Survival Trend With Palliative FOLFOX4 vs Doxorubicin in Asian Patients With Advanced Hepatocellular Carcinoma
In a study reported in Journal of Clinical Oncology, Shukui Qin, MD, of People’s Liberation Army Cancer Centre, Bayi Hospital, in Nanjing, and colleagues compared FOLFOX4 (infusional fluorouracil [5-FU], leucovorin, and oxaliplatin) with doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma. They found a trend toward improved overall survival and significantly improved progression-free survival with FOLFOX4 treatment.
Study Details
In this multicenter, open-label phase III trial conducted in mainland China, Taiwan, Korea, and Thailand, 371 patients aged 18 to 75 years with locally advanced or metastatic hepatocellular carcinoma who were ineligible for curative resection or local treatment were randomly assigned to receive FOLFOX4 (n = 184) or doxorubicin (n = 187). FOLFOX4 was given as oxaliplatin at 85 mg/m2 on day 1, leucovorin at 200 mg/m2 from hour 0 to 2 on days 1 and 2, and 5-FU at 400 mg/m2 by bolus at hour 2, then 600 mg/m2 over 22 hours on days 1 and 2 once every 2 weeks; doxorubicin was given at 50 mg/m2 once every 3 weeks. The primary endpoint was overall survival.
The FOLFOX4 and doxorubicin groups were generally well matched at baseline for age (mean, 50 and 49 years), sex (90% and 87% male), hepatocellular carcinoma risk factors (HBV infection in 93% and 90%), disease status (metastatic disease in 57% and 60%), Child-Pugh stage (A in 89% and 87%), Barcelona Clinic Liver Cancer stage (C in 79% and 81%), primary tumor stage (T3 in 67% and 63%), lymph node stage (N0 in 69% and 70%), distant metastasis stage (M1 in 57% and 60%), disease stage (IIIA in 28% and 27%), prior surgery (26% and 27%), prior radiotherapy (7% and 10%), prior chemotherapy (21% and 30%), and most common local treatment to target lesion (transarterial chemoembolization/transarterial embolization in 35% and 37%).
The median number of treatment cycles was four in the FOLFOX4 group and two in the doxorubicin group. The average percentage of projected dose-intensity was 85% and 93%, respectively.
Overall Survival Trend
At both first (hazard ratio [HR] = 0.56, P = .01) and second (HR = 0.69, P = .02) interim analyses, median overall survival was greater with FOLFOX4 than with doxorubicin. At the prespecified final analysis, median overall survival was 6.40 months with FOLFOX4 vs 4.97 months with doxorubicin (HR = 0.80, 95% confidence interval [CI] = 0.63–1.02, P = .07). At a follow-up analysis 7 months later, this trend toward increased survival with FOLFOX4 was maintained (median, 6.47 vs 4.90 months, HR = 0.79, P = .04).
Secondary Endpoints
Median progression-free survival at the prespecified final analysis was 2.93 months with FOLFOX4 vs 1.77 months with doxorubicin (HR = 0.62, P < .001), with the difference maintained at the follow-up analysis (HR = 0.68, P < .001). Overall response rate (8% vs 3%, P = .02) and disease control rate (52% vs 32%, P < .001) were significantly better with FOLFOX4. One patient (in the FOLFOX4 group) underwent secondary resection.
Toxicity
The most common treatment-related nonhematologic adverse events of any grade in the FOLFOX4 group were nausea, AST elevation, and anorexia, whereas alopecia, AST elevation, and nausea were the most common in the doxorubicin arm. There was a borderline significant greater frequency of grade 3 or 4 adverse events in the FOLFOX4 group (56% vs 45%, P = .05), with the most common nonhematologic events in the FOLFOX4 group being increased AST (12% vs 12%), increased ALT (4% vs 3%), and increased bilirubin (4% vs 5%), and the most common in the doxorubicin group being increased AST, increased bilirubin, and alopecia (5% vs 1%).
The most common grade 3 or 4 laboratory abnormalities were neutropenia (31% of FOLFOX4 patients vs 23% of doxorubicin patients), and leukopenia (9% vs 10%). No differences in cardiac toxicity were observed between the two treatment groups. Discontinuation of treatment due to adverse events occurred in 23% of the FOLFOX4 group and 17% of the doxorubicin group.
The investigators concluded, “Although the study did not meet its primary endpoint, the trend toward improved [overall survival] with FOLFOX4, along with increased [progression-free survival] and response rate suggests that this regimen may confer some benefit to Asian patients, but an [overall survival] benefit cannot be concluded from these data.”
The study was supported by Sanofi-Aventis.
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