Avastin)' above.)
Patients who cannot tolerate FOLFOX, XELOX, or FOLFIRI — If a person cannot tolerate an aggressive chemotherapy regimen like FOLFOX, XELOX, or FOLFIRI because of their age, physical condition, or other medical problems, there are a few options:
- Intravenous FU plus leucovorin, with or without bevacizumab is a reasonable and less toxic alternative. In the most commonly used variant of this regimen, the FU and leucovorin are given as an intravenous injection once weekly for six weeks, followed by a two-week break.
- Another alternative is capecitabine alone, which is taken in pill form twice daily for 14 days, followed by a seven-day break. Capecitabine is about as effective as is intravenous FU plus leucovorin.
These regimens may be slightly less effective than FOLFOX or FOLFIRI, but they tend to be less toxic, and they do not require a central venous access catheter or home infusion pump.
SECOND-LINE TREATMENT OF METASTATIC COLORECTAL CANCER
Combination regimens — If the colorectal cancer continues to grow despite chemotherapy or it begins to enlarge after an initial response to the first-line chemotherapy regimen, a different chemotherapy combination may be tried, as long as the patient is well enough to tolerate additional therapy.
It is probably more important for the person to be exposed to ALL of the available chemotherapy drugs at some point during the course of treatment rather than to give the drugs in a specific order. This is because survival may be prolonged by second-line (as well as third-line) therapy.
The choice of second-line treatment typically depends on what was given originally.
- If FOLFOX (or XELOX) was the first-line regimen, patients are typically switched to FOLFIRI (or irinotecan alone). For subsequent therapy, if the tumor does not have the K-ras mutation, cetuximab or panitumumab could then be added to irinotecan, or cetuximab could be given alone. (See 'Cetuximab (Erbitux)' above.)
- If FOLFIRI (with or without bevacizumab) was given as the first-line regimen, cetuximab or panitumumab can be added (if the tumor does not have the K-ras mutation), or the patient can be switched to an oxaliplatin regimen, such as FOLFOX or XELOX.
A drug targeting VEGF (bevacizumab, aflibercept) may be recommended as a component of second-line treatment even if bevacizumab was given as part of the first-line treatment. However, these drugs should not be used in combination with cetuximab or panitumumab.
COLORECTAL CANCER CHEMOTHERAPY SIDE EFFECTS
The side effects of colorectal cancer chemotherapy depend upon the type, combination, and schedule of drugs used. The most common side effects of each agent are listed below, but it is important to review the entire range of potential side effects of all of the individual drugs in the chemotherapy regimen with the healthcare team.
FU and leucovorin — The most common side effects are diarrhea, mucositis (soreness in the mouth), and temporarily lowered blood counts. In general, diarrhea and mucositis are more likely when FU and leucovorin are given five days in a row (rather than weekly), especially in older people. For this reason, most oncologists prefer the weekly, rather than the "five days in a row", regimen when using FU and leucovorin. Hair loss is less common with FU plus leucovorin alone than with combinations of irinotecan or oxaliplatin plus 5-FU/leucovorin.
Irinotecan — When given alone, 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; 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, avoid inhaling cold air, and avoid exposing the hands and feet to cold when possible in the several days surrounding their oxaliplatin infusions.
Bevacizumab and aflibercept — Bevacizumab and aflibercept both target VEGF and they share many of the same side effects. Because there is a small risk that these agents can impair wound healing, surgery should be avoided for at least four weeks before and after treatment with bevacizumab or aflibercept (if possible) to avoid this potential side effect.
Bevacizumab and aflibercept may also cause bleeding in the GI tract or uncommonly, a tear of the bowel during treatment. They can also increase blood pressure or cause protein to spill into the urine. Close monitoring is necessary to detect and treat these problems early.
There is an increased risk of blood clots for patients using bevacizumab or aflibercept in combination with 5-FU-containing chemotherapy. 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. For this reason, use of these drugs may not be recommended for people over age 65 who have had a stroke, transient ischemic attack (TIA), or heart attack within the previous 6 to 12 months.
Regorafenib — Like bevacizumab and aflibercept, regorafenib also targets the VEGF pathway and shares many of the same side effects, including bleeding or a tear of the bowel during treatment, and high blood pressure. Unlike bevacizumab and aflibercept, regorafenib is given by itself and not with other chemotherapy agents. Other reported side effects with regorafenib are fatigue, diarrhea, liver damage, and hand-foot syndrome, a condition in which there is soreness, redness, and peeling of the skin of the palms and soles of the feet.
Capecitabine — The most common side effect of capecitabine is hand-foot syndrome. Otherwise, oral 5-FU-like drugs such as capecitabine have the same side effects as intravenous 5-FU, although diarrhea and mucositis are somewhat less common. Side effects of capecitabine may be more common when it is given after a regimen including 5-FU and leucovorin.
Cetuximab — Cetuximab can cause allergic reactions slightly more frequently than bevacizumab. If severe, treatment with cetuximab may need to be stopped. Patients will be closely monitored for allergic reactions during and after their treatment.
Other side effects include a skin rash that resembles acne, diarrhea, blood clots in the legs, 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.
Panitumumab — While panitumumab can also cause allergic reactions that, if severe, may require that treatment be stopped, the risk is much lower than with either cetuximab or bevacizumab.
Other side effects are similar to those seen with cetuximab including an acne-like skin rash, which may be severe, diarrhea, blood clots in the legs, and low blood levels of magnesium.
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:
WHERE TO GET MORE INFORMATION
Your healthcare provider is the best source of information for questions and concerns related to your medical problem.
This article will be updated as needed on our Web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.
Patient level information — UpToDate offers two types of patient education materials.
The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.
Patient information: Colon and rectal cancer (The Basics)
Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.
Patient information: Colon and rectal cancer (Beyond the Basics)
Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.
Clinical manifestations, diagnosis, and staging of colorectal cancer
Management of potentially resectable colorectal cancer liver metastases
Surgical resection of pulmonary metastases: Benefits; indications; preoperative evaluation and techniques
Surgical resection of pulmonary metastases: Outcomes by histology
Nonsurgical local treatment strategies for colorectal cancer liver metastases
Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials
Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations
Locoregional methods for management and palliation in patients who present with stage IV colorectal cancer
Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects
Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects
Acneiform eruption secondary to epidermal growth factor (EGFR) inhibitors
The following organizations also provide reliable health information:
- American Society of Clinical Oncology
- National Comprehensive Cancer Network
- National Cancer Institute
- National Library of Medicine
- The American Gastroenterological Association
- The American College of Gastroenterology
Patient support — There are a number of online forums where patients can find information and support from other people with similar conditions.