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Overview

Colon cancer is classified as stage IV if the final evaluation following surgical removal of the cancer shows that the cancer has spread to distant locations in the body; this may include the liver, lungs, bones, distant lymph nodes or other sites. While it is commonly thought that patients diagnosed with stage IV colon cancer have few treatment options, certain patients can still be cured of their cancer, and others can derive significant benefit from additional treatment.

Patients with stage IV colon cancer can be broadly divided into two groups:

• Those with widespread, metastatic cancer that cannot be treated with surgery (sometimes called unresectable cancer )
• Those with cancer that has metastasized to a single site

When the site of metastasis is a single organ (such as the liver), and the cancer is confined to a single defined area within the organ, patients may benefit from local treatment directed at that single metastasis.

The majority of patients diagnosed with stage IV colon cancer have unresectable or widespread disease. Historically, treatment outcomes for these patients were poor. However, new combinations of chemotherapy drugs and the addition of targeted therapies such as Avastin® (bevacizumab) have improved outcomes.

The following is a general overview of treatment for stage IV colon cancer. Treatment may consist of surgery, radiation, chemotherapy, targeted therapy, or a combination of these treatment techniques.

Multi-modality treatment, which is treatment using two or more techniques, has become an important approach for increasing a patient’s chance of cure or prolonging survival. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Circumstances unique to each patient’s situation may influence how these general treatment principles are applied.

The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.

This section covers the initial, also called first-line, treatment of stage IV colon cancer. For information about the treatment of cancer that has recurred or progressed after initial treatment, visit Recurrent Colon Cancer.

• Systemic Therapy for Widespread, Metastatic Colon Cancer
  • Combination Chemotherapy
  • Adding Targeted Therapy to Chemotherapy
  • Oral Chemotherapy
• Treatment of Colon Cancer that Has Metastasized to a Single Site (i.e. Liver or Lungs)
• Treatment of the Elderly
• Strategies to Improve Treatment

Systemic Therapy for Widespread, Metastatic Colon Cancer

For over 30 years the chemotherapy drug fluorouracil (5-FU) was the standard treatment for metastatic stage IV colon cancer that had spread to several sites in the body. 5-FU is typically administered with leucovorin, a drug that is similar in structure and function to the essential vitamin folic acid. Leucovorin (LV) enhances the anticancer effects of fluorouracil by helping the chemotherapy drug bind to and stay inside the cell for a greater period of time, producing longer lasting anticancer effects.

More recently, the addition of other drugs to 5-FU/LV has been found to provide additional benefit. Not all patients can tolerate these multi-drug regimens, however, and less intensive regimens are available.

Combination Chemotherapy

The addition of either Eloxatin® (oxaliplatin) to 5-FU/LV or Camptosar® (irinotecan) to 5-FU/LV has been found to produce similar benefits. The drug combinations are often abbreviated FOLFOX and FOLFIRI, respectively.

Italian researchers compared FOLFOX and FOLFIRI in the treatment of 360 patients who had not received prior therapy. Half of the patients were treated with FOLFOX and the other half were treated with FOLFIRI. Overall, the patients experienced similar duration of survival: 15 months for patients treated with FOLFOX and 14 months for those treated with FOLFIRI. Patients survived, on average, for the same period of time (7 months) before their cancer progressed. Anticancer responses were the same in both groups; approximately one-third of patients experienced an anticancer response to treatment.

The two therapies differed only in observed side effects. Patients treated with the combination containing Eloxatin were more likely to have low platelet levels and sensory neuropathy (decreased sensation in the extremities). Patients treated with the combination containing Camptosar were more likely to experience hair loss and gastrointestinal distress, such as diarrhea.[1]

Adding Targeted Therapy to Chemotherapy

Targeted therapies are anticancer drugs that interfere with specific pathways involved in cancer cell growth or survival. Some targeted therapies block growth signals from reaching cancer cells; others reduce the blood supply to cancer cells; and still others stimulate the immune system to recognize and attack the cancer cell. Depending on the specific “target”, targeted therapies may slow cancer cell growth or increase cancer cell death. Targeted therapies may be used in combination with other cancer treatments such as conventional chemotherapy. Recently approved targeted therapies represent the most novel advance in the treatment of metastatic colorectal cancer in the last few years.

Avastin® (bevacizumab): Avastin is a targeted therapy that blocks a protein known as VEGF. VEGF plays a key role in the development of new blood vessels. By blocking VEGF, Avastin deprives the cancer of nutrients and oxygen and inhibits its growth. Avastin’s effects on blood vessels may also improve the delivery of chemotherapy to the tumor.

Multiple studies have shown that the addition of Avastin to standard chemotherapy improves outcomes in the treatment of patients with metastatic colorectal cancer.[2] Avastin has shown benefits when added to either 5-FU/LV or Camptosar/5-FU/LV chemotherapy. Patients treated with chemotherapy plus Avastin were free of cancer for longer and survived longer than patients treated with chemotherapy alone (see table 1).

Table 1. Adding Avastin to chemotherapy improves outcomes

	Anticancer response	Progression-free survival (months)	Overall survival (months)
5FU/LV	15.2%	5.5	12.9
Avastin/5FU/LV	26%	9.2	16.6
Camptosar/5FU/LV	35%	7.1	15.6
Avastin/Camptosar/5-FU/LV	45%	10.4	20.3

The addition of Avastin also appears to improve outcomes among patients treated with Xeloda plus Eloxatin (XELOX) or 5-FU/LV plus Eloxatin (FOLFOX). In a phase III clinical trial, progression-free survival was 9.4 months among patients treated with XELOX or FOLFOX plus Avastin, and 8.0 months among patients treated with chemotherapy alone.[3]

Oral Chemotherapy

Chemotherapy drugs have been developed that can be administered orally in the form of a pill. Xeloda® (capecitabine) is a form of the chemotherapy drug 5-FU that is administered orally, rather than into a vein, as is the case with 5-FU. Intravenous (IV) drug administration can be associated with more side effects than oral administration. Side effects of IV 5-FU may include pain and infection at the injection site.

Results from recent clinical trials have demonstrated that the oral Xeloda is associated with fewer side effects than IV 5-FU [4]^,[5] while providing similar treatment outcomes (see table 2) [6]^,[7] and allowing patients to be treated at home.

Table 2 Combined data from two large clinical trials show that oral Xeloda produces similar outcomes to IV 5-FU

	Oral Xeloda	IV 5-FU
Anticancer responses	26%	17%
Time to cancer progression	4.6 months	4.7 months
Overall survival	12.9 months	12.8 months

Researchers who evaluated data from two large clinical trials, involving a total of 1,200 patients who were treated with either Xeloda or IV 5-FU, have concluded that Xeloda may be an appropriate substitute for intravenous 5-FU.

Treatment of Colon Cancer that Has Metastasized to a Single Site

Stage IV colon cancer commonly spreads to the liver or the lungs. Treatment for patients with colon cancer that has spread to one of these locations may include:

• Surgery
• Specialized delivery of chemotherapy that targets the cancer (hepatic artery infusion)
• High-energy radio waves to kill the cancer, called radiofrequency ablation (RFA)

For patients with liver metastases, chemotherapy treatment delivered into the blood vessel that supplies the liver (hepatic artery infusion) has been shown to provide some benefit. Patients with colon cancer that has spread to the liver or lungs should be evaluated by doctors in a medical center that has significant experience treating patients with these conditions.

Surgery: Physicians from the Mayo Clinic have determined that surgical removal of cancer that has metastasized to the liver and lungs may help select patients live longer. These doctors removed metastases from the liver and lungs of 58 patients who had small, isolated metastatic disease and who did not have a relapse of their cancer at the original site. There were no deaths during surgery. Five years following surgery, 55% of patients remained cancer-free. The patients who responded best to treatment did not have thoracic lymph node involvement and did not have an elevated carcinoembryonic antigen level (a type of protein found on the surface of cancer cells).[8]

Hepatic artery infusion (HAI): The infusion of chemotherapy directly into the vessel that delivers blood to the liver is called hepatic artery infusion. This technique is used to treat patients with colon cancer that has metastasized to the liver. The pooled results of several small studies indicate that hepatic artery infusion produced more anticancer responses and caused patients to live longer than those treated with traditional systemic chemotherapy (see table 3).[9]

Table 3 Outcomes with hepatic artery infusion or systemic chemotherapy

	Hepatic artery infusion	Chemotherapy alone
Response rate	41%	14%
Average duration of survival	16 months	12 months

Also, treatment with hepatic artery infusion plus traditional chemotherapy has been shown to increase duration of survival and reduce recurrences compared to treatment with systemic chemotherapy only (see table 4).[10]

Table 4 Combination of hepatic artery infusion and chemotherapy produces better outcomes than chemotherapy alone

	Hepatic artery infusion plus chemotherapy	Chemotherapy alone
Average duration of survival	72 months	59 months
Cancer recurrence	10%	60%

Liver-directed treatment approaches, such as HAI, are highly specialized procedures and are best performed by experienced individuals. Complications, such as hepatitis, stomach ulcer and cholecystitis (gallstones), are frequent after HAI but are reduced considerably when an experienced surgeon performs the procedure. This approach is also only appropriate for select patients. The benefit of the procedure must outweigh the risk, and these must be carefully compared to the benefit and risk of undergoing standard surgical removal and systemic chemotherapy.

Radiofrequency ablation (RFA): RFA is a minimally invasive technique that kills cancer cells with intense heat generated from high-frequency radio waves. A number of small trials of RFA have shown it to be successful in controlling metastatic disease. When RFA was used to treat 135 patients with liver metastases from colon cancer, the patients survived for an average of 28 months. This is longer than the 11-14 months that patients typically survive with conventional chemotherapy.[11] Furthermore, a separate clinical trial has shown that the risk of local cancer recurrences following RFA is similar to the risk following surgery.[12]

Treatment of the Elderly

A large percentage of patients with advanced colorectal cancer are 65 years or older. Because elderly patients commonly have concurrent illnesses or other medical difficulties that are perceived to exacerbate the side effects of chemotherapy, elderly patients are often treated with reduced doses of chemotherapy.

Clinical studies have shown, however, that elderly patients get the same benefit from chemotherapy treatment as younger patients.

While a dose reduction or delay may sometimes be necessary, it may also compromise the optimal treatment of some patients.  All patients over 65 should be closely monitored for toxic side effects of chemotherapy, especially during their initial chemotherapy administration cycle.  Moreover, The NCCTG trial demonstrated that Eloxatin® when combined with 5-FU/LV had fewer side effects than Camptosar® and may represent a better treatment option for elderly patients.

Strategies to Improve Treatment of Stage IV Colon Cancer

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of stage IV colon cancer will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active exploration to improve the treatment of stage IV colon cancer include the following:

• New Combinations of Systemic Therapy
  • XELOX
  • Xeloda/Eloxatin/Avastin (XeloxA)
• New Targeted Therapy
  • Erbitux^® (cetuximab)
  • Vectibix^® (panitumumab)
• Liver-Directed Therapies
  • Laparoscopic surgery
  • Radioactive labetuzumab
• Immunotherapy
  • TroVax® vaccine
• Managing Side Effects
  • Glutathione
• Phase I Clinical Trials

New Combinations of Systemic Therapy

Xeloda/Eloxatin/Avastin (XeloxA): The combination of Xeloda (an oral form of 5-FU) and Eloxatin—called XELOX—appears to work as well as 5-FU/Eloxatin in the treatment of patients with advanced colon cancer.[13] The addition of the targeted therapy Avastin to XELOX—a regimen known as XeloxA—also appears to be a promising treatment.

Researchers at the Duke University treated 30 patients with XeloxA and reported the following preliminary results at the European Cancer Conference:

• Nearly all patients (94%) derived a clinical benefit from treatment.
• More than one-third of patients (37%) had their disease stabilized with treatment.
• More than half of patients (57%) experienced a partial or complete reduction of their cancer.
• On average, patients survived one year before their cancer progressed.[14]

New Targeted Therapy

Erbitux® (cetuximab): Erbitux is a drug that targets a protein known as EGFR. Erbitux plus chemotherapy has produced promising anticancer responses among patients with metastatic colon cancer. Erbitux, either alone or in combination with chemotherapy, has been approved for the treatment of stage IV colon cancer that has progressed following treatment with chemotherapy. In these patients, treatment with Erbitux plus chemotherapy has been shown to improve progression-free survival compared to chemotherapy alone.[15]

Vectibix® (panitumumab): Vectibix is another drug that targets EGFR. A phase III clinical trial assessed the use of Vectibix in patients with chemotherapy-resistant metastatic colorectal cancer.[16] Patients were assigned to receive Vectibix plus best supportive care (care to relieve symptoms) or best supportive care alone. Patients who received Vectibix had better progression-free survival than patients who received only best supportive care. Vectibix is approved for use in patients with metastatic colorectal cancer that has progressed during or after treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

Prior to using either Erbitux or Vectibix, patients may have a sample of their cancer tested for mutations in the KRAS gene. Cancers that contain a KRAS mutation are unlikely to respond to Erbitux or Vectibix.[17] [18]

Liver-Directed Therapies

Doctors continue to develop and refine techniques for treating patients with colon cancer that has spread to the liver, including hepatic artery infusion, chemoembolization, and other liver-directed therapies. For patients with liver-dominant disease, these strategies are being utilized to shrink the cancer and increase the number of patients eligible for surgical removal of their cancer.

Treatment planning with laparoscopic surgery: Laparoscopy is a minimally invasive surgical technique that allows physicians to view the inside of the body using probes that are inserted through a small incision in the abdomen.

Researchers from Oregon have reported that laparoscopic surgery provides a way to explore the extent of metastases and confirm, or change, treatment plans prior to conducting more extensive surgery. When 136 patients with liver metastases secondary to colorectal cancer were evaluated with laparoscopic surgery, one-quarter (25%) were found to have untreatable disease (meaning their cancer was more extensive than previously diagnosed). Overall, nearly half (48%) of the patients had their treatment plan changed based on the laparoscopy findings. For patients who were found to have untreatable cancer, this means that unnecessary and more extensive surgery was avoided.[19]

Radioactive (iodine 131-labeled) labetuzumab: Iodine 131-labeled labetuzumab is comprised of two separate portions: a monoclonal antibody, labetuzumab (a protein and a type of targeted therapy) and radioactive iodine-131 that releases radiation. Labetuzumab is designed to bind to a specific protein, called the carcinoembryonic antigen (CEA). CEA is present on colon cancer cells but not healthy cells. Once labetuzumab binds to the CEA on the cancer cell, the iodine-131 emits radiation to kill the cell.

Radioactive labetuzumab has shown initial promise in improving survival in the treatment of patients with colorectal cancer that has spread to the liver. After having their liver metastases completely removed with surgery, 23 patients were treated with one dose of radioactive labetuzumab. Patients survived, on average, nearly 5 years (58 months). A group of similar patients who just underwent surgery survived, on average, less than 3 years (31 months).[20] The benefit of labetuzumab in this trial warrants further study in larger clinical trials.

Immunotherapy

The goal of immunotherapy is to help the body to recognize cancer cells as a threat and activate immune cells to attack the cancer.

Cancer cells are once normal cells that have gone awry. However, the immune system—the body’s natural defense system against disease—does not distinguish cancer cells from normal cells. For this reason, cancer cells are permitted to grow in the body.

Immunotherapy stimulates the normal mechanisms of the immune system that allow it to recognize and target foreign invaders, such as viruses. For this reason, cancer immunotherapies may also be called cancer vaccines.

TroVax®: TroVax is a cancer vaccine that is designed to stimulate the immune system to recognize a small protein found on many cancer cells—called 5T4 antigen—and attack the cells that display the protein. Patients with colon cancer that expresses the 5T4 antigen are at a greater risk of cancer spread and have a poor prognosis.

TroVax plus chemotherapy may be a promising treatment for metastatic colorectal cancer.

Two phase II clinical trials have recently demonstrated the safety of the addition of TroVax to chemotherapy regimens in stage IV colorectal cancer. In both trials, TroVax induced immune responses in all patients, demonstrated control of cancer growth in a large majority of patients and was safe and well tolerated.[21],[22] Researchers are currently designing a phase III trial of Trovax given along with chemotherapy in stage IV colon or rectal cancer. The trial will aim to determine whether Trovax improves survival.

Managing Side Effects (Supportive Care)

Treatments designed to prevent or control the side effects of cancer and cancer therapies are called supportive care. Side effects not only cause patients discomfort, but also may prevent the delivery of therapy at its planned dose and schedule. In order to achieve optimal outcomes from treatment and improve quality of life, it is imperative that treatment is delivered as planned, and that side effects resulting from cancer and its treatment are appropriately managed. For more information, visit Managing Side Effects.

Glutathione: Glutathione is a small protein that is involved in detoxification; it binds to toxins in the body and transforms them into a form that can be excreted in urine or bile. Glutathione appears to significantly reduce numbness and tingling in the extremities, which is a common side effect of the chemotherapy drug Eloxatin.

In a clinical trial that involved 52 patients with advanced colorectal cancer undergoing Eloxatin chemotherapy, half were treated with glutathione and the other half received a placebo (inactive substitute). After eight courses of chemotherapy, only 43% of patients treated with glutathione experienced peripheral neuropathy, compared to 79% of patients who received placebo. Severe numbness and tingling did not occur in any patients treated with GSH, but occurred in 26% of patients who received placebo.Glutathione did not alter the effectiveness of chemotherapy, as anticancer responses, progression-free survival, and overall survival at nearly one year were the same between the two groups of patients.[23]

Phase I Clinical Trials

New chemotherapy drugs continue to be developed and evaluated in patients with recurrent cancers in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the best way of administering the drug and whether the drug has any anticancer activity in patients.

References

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