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.