Patient information: Colorectal cancer treatment; metastatic cancer

COLORECTAL CANCER OVERVIEW

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. This reappearance of the colorectal 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 distant site. When the recurrence develops at a site away from the colon or rectum it is called a metastasis.

The treatment of patients with colorectal cancer that has spread or metastasized depends upon the extent and location of the tumor. 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".)

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") [1]. In order for surgery to be considered, there must be no evidence of cancer outside of the liver.

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 not a candidate or 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 [2].

If surgical removal of the liver metastases is successful, additional chemotherapy is usually recommended after surgery. Several clinical trials have studied this issue. Although none have shown that survival is prolonged when chemotherapy is given after surgery, the studies did not use "modern" chemotherapy regimens. Treatment guidelines from groups such as the National Comprehensive Cancer Network (NCCN) recommend four to six months of an active chemotherapy regimen for patients who have undergone resection of colorectal cancer liver metastases [3]. "Modern" chemotherapy regimens for metastatic colorectal cancer are described in detail below. (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) [4]. However, it is unclear if this approach is better than intravenous chemotherapy alone; the most commonly used approach is intravenous chemotherapy.

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 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 '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. Avastin® also enhances the antitumor effect of other chemotherapy drugs. Avastin® is not effective when given by itself, but is generally given in combination with other drugs such as oxaliplatin and irinotecan (see below).

Cetuximab (Erbitux®) — Cetuximab targets a different protein, the epidermal growth factor receptor (EGFR), which is found in approximately 80 percent of colorectal cancers. However, Erbitux® is effective even if EGFR is not detected in an individual tumor. Studies are ongoing to determine how best to identify patients who will benefit from treatment with this drug.

Unlike Avastin, Erbitux is active when given alone, as well as in combination with other drugs such as irinotecan. The best way to combine Erbitux with other chemotherapy drugs is not yet established. However, Erbitux® is not yet considered a standard first-line treatment. Instead, it is typically used later in the course of treatment.

Panitumumab (Vectibix®) — Like Erbitux, Vectibix also targets the EGFR. In the United States, Vectibix® is only approved as a "last resort" treatment for metastatic colorectal cancer, after other drugs have failed. Its role in combination with traditional chemotherapy drugs is under study.

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 Avastin, 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 5-FU and leucovorin (referred to as FOLFOX)
• Irinotecan plus 5-FU and leucovorin (referred to as FOLFIRI)
• Oxaliplatin plus capecitabine (referred to as XELOX)

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 (day 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 5-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 six to eight cycles of FOLFOX or XELOX 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.

Avastin® — Adding Avastin® to FOLFOX or FOLFIRI significantly increases the likelihood that the tumor will respond and prolongs survival compared to treatment without Avastin®. Avastin® is given intravenously every two weeks.

In most cases, Avastin® 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 Avastin® to these chemotherapy regimens must be balanced against the potentially serious side effects that can occur with this drug (eg, bleeding, blood clots). (See '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 5-FU plus leucovorin, with or without Avastin®, is a reasonable and less toxic alternative. In the most commonly used variant of this regimen, the 5-FU and leucovorin are given as an intravenous injection once weekly for six weeks, followed by a two week break. If Avastin® is given, it is administered intravenously every two weeks.
• Another alternative is Xeloda® alone, which is taken in pill form twice daily for 14 days followed by a seven-day break. Xeloda® is about as effective as is intravenous 5-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) with or without Avastin® was the first-line regimen, patients are typically switched to FOLFIRI (or irinotecan alone). For subsequent therapy, Erbitux® could then be added to irinotecan, or Erbitux® could be given alone.
• If FOLFIRI (with or without Avastin®) was given as the first-line regimen, Erbitux® can be added, or the patient can be switched to an oxaliplatin regimen such as FOLFOX or XELOX.

Avastin® is not usually recommended as a second-line treatment if it was given as part of the first-line treatment.

Vectibix® — In the United States, panitumumab (Vectibix®) is approved as a "last resort" treatment of metastatic colorectal cancer, after other drugs have failed. In one trial, patients who were given panitumumab after failing irinotecan- and oxaliplatin-containing chemotherapy were significantly more likely to be alive and disease-free eight weeks after treatment, compared to those who had supportive care only (49 versus 30 percent) [7]. However, it is not clear if panitumumab works after failure of Erbitux®; some physicians feel the two drugs are interchangeable.

Combined therapy with two targeted chemotherapy agents — Patients who stop responding to conventional chemotherapy regimens may benefit from a combination of two targeted chemotherapy drugs, Avastin® and Erbitux®. One small trial reported an unexpectedly long survival duration for people who were given this combination after failing multiple other chemotherapy drugs [8].

However, this study was small and enrollment was limited to people who were healthy after being given a number of chemotherapy regimens. In addition, none of the participants had taken Avastin® previously. A clinical trial is currently ongoing to determine the benefits and risks of this strategy; eligible patients are encouraged to enroll [9].

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.

5-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 5-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 5-FU and leucovorin. Hair loss is less common with 5-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.

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 in the GI tract or uncommonly, a tear of the bowel during treatment. It 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 Avastin® 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, Avastin® is not 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.

Xeloda® — The most common side effect of Xeloda® is hand-foot syndrome, a condition in which there is 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. Side effects of Xeloda® may be more common when it is given after a regimen including 5-FU and leucovorin.

Erbitux® — Erbitux® can cause allergic reactions slightly more frequently than Avastin®. If severe, treatment with Erbitux® 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 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® — While Vectibix® can also cause allergic reactions which, if severe, may require that treatment be stopped, the risk is much lower than with either Erbitux or Avastin.

Other side effects are similar to those seen with Erbitux®, including an acne-like skin rash, which may be severe, 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/

       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 people 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.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

Some of the most pertinent include:

Patient Level Information:
Patient information: Colon and rectal cancer

Professional Level Information:
Adjuvant therapy for resected colon cancer
Clinical manifestations, diagnosis, and staging of colorectal cancer
Colorectal cancer: Epidemiology, risk factors, and protective factors
Management of potentially resectable colorectal cancer liver metastases
Molecular genetics of colorectal cancer
Nonsurgical treatment strategies for colorectal cancer liver metastases
NSAIDs (including aspirin): Role in prevention of colorectal cancer
Pathology and prognostic determinants of colorectal cancer
Screening for colorectal cancer: Strategies in patients at average risk
Screening for colorectal cancer: Strategies in patients with possible increased risk due to family history
Surgical management of primary colon cancer
Surveillance after colorectal cancer resection
Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials
Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations

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.

• American Society of Clinical Oncology

      (www.cancer.net/portal/site/patient)

• National Comprehensive Cancer Network

      (www.nccn.com)

• 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)

Patient Support — There are a number of online forums where patients can find information and support from other people with similar conditions.

• About.com Cancer Forum

      (http://cancer.about.com/forum)

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