Gemcitabine and doxorubicin for the treatment of patients with advanced hepatocellular carcinoma: a phase I-II trial

Background: We determined the maximum tolerated dose (MTD) and then further evaluated the response rate and safety profile of gemcitabine (Gem) plus doxorubicin (Dox) in chemonaive patients with advanced hepatocellular carcinoma (HCC). Patients and methods: Dose escalation was tested over four dose levels in each 21-day cycle: level 1 (Gem 1000 mg/m(2) on days 1 and 8, Dox 30 mg/m(2) on day 1), level 2 (Gem/Dox 1250/30), level 3 (Gem/Dox 1250/45) and level 4 (Gem/Dox 1250/60). The MTD was further evaluated in phase II. Results: Patients' characteristics were: 47 men, three women; median age 53 years (range 28-70); Zubrod performance status (PS) scores 0-1 (74%), PS 2 (26%); Okuda stage I (24%) and stage II (76%). Fifteen patients were enrolled in phase I: level 1 (n = 3), level 2 (n = 6), level 3 (n = 6), level 4 (n = 0). Level 2 was identified as the MTD. Dose-limiting toxicities included esophageal bleeding, grade 4 neutropenia and neutropenic fever. Of the 34 patients evaluable for response in phase II (of 35 total), there were four (11.8%) partial responses (95% CI, 0.8% to 22.8%) and six (17.6%) minor responses; nine (26.5%) had stable disease and 15 (44.1%) progressed. Sixteen per cent of patients had a decline of greater than or equal to50% in alpha-fetoprotein levels after treatment. Median survival and progression-free survival were 4.6 months (range 0.3-19.2) and 2.5 months (range 0.2-7.8), respectively, for 35 patients. Grade 3/4 hematological toxicities included anemia (45.7%), neutropenia (51.4%), thrombocytopenia (25.7%); febrile neutropenia (11.8%) and non-hematological toxicities were mild to moderate. Conclusions: Gemcitabine plus doxorubicin produces modest activity and moderate toxicity in this cohort of Chinese patients with advanced HCC.