Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma.
OBJECTIVE
Sorafenib, a multi-kinase inhibitor with anti-angiogenic activity, was recently approved for the treatment of advanced hepatocellular carcinoma (HCC). Metronomic chemotherapy using tegafur/uracil (4:1 molar ratio), an oral fluoropyrimidine, has been shown to enhance the anti-tumor effect of anti-angiogenic agents in preclinical models. This phase II study evaluated the efficacy and safety of combining metronomic tegafur/uracil with sorafenib in patients with advanced HCC.


METHODS
Patients with histologically- or cytologically-proven HCC and Child-Pugh class A liver function were treated with sorafenib (400mg twice daily) and tegafur/uracil (125 mg/m(2) based on tegafur twice daily) continuously as first-line therapy for metastatic or locally advanced disease that could not be treated by loco-regional therapies. The primary endpoint was progression-free survival (PFS).


RESULTS
The study enrolled 53 patients. Thirty-eight patients (72%) were hepatitis B surface antigen-positive. The median PFS was 3.7 months (95% C.I., 1.9-5.5) and the median overall survival was 7.4 months (95% C.I., 3.4-11.4). According to RECIST criteria, 4 patients (8%) had a partial response and 26 patients (49%) had a stable disease. Major grade 3/4 toxicities included fatigue (15%), abnormal liver function (13%), elevated serum lipase (10%) hand-foot skin reaction (HFSR) (9%), and bleeding (8%). HFSR was the major adverse event resulting in dose reduction (19%) or treatment delay (21%).


CONCLUSIONS
Metronomic chemotherapy with tegafur/uracil can be safely combined with sorafenib and shows preliminary activity to improve the efficacy of sorafenib in advanced HCC patients.
Hsu
Chih-Hung
CH
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
Shen
Ying-Chun
YC
Lin
Zhong-Zhe
ZZ
Chen
Pei-Jer
PJ
Shao
Yu-Yun
YY
Ding
Yea-Hui
YH
Hsu
Chiun
C
Cheng
Ann-Lii
AL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000855:Anorexia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D001557:Benzenesulfonates / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D003875:Drug Eruptions / Q000209:etiology; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D000077157:Sorafenib; D005641:Tegafur / Q000008:administration & dosage; D014498:Uracil / Q000008:administration & dosage
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D005641:Tegafur; D009536:Niacinamide; D014498:Uracil; D000077157:Sorafenib