Elsevier

Journal of Hepatology

Volume 53, Issue 1, July 2010, Pages 126-131
Journal of Hepatology

Research Article
Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma

https://doi.org/10.1016/j.jhep.2010.01.035Get rights and content

Background & Aims

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 (400 mg twice daily) and tegafur/uracil (125 mg/m2 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.

Introduction

Patients with metastatic or advanced hepatocellular carcinoma (HCC) that cannot be treated by loco-regional therapies face a dismal outcome [1], [2], [3]. In Asian countries, the median survival of these patients is in the range of 2–4 months with the best supportive care [1], [2]. Until recently, conventional cytotoxic chemotherapy has shown little effect. This limited success has been attributed to the inherent chemo-resistance of HCC cells, as well as chemo-intolerance of HCC patients as a result of concomitant chronic liver disease.

Since 2007, sorafenib, a multi-kinase inhibitor against Raf kinase and vascular endothelial cell growth factor receptor (VEGFR) [4], has been approved for the indication of unresectable HCC by regulatory agencies of the EU, US, and other countries. This approval was based on the positive results of a placebo-controlled randomized phase III study in advanced HCC patients with good liver reserve [5]. Subsequently, another phase III study conducted in the Asia–Pacific region where hepatitis B virus infection is the dominant etiologic factor of chronic liver disease, also demonstrated the survival benefits of sorafenib [1]. Sorafenib is generally well tolerated [1], [5], [6], [7], [8], [9], [10] and combination therapy may further improve the efficacy of sorafenib in advanced HCC.

Metronomic chemotherapy refers to administrating chemotherapeutics at doses significantly less than the maximum-tolerated doses on a frequent basis for a prolonged period of time [11]. In preclinical models, metronomic chemotherapy is identified to have anti-angiogenic activity. The anti-angiogenic mechanisms of metronomic chemotherapy include inhibiting proliferation of activated endothelial cells in tumor neovasculature, suppressing mobilization of endothelial progenitor cells from bone marrow, and inducing anti-angiogenic factors [11], [12]. The combination of metronomic chemotherapy and inhibitors of vascular endothelial growth factor (VEGF)/VEGFR has shown synergistic anti-tumor effects in experimental tumor models [12], [13]. Recently, metronomic chemotherapy, alone or in combination with anti-VEGF agents, has demonstrated clinical benefits without eliciting serious toxicity in heavily pretreated breast cancer patients [14], [15].

Tegafur/uracil, composed of tegafur and uracil in a molar ratio of 4:1, is an orally active fluoropyrimidine [16]. Tegafur, as a prodrug, is metabolized to 5-fluorouracil (5-FU) mainly in the liver. Uracil, an inhibitor of dihydropyrimidine dehydrogenase which is the rate-limiting enzyme of 5-FU degradation, helps maintain a stably high concentration of 5-FU in the liver and in the circulation [17]. Tegafur/uracil has been approved for the treatment of various types of advanced gastrointestinal (GI) cancers in Japan and Taiwan. The single-agent activity of tegafur/uracil in advanced HCC was previously reported in small-scale phase II studies in Japan, with response rates of 3.8–17% [18], [19]. Interestingly, tegafur and its metabolites have shown potent anti-angiogenic effects in preclinical models [20], [21]. In mice bearing high-volume metastatic breast cancer, metronomic chemotherapy with tegafur/uracil is effective in reducing tumor metastasis and prolonging survival [22].

We hypothesized that the efficacy of sorafenib in advanced HCC can be improved by adding metronomic tegafur/uracil, and the toxicity profiles of this combination would not be significantly different from those of sorafenib alone.

Section snippets

Study design and conduction

The study was an open-labeled, single-arm, single-institute, investigator-initiated phase II clinical study. The study was approved by the Institute Research Ethical Committee of National Taiwan University Hospital, and was conducted in accordance with the principles of the Declaration of Helsinki. The recruitment notification has been posted on www.clinicaltrials.gov (NCT 00464919).

Eligibility of patients

The study targeted HCC patients with metastatic diseases or locally advanced diseases that were not amenable to

Patient characteristics

Between April 2007 and April 2008, a total of 53 patients with advanced HCC were enrolled at the National Taiwan University Hospital, Taipei, Taiwan. Table 1 summarizes the pertinent characteristics of the patients. The median age was 57 years; the majority of the patients were males (89%) and hepatitis B virus surface antigen-positive (72%). All but 6 patients had extrahepatic metastases and/or macroscopic vascular invasion (89%). Fifty patients (94%) had Barcelona Clinic Liver Cancer (BCLC)

Discussion

The current study demonstrates that the combination of sorafenib and tegafur/uracil at the current dose/schedule is a safe outpatient regimen for patients with advanced HCC. As expected, the combination was associated with minimal hematologic toxicities, and the most frequent AEs were HFSR, fatigue, diarrhea, and anorexia (Table 3). The toxicity profile of the combination is similar to that of sorafenib alone as reported previously [1], [5], [6], [7], [8]. On the other hand, the combination

Financial disclosure

C.-H. Hsu received honoraria from Bayer and research funding from Bayer. P.-J. Chen was a consultant of BMS and Bayer, and received honoraria from Medigene. C. Hsu received honoraria from Bayer. A.-L. Cheng was a consultant of Bayer, Pfizer, and Merck Serono, and received honoraria from Bayer, Pfizer, and Merck Serono. The other authors declared they have no conflict of interest to disclose.

Acknowledgements

This work was supported by Bayer HealthCare and by a Grant from the Department of Health, Executive Yuan of Taiwan to “National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital” (Grant No. DOH96-TD-B-111-001). The work was also supported partly by Grants NSC 97-2628-B-002-004-MY3 and NSC 98-3112-B-002-038. This study was presented in part at the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL.

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