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Overview

When colon cancer has returned following an initial treatment with surgery, radiation therapy, and/or chemotherapy or has stopped responding to treatment, it is said to be recurrent or relapsed.

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

• Those with recurrent cancer that can be surgically removed with the goal of a cure
• Those with more widespread cancer

Colon cancer may metastasize to the liver, lung, or other locations. 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 have unresectable or widespread disease. Historically, treatment outcomes for these patients were poor. However, new combinations of chemotherapy drugs and use of targeted therapies such as Avastin® (bevacizumab), Erbitux® (cetuximab), and Vectibix® (panitumumab) have improved outcomes.

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.[1] [2]

About this Treatment Information

The following is a general overview of treatment for recurrent colon cancer. Cancer treatment may consist of surgery, radiation, chemotherapy, targeted therapy, or a combination of these treatment techniques. Combining two or more of these treatment techniques–called multi-modality care–has become an important approach for increasing a patient’s chance of cure and 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 influence which treatments are utilized. 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.

Treatment for recurrent colon cancer is divided into the following topics:

• Systemic Therapy for Colon Cancer that Has Recurred at Multiple Sites in the Body
  • Combination Chemotherapy
  • Adding Targeted Therapy to Chemotherapy
  • Use of Targeted Therapy Alone
  • Oral Chemotherapy
• Treatment of Colon Cancer that has Metastasized to a Single Site in the Body
• Treatment of the Elderly
• Strategies to Improve Treatment of Recurrent Colon Cancer

Systemic Therapy for Colon Cancer that Has Recurred at Multiple Sites in the Body

Most patients with recurrent colon cancer have previously been treated with chemotherapy; the recurrent cancer may be resistant to whatever regimen the patient has already taken.. Typically, doctors will prescribe a different treatment regimen from the previous regimen.

Combination Chemotherapy

Standard treatment of advanced colon cancer generally includes chemotherapy with 5-FU. Eloxatin® (oxaliplatin) and Camptosar® (irinotecan) are chemotherapy drugs that are often added to 5-FU. Eloxatin/5-FU/LV (FOLFOX) and Camptosar/5-FU/LV (FOLFIRI) have been shown to improve survival in patients with advanced colon cancer when compared to treatment with 5-FU/LV alone.[3] FOLFOX and FOLFIRI have been shown to produce similar survival benefits, but have slightly different side effects.

Adding Targeted Therapy to Chemotherapy

A targeted therapy is designed to treat only the cancer cells and minimize damage to normal, healthy cells. The addition of targeted therapy to conventional therapy offers the advantage of increasing the intensity of treatment delivered to the cancer and improving outcomes without increasing treatment-related side effects. 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.

Avastin plays an important role in the initial (first-line) treatment of patients with metastatic colon cancer. In addition, Avastin may be used in second-line treatment if it was not used during first-line treatment. For patients who experience cancer progression following chemotherapy alone (without Avastin), the addition of Avastin to second-line chemotherapy has been shown to improve both progression-free and overall survival.[4]

Erbitux® (cetuximab): Erbitux plus combination chemotherapy has been shown to produce promising anticancer responses among patients with recurrent colon cancer. This combination appears to benefit patients whose cancer cells express certain proteins on their surface, called epidermal growth factor receptors (EGFR).

EGFRs are found on the surface of all cells and bind exclusively to small proteins circulating in the blood called growth factors. The binding action between EGFR and growth factors stimulates carefully controlled cell growth. However, many cancer cells have EGFRs that are over expressed and/or overactive; this leads to the uncontrolled and excessive growth of the cancer cell. It is estimated that approximately 70% of patients with colon cancer are positive for EGFR.

Erbitux is a type of targeted therapy that blocks the binding activity between growth factors and EGFR. Erbitux appears to produce anticancer benefits in the treatment of patients with colorectal cancer that has stopped responding to Camptosar-based chemotherapy. Researchers from Europe have evaluated Erbitux in the treatment of 329 patients who had all received prior treatment with Camptosar-based chemotherapy and whose cancer had progressed during treatment or three months following treatment. Approximately half of the patients were treated with Erbitux plus Camptosar chemotherapy and the other half were treated with Erbitux alone.

Both treatment regimens produced significant anticancer effects. The researchers suggest that Erbitux may re-sensitize the cancer cells to the killing effects of chemotherapy; this suggestion is based on the fact that patients treated with the combination of Erbitux plus Camptosar experienced more anticancer responses and survived longer without cancer progression than patients treated with Erbitux alone. Despite these differences in anticancer responses and time to cancer progression, overall survival was similar in both regimens. Nearly one-third of the patients survived one year or more after treatment (29% of patients treated with Erbitux plus Camptosar and 32% of patients treated with Erbitux alone).[5]

Use of Targeted Therapy Alone

Erbitux: In addition to being used in combination with the chemotherapy drug Camptosar (see section above), Erbitux may be used alone in the treatment of patients who cannot tolerate Camptosar.

Vectibix™ (panitumumab): Vectibix is another drug that targets the epidermal growth factor receptor (EGFR). A phase III clinical trial assessed the use of Vectibix in patients with chemotherapy-resistant metastatic colorectal cancer.[6] 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 has not yet been shown to improve overall survival.

Vectibix is approved for use in patients with EGFR-expressing, metastatic colorectal cancer that has progressed during or after treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

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[7]^,[8] while providing similar treatment outcomes[9]^,[10] and allowing patients to be treated at home.

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 (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. Results were as follows:

• 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).[11]

Hepatic artery infusion (HIA): 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[12] (see table 1).

Table 1 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 2).[13]

Table 2 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 hepatic artery infusion, 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. Furthermore, this approach is 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.[14] Furthermore, a separate clinical trial has shown that the risk of local cancer recurrences following RFA is similar to the risk following surgery.[15]

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 thought to intensify 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 recurrent 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 recurrent colon cancer include the following:

• New Combinations of Systemic Therapy
  • Xeloda/Eloxatin (XELOX)
• Liver-Directed Therapies
  • Laparoscopic surgery
  • Radioactive labetuzumab
• Immunotherapy
  • TroVax® vaccine
  • GM-CSF and IL-2
• Managing Side Effects
  • Glutathione
• Phase I Clinical Trials

New Combinations of Systemic Therapy

Xeloda plus Eloxatin (XELOX): The chemotherapy combination referred to as XELOX appears to be a highly effective regimen for patients with advanced colorectal cancer who have stopped responding to prior chemotherapy. Among 36 patients who were treated with XELOX, two-thirds (66%) experienced an anticancer response or disease stabilization. Even the patients who had stopped responding to prior Eloxatin-based therapy benefited from XELOX treatment; nearly 70% achieved an anticancer response or disease stabilization. The average time before the cancer progressed was nearly 7 months, and over half of the patients (54%) survived one year or more following therapy.[16]

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.[17]

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). [18] 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 immune system to recognize and attack threats to health, such as viruses. For this reason, cancer immunotherapies may also be called cancer vaccines. Treatment with combination chemotherapy plus agents that stimulate the immune system to attack the cancer—called immunotherapies—may delay disease progression substantially in patients with metastatic colon cancer.

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 this protein. Patients with cancer cells that express the 5T4 antigen have a poor prognosis and are at a greater risk of cancer spread.

TroVax plus chemotherapy may be a promising treatment for 5T4-expressing 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.[19]^,[20] 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.

GM-CSF and IL-2: Granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) are proteins produced by the body that stimulate the immune system. GM-CSF is a growth factor that stimulates the body to produce white blood cells. Both GM-CSF and IL-2 can be produced in a laboratory. These substances have been administered to cancer patients to help their immune system attack the cancer.

GM-CSF and IL-2 were administered to 29 patients with advanced colorectal cancer in combination with Eloxatin, 5-FU, and Gemzar® (gemcitabine) chemotherapy. Nearly all patients (96.5%) experienced either anticancer responses or had their disease stabilized with treatment. The average time before cancer progressed was over one year (12.5 months). Laboratory evaluation of blood samples from the patients indicated that their immune systems did increase their anticancer response. Clinical trials are ongoing to determine if these treatments improve survival.[21]

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.[22]

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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