HIA Chemo Promising in Colon Cancer Liver Mets

PARIS--Hepatic intraarterial (HIA) chemotherapy coupled with aggressive resection may improve the outlook for patients with liver metastases from colorectal cancer, Nancy Kemeny, MD, of Memorial Sloan-Kettering Cancer Center, said at the Eighth International Congress on Anti-Cancer Treatment (ICACT).

The rationale for direct hepatic infusion, Dr. Kemeny said, is that liver metastases are perfused mainly by the hepatic artery and that certain drugs are extracted by the liver during first-pass metabolism.

Targeting the liver also makes sense, she said, because the liver may be the first site of metastasis, from which the disease may spread via the portal vein to the lungs and other organs. "If you can get the disease while it is still in the liver, you might be able to control it," she said.

Dr. Kemeny spotlighted floxuridine as the best candidate for HIA chemotherapy, because this drug is extracted to such a great extent by the liver. She noted that the first trials of floxuridine administered by a hepatic pump produced a mean response rate of 57%, which is higher than that achieved with systemic chemotherapy.

She acknowledged, however, that proving a survival advantage for HIA has been hampered by such stumbling blocks as the crossover design used in the randomized Memorial Sloan-Kettering trial, the small number of patients enrolled in the National Cancer Institute study, and the inadequate systemic chemotherapy given in the Mayo Clinic study.

Nevertheless, a French study and an English study have both revealed significant increases in median survival with HIA chemotherapy, compared with systemic chemotherapy (15 versus 11 months in the French trial and 425 days versus 215 days in the English trial). "An important finding of the English study was that this treatment did not worsen quality of life--if anything, it improved quality of life," she added.

Minimizing Risks

Dose-limiting toxic effects of intraar-terial floxuridine are quite distinct from those of systemic chemotherapy and include ulcer disease and hepatic toxicity, most notably, biliary sclerosis. For this reason, Dr. Kemeny said, a key challenge for clinical trialists is to shape HIA regimens that will minimize these risks.

In a small randomized study conducted at Memorial Sloan-Kettering, an attempt to protect the liver with dexameth-asone during HIA resulted in decreased bilirubin levels, although the improvement did not reach statistical significance. However, the addition of dexamethasone increased the cytotoxicity of floxuridine and thereby boosted response rates and survival.

The Sloan-Kettering investigators also showed that the combination of intra-arterial floxuridine and leucovorin prolongs survival, although low doses of leucovorin are necessary to prevent biliary toxicity.

"The type of responses we saw with this particular treatment were really dramatic," Dr. Kemeny reported. "With floxuridine-leucovorin or floxuridine-dexamethasone, at 2 years, almost 60% of patients are alive." Median survival is 21 months in patients positive for p53 expression, and has reached 53 months in p53-negative patients.

A randomized CALGB study involving previously untreated patients will compare the efficacy, tolerability, and cost of intraarterial floxuridine, leucovorin, and dexamethasone with those of systemic fluorouracil and leucovorin.

Adjuvant Therapy

Dr. Kemeny’s team is now addressing the issue of whether adjuvant therapy is useful after resection of hepatic metastases. "We know that in patients who have a liver resection, 50% will recur in the liver and 50% will recur systemically, so we felt we need to cover both areas," she said.

For this reason, the Memorial Sloan- Kettering trial is comparing the combination of adjuvant HIA plus systemic fluorouracil and leucovorin versus systemic therapy alone.

Although survival data are not yet available for each of the two arms in this study, overall 5-year survival for the entire group has reached 45%, in contrast to the 30% rate reported in most liver resection studies, she said.

Even in patients who had more than four metastases resected, the median survival is 37 months. Likewise, among high-risk individuals with synchronous disease, 3-year survival is 40%.

"So we may actually be doing something for these patients," Dr. Kemeny commented.