Jacqueline Whang-Peng

Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) is a common lethal disease in Asia and there is no effective chemotherapy. Identification of new effective drugs in the treatment of inoperable HCC is urgently need. This is a phase II clinical study to investigate the efficacy, toxicity and pharmacokinetics of paclitaxel in HCC patients. Twenty patients with measurable, unresectable HCC, normal serum bilirubin, normal bone marrow and renal functions were studied. Paclitaxel 175 mg m(-2) was given intravenously over 3 h every 3 weeks. No complete or partial responses were observed. Five patients had stable disease. Major treatment toxicities (grade 3-4) were neutropenia (25%), thrombocytopenia (15%), infection (10%) and allergy (10%). Treatment-related deaths occurred in two patients. The median survival was 12 weeks (range 1-36). Paclitaxel is metabolized by the liver and the pharmacokinetics of paclitaxel in cancer patients with liver involvement or impairment may be important clinically. Pharmacokinetic study was completed in 13 HCC patients. The paclitaxel area under the curve was significantly increased (P < 0.02), clearance decreased (P < 0.02) and treatment-related deaths increased (P = 0.03) in patients with hepatic impairment. In conclusion, paclitaxel in this dose and schedule has no significant anti-cancer effect in HCC patients. Paclitaxel should be used with caution in cancer patients with liver impairment.

Generation of Carcinoembryonic Antigen (CEA)-Specific T-Cell Responses in HLA-A*0201 and HLA-A*2402 Late-Stage Colorectal Cancer Patients after Vaccination with Dendritic Cells Loaded with CEA Peptides

Purpose: We intranodally immunized metastatic colorectal carcinoma patients, who had failed standard chemotherapy, with dendritic cells (DCs) pulsed with HLA-A*0201- or HLA-A*2402-restricted carcinoembryonic antigen (CEA) peptides to evaluate the safety of this treatment and the immune response against CEA peptides before and after the treatment. Experimental Design: Six patients with the HLA-A*2402 genotype and 4 patients with the HLA-A*0201 genotype were enrolled. A single CEA peptide (YLSGANLNL) or two CEA peptides (QYSWFVNGTF and TYACFVSNL) were used for patients with the HLA-A*0201 or HLA-A*2402 genotype, respectively. Autologous DCs were generated by culturing adherent mononuclear cells with interleukin 4 and granulocyte macrophage colony-stimulating factor for 6 days. Maturation of DCs was then induced with tumor necrosis factor α for 40 h. Mature DCs were pulsed with appropriate CEA peptides for 2 h. After washing, 1 million peptide-pulsed DCs were injected into one inguinal lymph node under sonographic guidance. Each patient received four injections. Results: No grade II/III toxicity or autoimmunity was observed. An increase in the number of CEA-specific T cells after DC vaccination could be detected in 7 of 10 (70%) patients. Two (20%) patients had stable disease for at least 12 weeks. One of these 2 patients experienced a transient decrease in CEA levels during the treatment period and also had the most significant T-cell response against the immunizing CEA peptides. Conclusions: These results suggest that our vaccination procedure can generate or boost specific T-cell responses and may provide clinical benefit in certain cancer patients.

Long-term results of a randomized, observation-controlled, phase III Trial of Adjuvant Interferon alfa-2b in hepatocellular carcinoma after curative resection

Objective:To investigate the clinical efficacy of adjuvant interferon alfa-2b (IFN&agr;-2b) therapy on recurrence-free survival (RFS) of patients with postoperative viral hepatitis-related hepatocellular carcinoma (HCC). Background:Despite most individual trials have failed to meet their primary endpoint, recent pooled-data meta-analyses suggest that adjuvant IFN therapy may significantly reduce the incidence of recurrence in curatively ablated HCC. Methods:Patients with curative resection of viral hepatitis-related HCC were eligible, and were stratified by underlying viral etiology and randomly allocated to receive either 53 weeks of adjuvant IFN&agr;-2b treatment or observation alone. The primary endpoint of this study was RFS. Results:A total of 268 patients were enrolled with 133 in the IFN&agr;-2b arm and 135 in the control arm. Eighty percent of them were hepatitis B surface antigen seropositive. At a median follow-up of 63.8 months, 154 (57.5%) patients had tumor recurrence and 84 (31.3%) were deceased. The cumulative 5-year recurrence-free and overall survival rates of intent-to-treat cohort were 44.2% and 73.9%, respectively. The median RFS in the IFN&agr;-2b and control arms were 42.2 (95% confidence interval [CI], 28.1–87.1) and 48.6 (95% CI, 25.5 to infinity) months, respectively (P = 0.828, log-rank test). Adjuvant IFN&agr;-2b treatment was associated with a significantly higher incidence of leucopenia and thrombocytopenia. Thirty-four (24.8%) of treated patients required dose reduction, and 5 (3.8%) of these patients subsequently withdrew from therapy because of excessive toxicity. Adjuvant IFN&agr;-2b only temporarily suppressed viral replication during treatment period. Conclusions:In this study, adjuvant IFN&agr;-2b did not reduce the postoperative recurrence of viral hepatitis-related HCC. More potent antiviral therapy deserves to be explored for this patient population. This study is registered at ClinicalTrials.gov and carries the identifier NCT00149565.

Phase II study of flutamide in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a male predominant disease and may be an androgen‐dependent or androgen‐responsive tumor. This Phase II study was designed to investigate the clinical activity and toxicity of flutamide in the treatment of patients with advanced HCC.

Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma

Deregulation of mammalian target of rapamycin (mTOR) signalling is common in human hepatocellular carcinoma (HCC).

Diagnostic and therapeutic evaluation of 111In-vinorelbine-liposomes in a human colorectal carcinoma HT-29/luc-bearing animal model

Colorectal carcinoma is a highly prevalent and common cause of cancer in Taiwan. There is still no available cure for this malignant disease. To address this issue, we applied the multimodality of molecular imaging to explore the efficacy of diagnostic and therapeutic nanoradiopharmaceuticals in an animal model of human colorectal adenocarcinoma [colorectal cancer (CRC)] that stably expresses luciferase (luc) as a reporter. In this study, an in vivo therapeutic efficacy evaluation of dual-nanoliposome (100 nm in diameter) encaged vinorelbine (VNB) and (111)In-oxine on HT-29/luc mouse xenografts was carried out. HT-29/luc tumor cells were transplanted subcutaneously into male SCID mice. Multimodality of molecular imaging approaches including bioluminescence imaging (BLI), gamma scintigraphy, whole-body autoradiography (WBAR) and in vivo tumor growth tracing, histopathology and biochemistry/hematology analyses were applied on xenografted SCID mice to study the treatments with 6% polyethylene glycol (PEG) of (111)In-NanoX/VNB-liposomes. In vivo tumor growth tracing and BLI showed that tumor volume could be completely inhibited by the combination therapy with (111)In-VNB-liposomes and by chemotherapy with NanoX/VNB-liposomes (i.e., without Indium-111) (P<.01). The nuclear medicine images of gamma scintigraphy and WBAR also revealed the conspicuous inhibition of tumor growth by the combination therapy with (111)In-VNB-liposomes. Animal body weights, histopathology and biochemistry/hematology analyses were used to confirm the safety and feasibility of radiopharmaceuticals. A synergistic therapeutic effect on CRC xenografted SCID mice was proven by combining an Auger electron-emitting radioisotope (Indium-111) with an anticancer drug (VNB). This study further demonstrates the beneficial potential applications of multimodality molecular imaging as part of the diagnostic and therapeutic approaches available for the evaluation of new drugs and other strategic approaches to disease treatment.

Phase II randomized trial of erlotinib or vinorelbine in chemonaive, advanced, non-small cell lung cancer patients aged 70 years or older

Introduction: The primary objective of this study was to compare the response rates of elderly, chemonaive patients with advanced non-small cell lung cancer (NSCLC) treated with daily oral erlotinib versus oral vinorelbine. Methods: Chemonaive Taiwanese patients aged 70 years or older who had advanced NSCLC were randomized to receive either oral erlotinib 150 mg (E) daily or oral vinorelbine 60 mg/m2 (V) on days 1 and 8 every 3 weeks. Results: From February 2007 to July 2008, 116 patients were enrolled and 113 were included in the intent-to-treat population: 57 patients in the E group and 56 patients in the V group. Objective response rates were 22.8% (13 of 57) in E and 8.9% (5 of 56) in V (p = 0.0388). Median progression-free survival (PFS) was 4.57 months in E and 2.53 months in V (p = 0.0287), with an 80.6% increase in median PFS for E compared with V. Median survival time was 11.67 months in E and 9.3 months in V (p = 0.6975). Toxicities were generally mild in both groups. Median PFS was longest for epidermal growth factor receptor gene (EGFR)-mutated patients in the E group, followed by EGFR-mutated patients in V, EGFR wild type in E, and EGFR wild type in V (p = 0.0034). Overall survival was longer for EGFR-mutated patients than for EGFR wild-type patients (p < 0.0001). Conclusions: Erlotinib is highly effective compared with oral vinorelbine in elderly, chemonaive, Taiwanese patients with NSCLC. EGFR-mutated patients had better survival than those with EGFR wild-type disease, regardless of the treatment received.

A phase II randomized trial of gefitinib alone or with Tegafur/uracil treatment in patients with pulmonary adenocarcinoma who had failed previous chemotherapy

Background: Tegafur/uracil (UFT) is suitable for metronomic chemotherapy because of its underlying antiangiogenesis mechanism. This study aimed to assess the efficacy of adding daily oral UFT to gefitinib treatment in patients with pulmonary adenocarcinoma who had failed previous chemotherapy. Methods: Taiwanese patients who had adenocarcinoma of the lung and failed previous chemotherapy were randomized into gefitinib 250 mg daily alone (G) or plus daily oral UFT (GU). From November 2005 to August 2009, 115 patients were enrolled. Results: There were 58 patients in the G arm and 57 in the GU arm. One-year progression-free survival (PFS) was 18% in the G arm and 36.7% in the GU arm (p = 0.03). Fifty-four patients had tissue samples available for tumor epidermal growth factor receptor (EGFR) sequence analysis: 16 classical mutations and 8 wild types in the G arm, and 20 classical mutations and 10 wild-types in the GU arm. The addition of UFT significantly improved PFS in patients with EGFR mutations (14.4 versus 7.6 months, p = 0.0061). Forty-three patients underwent tumor tissue microvessel density measurement, and a trend favoring the addition of UFT to gefitinib treatment was found in those with low microvessel density (median PFS: 11.8 versus 2.8 months, p = 0.0536). The median survival time was 18.3 months in the G arm and 23.6 months in the GU arm (p = 0.381). Conclusion: Gefitinib plus UFT treatment had better PFS than gefitinib alone treatment. Gefitinib is effective in patients with EGFR mutations, and the addition of UFT treatment produced better PFS in these patients with mutations.

Honokiol Eliminates Human Oral Cancer Stem-Like Cells Accompanied with Suppression of Wnt/β-Catenin Signaling and Apoptosis Induction

Honokiol, an active compound of Magnolia officinalis, exerted many anticancer effects on various types of cancer cells. We explored its effects on the elimination of cancer stem-like side population (SP) cells in human oral squamous cell carcinoma SAS cells. The sorted SP cells possessed much higher expression of stemness genes, such as ABCG2, ABCC5, EpCAM, OCT-4, CD133, CD44, and β-catenin, and more clonogenicity as compared with the Non-SP cells. After 48 h of treatment, honokiol dose dependently reduced the proportion of SP from 2.53% to 0.09%. Apoptosis of honokiol-treated SP cells was evidenced by increased annexin V staining and cleaved caspase-3 as well as decreased Survivin and Bcl-2. Mechanistically, honokiol inhibited the CD44 and Wnt/β-catenin signaling of SP cells. The Wnt signaling transducers such as β-catenin and TCF-4 were decreased in honokiol-treated SP cells, while the β-catenin degradation promoting kinase GSK-3α/β was increased. Consistently, the protein levels of β-catenin downstream targets such as c-Myc and Cyclin D1 were also downregulated. Furthermore, the β-catenin-related EMT markers such as Slug and Snail were markedly suppressed by honokiol. Our findings indicate honokiol may be able to eliminate oral cancer stem cells through apoptosis induction, suppression of Wnt/β-catenin signaling, and inhibition of EMT.

Clinical Development and Future Direction for the Treatment of Hepatocellular Carcinoma

Abstract Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and about 600,000 patients suffer from HCC annually. The highest incidence is in Southeastern and Eastern Asia, with an incident rate of 18.3-35.5 per 100,000 population, and the lowest is in Central America with a rate of 2.1 per 100,000 population. HCC is one of the leading malignancies in Taiwan. Hepatitis B or C virus infections are the major factors for liver cancer in Taiwan. The survival time for patients with HCC without therapy after diagnosis averages 1-4 months. In this article, we review the risk factors, diagnostic criteria, staging systems, management and treatment of HCC. Treatments include liver transplantation, surgery, transcatheter arterial chemoembolization and transcatheter arterial embolization, percutaneous injection or radiofrequency ablation, chemotherapies, hormone therapy, internal radiation therapy, targeted therapy, a combination of chemotherapeutic agents and tyrosine kinase inhibitors, antiangiogenesis therapy, metabolic targets and Chinese herbal medicine. We propose three flow charts to guide surveillance, diagnosis, and treatment. Patients with high risk of HCC should be followed-up using the HCC High Risk Group Surveillance Flow Chart 1 . If a mass is suspected, patients can be diagnosed using the HCC Diagnosis Flow Chart 2 . On confirmation of HCC diagnosis, treatment should follow the HCC Treatment Flow Chart 3 . Because the liver is the bodys detoxification organ, its cells are already numerous with a high expression of the MDR gene. This makes chemotherapeutic drug treatment difficult. New molecular targeted therapy or new effective drugs are needed for difficult-to-treat HCC.