Hepatic arterial infusion improves survival among patients with liver metastases

Delivering therapy directly to the liver delays overall survival and time-to-progression in patients with advanced-stage liver cancer.

Issue: April 1, 2006

Hepatic arterial infusion (HAI) significantly increases survival in patients with colorectal cancer that has metastasized to the liver compared with systemic chemotherapy, according to the results of a study by the Cancer and Leukemia Group B (CALGB).

Nancy E. Kemeny, MD [photo]
Nancy E. Kemeny

Patients who received fluoropyrimidines through HAI had increased overall survival, response rates and time to hepatic progression compared with those who received fluoropyrimidines systemically, said lead researcher Nancy E. Kemeny, MD, attending physician in the department of medicine at Memorial Sloan-Kettering Cancer Center in New York.

“It was a similar chemotherapy agent with a different means of delivery,” Kemeny said. “Giving a similar drug but changing the method of delivery increases survival and quality of life.”

In HAI, chemotherapy is delivered directly to the liver through a pump inserted in the abdomen. The blood supply for hepatic metastases is primarily from the hepatic artery, rather than the portal vein, which supplies a healthy liver.

Direct vs. indirect

Previous studies comparing HAI with systemic chemotherapy have found improved response rates with HAI. Those studies, however, had small patient populations. Furthermore, researchers permitted patients to crossover from the systemic therapy arm to the HAI arm, making survival assessments difficult. Kemeny and colleagues had no crossover from systemic therapy to HAI.

They included 135 colorectal cancer patients with unresectable liver metastases whom they randomized to receive fluorouracil and leucovorin systemically, or floxuridine plus leucovorin and dexamethasone through HAI.

Overall survival was 24.4 months in the HAI group compared with 20 months in the systemic group (P = .0034). Two-year survival was also greater in the HAI group compared with systemic therapy: 51% vs. 35%, respectively. Previous research has established a median survival of eight months for patients who have developed liver metastases.

Response rates were higher among patients who received HAI compared with systemic therapy: 47% vs. 24%, respectively, and time to hepatic progression was also significantly longer for patients receiving HAI than systemic therapy: 9.8 vs. 7.3 months, respectively (P = .034). Time to extrahepatic progression was significantly shorter for the HAI group compared with systemic therapy: 7.7 vs. 14.8 months, respectively (P = .029). Researchers observed no significant differences between the groups for time-to-progression: 5.3 months for HAI vs. 6.8 months for systemic therapy (P = .95).

Additionally, patients in the HAI group reported improved quality of life, as measured by physical functioning, compared with those receiving systemic therapy. Patients in the HAI group had better physical functioning during active treatment at three, six and 12 months compared with patients in the systemic therapy group. Kemeny and colleagues found no significant differences between the groups for measures of social functioning, and no role limitations due to emotional problems.

In both treatment arms, women experienced higher survival rates compared with men. Median survival rates for women were 29.4 months for HAI and 20.1 for systemic therapy. In comparison, median survival rates for men were 22 months for HAI vs. 18.3 months for systemic therapy. The researchers did not speculate on the reason for the gender discrepancies.

Treatment-associated systemic toxicities were lower among patients receiving HAI compared with systemic therapy. Patients who received systemic therapy had a higher incidence of grade-3 neutropenia, diarrhea and stomatitis. However, there was a risk of liver toxicity in the HAI group.

“Liver toxicity was increased with HAI,” Kemeny said. “This means we need to monitor liver function very closely. There were no systemic effects.”

Ongoing validation

It should be noted that researchers initiated the study in 1996, prior to the availability of therapeutic agents such as bevacizumab (Avastin, Genentech), oxaliplatin (Eloxatin, Sanofi-Aventis) and irinotecan (Camptosar, Pfizer). The addition of these newer agents to fluorouracil and leucovorin has resulted in higher survival rates than observed with fluorouracil and leucovorin alone.

In this study, patients who had tumor progression while receiving fluorouracil and leucovorin were able to receive the newer agents at the time of progression. Thus, even with equal access to the newer agents, patients in the HAI group had improved survival.

HAI has wide applications. Physicians are already using the technique for patients with cancers, other than colorectal, that have metastasized to the liver, according to Kemeny. However, HAI is appropriate only for patients with liver involvement and is not intended for patients with widespread cancer.

Kemeny noted that surgeons and health care professionals need to be trained in the proper technique for insertion of the abdominal pump and patient care.

“Liver adverse events increase if the proper techniques are not followed,” Kemeny said. Health care professionals “must ensure the drug actually gets into the liver, and they need to know how to check liver function tests.”

Studies are under way to investigate the effects of combining HAI with systemic chemotherapy to further increase response rates, she said. – by Cheryl L. Jones

For more information:

Kemeny NE, Niedzwiecki D, Hollis DR, et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol. 2006;24:1395-1403.