PURPOSE: To conduct a pilot trial of hepatic arterial infusion (HAI) of floxuridine (FUDR), leucovorin, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (FLAP) in nonresectable hepatocellular cancer (HCC) confined to the liver and assess the effects of hepatitis B (HBV) and hepatitis C (HCV) viral markers on toxicity, response to treatment, and patient survival. PATIENTS AND METHODS: Of 31 HCC patients, 13 were HBV- and HCV-nonreactive, and 18 had evidence of either current or prior HBV and/or HCV infection. Treatment was delivered through percutaneous hepatic arterial catheters, and Infusaid pumps (Shiley Infusaid, Norwood, MA) were placed in responding patients. Cisplatin (100 mg/m2) and Adriamycin (30 to 35 mg/m2) were administered on day 1, followed by a continuous 24-hour HAI of an admixture of floxuridine (60 mg/m2) and leucovorin (15 mg/m2) daily for 4 days. Treatment was repeated every 5 weeks. RESULTS: Twelve (41%) of 29 assessable patients had a partial response (PR), with a median time to disease progression of 13 months. Six (50%) of 12 HBV-negative (HBV-)/HCV-negative (HCV-) and six of 17 (35%) HBV-positive (HCV+) and/or HCV-positive (HCV+) patients achieved a PR. Eight patients have been maintained in remission for a median duration greater than 15.5 months. The median survival duration of all 31 patients was 15 months, 7.5 months among HBV+ and/or HCV+ patients, and significantly longer among hepatitis-non-reactive patients (P = .007). (A median has not yet been reached.) Granulocylopenia (< 0.1 x 10(3)/microL), thrombocytopenia (< 25 x 10(3)/microL), and hospitalizations for infectious complications were significantly more common among HBV-HCV-reactive than -nonreactive patients: 56%, 50%, and 67% versus 15%, 15%, and 8%, respectively (P < .05 for all). CONCLUSION: HAI of FLAP has induced long-term PR and has palliated extensive nonresectable HCC. Positive hepatitis serology appeared to increase bone marrow susceptibility to myelotoxic drugs. Conceivably, one or both viruses may have a direct inhibitory effect on bone marrow progenitors and thereby contribute to the observed myelotoxicity.