Delivering Drugs to the Liver When Colon Cancer Spreads

In the early 1980s, an experimental treatment was developed for patients with advanced colorectal cancer whose disease had invaded the liver. In the treatment, chemotherapy is delivered directly to the liver through a surgically implanted catheter and pump.

A decade ago, after preliminary studies indicated that the treatment - hepatic arterial infusion chemotherapy - might improve survival in an often fatal disease, a randomized clinical trial was launched. The results were published last week.

The study showed that patients who received "pump" chemotherapy lived on average 4 months longer than patients who received essentially the same chemotherapy intravenously (24 versus 20 months).

"There are many new treatments for colorectal cancer, and this is one more option for patients," says lead researcher Dr. Nancy Kemeny of Memorial Sloan-Kettering Cancer Center.

Colorectal cancer spreads to the liver in more than half of the 160,000 patients in the United States who develop advanced disease each year. This is a major cause of death, and most patients do not live beyond 2 years.

A median survival of 24 months for metastatic colorectal cancer is the longest survival in any clinical trial to date. Patients in the pump group received floxuridine, leucovorin, and dexamethasone, while those on systemic therapy received fluorouracil and leucovorin. The researchers note that the drugs used in the systemic arm of the trial have largely been replaced by newer medicines such as irinotecan and oxaliplatin.

Long before the trial was completed, the researchers began to evaluate whether the newer drugs might provide even greater survival increases than the older drugs if delivered to the liver.

In addition, because pump therapy is ineffective against cancer that has spread beyond the liver, Dr. Kemeny and her colleagues are testing the therapy in combination with conventional chemotherapy and as a second-line treatment.

"The treatments of the future will involve combinations of the best systemic agents with hepatic arterial infusion," says Dr. Kemeny.

The ideal candidate for the treatment is someone who has metastatic colon cancer that is confined to the liver and unlikely to spread.

Pump therapy uses higher doses of chemotherapy than are possible with systemic delivery. The drugs are extracted by the liver, so there is typically less systemic toxicity than is associated with conventional chemotherapy.

The treatment begins by having a catheter inserted into the hepatic artery, which provides the blood supply to tumors in the liver. The catheter is then connected to a pump beneath the skin (about the size of a hockey puck) that delivers the drugs.

After recovering from this initial surgery, patients receiving hepatic arterial therapy tend to feel better than patients who have intravenous chemotherapy, the researchers say. This was confirmed by the trial, which included a quality-of-life assessment for both groups.

Overall, patients in the pump group felt better physically than did patients in the intravenous group, particularly during the treatment phases of the trial. This was true at 3 months, 6 months, and 12 months after starting treatment.

"We believe that patients who had pump therapy were physically able to do more things, and that made them feel better," says Dr. Michelle Naughton of Wake Forest University School of Medicine, who led the quality-of-life analysis.

Findings from the multicenter phase III trial, which included 135 patients, were published online February 27 in the Journal of Clinical Oncology.

Pump therapy has been administered mainly at cancer centers that have experience installing the devices and monitoring the liver. The treatment has risks associated with the use of devices, such as infection and mechanical failure, as well as liver toxicity if the liver function tests are not monitored carefully.

Some critics of pump therapy have argued that by using the newer medications, doctors can achieve similar survival rates of nearly 24 months without installing a catheter and a pump in someone with advanced cancer.

Dr. Elin Sigurdson of the Fox Chase Cancer Center, who has treated patients with pump therapy since the early 1980s and was a co-author of the study, says that liver-directed treatments will always have a role in the disease.

"There will always be a population that will benefit from having the pump put in," says Dr. Sigurdson, noting that the challenge now is to identify that population. "Research on delivering newer drugs directly to the liver is promising and has only just begun," she adds.

By Edward R. Winstead