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uracil for advanced hepatocellular carcinoma
Research Article
Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma Chih-Hung Hsu1,4, Ying-Chun Shen1,2, Zhong-Zhe Lin1,4, Pei-Jer Chen2,3, Yu-Yun Shao1, Yea-Hui Ding1, Chiun Hsu1,4,*, Ann-Lii Cheng1,3,4,5,** 1
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; 2Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; 3Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 4Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan; 5Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
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%)
Keywords: Sorafenib; Tegafur/uracil; Metronomic chemotherapy; Hepatocellular carcinoma. Received 7 November 2009; received in revised form 12 December 2009; accepted 27 January 2010; available online 30 March 2010 * Correspondence to: Chiun Hsu, Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan 10002. Tel.: +886 2 231 23456x67789; fax: +886 2 23711174. ** Correspondence to: Ann-Lii Cheng, Departments of Internal Medicine and Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan 10002. Tel.: +886 2 23123456x67251; fax: +886 2 23711174. E-mail addresses: [email protected] (C. Hsu), [email protected] (A.-L. Cheng). Abbreviations: HCC, hepatocellular carcinoma; PFS, progression-free survival; C.I., confidence interval; RECIST, response evaluation criteria in solid tumors; HFSR, hand-foot skin reaction; VEGFR, vascular endothelial growth factor receptor; EU, European Union; US, United States; VEGF, vascular endothelial growth factor; 5FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; ULN, upper limit of normal; PT, prothrombin time; AE, adverse event; ORR, overall response rate; DSR, disease stabilization rate; CR, complete response; PR, partial response; PD, progressive disease; SD, stable disease; OS, overall survival; ITT, intent-to-treat; BCLC, Barcelona Clinic Liver Cancer; CLIP, the Cancer of the Liver Italian Program; AFP, alpha-fetal protein; CEC, circulating endothelial cell.
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. Ó 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Introduction Patients with metastatic or advanced hepatocellular carcinoma (HCC) that cannot be treated by loco-regional therapies face a dismal outcome [1–3]. 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 [1,5–10] 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
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JOURNAL OF HEPATOLOGY 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 ratelimiting 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.
Treatment Patients received sorafenib (400 mg orally, twice per day), and tegafur/uracil (UFURÒ, 125 mg/m2 based on tegafur orally, twice per day; TTY Biopharm Co., Ltd., Taipei, Taiwan) continuously. The treatment was continued until disease progression or development of unacceptable toxicity. The dose of tegafur/uracil was based on the published report of adjuvant tegafur/uracil in patients with completely resected pathological stage I adenocarcinoma of the lung [24]. Dose modification of sorafenib and tegafur/uracil was according to the toxicities, graded by NCI-CTC AE v3.0. When symptomatic grade 2 or grade 3 hypertension occurred, sorafenib was held and the patients were treated accordingly. When the AEs recovered to 5grade 1, sorafenib was resumed with the dose of 400 mg per day. If symptomatic grade 2 or grade 3 hypertension recurred, sorafenib was further reduced to 400 mg every 2 days. Sorafenib was discontinued permanently when grade 4 hypertension occurred, when more than 2 dose reductions for the toxicities of hypertension were required, or when treatment delay was more than 30 days due to insufficient recovery from toxicities. When grade 2 or 3 HFSR occurred, sorafenib was held until HFSR recovered to 5grade 1. Sorafenib was resumed with the original dose without dose reduction for the first occurrence of grade 2 HFSR, and was resumed with the dose of 400 mg per day for the second grade 2 HFSR and first grade 3 HFSR. Sorafenib was further reduced to 400 mg every two days if similar toxicities recurred. Sorafenib was discontinued permanently when more than two dose reductions for the toxicity of HFSR were required, or when treatment delay was more than 30 days due to insufficient recovery from toxicities. When grade 3 diarrhea or mucositis occurred, tegafur/uracil was withheld, and was resumed with the dose of 62.5 mg/m2 twice per day when the toxicities recovered to 5grade 1. Tegafur/uracil was discontinued permanently when similar grade 3 toxicities recurred despite a dose reduction, or when treatment delay was more than 30 days. For grade 3 or 4 hematologic toxicities, hepatic toxicities, and other adverse events (AEs) which were considered treatment-related, the dose modification was as follows: reduced dose level 1, sorafenib 400 mg twice per day and tegafur/uracil 62.5 mg/m2 based on tegafur twice per day; reduced dose level 2, sorafenib 400 mg per day and tegafur/uracil 62.5 mg/m2 based on tegafur twice per day; and reduced dose level 3, sorafenib 400 mg every 2 days. The combination was discontinued permanently when more than 3 dose reductions were required, or when treatment delay was more than 30 days.
Patients and methods Disease assessment 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 loco-regional therapies, including surgery, transcatheter arterial (chemo)embolization, or local ablation. The eligibility criteria included an age P18 years; histologically- or cytologically-documented HCC; Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; serum creatinine 61.5 upper limit of normal (ULN); adequate liver function reserves defined by Child-Pugh classification A, liver transaminases 65 ULN, albumin P2.8 g/dl, serum total bilirubin 63 mg/dl, prothrombin time (PT)-international normalized ratio 62.3 or PT 66 s prolongation; and adequate bone marrow reserves, defined by white blood cells P3000/ll, neutrophil count P1500/ll, platelets P100,000/ll, and hemoglobin P8.5 g/dl. Patients needed to have at least one measurable lesion, according to Response Evaluation Criteria in Solid Tumors (RECIST) [23], which was not previously treated with any loco-regional therapy. However, patients with prior local treatments were allowed if the local treatments were completed at least 6 weeks prior to enrollment. Any treatmentrelated acute toxicity should have returned to 5grade 1, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC AE) v3.0. Key exclusion criteria included prior or concomitant systemic anti-cancer treatment for HCC, metastatic brain or leptomeningeal tumors, a history of organ transplantation, and life expectancy <2 months. Patients with significant gastrointestinal bleeding within 30 days prior to enrollment were not eligible. All patients were required to provide written informed consent.
Tumor assessment was performed every 8 weeks using RECIST criteria [23]. Confirmation of responses was required at least 4 weeks after the initial response was recorded. Statistical analyses The primary endpoint of the study was progression-free survival (PFS). At the time when this study was designed, the available data about the clinical efficacy of sorafenib was a phase II trial of sorafenib involving 137 advanced HCC patients, reported by Abou-Alfa et al. [6]. In that trial, 40% of patients treated with sorafenib monotherapy remained progression-free at 6 months. It was estimated that adding metronomic chemotherapy of tegafur/uracil to sorafenib would improve the 6-month PFS rate from 40% to 60%. To detect an improvement of at least 20%, a sample size of 50 patients was required to provide a power of 80% with an one-sided 5% significance level according to sample size planning by Makuch and Simon [25]. The secondary endpoints included 6-month PFS rate, objective tumor response rate (ORR), disease stabilization rate (DSR; defined as the sum of complete response [CR], partial response [PR], and stable disease [SD] for at least 2 months), overall survival (OS), and the safety profile of the combination. All the statistics were performed for an ‘‘intent-to-treat (ITT) population”, which was defined as patients who received at least one dose of the study drugs. The PFS and OS were analyzed using Kaplan–Meier method.
Results Patient characteristics Between April 2007 and April 2008, a total of 53 patients with advanced HCC were enrolled at the National Taiwan University
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Research Article Table 1. Patient characteristics (n = 53).
57 31–83
Efficacy
6 47
11 89
38 13 4 6
72 25 8 11
48 19 12 6 7
91 36 23 11 13
47 34 30
89 64 57
24
45
40 11 2
75 21 4
53 0
100 0
4 15 34
8 28 64
3 50
6 94
38 15
72 28
4 14 17 13 5
8 26 32 25 9
34 20 24 3 2
64 38 45 6 4
Abbreviations used: HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; AFP, alpha-fetoprotein; ECOG PS, eastern cooperative group performance status; AJCC, american joint committee on cancer staging; BCLC, barcelona clinic liver cancer; TACE, transcatheter arterial chemoembolization; CLIP, cancer of the liver italian program. * According to American Joint Committee on Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag, New York. According to the Cancer of the Liver Italian Program (CLIP) Investigators [27,28].
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) 128
stage C disease. The characteristics of the patient cohort are very similar to those of the patients enrolled in Asia–Pacific study of sorafenib [1].
The patients received a median of 3.7 months of treatment (range, 0.3–20.8 + months). After a median follow-up of 16.1 months, the median PFS was 3.7 months (95% C.I., 1.9–5.5) and the median OS was 7.4 months (95% C.I., 3.4–11.4) (Fig. 1). At 6 months, 17 patients were alive and remained progressionfree, accounting for a 6-month PFS of 32.1% (95% C.I., 19.5– 44.6). The 6-month OS and 1-year OS were 56.6% and 37.4%, respectively. The best tumor response for the 53 patients was as follows: 4 patients had confirmed PR; 26 patients had SD; 22 patients had PD; and one patient did not receive tumor response evaluation. The ORR was 8% and the DSR was 57% (Table 2). The 4 PR patients were treated with the combined medications for 4.7, 12.1, 15.1+, and 20.8 + months. In addition, 13 of the 26 SD patients had been treated for a period of >6 months, and 5 had been treated for >1 year. The correlation between the patients’ baseline characteristics and the PFS/OS was explored (Supplemental tables). Univariate analysis, male gender, age younger than 60 years, macroscopic vascular invasion, a high Okuda stage, a high CLIP (the Cancer
A
100 90
PFS Probability (%)
Age, years Median Range Sex Female Male Hepatitis virus HBsAg positive Anti-HCV positive Both positive Both negative Sites of disease Liver Lung Abdominal lymph nodes Bone Others Extrahepatic metastasis or macroscopic vascular invasion Any Extrahepatic metastasis Macroscopic vascular invasion Serum AFP level >400 ng/ml ECOG PS 0 1 2 Child-Puch class A B AJCC stage* II III IV BCLC stage B C Okuda stage I II CLIP score 0 1 2 3 4 Prior treatment Any Operation TACE Local ablation Radiotherapy
%
80 70 60
Median PFS 3.7 months (95 % CI, 1.9 - 5.5)
50 40 30 20 10 0 0
B
5
10 15 Time (Months)
20
25
100 90 OS Probability (%)
No.
80 70 60
Median OS 7.4 months (95 % CI, 3.2 - 11.6)
50 40 30 20 10 0 0
5
10 15 Time (Months)
20
25
Fig. 1. Kaplan–Meier estimates of progression-free survival (A) and overall survival (B) in patients treated with sorafenib and tegafur/uracil (n = 53).
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JOURNAL OF HEPATOLOGY Table 2. Tumor response and patients’ survival (n = 53). Estimates Best tumor response (Patient No. (%)) Complete response Partial response Stable disease Progressive disease Not evaluable Disease control rate (CR + PR + SD) Survival endpoints Time to progression (TTP) Median (range) 95% C.I. Progression-free survival (PFS) Median (range) 95% C.I. 4-month PFS rate 6-month PFS rate 12-month PFS rate Overall survival (OS) Median (range) 95% C.I. 4-month OS rate 6-month OS rate 12-month OS rate
Table 3. Treatment-related adverse events and laboratory abnormalities (n = 53). Grade
0 4 (8%) 26 (49%) 22 (42%) 1 (2%) 30 (57%)
3.9 (0.3–18.9) months 1.5–6.3 3.7 (0.3–18.9) months 1.9–5.5 43.4% 32.1% 18.4% 7.4 (0.5–21.7) months 3.2–11.6 67.9% 56.6% 37.4%
Abbreviations used: CR, complete response; PR, partial response; SD, stable disease; DCR, disease control rate; TTP, time to progression; C.I., confidence interval; PFS, progression-free survival; OS, overall survival.
of the Liver Italian Program) score [26], and no prior treatment predicted a poor PFS. Age younger than 60 years, macroscopic vascular invasion, high alpha-fetal protein (AFP) level, a high Okuda stage, a high CLIP score, and no prior treatment predicted a poor OS. Multivariate analysis, younger age, male gender, and ECOG performance status (=1 versus 0) were independent prognostic factors for poor PFS; a high CLIP score (CLIP 3 or 4 versus 0–2) was the only independent prognostic factor for poor OS. Toxicity All 53 patients were evaluable for toxicities. The treatmentrelated AEs are listed in Table 3. HFSR, fatigue, diarrhea, and anorexia were the most common AEs, and were reported in 53%, 51%, 49%, and 49% of the patients, respectively. The grade 3 or 4 AEs were relatively infrequent, including fatigue [n = 8 (15%)], HFSR [n = 5 (9%)], bleeding [n = 4 (8%)], mucositis [n = 2 (4%)], diarrhea [n = 1 (2%)], and fever, infection, epigastralgia, and edema [n = 1 (2%) each]. The four grade 3 or 4 bleeding AEs included three displaying esophageal variceal bleeding and one displaying gastric ulcer bleeding. All the bleeding episodes were successfully managed by conservative treatment; two of the patients could resume the protocol treatment within one week. However, all four patients eventually died of disease progression 4–11 weeks after the onset of bleeding AEs. The treatment-related laboratory abnormalities are listed in Table 3, too. The most common abnormalities included abnormal liver function tests, thrombocytopenia, leukopenia, neutropenia, and elevated lipase levels; all of these abnormalities occurred in no more than 30% of patients. The grade 3 or 4 laboratory abnormalities included elevated hepatic transaminases [n = 7 (13%)], elevated lipase level [n = 5 (10%)], hyponatremia [n = 3 (6%)], neutropenia [n = 2 (4%)], anemia [n = 1 (2%)], hypocalcemia [n = 1 (2%)], and hypermagnesemia [n = 1 (2%)]. Three patients developed a grade 3 elevation of lipase, and were able to continue sorafenib treatment at 400 mg daily. Two patients developed a
All
3
4
Patient No. (%) Adverse events Hand–foot skin reaction Fatigue Diarrhea Anorexia Epigastralgia Hair loss Fever Bleeding Hypertension Mucositis Hoarseness Vomiting Nausea Edema Taste change Infection Proteinuria
28 (53) 27 (51) 26 (49) 26 (49) 21 (39) 15 (28) 14 (27) 11 (21) 11 (21) 10 (19) 9 (17) 8 (15) 7 (13) 4 (8) 3 (6) 2 (4) 1 (2)
5 8 1 0 1 0 1 4 0 2 0 0 0 1 0 1 0
Laboratory abnormalities Elevated transaminase level Hyperbilirubinemia Thrombocytopenia Leukopenia Neutropenia Elevated lipase level Hyponatremia Hypocalcemia Anemia Hypermagnesemia Elevated creatinine level
14 (26) 13 (25) 11 (20) 9 (17) 9 (17) 5 (10) 4 (8) 2 (4) 2 (4) 2 (4) 1 (2)
7 1 0 0 2 3 3 1 1 1 0
(9) (15) (2) (2) (2) (8) (4)
(2)
0 0 0 0 0 0 0 0 0 0 0 0 0 0
(2)
0 0
(13) (2)
0 0 0 0 0 2 (4) 0 0 0 0 0
(4) (6) (6) (2) (2) (2)
grade 4 elevation of lipase, and resumed sorafenib at 400 mg daily after a temporary discontinuation of sorafenib treatment. None of these patients had clinical symptoms or signs of acute pancreatitis. Twenty-eight patients (53%) required a delay in treatment as a result of HFSR [n = 11 (21%)], elevated hepatic transaminases [n = 5 (9%)], malaise [n = 4 (8%)], bleeding [n = 3 (6%)], elevated lipase [n = 2 (4%)], infection [n = 2 (4%)], epigastralgia [n = 2 (4%)], and hyponatremia [n = 1 (2%)], and diarrhea, mucositis, fever, itching, and edema [n = 1 (2%) each]. The most common reasons leading to a reduction of sorafenib dosing included HFSR [n = 10 (19%)], elevated lipase [n = 5 (10%)], elevated hepatic transaminases [n = 2 (4%)], diarrhea [n = 1 (2%)], malaise [n = 1 (2%)], and hyperbilirubinemia [n = 1 (2%)]. As of February 2009, three patients remained under the treatment protocol. Thirty-eight patients died, but none of the deaths were attributed to the study treatment.
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 [1,5–8]. On the other hand, the combination appears to have a higher incidence rate of grade 3 fatigue (15%) and grade 3 bleeding (8%).
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Research Article Nevertheless, both AEs could be managed by appropriate supportive care. The study also demonstrates that the combination of sorafenib with metronomic tegafur/uracil results in a RR of 8% and a median TTP of 3.9 months in a cohort of patients enrolled from Asian countries where HBV infection in endemic. These efficacy endpoints appear to suggest a modest improvement, when compared to previous reports in similar patient cohorts treated with sorafenib alone [1,8]. This preliminary observation supports further studies to investigate the potential benefit of adding metronomic chemotherapy to sorafenib in patients with advanced HCC, especially conducting prospective randomized studies using sorafenib as a reference treatment. Furthermore, since our patients were mostly HBV-related, whether HCC patients of other etiologies also benefit from combinations of metronomic chemotherapy and sorafenib requires additional studies. The study did not fulfill its original assumptive goal to improve the 6-month PFS rate from 40% (the historical control of sorafenib alone) to 60%. However, this failure is largely attributed to the inappropriate statistical assumption by adopting a historical-control data derived from patients whose clinical characteristics are different from our patients. Specifically, it is now well established that patients enrolled from the Asia–Pacific region where HBV is endemic have a shorter survival time than those from Europe and North America [1,5–8] This is better illustrated by two phase III studies of sorafenib, i.e., the SHARP study which enrolled patients exclusively from Europe and North America [5], and the Asia–Pacific study which enrolled patients from China, Korea, and Taiwan [1]. Both studies used the same eligibility criteria. Although the survival benefit conferred by sorafenib, shown in the hazard ratio, was almost identical in the two studies, the OS and TTP were much shorter in patients enrolled in the Asia–Pacific study. The median OS was 4.2 and 6.5 months for placebo- and sorafenib-treated patients in the Asia–Pacific study, respectively, compared to 7.9 and 10.7 months in the SHARP study, respectively. The chosen dose of tegafur/uracil in this report is the same as that used in the published study testing adjuvant tegafur/uracil in patients with completely resected pathologic stage I lung adenocarcinoma [24]. In that study, patients were treated with tegafur/ uracil, at the same dose as the current report, for two years. The continuous use of tegafur/uracil for two years as an adjuvant therapy was associated with excellent patient compliance and no grade 3 or 4 bone marrow toxicities. Importantly, these lung adenocarcinoma patients treated with adjuvant tegafur/uracil had a statistically improved overall survival [24]. An important issue is to define the optimal metronomic dosage of chemotherapeutic agents to achieve the best anti-angiogenic effects. It has been proposed that the clinical metronomic dose should be the highest dose that can be delivered in a metronomic schedule without causing a clinical bone marrow perturbation [27]. In preclinical models, the circulating endothelial cells (CECs) and circulating endothelial progenitors have been shown to help determine the optimal biological dose of various anti-angiogenic therapies, including metronomic chemotherapy [28,29]. In advanced breast cancer patients treated with bevacizumab and metronomic cyclophosphamide and capecitabine, it was found that the baseline CEC number was correlated with response and outcome. In the current report, four patients developed grade 3 or 4 GI bleeding, including three patients with variceal bleeding. A pretreatment screening endoscopy may help reduce the risk of
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bleeding AE by excluding patients who are at risk of variceal bleeding and by treating varices with appropriate procedures. The exploration of potential prognostic factors in the present patient cohort indicates that high tumor stage, especially a high CLIP score, is a poor independent prognostic factor for OS. This is in agreement with a previous report involving HCC patients in palliative care enrolled in two randomized trials of the FFCD (Fédération Francophone de Cancerologie Digestive) [30]. This also corroborates with our previous observation in another phase II study of advanced HCC patients treated with bevacizumab in combination with capecitabine [31]. Whether the CLIP score can be considered as an important factor to stratify advanced HCC patients receiving anti-angiogenic or other empirical therapies needs further confirmatory studies. In conclusion, the current phase II study demonstrates that metronomic chemotherapy with tegafur/uracil can be safely combined with sorafenib and shows a potential activity to improve the efficacy of sorafenib in advanced HCC patients. The data justify prospective randomized trials comparing the combination of metronomic tegafur/uracil plus sorafenib versus sorafenib alone for patients with advanced HCC.
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-TDB-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.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jhep.2010.01.035.
References [1] Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia–Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25–34. [2] Hsu C, Shen YC, Cheng CC, Hu FC, Cheng AL. Geographic difference in survival outcome for advanced hepatocellular carcinoma: implications on future clinical trial design. Contemp Clin Trials 2010;31:55–61.
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JOURNAL OF HEPATOLOGY [3] Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907–1917. [4] Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43– 9006 exhibits broad spectrum oral antitumor activity and targets the RAF/ MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099–7109. [5] Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–390. [6] Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24:4293–4300. [7] Furuse J, Ishii H, Nakachi K, Suzuki E, Shimizu S, Nakajima K. Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma. Cancer Sci 2008;99:159–165. [8] Yau T, Chan P, Ng KK, Chok SH, Cheung TT, Fan ST, et al. Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: presence of lung metastasis predicts poor response. Cancer 2009;115:428–436. [9] Pinter M, Sieghart W, Graziadei I, Vogel W, Maieron A, Königsberg R, et al. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist 2009;14:70–76. [10] Wörns MA, Weinmann A, Pfingst K, Schulte-Sasse C, Messow CM, SchulzeBergkamen H, et al. Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma in consideration of concomitant stage of liver cirrhosis. J Clin Gastroenterol 2009;43:489–495. [11] Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 2004;4:423–436. [12] Shaked Y, Emmenegger U, Man S, Cervi D, Bertolini F, Ben-David Y, et al. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 2005;106:3058– 3061. [13] Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105:R15–24. [14] Colleoni M, Orlando L, Sanna G, Rocca A, Maisonneuve P, Peruzzotti G, et al. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol 2006;17:232–238. [15] Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R, et al. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol 2008;26:4899– 4905. [16] Kohne CH, Peters GJ. UFT: mechanism of drug action. Oncology (Huntingt) 2000;14:13–18. [17] Schmoll HJ. Dihydropyrimidine dehydrogenase inhibition as a strategy for the oral administration of 5-fluorouracil: utility in the treatment of advanced colorectal cancer. Anticancer Drugs 2003;14:695–702.
[18] Tokyo Liver Cancer Chemotherapy Study Group. Phase II study of coadministration of uracil and tegafur (UFT) in hepatocellular carcinoma. Japan J Clin Oncol 1985;15:559–62. [19] Ishikawa T, Ichida T, Sugitani S, Tsuboi Y, Genda T, Sugahara S, et al. Improved survival with oral administration of enteric-coated tegafur/uracil for advanced stage IV-A hepatocellular carcinoma. J Gastroenterol Hepatol 2001;16:452–459. [20] Yonekura K, Basaki Y, Chikahisa L, Okabe S, Hashimoto A, Miyadera K, et al. UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin Cancer Res 1999;5:2185–2191. [21] Basaki Y, Chikahisa L, Aoyagi K, Miyadera K, Yonekura K, Hashimoto A, et al. Gamma-hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor. Angiogenesis 2001;4:163–173. [22] Munoz R, Man S, Shaked Y, Lee CR, Wong J, Francia G, et al. Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide metronomic chemotherapy. Cancer Res 2006;66:3386–3391. [23] Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–216. [24] Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Eng J Med 2004;350:1713–1721. [25] Makuch R, Simon R. Sample size requirements for evaluating a conservative therapy. Cancer Treat Rep 1978;62:1037–1040. [26] A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998;28:751–5. [27] Maraveyas A, Lam T, Hetherington JW, Greenman J. Can a rational design for metronomic chemotherapy dosing be devised? Br J Cancer 2005;92:1588–1590. [28] Bertolini F, Shaked Y, Mancuso P, Kerbel RS. The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 2006;6:835–845. [29] Bertolini F, Mancuso P, Shaked Y, Kerbel RS. Molecular and cellular biomarkers for angiogenesis in clinical oncology. Drug Discov Today 2007;12:806–812. [30] Collette S, Bonnetain F, Paoletti X, Doffoel M, Bouché O, Raoul JL, et al. Prognosis of advanced hepatocellular carcinoma: comparison of three staging systems in two French clinical trials. Ann Oncol 2008;19:1117–1126. [31] Hsu CH, Yang TS, Hsu C, Toh HC, Epstein RJ, Hsiao LT, et al. Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma. Br J Cancer 2010;102:981–6.
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Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma Chih-Hung Hsu1,4, Ying-Chun Shen1,2, Zhong-Zhe Lin1,4, Pei-Jer Chen2,3, Yu-Yun Shao1, Yea-Hui Ding1, Chiun Hsu1,4,*, Ann-Lii Cheng1,3,4,5,** 1
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; 2Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; 3Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 4Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan; 5Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
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%)
Keywords: Sorafenib; Tegafur/uracil; Metronomic chemotherapy; Hepatocellular carcinoma. Received 7 November 2009; received in revised form 12 December 2009; accepted 27 January 2010; available online 30 March 2010 * Correspondence to: Chiun Hsu, Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan 10002. Tel.: +886 2 231 23456x67789; fax: +886 2 23711174. ** Correspondence to: Ann-Lii Cheng, Departments of Internal Medicine and Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan 10002. Tel.: +886 2 23123456x67251; fax: +886 2 23711174. E-mail addresses: [email protected] (C. Hsu), [email protected] (A.-L. Cheng). Abbreviations: HCC, hepatocellular carcinoma; PFS, progression-free survival; C.I., confidence interval; RECIST, response evaluation criteria in solid tumors; HFSR, hand-foot skin reaction; VEGFR, vascular endothelial growth factor receptor; EU, European Union; US, United States; VEGF, vascular endothelial growth factor; 5FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; ULN, upper limit of normal; PT, prothrombin time; AE, adverse event; ORR, overall response rate; DSR, disease stabilization rate; CR, complete response; PR, partial response; PD, progressive disease; SD, stable disease; OS, overall survival; ITT, intent-to-treat; BCLC, Barcelona Clinic Liver Cancer; CLIP, the Cancer of the Liver Italian Program; AFP, alpha-fetal protein; CEC, circulating endothelial cell.
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. Ó 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Introduction Patients with metastatic or advanced hepatocellular carcinoma (HCC) that cannot be treated by loco-regional therapies face a dismal outcome [1–3]. 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 [1,5–10] 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
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JOURNAL OF HEPATOLOGY 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 ratelimiting 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.
Treatment Patients received sorafenib (400 mg orally, twice per day), and tegafur/uracil (UFURÒ, 125 mg/m2 based on tegafur orally, twice per day; TTY Biopharm Co., Ltd., Taipei, Taiwan) continuously. The treatment was continued until disease progression or development of unacceptable toxicity. The dose of tegafur/uracil was based on the published report of adjuvant tegafur/uracil in patients with completely resected pathological stage I adenocarcinoma of the lung [24]. Dose modification of sorafenib and tegafur/uracil was according to the toxicities, graded by NCI-CTC AE v3.0. When symptomatic grade 2 or grade 3 hypertension occurred, sorafenib was held and the patients were treated accordingly. When the AEs recovered to 5grade 1, sorafenib was resumed with the dose of 400 mg per day. If symptomatic grade 2 or grade 3 hypertension recurred, sorafenib was further reduced to 400 mg every 2 days. Sorafenib was discontinued permanently when grade 4 hypertension occurred, when more than 2 dose reductions for the toxicities of hypertension were required, or when treatment delay was more than 30 days due to insufficient recovery from toxicities. When grade 2 or 3 HFSR occurred, sorafenib was held until HFSR recovered to 5grade 1. Sorafenib was resumed with the original dose without dose reduction for the first occurrence of grade 2 HFSR, and was resumed with the dose of 400 mg per day for the second grade 2 HFSR and first grade 3 HFSR. Sorafenib was further reduced to 400 mg every two days if similar toxicities recurred. Sorafenib was discontinued permanently when more than two dose reductions for the toxicity of HFSR were required, or when treatment delay was more than 30 days due to insufficient recovery from toxicities. When grade 3 diarrhea or mucositis occurred, tegafur/uracil was withheld, and was resumed with the dose of 62.5 mg/m2 twice per day when the toxicities recovered to 5grade 1. Tegafur/uracil was discontinued permanently when similar grade 3 toxicities recurred despite a dose reduction, or when treatment delay was more than 30 days. For grade 3 or 4 hematologic toxicities, hepatic toxicities, and other adverse events (AEs) which were considered treatment-related, the dose modification was as follows: reduced dose level 1, sorafenib 400 mg twice per day and tegafur/uracil 62.5 mg/m2 based on tegafur twice per day; reduced dose level 2, sorafenib 400 mg per day and tegafur/uracil 62.5 mg/m2 based on tegafur twice per day; and reduced dose level 3, sorafenib 400 mg every 2 days. The combination was discontinued permanently when more than 3 dose reductions were required, or when treatment delay was more than 30 days.
Patients and methods Disease assessment 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 loco-regional therapies, including surgery, transcatheter arterial (chemo)embolization, or local ablation. The eligibility criteria included an age P18 years; histologically- or cytologically-documented HCC; Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; serum creatinine 61.5 upper limit of normal (ULN); adequate liver function reserves defined by Child-Pugh classification A, liver transaminases 65 ULN, albumin P2.8 g/dl, serum total bilirubin 63 mg/dl, prothrombin time (PT)-international normalized ratio 62.3 or PT 66 s prolongation; and adequate bone marrow reserves, defined by white blood cells P3000/ll, neutrophil count P1500/ll, platelets P100,000/ll, and hemoglobin P8.5 g/dl. Patients needed to have at least one measurable lesion, according to Response Evaluation Criteria in Solid Tumors (RECIST) [23], which was not previously treated with any loco-regional therapy. However, patients with prior local treatments were allowed if the local treatments were completed at least 6 weeks prior to enrollment. Any treatmentrelated acute toxicity should have returned to 5grade 1, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC AE) v3.0. Key exclusion criteria included prior or concomitant systemic anti-cancer treatment for HCC, metastatic brain or leptomeningeal tumors, a history of organ transplantation, and life expectancy <2 months. Patients with significant gastrointestinal bleeding within 30 days prior to enrollment were not eligible. All patients were required to provide written informed consent.
Tumor assessment was performed every 8 weeks using RECIST criteria [23]. Confirmation of responses was required at least 4 weeks after the initial response was recorded. Statistical analyses The primary endpoint of the study was progression-free survival (PFS). At the time when this study was designed, the available data about the clinical efficacy of sorafenib was a phase II trial of sorafenib involving 137 advanced HCC patients, reported by Abou-Alfa et al. [6]. In that trial, 40% of patients treated with sorafenib monotherapy remained progression-free at 6 months. It was estimated that adding metronomic chemotherapy of tegafur/uracil to sorafenib would improve the 6-month PFS rate from 40% to 60%. To detect an improvement of at least 20%, a sample size of 50 patients was required to provide a power of 80% with an one-sided 5% significance level according to sample size planning by Makuch and Simon [25]. The secondary endpoints included 6-month PFS rate, objective tumor response rate (ORR), disease stabilization rate (DSR; defined as the sum of complete response [CR], partial response [PR], and stable disease [SD] for at least 2 months), overall survival (OS), and the safety profile of the combination. All the statistics were performed for an ‘‘intent-to-treat (ITT) population”, which was defined as patients who received at least one dose of the study drugs. The PFS and OS were analyzed using Kaplan–Meier method.
Results Patient characteristics Between April 2007 and April 2008, a total of 53 patients with advanced HCC were enrolled at the National Taiwan University
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Research Article Table 1. Patient characteristics (n = 53).
57 31–83
Efficacy
6 47
11 89
38 13 4 6
72 25 8 11
48 19 12 6 7
91 36 23 11 13
47 34 30
89 64 57
24
45
40 11 2
75 21 4
53 0
100 0
4 15 34
8 28 64
3 50
6 94
38 15
72 28
4 14 17 13 5
8 26 32 25 9
34 20 24 3 2
64 38 45 6 4
Abbreviations used: HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; AFP, alpha-fetoprotein; ECOG PS, eastern cooperative group performance status; AJCC, american joint committee on cancer staging; BCLC, barcelona clinic liver cancer; TACE, transcatheter arterial chemoembolization; CLIP, cancer of the liver italian program. * According to American Joint Committee on Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag, New York. According to the Cancer of the Liver Italian Program (CLIP) Investigators [27,28].
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) 128
stage C disease. The characteristics of the patient cohort are very similar to those of the patients enrolled in Asia–Pacific study of sorafenib [1].
The patients received a median of 3.7 months of treatment (range, 0.3–20.8 + months). After a median follow-up of 16.1 months, the median PFS was 3.7 months (95% C.I., 1.9–5.5) and the median OS was 7.4 months (95% C.I., 3.4–11.4) (Fig. 1). At 6 months, 17 patients were alive and remained progressionfree, accounting for a 6-month PFS of 32.1% (95% C.I., 19.5– 44.6). The 6-month OS and 1-year OS were 56.6% and 37.4%, respectively. The best tumor response for the 53 patients was as follows: 4 patients had confirmed PR; 26 patients had SD; 22 patients had PD; and one patient did not receive tumor response evaluation. The ORR was 8% and the DSR was 57% (Table 2). The 4 PR patients were treated with the combined medications for 4.7, 12.1, 15.1+, and 20.8 + months. In addition, 13 of the 26 SD patients had been treated for a period of >6 months, and 5 had been treated for >1 year. The correlation between the patients’ baseline characteristics and the PFS/OS was explored (Supplemental tables). Univariate analysis, male gender, age younger than 60 years, macroscopic vascular invasion, a high Okuda stage, a high CLIP (the Cancer
A
100 90
PFS Probability (%)
Age, years Median Range Sex Female Male Hepatitis virus HBsAg positive Anti-HCV positive Both positive Both negative Sites of disease Liver Lung Abdominal lymph nodes Bone Others Extrahepatic metastasis or macroscopic vascular invasion Any Extrahepatic metastasis Macroscopic vascular invasion Serum AFP level >400 ng/ml ECOG PS 0 1 2 Child-Puch class A B AJCC stage* II III IV BCLC stage B C Okuda stage I II CLIP score 0 1 2 3 4 Prior treatment Any Operation TACE Local ablation Radiotherapy
%
80 70 60
Median PFS 3.7 months (95 % CI, 1.9 - 5.5)
50 40 30 20 10 0 0
B
5
10 15 Time (Months)
20
25
100 90 OS Probability (%)
No.
80 70 60
Median OS 7.4 months (95 % CI, 3.2 - 11.6)
50 40 30 20 10 0 0
5
10 15 Time (Months)
20
25
Fig. 1. Kaplan–Meier estimates of progression-free survival (A) and overall survival (B) in patients treated with sorafenib and tegafur/uracil (n = 53).
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JOURNAL OF HEPATOLOGY Table 2. Tumor response and patients’ survival (n = 53). Estimates Best tumor response (Patient No. (%)) Complete response Partial response Stable disease Progressive disease Not evaluable Disease control rate (CR + PR + SD) Survival endpoints Time to progression (TTP) Median (range) 95% C.I. Progression-free survival (PFS) Median (range) 95% C.I. 4-month PFS rate 6-month PFS rate 12-month PFS rate Overall survival (OS) Median (range) 95% C.I. 4-month OS rate 6-month OS rate 12-month OS rate
Table 3. Treatment-related adverse events and laboratory abnormalities (n = 53). Grade
0 4 (8%) 26 (49%) 22 (42%) 1 (2%) 30 (57%)
3.9 (0.3–18.9) months 1.5–6.3 3.7 (0.3–18.9) months 1.9–5.5 43.4% 32.1% 18.4% 7.4 (0.5–21.7) months 3.2–11.6 67.9% 56.6% 37.4%
Abbreviations used: CR, complete response; PR, partial response; SD, stable disease; DCR, disease control rate; TTP, time to progression; C.I., confidence interval; PFS, progression-free survival; OS, overall survival.
of the Liver Italian Program) score [26], and no prior treatment predicted a poor PFS. Age younger than 60 years, macroscopic vascular invasion, high alpha-fetal protein (AFP) level, a high Okuda stage, a high CLIP score, and no prior treatment predicted a poor OS. Multivariate analysis, younger age, male gender, and ECOG performance status (=1 versus 0) were independent prognostic factors for poor PFS; a high CLIP score (CLIP 3 or 4 versus 0–2) was the only independent prognostic factor for poor OS. Toxicity All 53 patients were evaluable for toxicities. The treatmentrelated AEs are listed in Table 3. HFSR, fatigue, diarrhea, and anorexia were the most common AEs, and were reported in 53%, 51%, 49%, and 49% of the patients, respectively. The grade 3 or 4 AEs were relatively infrequent, including fatigue [n = 8 (15%)], HFSR [n = 5 (9%)], bleeding [n = 4 (8%)], mucositis [n = 2 (4%)], diarrhea [n = 1 (2%)], and fever, infection, epigastralgia, and edema [n = 1 (2%) each]. The four grade 3 or 4 bleeding AEs included three displaying esophageal variceal bleeding and one displaying gastric ulcer bleeding. All the bleeding episodes were successfully managed by conservative treatment; two of the patients could resume the protocol treatment within one week. However, all four patients eventually died of disease progression 4–11 weeks after the onset of bleeding AEs. The treatment-related laboratory abnormalities are listed in Table 3, too. The most common abnormalities included abnormal liver function tests, thrombocytopenia, leukopenia, neutropenia, and elevated lipase levels; all of these abnormalities occurred in no more than 30% of patients. The grade 3 or 4 laboratory abnormalities included elevated hepatic transaminases [n = 7 (13%)], elevated lipase level [n = 5 (10%)], hyponatremia [n = 3 (6%)], neutropenia [n = 2 (4%)], anemia [n = 1 (2%)], hypocalcemia [n = 1 (2%)], and hypermagnesemia [n = 1 (2%)]. Three patients developed a grade 3 elevation of lipase, and were able to continue sorafenib treatment at 400 mg daily. Two patients developed a
All
3
4
Patient No. (%) Adverse events Hand–foot skin reaction Fatigue Diarrhea Anorexia Epigastralgia Hair loss Fever Bleeding Hypertension Mucositis Hoarseness Vomiting Nausea Edema Taste change Infection Proteinuria
28 (53) 27 (51) 26 (49) 26 (49) 21 (39) 15 (28) 14 (27) 11 (21) 11 (21) 10 (19) 9 (17) 8 (15) 7 (13) 4 (8) 3 (6) 2 (4) 1 (2)
5 8 1 0 1 0 1 4 0 2 0 0 0 1 0 1 0
Laboratory abnormalities Elevated transaminase level Hyperbilirubinemia Thrombocytopenia Leukopenia Neutropenia Elevated lipase level Hyponatremia Hypocalcemia Anemia Hypermagnesemia Elevated creatinine level
14 (26) 13 (25) 11 (20) 9 (17) 9 (17) 5 (10) 4 (8) 2 (4) 2 (4) 2 (4) 1 (2)
7 1 0 0 2 3 3 1 1 1 0
(9) (15) (2) (2) (2) (8) (4)
(2)
0 0 0 0 0 0 0 0 0 0 0 0 0 0
(2)
0 0
(13) (2)
0 0 0 0 0 2 (4) 0 0 0 0 0
(4) (6) (6) (2) (2) (2)
grade 4 elevation of lipase, and resumed sorafenib at 400 mg daily after a temporary discontinuation of sorafenib treatment. None of these patients had clinical symptoms or signs of acute pancreatitis. Twenty-eight patients (53%) required a delay in treatment as a result of HFSR [n = 11 (21%)], elevated hepatic transaminases [n = 5 (9%)], malaise [n = 4 (8%)], bleeding [n = 3 (6%)], elevated lipase [n = 2 (4%)], infection [n = 2 (4%)], epigastralgia [n = 2 (4%)], and hyponatremia [n = 1 (2%)], and diarrhea, mucositis, fever, itching, and edema [n = 1 (2%) each]. The most common reasons leading to a reduction of sorafenib dosing included HFSR [n = 10 (19%)], elevated lipase [n = 5 (10%)], elevated hepatic transaminases [n = 2 (4%)], diarrhea [n = 1 (2%)], malaise [n = 1 (2%)], and hyperbilirubinemia [n = 1 (2%)]. As of February 2009, three patients remained under the treatment protocol. Thirty-eight patients died, but none of the deaths were attributed to the study treatment.
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 [1,5–8]. On the other hand, the combination appears to have a higher incidence rate of grade 3 fatigue (15%) and grade 3 bleeding (8%).
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Research Article Nevertheless, both AEs could be managed by appropriate supportive care. The study also demonstrates that the combination of sorafenib with metronomic tegafur/uracil results in a RR of 8% and a median TTP of 3.9 months in a cohort of patients enrolled from Asian countries where HBV infection in endemic. These efficacy endpoints appear to suggest a modest improvement, when compared to previous reports in similar patient cohorts treated with sorafenib alone [1,8]. This preliminary observation supports further studies to investigate the potential benefit of adding metronomic chemotherapy to sorafenib in patients with advanced HCC, especially conducting prospective randomized studies using sorafenib as a reference treatment. Furthermore, since our patients were mostly HBV-related, whether HCC patients of other etiologies also benefit from combinations of metronomic chemotherapy and sorafenib requires additional studies. The study did not fulfill its original assumptive goal to improve the 6-month PFS rate from 40% (the historical control of sorafenib alone) to 60%. However, this failure is largely attributed to the inappropriate statistical assumption by adopting a historical-control data derived from patients whose clinical characteristics are different from our patients. Specifically, it is now well established that patients enrolled from the Asia–Pacific region where HBV is endemic have a shorter survival time than those from Europe and North America [1,5–8] This is better illustrated by two phase III studies of sorafenib, i.e., the SHARP study which enrolled patients exclusively from Europe and North America [5], and the Asia–Pacific study which enrolled patients from China, Korea, and Taiwan [1]. Both studies used the same eligibility criteria. Although the survival benefit conferred by sorafenib, shown in the hazard ratio, was almost identical in the two studies, the OS and TTP were much shorter in patients enrolled in the Asia–Pacific study. The median OS was 4.2 and 6.5 months for placebo- and sorafenib-treated patients in the Asia–Pacific study, respectively, compared to 7.9 and 10.7 months in the SHARP study, respectively. The chosen dose of tegafur/uracil in this report is the same as that used in the published study testing adjuvant tegafur/uracil in patients with completely resected pathologic stage I lung adenocarcinoma [24]. In that study, patients were treated with tegafur/ uracil, at the same dose as the current report, for two years. The continuous use of tegafur/uracil for two years as an adjuvant therapy was associated with excellent patient compliance and no grade 3 or 4 bone marrow toxicities. Importantly, these lung adenocarcinoma patients treated with adjuvant tegafur/uracil had a statistically improved overall survival [24]. An important issue is to define the optimal metronomic dosage of chemotherapeutic agents to achieve the best anti-angiogenic effects. It has been proposed that the clinical metronomic dose should be the highest dose that can be delivered in a metronomic schedule without causing a clinical bone marrow perturbation [27]. In preclinical models, the circulating endothelial cells (CECs) and circulating endothelial progenitors have been shown to help determine the optimal biological dose of various anti-angiogenic therapies, including metronomic chemotherapy [28,29]. In advanced breast cancer patients treated with bevacizumab and metronomic cyclophosphamide and capecitabine, it was found that the baseline CEC number was correlated with response and outcome. In the current report, four patients developed grade 3 or 4 GI bleeding, including three patients with variceal bleeding. A pretreatment screening endoscopy may help reduce the risk of
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bleeding AE by excluding patients who are at risk of variceal bleeding and by treating varices with appropriate procedures. The exploration of potential prognostic factors in the present patient cohort indicates that high tumor stage, especially a high CLIP score, is a poor independent prognostic factor for OS. This is in agreement with a previous report involving HCC patients in palliative care enrolled in two randomized trials of the FFCD (Fédération Francophone de Cancerologie Digestive) [30]. This also corroborates with our previous observation in another phase II study of advanced HCC patients treated with bevacizumab in combination with capecitabine [31]. Whether the CLIP score can be considered as an important factor to stratify advanced HCC patients receiving anti-angiogenic or other empirical therapies needs further confirmatory studies. In conclusion, the current phase II study demonstrates that metronomic chemotherapy with tegafur/uracil can be safely combined with sorafenib and shows a potential activity to improve the efficacy of sorafenib in advanced HCC patients. The data justify prospective randomized trials comparing the combination of metronomic tegafur/uracil plus sorafenib versus sorafenib alone for patients with advanced HCC.
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-TDB-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.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jhep.2010.01.035.
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