Yu-Yun Shao

Phase Ii Study of Combining Sorafenib with Metronomic Tegafur/Uracil for Advanced Hepatocellular Carcinoma

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 (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.

Early Alpha-Fetoprotein Response Predicts Treatment Efficacy of Antiangiogenic Systemic Therapy in Patients With Advanced Hepatocellular Carcinoma

Antiangiogenic therapy has become the most important treatment modality for patients with advanced hepatocellular carcinoma (HCC). In this study, the authors investigated levels of alpha‐fetoprotein (AFP) as a potential biomarker for treatment efficacy of antiangiogenic therapy.

Clinical trials in hepatocellular carcinoma: an update.

The success of sorafenib has spurred an explosive increase of clinical trials testing novel molecular targets and other agents in the treatment of hepatocellular carcinoma (HCC). The paradigm of the studies has been characterized by three noticeable changes. First, the molecular targets of interest have expanded from angiogenesis to cancer cell-directed oncogenic signaling pathways for advanced HCC treatment. Agents targeting EGFR, FGFR, PI3K/Akt/mTOR, TGF-β, c-Met, MEK, IGF signaling, and histone deacetylase have been actively explored. Second, the target indication has shifted from advanced stage to early or intermediate stages of disease. The feasibility of combining locoregional therapies and targeted agents, and the use of novel agents after curative treatments are currently under active investigation. Finally, the therapeutic strategy has shifted from monotherapy to combination targeted therapy. We aim to provide a comprehensive overview of newly disclosed and ongoing clinical trials for the treatment of HCC.

Bevacizumab with Erlotinib as First-line Therapy in Asian Patients with Advanced Hepatocellular Carcinoma: A Multicenter Phase II Study

Objectives: The bevacizumab/erlotinib combination was reported with high clinical activity for advanced hepatocellular carcinoma (HCC) by a phase II study conducted in the USA. This multicenter study across several Asian countries was to evaluate the safety and efficacy of the combination in this population. Methods: Patients with histology-proven HCC, advanced disease and Child-Pugh class A liver function received bevacizumab 5 mg/kg intravenously every 2 weeks and erlotinib 150 mg/day orally as first-line therapy. The primary end point was progression-free survival at 16 weeks (PFS-16W). The expression of epidermal growth factor receptor (EGFR), phospho-AKT and vascular endothelial growth factor, the microvessel density and the EGFR gene copy number in HCC tissues were correlated with treatment efficacy. Results: Fifty-one patients were enrolled. The PFS-16W was 35.3% (95% CI 22.4-49.9), the median PFS was 2.9 months (95% CI, 1.3-4.4) and the median overall survival was 10.7 months (95% CI, 6.2-15.2). Grade 3/4 toxicities were uncommon, including rash, acne (10% each), diarrhea (6%) and gastrointestinal bleeding (4%). None of the evaluated biomarkers correlated with disease control or PFS. Conclusions: Bevacizumab plus erlotinib showed good tolerability and modest activity in this Asian cohort. Further studies are warranted to identify the predictive biomarkers of this combination.

Prognosis of patients with advanced hepatocellular carcinoma who failed first-line systemic therapy.

BACKGROUND & AIMS No approved therapy is available for patients with advanced hepatocellular carcinoma (HCC) who fail first-line therapy. The prognosis of these patients, especially those eligible for clinical trials of second-line therapy, is unclear. METHODS All patients who participated in clinical trials of first-line systemic therapy for metastatic or locally advanced HCC in a referral center of Taiwan between 2005 and 2011 were included. Their clinicopathologic characteristics, when the first-line treatment failed, were analyzed and correlated with the overall survival (OS) from the date of first-line treatment failure. RESULTS A total of 192 patients were included. Before the start of the first-line therapy, all patients had Child-Pugh class A liver reserves and Cancer of the Liver Italian Program (CLIP) scores ≤4. After the failure of the first-line therapy, the median OS of the entire group was 4.0 months. Patients with Child-Pugh class A liver reserves, when the first-line treatment failed, had significantly better OS than patients with Child-Pugh class B or C liver reserves (median, A vs. B vs. C=7.5 vs. 1.3 vs. 1.0 month, p<0.001). According to the key eligibility criteria of 3 published clinical trials for second-line therapy, 41%-56% of patients were potentially eligible. Compared to patients who were ineligible for clinical trials, potentially eligible patients had longer OS with a median of 7.8-8.6 months. CONCLUSIONS Patients with advanced HCC who failed first-line therapy could have substantially improved prognosis if they had Child-Pugh A liver reserves or were potentially eligible for clinical trials.

Predictive Biomarkers of Antiangiogenic Therapy for Advanced Hepatocellular Carcinoma: Where Are We?

Antiangiogenic therapy, especially treatment with sorafenib, is the primary treatment for patients with advanced hepatocellular carcinoma (HCC). However, the efficacy of such therapy is modest, with low objective response rates and limited prolongation of survival times. Several researchers have investigated predictive biomarkers to help identify patients who can benefit most from antiangiogenic therapy. The largest study on this topic to date was based on the pivotal phase III study of sorafenib (the SHARP study) and did not find any plasma markers that could predict the efficacy of sorafenib. Other studies based on single-arm phase II clinical trials found some potential predictive markers, such as early alpha-fetoprotein response, the serum insulin-like growth factor-1 level at baseline, and the volume transfer constants of dynamic contrast-enhanced magnetic resonance imaging. These findings require validation by further studies. Identifying predictive biomarkers of antiangiogenic therapy for HCC remains challenging and warrants further investigations.

The Impact of Diabetes Mellitus on Prognosis of Early Breast Cancer in Asia

BACKGROUND Diabetes mellitus (DM) has been implicated in influencing the survival duration of patients with breast cancer. However, less is known about the impact of DM and other comorbidities on the breast cancer-specific survival (BCS) and overall survival (OS) outcomes of Asian patients with early-stage breast cancer. PATIENTS AND METHODS The characteristics of female patients with newly diagnosed, early-stage breast cancer were collected from the Taiwan Cancer Registry database for 2003-2004. DM status and other comorbidities were retrieved from Taiwans National Health Insurance database. The BCS and OS times of patients according to DM status were estimated via the Kaplan-Meier method. Coxs proportional hazard model was used to estimate adjusted hazard ratios (HRs) for the effects of DM, comorbidities, and other risk factors on mortality. RESULTS In total, 4,390 patients were identified and 341 (7.7%) presented with DM. The 5-year BCS and OS rates were significantly greater in DM patients than in non-DM patients (BCS, 85% versus 91%; OS, 79% versus 90%). Furthermore, after adjusting for clinicopathologic variables and comorbidities, DM remained an independent predictor of shorter BCS (adjusted HR, 1.53) and OS (adjusted HR, 1.71) times. Subgroup analyses also demonstrated a consistent prognostic influence of DM across different groups. CONCLUSION In Asian patients with early-stage breast cancer, DM is an independent predictor of lower BCS and OS rates, even after adjusting for other comorbidities. The integration of DM care as part of the continuum of care for early-stage breast cancer should be emphasized.

High Serum Transforming Growth Factor-β1 Levels Predict Outcome in Hepatocellular Carcinoma Patients Treated with Sorafenib

Background: The TGF-β signaling pathway is crucial in the progression and metastasis of malignancies. We investigated whether the serum TGF-β1 level was related to the outcomes of patients treated with sorafenib for advanced hepatocellular carcinoma (HCC). Experimental Design: We selected patients who had received sorafenib-containing regimens as first-line therapy for advanced HCC between 2007 and 2012. Serum TGF-β1 levels were measured and correlated with the treatment outcomes. The expression TGF-β1 and the sensitivity to sorafenib were examined in HCC cell lines. Results:Ninety-one patients were included; 62 (68%) were hepatitis B virus surface antigen (+), and 11 (12%) were anti-hepatitis C virus (+). High (≥ median) pretreatment serum TGF-β1 levels (median 13.7 ng/mL; range, 3.0–41.8) were associated with high α-fetoprotein levels, but not with age, gender, or disease stage. Patients with high pretreatment serum TGF-β1 levels exhibited significantly shorter progression-free survival (median, 2.5 vs. 4.3 months; P = 0.022) and overall survival (median 5.6 vs. 11.6 months; P = 0.029) than did patients with low serum TGF-β1 levels. Compared with pretreatment levels, the serum TGF-β1 levels were significantly increased at disease progression (n = 29, P = 0.010). In preclinical models of HCC, higher TGF-β1 expression levels were associated with poorer sensitivity to sorafenib. Conclusions: High pretreatment serum TGF-β1 levels were associated with poor prognoses, and increased serum TGF-β1 levels were associated with the disease progression of advanced HCC patients. TGF-β pathway may be explored as a therapeutic target for advanced HCC. Clin Cancer Res; 21(16); 3678–84. ©2015 AACR.

Efficacy, Safety, and Potential Biomarkers of Thalidomide plus Metronomic Chemotherapy for Advanced Hepatocellular Carcinoma

Objectives: Thalidomide has been shown to have antitumor activity in some patients with advanced hepatocellular carcinoma (HCC). We initiated a phase II study to determine the safety and efficacy of adding metronomic chemotherapy to thalidomide as first-line therapy. Methods: This open- labeled, single-arm, multicentered, investigator-initiated study enrolled patients with treatment-naïve advanced HCC not amenable to locoregional therapies. Treatment included oral thalidomide (100 mg twice daily) and tegafur/uracil [125 mg/m2 (based on tegafur) twice daily]. Tumor assessment was performed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Pretreatment plasma levels of angiogenesis factors were correlated with patient outcomes. Results: Forty-three patients were included. Sixteen (37%) patients had a Cancer of the Liver Italian Program (CLIP) score of 4, and 31 (72%) patients had chronic hepatitis B virus infection. The objective response rate was 9%, and the disease stabilization rate was 33%. The median progression-free survival was 1.9 months (95% CI 1.7–2.1 months), and the median OS was 4.6 months (95% CI 2.3–6.9 months). Treatment was generally tolerable. High baseline plasma levels of interleukin (IL)-6 and IL-8 were adversely correlated with patient survivals. Conclusions: The combination of thalidomide and tegafur/uracil was safe and demonstrated modest activity in patients with advanced HCC.

Serum Insulin-Like Growth Factor-1 Levels Predict Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Antiangiogenic Therapy

Purpose: Patients with liver cirrhosis or hepatocellular carcinoma (HCC) have decreased serum insulin-like growth factor (IGF)-1 levels. We evaluated whether IGF-1 levels were associated with the outcomes of patients with advanced HCC treated with systemic antiangiogenic therapy. Experimental Design: The study was based on patients with advanced HCC who were enrolled in two clinical trials evaluating first-line combination antiangiogenic therapy. Serum samples were collected before treatment and four to six weeks after the start of treatment. The levels of IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP3) were analyzed for their associations with treatment outcomes. Results: A total of 83 patients were included in the study. Patients who had high (≥the median level) baseline IGF-1 levels had significantly higher disease control rate (DCR) than patients who had low (<the median level) levels (71% vs. 39%, P = 0.003). The levels of posttreatment IGF-1, and pre- or posttreatment IGF-2 and IGFBP3 were not associated with DCR. Patients with high baseline IGF-1 levels, compared with patients with low levels, had significantly longer progression-free survival (PFS; median, 4.3 vs. 1.9 months, P = 0.014) and overall survival (OS; median, 10.7 vs. 3.9 months, P = 0.009). The high baseline IGF-1 level remains an independent factor associated with favorable PFS and OS in multivariate analysis. Conclusions: High pretreatment IGF-1 levels were associated with better DCR, PFS, and OS of patients who received antiangiogenic therapy for advanced HCC. This finding warrants validation in large studies. Clin Cancer Res; 18(14); 3992–7. ©2012 AACR.