A phase II study of sorafenib in combination with tegafur/uracil (UFT) for Asian patients with advanced hepatocellular carcinoma

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Author(s): Y. Shen, C. Hsu, C. Hsu, Z. Lin, P. Chen, Y. Shao, T. Huang, Y. Ding, A. Cheng; National Taiwan University Hospital, Taipei, Taiwan



Background: Sorafenib, a multikinase inhibitor with antiangiogenic activity, has recently been approved for the treatment of unresectable HCC. Combination of sorafenib with metronomic chemotherapy has theoretic advantage in improving antitumor activity without increasing toxicities. UFT (tegafur: uracil = 4:1 in molar ratio), an oral fluoropyrimidine, is active in various gastrointestinal cancers. We conducted a phase II study to evaluate the efficacy and safety of sorafenib plus low-dose UFT in advanced HCC patients (pts).


Methods: Pts with histologically or cytologically proven unresectable/metastatic HCC, ECOG PS 0-2, Child-Puch class A, platelets ? 100 K/µl, transaminases ? 5 × ULN, bilirubin ? 3 mg/dl, INR ? 2.3 and creatinine ? 1.5 × ULN were enrolled. Prior systemic therapy for advanced disease is not allowed. Sorafenib (400 mg bid) and UFT (125 mg/m2 based on tegafur bid) were taken per os continuously. Tumor assessment was performed q8w by RECIST criteria. Primary endpoint is progression-free survival (PFS).


Results: Between April 2007 and April 2008, 53 pts were enrolled. Baseline pts characteristics were: M/F, 47/6; median age 57 (range, 31-83); CLIP score 0-3/4, 48/5; extrahepatic spread/macroscopic vascular invasion, 33/30; and HBsAg(+)/anti-HCV(+)/both(+), 38/13/4. 89% of pts were BCLC stage C. Pts received a median of 3.7 (range 0.3- 18.9+) months of treatment. There were 3 (6%) PR and 27 (51%) SD. The median PFS and OS were of 3.7 months (95% C.I., 1.9- 5.5) and 7.4 months (95% C.I., 3.4- 11.4), respectively. Adverse events (AEs) were summarized in Table. Hand-foot skin reaction (HFSR), fatigue, and diarrhea were most common AEs. HFSR was the major AE resulting in dose reduction (19%) or treatment delay (21%). Grade 3/4 neutropenia occurred in 2 pts (4%).


Conclusions: Adding metronomic UFT chemotherapy to sorafenib may improve therapeutic efficacy of the latter in pts with advanced HCC. The toxicity profile of the combination is similar to that of sorafenib alone.