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Brand name(s): Eloxatin™

• Approved for adjuvant therapy for stage III colorectal cancer
• Approved for initial therapy of advanced colorectal cancer

Full prescribing information ³ is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

Adjuvant Therapy for Stage III Colorectal Cancer

Safety and efficacy were demonstrated in a multicenter, randomized, open-label, international clinical trial. There were 2,246 patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor, that were equally randomized to one of two arms: oxaliplatin plus infusional 5FU/LV (FOLFOX 4 regimen) and infusional 5FU/LV (De Gramont regimen). Treatment was administered every two weeks for 12 cycles (6 months).

At a median follow-up of four years, there was a statistically significant improvement in the primary endpoint of DFS for the oxaliplatin combination compared to infusional 5FU/LV, both in the overall study population (four year DFS: 76 percent vs. 69 percent hazard ratio = 0.76, 95 percent CI: 0.65, 0.90; p=0.0008) and in the subgroup with stage III disease (four year DFS: 70 percent vs. 61 percent; hazard ratio = 0.75, 95 percent CI: 0.62, 0.90; p=0.002; N=1347). Survival data were not mature at the time of the analysis with a median follow-up of 47 months. No statistical difference in overall survival was shown between the treatment arms in the overall study population (hazard ratio 0.89, 95 percent CI: 0.72, 1.09; p=0.236) or in stage III patients. No statistical difference was observed either in DFS or survival in stage II patients.

The incidence of grade 3 or grade 4 events was 70 percent and 31 percent on the oxaliplatin combination arm and infusional 5FU/LV arm, respectively. Granulocytopenia, paresthesia, diarrhea, vomiting and nausea were the most common grade 3 or 4 adverse events. Paresthesia was seen in 92 percent of patients on the oxaliplatin combination; 21 percent had residual paresthesia at 18 month follow-up. Three percent and 0.5 percent had grade 2 and 3 paresthesias, respectively, at 18 month follow-up.

Grade 3 or 4 hypersensitivity was noted in 3 percent and may require discontinuation of therapy. Hepatotoxicity (damaging effects on the liver), evidenced by increase in transaminases (57 percent vs. 34 percent) and alkaline phosphatases (42 percent vs. 20 percent), was observed more commonly in the oxaliplatin combination arm. The incidence of increased bilirubin was similar on both arms. Hepatic vascular disorders should be considered and investigated if abnormal liver function tests or portal hypertension (increased pressure in the vein connecting the vein connecting the intestines and the liver) are present and can not be explained by liver metastases or other known etiologies.

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Initial Therapy for Advanced Colorectal Cancer

Oxaliplatin previously received accelerated approval on August 9, 2002, for use in combination with infusional 5-FU/LV for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within six months of completion of first-line therapy with the combination of bolus 5-FU/LV and irinotecan.

Safety and efficacy were demonstrated in one multicenter, randomized controlled clinical trial sponsored by the National Cancer Institute as an inter-group study led by the North Central Cancer Treatment Group. The study had seven arms at different times during its conduct, four of which were closed either due to changes in the standard of care, toxicity, or simplification.

During the study, the control arm was changed to irinotecan plus bolus 5-FU/LV. The oxaliplatin + infusional FU/LV regimen was compared to an approved control regimen of irinotecan plus bolus 5-FU/LV in 531 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. Patients may have received adjuvant therapy for resected stage II or III disease without recurrence within 12 months. After completion of enrollment, the dose of irinotecan plus 5-FU/LV was decreased due to toxicity.

The oxaliplatin + infusional FU/LV regimen showed superior survival to the irinotecan plus bolus FU/LV regimen with median survivals of 19.4 and 14.6 months (p=0.0001), respectively. Time to tumor progression and tumor response rate were also superior on the oxaliplatin + infusional FU/LV regimen.

Fatigue, neuropathy, nausea, vomiting, diarrhea, stomatitis, neutropenia, and thrombocytopenia were the more common adverse events. Febrile neutropenia or requirement for platelet transfusion were not increased as compared to the irinotecan + bolus 5-FU/LV.

Oxaliplatin has been associated with pulmonary fibrosis (<1 percent of study patients), which may be fatal. There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received oxaliplatin plus 5-FU/LV while on anticoagulants. Patients requiring oral anticoagulants may require closer monitoring.

Hypersensitivity has been observed (<2 percent Grade 3/4) in clinical studies and was usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and may require discontinuation of therapy.

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Glossary Terms

A drug used to treat symptoms of cancer of the colon, breast, stomach, and pancreas. It is also used in a cream to treat certain skin conditions. 5-FU stops cells from making DNA and it may kill cancer cells. It is a type of antimetabolite. Also called 5-fluorouracil and fluorouracil.

Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.

A drug that helps prevent blood clots from forming. Also called blood thinner.

Substance formed when red blood cells are broken down. Bilirubin is part of the bile, which is made in the liver and is stored in the gallbladder. The abnormal buildup of bilirubin causes jaundice.

In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works.

The length of time after treatment for a specific disease during which a patient survives with no sign of the disease. Disease-free survival may be used in a clinical study or trial to help measure how well a new treatment works. Also called DFS and disease-free survival time.

Initial treatment used to reduce a cancer. First-line therapy is followed by other treatments, such as chemotherapy, radiation therapy, and hormone therapy to get rid of cancer that remains. Also called induction therapy, primary therapy, and primary treatment.

The active ingredient in a drug used alone or in combination with other drugs to treat colon cancer or rectal cancer that has spread to other parts of the body or has come back after treatment with fluorouracil. It is also being studied in the treatment of other types of cancer. Irinotecan blocks certain enzymes needed for cell division and DNA repair, and it may kill cancer cells. It is a type of topoisomerase inhibitor and a type of camptothecin analog.

The active ingredient in a drug used to lessen the toxic effects of substances that block the action of folic acid, especially the anticancer drug methotrexate. Leucovorin is used to treat some types of anemia and is also used together with fluorouracil to treat colorectal cancer. It is also being studied in the treatment of other types of cancer and other conditions. Leucovorin is a form of folic acid. It is a type of chemoprotective agent and a type of chemosensitizing agent. Also called folinic acid.

A statistics term. The middle value in a set of measurements.

The time from either diagnosis or treatment at which half of the patients with a given disease are found to be, or expected to be, still alive. In a clinical trial, median survival time is one way to measure how effective a treatment is. Also called median overall survival and median survival.

A nerve problem that causes pain, numbness, tingling, swelling, or muscle weakness in different parts of the body. It usually begins in the hands or feet and gets worse over time. Neuropathy may be caused by physical injury, infection, toxic substances, disease (such as cancer, diabetes, kidney failure, or malnutrition), or drugs, including anticancer drugs. Also called peripheral neuropathy.

A condition in which there is a lower-than-normal number of neutrophils (a type of white blood cell).

A type of study in which both the health providers and the patients are aware of the drug or treatment being given.

The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

Removed by surgery.

Surgery to remove tissue or part or all of an organ.

The extent of a cancer in the body. Staging is usually based on the size of the tumor, whether lymph nodes contain cancer, and whether the cancer has spread from the original site to other parts of the body.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.

Inflammation or irritation of the mucous membranes in the mouth.

A condition in which there is a lower-than-normal number of platelets in the blood. It may result in easy bruising and excessive bleeding from wounds or bleeding in mucous membranes and other tissues.