Colon and Rectal Cancers

Description

Alternative Names

Medications

Chemotherapy uses drugs that kill cancer cells throughout the body. There are two situations in which chemotherapy is used:

• The adjuvant setting. Adjuvant refers to the use of chemotherapy after surgery in patients with stage III tumors and selected patients with high-risk stage II tumors (i.e., disease that is potentially curable). The goal of this therapy is to eliminate any cancer cells that surgery may have missed, thereby preventing recurrence and increasing the chance of cure. Patients of all ages, including the elderly, can benefit.
• In metastatic disease. In patients with metastatic disease the goal of chemotherapy is to shrink tumors, improve symptoms and quality of life, and to lengthen life.

In the adjuvant setting, there are some differences in chemotherapy treatments between colon and rectal cancers:

• Chemotherapy for Stage II patients is considered standard care for stage II rectal cancer but is under debate for colon cancer.
• Chemotherapy is standard for stage III colon cancer patients. Chemotherapy is also standard for stage III rectal cancer patients but is used in combination with radiation.

Chemotherapy for Stage II Patients with Colon Cancer. Adjuvant chemotherapy for Stage II colon cancer patients is controversial. Such patients tend to have a good outcome after surgery and the positive effects of chemotherapy have been difficult to demonstrate. To date, the survival advantage of adjuvant chemotherapy in this group has been reported to be only in the range of 2%. However, better trials are still needed to confirm or refute the benefits in specific patient groups.

Although not yet known with certainty, some data suggest that certain Stage II patients may be at higher risk of recurrence and would theoretically benefit from adjuvant therapy. These include patients with the following conditions:

• Cancers that have obstructed the bowel,
• Cancers that have perforated the wall of the colon, or
• Cancers that have adhered to structures outside the intestine.

Advanced diagnostic techniques are under investigation for helping to select appropriate Stage II candidates for adjuvant therapy. None of these methods, however, are ready to be used routinely to help make treatment decisions. The decision whether to pursue chemotherapy for stage II disease should be made after careful discussion between the patient and his or her oncologist, especially after features, such as bowel perforation or obstruction, are taken into account.

Chemotherapy for Stage III Patients with Colon Cancer. Since the early 1990s, adjuvant chemotherapy with 5-FU and leucovorin has been the standard of care for stage III colon cancer. Numerous trials have shown that adjuvant chemotherapy in this setting reduces the absolute risk of death from colon cancer by approximately one-third and improves survival by 10%. Current clinical trials are investigating whether the addition of new chemotherapy drugs, suchas irinotecan, oxaliplatin, capecitabine, and antibody therapies, will improve cure rates over 5-FU and leucovorin alone. However, most of these new agents should currently not be used for adjuvant treatment of colon cancer unless as part of a clinical trial.

Chemotherapy for Advanced Colorectal Cancer. Chemotherapy and radiation are generally used to reduce symptoms and prolong life in advanced colorectal cancer. Some experts suggest that chemotherapy should be considered for the following patients:

• Able to carry out all normal activity without restriction.
• Restricted in physically strenuous activity, but able to walk about and carry out light work.
• Able to walk about and capable of all self care, but unable to carry out any work. Out of bed or chair for more than 50% of waking hours.

Chemotherapy in most studies offers a modest improvement in survival and often relieves symptoms. One 2003 study suggested that for these patients chemotherapy given intermittently has fewer toxic or serious adverse effects and may be as beneficial as continuous administration.

The following patients are unlikely to benefit from chemotherapy:

• Those capable only of limited self care. Confined to bed or chair for more than 50% of waking hours.
• Severely disabled. Cannot carry out any self care. Totally confined to bed or chair.

Specific Chemotherapy Agents

5-Fluorouracil (5-FU) with Leucovorin. Adjuvant therapy using 5-fluorouracil along with leucovorin (5-FU/LV) is currently the standard treatment for patients with high-risk colon cancer (Stage III or selected patients with Stage II tumors). Leucovorin, also called folinic acid, is a form of the B vitamin folic acid. Patients are given a series of cycles that usually continue for at least six months. 5-FU is given intravenously at present, but oral preparations are currently being tested in clinical trials.

There are many different ways of giving 5-FU, including intravenously over several hours once a week, intravenously daily for five consecutive days every month, or as continuous infusion with a portable pump.

The side effects can be quite different depending on the way 5-FU is given, and women may be more susceptible than men. In one analysis, 53% of women and 40% of men experienced severe side effects, while response rates and survival were similar for both sexes. Many patients, however, tolerate 5-FU with leucovorin well, with manageable side effects.

Irinotecan. Irinotecan (Camptosar) inhibits an enzyme essential for cell division and works in combination with 5-FU and LV. This combination therapy (irinotecan plus 5-FU/LV) is also referred to as the "Salz regimen" or IFL. When it was approved in the mid 1990s, irinotecan was the first new drug developed for colon cancer in over 30 years. Two studies in 2000 reported that a combination of irinotecan along with 5-fluorouracil and leucovorin (5-FU/LV) significantly delays the time at which tumors progress and improves survival in metastatic cancer compared to 5-FU/LV alone. While the survival advantage is small, the combination has become the standard of care for metastatic cancer for many oncologists. Of concern, however, were 2001 studies reporting an increased risk of death from toxic effects with the use of the three-drug combination. Such deaths appeared to be related to blood clotting complications. Experts recommend careful monitoring and use of lower drug doses.

Capecitabine. Capecitabine (Xeloda) is the first oral agent approved for metastatic colorectal cancer. It allows fewer days of hospitalization, and side effects are manageable. In the body, it is taken up by tumor cells, then converted to 5-FU, which kills the cancer cells. Compared to standard therapy, capecitabine has demonstrated similar results, although combinations with 5-FU, irinotecan, and oxaliplatin are being investigated. It is also showing promise when used with radiation therapy for rectal cancers. (Doxifluridine, an oral drug with similar properties, is under investigation.)

Oxaliplatin. Oxaliplatin (Eloxatin) is a variant of cisplatin, a widely used platinum-based chemotherapy drug. Oxaliplatin was approved in 2002 for use in combination with 5-FU and leucovorin for recurring cancer or cancer has progressed after initial therapy (second-line treatment). This combination therapy is also referred to as the FOLFOX regimen. In January 2004, oxaliplatin received an additional approval as a first-line treatment for advanced colorectal cancer. Additional trials are investigating its potential in combination with other standard chemotherapy agents as well as new targeted therapies such as bevacizumab. Oxaliplatin can cause a unique peripheral neuropathy (pain and tingling sensations in the hands and feet) that is exacerbated by exposure to cold.

Raltitrexed. Raltitrexed (Tomudex) may be effective and may have additive or synergistic effects with 5-FU.

Newly Approved Treatments

Bevacizumab. Bevacizumab (Avastin) was approved in February 2004 as a first-line treatment for patients with metastatic colorectal cancer (advanced cancer that has spread in the body). It is used in combination with IFL (irinotecan, 5-FU, leucovorin). Bevacizumab is a genetically engineered monoclonal antibody that targets and inhibits vascular endothelial growth factor (VEGF), a protein that regulates angiogenesis (the development of new blood vessels that feed a tumor's blood supply). It is the first anti-angiogenic therapy approved for the treatment of colorectal cancer. In a study of 800 patients with metastatic colorectal cancer, bevacizumab administered intravenously along with IFL extended survival by approximately 5 months longer than IFL alone.

Cetuximab. Cetuximab (Erbitux) was approved in February 2004 for the treatment of metastatic colorectal cancer. This monoclonal antibody drug targets epidermal growth factor receptor (EGFR), a protein required by cancer cells in order to proliferate. It can be used either in combination with irinotecan, or alone for patients who have not responded to irinotecan. Clinical research demonstrated that combination treatment delayed tumor growth by 4 months. For patients who received only cetuximab, tumor growth was delayed by 1.5 months.

Oxaliplatin. Oxaliplatin (Eloxatin) received a new indication approval in January 2004 as a first-line treatment for advanced colorectal cancer. The drug is used in combination with 5-FU and leucovorin (LV). In data submitted for the approval process, patients who received oxaliplatin in combination with 5-FU and LV survived an average of nearly 5 months longer than patients who received only 5-FU and LV.

Side Effects of Chemotherapy

Side effects occur with all chemotherapeutic drugs; they are more severe with higher doses and increase over the course of treatment. Because cancer cells grow and divide rapidly, anticancer drugs work by killing fast-growing cells. This means that healthy cells that multiply quickly can also be affected. The fast-growing normal cells most likely to be affected are blood cells forming in the bone marrow, and cells in the digestive tract, reproductive system, and hair follicles.

Side effects vary specifically with different drugs, but, in general, they include the following:

• Nausea and vomiting. Drugs are available to significantly reduce these dreaded side effects. Serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs. In one study, a combination of dexamethasone (a corticosteroid) with ondansetron taken within 24 hours of chemotherapy achieved either a major or complete reduction in nausea and vomiting.
• Diarrhea (very common with 5-FU).
• Temporary hair loss (usually minimal with 5-FU).
• Weight loss.
• Mouth ulcers.
• Pain and redness of the hands and feet.
• Fatigue.
• Anemia.
• Depression.

These side effects are nearly always temporary, and medications are available to help manage them. Most patients are able to continue with normal activities for all but perhaps one or two days a month.

More serious complications can also occur and may vary depending on the specific agents used. They include the following:

• Increased chance for infection (from suppression of the immune system).
• Bleeding.

Targeted Therapies and Biologics

One of the most promising recent developments in cancer treatment research has been the emergence of so-called "targeted therapies". Traditional chemotherapeutic agents can be effective, but because they do not distinguish between healthy and cancerous cells their generalized toxicity can cause severe side effects. Targeted therapies work on a molecular level by blocking specific mechanisms associated with cancer cell growth and division. Because they selectively target cancerous cells, they may induce less severe side effects. In addition, these drugs hold the promise of creating options for more individualized cancer treatment based on a patient's genotype. In the future, diagnostic tests may help doctors identify which patients are more likely to respond successfully to specific drugs.

Biologic therapies use the body's immune system to attack the cancer (immunotherapy). These drugs are derived from biological sources and include vaccines, monoclonal antibodies (MAbs), and gene therapies. Many targeted therapies are classified as biologics.

Targeted therapies involve many different types of drugs and molecular pathways. These include:

Angiogenesis Inhibitors. Anti-angiogenesis drugs inhibit the formation of new blood vessels that supply tumors with the blood, oxygen, and nutrients vital to tumor growth. Angiogenesis inhibitors, such as the monoclonal antibody bevacizumab (Avastin), target vascular endothelial growth factor (VEGF).

Tumor Growth Factor Inhibitors. Tumor growth factors, such as epidermal growth factor, stimulate cell growth. Drugs that target the epidermal growth factor receptor (EGFR) include the recently approved cetixumab (Erbitux).

Tyrosine Kinase Inhibitors. Tyrosine kinase is an enzyme associated with EGFR that is involved with the signaling mechanisms that prompt cell growth. Clinical trials are currently investigating the use of the lung cancer drug gefitinib (Iressa), in combination with oxaliplatin and standard chemotherapy agents, for the treatment of advanced colorectal cancer. Gefitinib blocks tyrosine kinase growth signaling capacities. Similarly, the EGFR/tyosine kinase inhibitor erlotinib (Tarceva), which is in late-stage trials for the treatment of pancreatic and lung cancer, is also being investigated as an adjuvant treatment for metastatic colorectal cancer.

Vaccines. ALVAC is an experimental vaccine derived from the canarypox virus. It is designed to trigger the body's immune system to fight cancer cells. It is currently in early-stage clinical trials to determine its efficacy in combination with chemotherapy for treatment of metastatic colorectal cancer.