Publications by authors named "Zhong-Zhe Lin"

57 Publications

The Short- and Long-term Causal Relationships Between Self-compassion, Trait Mindfulness, Caregiver Stress, and Depressive Symptoms in Family Caregivers of Patients with Lung Cancer.

Mindfulness (N Y) 2021 May 5:1-10. Epub 2021 May 5.

School of Nursing, College of Medicine, National Taiwan University, Taipei, Taiwan.

Objectives: Using a prospective longitudinal design, this paper examines a serial mediation model of the associations between self-compassion, trait mindfulness, caregiver stress, and depressive symptoms among the family caregivers of patients with lung cancer.

Methods: A four-wave design was used, with initial assessment (T1) and three follow-ups, at the 2 month (T2), the 5 month (T3), and the 8 month (T4). A total of 123 family caregivers completed the baseline measurements, including caregiver stress, self-compassion, trait mindfulness, and depressive symptoms. Data were analyzed by serial mediation models to determine the causal ordering of these variables.

Results: Nearly one-quarter of the family caregivers suffered from clinically significant depressive symptoms and the severity of their depression remained unchanged throughout the 8-month follow-up period. Both cross-sectional and longitudinal path analyses revealed that the relationship between self-compassion and depressive symptoms was mediated sequentially by trait mindfulness and caregiver stress. The subscale analysis indicated that the association of higher compassionate action with fewer depressive symptoms was through chain-mediating effects of higher mindful awareness and lower caregiver stress.

Conclusions: Family caregivers who have higher levels of self-compassion tend to have more mindfulness; greater mindfulness leads to lower levels of perceived caregiving stress which, in turn, links to fewer symptoms of depression. Both self-compassion and mindfulness could be regarded as protective factors for caregivers to reduce caregiving stress and depression.
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http://dx.doi.org/10.1007/s12671-021-01642-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096886PMC
May 2021

Trait mindfulness and depressive symptoms in non-small cell lung cancer patients: the mediating roles of quality of life and meaning in life.

Psychol Health 2020 Sep 30:1-13. Epub 2020 Sep 30.

School of Nursing, College of Medicine, National Taiwan University, Taipei, Taiwan.

Objective: The present study examined the potential mediating influences of meaning in life and quality of life in the relationship of trait mindfulness and depressive symptoms in lung cancer patients. We adopted a cross-sectional design studying a sample of patients with non-small cell lung cancer, aged 20-65 years, and receiving cancer treatments or follow-up care. The outcome measures included Beck Depression Inventory-II, European Organisation for Research and Treatment of Cancer Core Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and lung cancer specific complementary measure (EORTC QLQ-LC13), Five Facet Mindfulness Questionnaire, and the meaning in life questionnaire. Among 116 lung cancer patients, 26.72% of them had clinically significant depressive symptoms. The presence of meaning, quality of life (QOL) functioning and symptom distress mediated the relationship of trait mindfulness and depressive symptoms. Multiple mediation analyses found that the presence of meaning in life was the main mediator. The reductions of depressive symptoms might be related to trait mindfulness enhancing lung cancer patients' perceptions of meaning in life. A mindfulness program has the potential to improve depressive symptoms in people with lung cancer.
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http://dx.doi.org/10.1080/08870446.2020.1825713DOI Listing
September 2020

Clinical outcomes and toxicity predictors of thoracic re-irradiation for locoregionally recurrent lung cancer.

Clin Transl Radiat Oncol 2020 May 23;22:76-82. Epub 2020 Mar 23.

Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Background And Purpose: Thoracic re-irradiation may be an alternative treatment for lung cancer patients who develop intrathoracic locoregional recurrence without systemic progression. This study aimed to retrospectively assess locoregional control, clinical outcomes, and toxicities in lung cancer patients who received thoracic re-irradiation.

Materials And Methods: We retrospectively reviewed 50 lung cancer patients who received thoracic re-irradiation using conventional photon radiotherapy (RT) and stereotactic body radiotherapy (SBRT) between 2009 and 2017. The correlations of clinicopathologic factors, treatment factors, and dosimetric factors of RT with time to local progression (TTLP), progression-free survival (PFS), and overall survival (OS) after starting thoracic re-irradiation were calculated using log-rank tests and Cox regression models.

Results: The median re-irradiation dose in equivalent dose in 2-Gy fractions was 51.1 Gy, and the mean re-irradiation planning target volume was 201.58 ml. The median mean lung dose (MLD) was 4.18 Gy, and the total lung volumes receiving a dose of 5 Gy (lung V5) and of 20 Gy (V20) were 19.8% and 5.85%, respectively. The TTLP, PFS, and OS were 18.0, 5.9, and 25.1 months, respectively. Lung V5 ( < 0.001), V20 ( = 0.011), and MLD ( = 0.002) were significantly associated with grade ≥2 lung toxicity. Seven (14%) patients developed lethal lung events. Subsequent chemotherapy following thoracic re-irradiation was significantly correlated with lethal lung events ( = 0.009).

Conclusion: Promising local control can be achieved with thoracic re-irradiation in lung cancer patients with locoregional recurrence. However, unexpected lethal lung events may occur, especially in patients receiving systemic therapy following thoracic re-irradiation.
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http://dx.doi.org/10.1016/j.ctro.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139144PMC
May 2020

A Multicenter Phase II Study of Second-Line Axitinib for Patients with Advanced Hepatocellular Carcinoma Failing First-Line Sorafenib Monotherapy.

Oncologist 2020 09 9;25(9):e1280-e1285. Epub 2020 Apr 9.

Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.

Lessons Learned: For patients with advanced hepatocellular carcinoma after failure of first-line sorafenib monotherapy, second-line axitinib provides modest efficacy with tolerable toxicity. The discrepant tumor responses and survival outcomes in trials using axitinib as salvage therapy highlight the importance of optimal patient selection with the aid of clinical biomarkers.

Background: Multikinase inhibitors have been effective treatment for hepatocellular carcinoma (HCC). This multicenter phase II study explored the efficacy and safety of second-line axitinib for advanced HCC.

Methods: Patients with advanced HCC and Child-Pugh A liver function, experiencing progression on first-line sorafenib monotherapy, were eligible. Axitinib 5 mg twice daily was given continuously with allowed dose escalation. Tumor assessment was performed according to RECIST version 1.1. The primary endpoint was rate of disease control.

Results: From April 2011 to March 2016, 45 patients were enrolled. Thirty-seven patients (82%) tested positive for hepatitis B surface antigen. The disease control rate was 62.2%, and the response rate was 6.7%, according to RECIST criteria. Median progression-free survival (PFS) and overall survival (OS) were 2.2 months and 10.1 months, respectively. Treatment-related adverse events were compatible with previous reports of axitinib.

Conclusion: Second-line axitinib has moderate activity and acceptable toxicity for patients with advanced HCC after failing the first-line sorafenib monotherapy.
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http://dx.doi.org/10.1634/theoncologist.2020-0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485356PMC
September 2020

A phase II study of the efficacy and safety of the MET inhibitor capmatinib (INC280) in patients with advanced hepatocellular carcinoma.

Ther Adv Med Oncol 2019 11;11:1758835919889001. Epub 2019 Dec 11.

Division of Gastroenterology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Background: The objectives of this phase II study were to determine the clinical activity of the MET tyrosine kinase inhibitor capmatinib (INC280) in patients with MET-dysregulated advanced hepatocellular carcinoma (HCC) and to assess the safety, pharmacokinetics, and correlation of biomarkers with the response.

Methods: This phase II, open-label, single-arm study evaluated twice daily (BID) oral capmatinib in a dose-determining stage, utilizing a Bayesian Logistic Regression Model (BLRM) subject to Escalation with Overdose Control criteria, safety, pharmacokinetics, and pharmacodynamic information to determine a recommended dose for expansion (RDE) evaluating efficacy in patients with MET-dysregulated HCC.

Results: A total of 38 patients received treatment. In the dose-determining stage, patients received capmatinib 300 mg BID capsules ( = 8), and in the expansion, patients received 600 mg BID capsules ( = 28) or 400 mg BID tablets ( = 2) based on the BLRM and other relevant clinical data. No predefined qualifying adverse events (AEs) were observed during the first 28 days of treatment, and the RDE was 600 mg BID capsules (equivalent pharmacokinetics to 400 mg BID tablets). The most common any causality AEs were nausea (42%), vomiting (37%), and diarrhea (34%). In the expansion stage, in a subgroup of 10 patients with MET-high HCC, the overall response rate was 30%, including 1 durable complete response (>600 days) and 2 partial responses [1 durable (>600 days)].

Conclusions: Single agent capmatinib at the RDE is tolerable with a manageable safety profile. Antitumor activity was seen in a subset of patients with MET-dysregulated (MET-high) HCC.

Trial Registration: ClinicalTrials.gov: NCT01737827. https://clinicaltrials.gov/ct2/show/NCT01737827.
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http://dx.doi.org/10.1177/1758835919889001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906348PMC
December 2019

First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma.

Cancer Discov 2019 12 1;9(12):1696-1707. Epub 2019 Oct 1.

Blueprint Medicines Corporation, Cambridge, Massachusetts.

Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients [median duration of response: 5.3 months (95% CI, 3.7-not reached)] and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC. SIGNIFICANCE: Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection...
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http://dx.doi.org/10.1158/2159-8290.CD-19-0555DOI Listing
December 2019

Development and validation of nomograms for predicting survival probability of patients with advanced adenocarcinoma in different EGFR mutation status.

PLoS One 2019 16;14(8):e0220730. Epub 2019 Aug 16.

Institute of Health Policy and Management, College of Public Health, National Taiwan University, Taipei, Taiwan.

Introduction: Molecular markers are important variables in the selection of treatment for cancer patients and highly associated with their survival. Therefore, a nomogram that can predict survival probability by incorporating epidermal growth factor receptor mutation status and treatments for patients with advanced adenocarcinoma would be highly valuable. The aim of the study is to develop and validate a novel nomogram, incorporating epidermal growth factor receptor mutation status and treatments, for predicting 1-year and 2-year survival probability of patients with advanced adenocarcinoma.

Material And Methods: Data on 13,043 patients between June 1, 2011, and December 31, 2014 were collected. Seventy percent of them were randomly assigned to the training cohort for nomogram development, and the remaining 30% assigned to the validation cohort. The most important factors for constructing the nomogram were identified using multivariable Cox regression analysis. The discriminative ability and calibration of the nomograms were tested using C-statistics, calibration plots, and Kaplan-Meier curves.

Results: In the training cohort, 1-year and 2-year OS were 52.8% and 28.5% in EGFR(-) patients, and 73.9% and 44.1% in EGFR(+) patients, respectively. In EGFR(+) group, factors selected were age, gender, congestive heart failure, renal disease, number of lymph node examined, tumor stage, surgical intervention, radiotherapy, first-line chemotherapy, ECOG performance status, malignant pleural effusion, and smoking. In EGFR(-) group, factors selected were age, gender, myocardial infarction, cerebrovascular disease, chronic pulmonary disease, number of lymph node examined, tumor stage, surgical intervention, radiotherapy, ECOG performance status, malignant pleural effusion, and a history of smoking. Two nomograms show good accuracy in predicting OS, with a concordance index of 0.83 in EGFR(+) and of 0.88 in EGFR(-).

Conclusions: The survival prediction models can be used to make individualized predictions with different EGFR mutation status and a useful tool for selecting regimens for treating advanced adenocarcinoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220730PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697331PMC
March 2020

Early alpha-foetoprotein response associated with treatment efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma.

Liver Int 2019 11 31;39(11):2184-2189. Epub 2019 Aug 31.

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, Taiwan.

Background: Post-treatment decline in serum alpha-foetoprotein (AFP) levels has been shown to predict the treatment efficacy of antiangiogenic therapy for advanced hepatocellular carcinoma (HCC). We explored whether a decline in AFP levels was also associated with treatment outcomes of immune checkpoint inhibitors (ICIs) in patients with advanced HCC.

Methods: We reviewed all patients who received ICI therapy for advanced HCC. AFP response was evaluated in patients with the pretreatment AFP level of >20 ng/mL. We defined early AFP response as a >20% decline in serum AFP levels within the first 4 weeks of treatment initiation relative to pretreatment levels. We then studied whether early AFP response was associated with treatment outcomes.

Results: Sixty patients were enrolled in this study; 43 of them were evaluable for early AFP response. The objective response rate of early AFP responders was significantly higher than that of early AFP nonresponders (73% vs. 14%, P < .001). Early AFP responders, compared with early AFP nonresponders, exhibited significantly longer overall survival (OS) (median, 28.0 vs 11.2 months, P = .048) and progression-free survival (PFS) (median, 15.2 vs 2.7 months, P = .002). After adjusting for other clinicopathological variables and treatments, early AFP response remained an independent predictor for longer OS (hazard ratio [HR] = 0.089, 95% confidence interval [CI] = 0.018-0.441; P = .003) and PFS (HR = 0.128, 95% CI = 0.041-0.399; P < .001).

Conclusion: Early AFP response was associated with higher treatment efficacy of ICIs for advanced HCC. Additional validation studies are nonetheless warranted.
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http://dx.doi.org/10.1111/liv.14210DOI Listing
November 2019

Incidence of hepatitis B reactivation during epidermal growth factor receptor tyrosine kinase inhibitor treatment in non-small-cell lung cancer patients.

Eur J Cancer 2019 08 3;117:107-115. Epub 2019 Jul 3.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, ROC. Electronic address:

Background: Reactivation of hepatitis B virus (HBV) is a documented risk during cytotoxic chemotherapy in patients with lung cancer. Cases of HBV reactivation in non-small-cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment have been reported; however, the incidence of HBV reactivation in patients treated with EGFR TKIs has not yet been reported.

Materials And Methods: We enrolled 171 patients who were diagnosed as having NSCLC from 2011 through 2017 and who also had positive hepatitis B surface antigen (HBsAg). All patients had received EGFR TKIs as anticancer treatment for at least 2 weeks during their treatment course. Reactivation of HBV is defined as one of the following: an increase in HBV DNA by at least 10-fold compared to baseline or an absolute increase to >10ˆ5 IU/mL with abnormal liver function.

Results: The median duration of EGFR TKI treatment was 10.5 months (95% confidence interval: 8.2-12.8). Sixteen (9.36%) patients met the criteria of HBV reactivation during EGFR TKI treatment, with an annual incidence of 7.86%. HBV reactivation occurred during erlotinib treatment in 6 patients, followed by 5 patients with gefitinib treatments, 3 patients with osimertinib treatment and 2 with afatinib treatment. No independent risk factor for HBV reactivation was identified.

Conclusion: NSCLC patients receiving EGFR TKI treatment may have a clinically meaningful risk of HBV reactivation during the treatment period. Thus, monitoring liver function, HBV viral load and serology of HBV (i.e., HBeAg and anti-HBc) during EGFR TKI therapy is recommended for NSCLC patients with positive HBsAg.
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http://dx.doi.org/10.1016/j.ejca.2019.05.032DOI Listing
August 2019

Considerations of heterogeneity in clinical trials for hepatocellular carcinoma.

Expert Rev Gastroenterol Hepatol 2019 Jul 27;13(7):615-621. Epub 2019 May 27.

b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.

: Clinical trials in hepatocellular carcinoma (HCC) exhibit a high degree of heterogeneity. These heterogeneities may lead to unexpected results among clinical trials. : In this review, we address the heterogeneity noted in early phase HCC trials, trials involving transarterial chemoembolization, and advanced HCC trials. Furthermore, we discuss possible methods to attenuate the detrimental effects of heterogeneity when conducting clinical trials. : Clinical trials in HCC exhibit an inherently high degree of heterogeneity because of various reasons: tumor heterogeneity, different cirrhotic backgrounds, various etiologies of cirrhosis, and geographical differences in practice and expertise. Such heterogeneity may cause imbalance among the enrolled patient population, premature withdrawal from the clinical trial, and variable response to the treatment. In addition, methodological heterogeneity also exists in designing trial protocol and response evaluation. All these factors may eventually lead to conflicting results among clinical trials. Accounting for these heterogeneities is important to foster the success of future trials. In recent years, significant progress with molecular targeted agents and immune checkpoint inhibitors was made in advanced HCC. These new agents are also being tested in clinical trials involving earlier stage HCC and will also face the challenge of these issues.
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http://dx.doi.org/10.1080/17474124.2019.1621165DOI Listing
July 2019

Klotho-beta and fibroblast growth factor 19 expression correlates with early recurrence of resectable hepatocellular carcinoma.

Liver Int 2019 09 11;39(9):1682-1691. Epub 2019 Jul 11.

Department of Oncology, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.

Background And Aims: Fibroblast growth factor 19 (FGF19) and fibroblast growth factor receptor 4 (FGFR4) signalling play critical roles in hepatocarcinogenesis. This study explored the potential of FGF19- and FGFR4-related biomarkers in predicting early tumour recurrence (ETR) and survival in patients with resectable hepatocellular carcinoma (HCC).

Methods: We examined the mRNA expressions of FGF19, FGFR4, klotho-beta (KLB), cyclin D1 (CCND1) and FGF4 in 151 surgically resected, primary unifocal HCCs through quantitative real-time polymerase chain reaction. Generalized additive models were fitted to detect nonlinear effects of continuous covariates and define thresholds of biomarker expressions. Univariate and multivariate analyses were performed to evaluate prognostic values of these biomarkers for tumour recurrence and patient survival.

Results: Overexpression of FGF19, FGFR4, KLB, CCND1 and FGF4 mRNA was detected in 40%, 32%, 26%, 15% and 35% of 151 tumours respectively. ETR was the strongest prognostic factor predicting worse overall survival (hazard ratio [HR], 5.678; 95% confidence interval, 3.7-8.713; P < 0.001). Furthermore, we revealed that mRNA expression levels of KLB (HR, 3.857; P = 0.021) and FGF19 (HR, 3.248; P = 0.017) were significantly associated with the occurrence of ETR.

Conclusions: Frequent overexpression of FGF19/FGFR4-related biomarkers was detected in resectable HCC. Expression levels of KLB and FGF19 may determine patient survival outcomes through their effects on ETR.
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http://dx.doi.org/10.1111/liv.14055DOI Listing
September 2019

Clinical outcomes and secondary epidermal growth factor receptor (EGFR) T790M mutation among first-line gefitinib, erlotinib and afatinib-treated non-small cell lung cancer patients with activating EGFR mutations.

Int J Cancer 2019 06 5;144(11):2887-2896. Epub 2019 Jan 5.

Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.

Gefitinib, erlotinib and afatinib are approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) bearing an activating epidermal growth factor receptor (EGFR) mutation. However, the clinical outcomes among the three EGFR tyrosine kinase inhibitors (TKIs) are still controversial. We aimed to evaluate clinical outcomes and secondary EGFR T790M mutation among the three EGFR TKIs. From May 2014 to January 2016, a total of 301 patients received treatment with gefitinib, erlotinib or afatinib, for first-line treatment of advanced NSCLC with an activating EGFR mutation, based on their clinicians' choice. The median overall survival (OS) was 37.0 months. Although the baseline characteristics of patients were unequal, progression-free survival and OS did not differ among the 3 groups. Multivariate analysis found that gefitinib (adjusted odds ratio [aOR] 3.29, 95% confidence interval [CI], 1.15-9.46, p = 0.027), EGFR TKI treatment duration more than 13 months (aOR 3.16, 95% CI, 1.20-8.33, p = 0.020), male (aOR 3.25, 95% CI, 1.10-9.66, p = 0.034), initial liver metastasis (aOR 4.97, 95% CI 1.18-20.96, p = 0.029) and uncommon EGFR mutation (aOR 0.14, 95% CI, 0.02-0.97, compared to EGFR deletion 19, p = 0.047) were independent factors for secondary T790M mutation. In real-world practice, choosing first line EGFR TKI based on the patients' clinical characteristics yielded good clinical outcomes. First-line gefitinib, longer EGFR TKI treatment duration, male, initial liver metastasis and uncommon EGFR mutations may be independent factors for secondary EGFR T790M mutation.
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http://dx.doi.org/10.1002/ijc.32025DOI Listing
June 2019

Real-World Data on Prognostic Factors for Overall Survival in EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Gefitinib.

Oncologist 2017 09 15;22(9):1075-1083. Epub 2017 May 15.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Background: This study aimed to identify independent prognostic factors for overall survival (OS) of patients with advanced non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation and receiving gefitinib as first-line treatment in real-world practice.

Materials And Methods: We enrolled 226 patients from June 2011 to May 2013. During this period, gefitinib was the only EGFR-tyrosine kinase inhibitor reimbursed by the Bureau of National Health Insurance of Taiwan.

Results: The median progression-free survival and median OS were 11.9 months (95% confidence interval [CI]: 9.7-14.2) and 26.9 months (21.2-32.5), respectively. The Cox proportional hazards regression model revealed that postoperative recurrence, performance status (Eastern Cooperative Oncology Grade [ECOG] ≥2), smoking index (≥20 pack-years), liver metastasis at initial diagnosis, and chronic hepatitis C virus (HCV) infection were independent prognostic factors for OS (hazard ratio [95% CI] 0.3 [0.11-0.83],  = .02; 2.69 [1.60-4.51],  < .001; 1.92 [1.24-2.97],  = .003; 2.26 [1.34-3.82],  = .002; 3.38 [1.85-7.78],  < .001, respectively). However, brain metastasis (BM) at initial diagnosis or intracranial progression during gefitinib treatment had no impact on OS (1.266 [0.83-1.93],  = .275 and 0.75 [0.48-1.19],  = .211, respectively).

Conclusion: HCV infection, performance status (ECOG ≥2), newly diagnosed advanced NSCLC without prior operation, and liver metastasis predicted poor OS in EGFR mutation-positive advanced NSCLC patients treated with first-line gefitinib; however, neither BM at initial diagnosis nor intracranial progression during gefitinib treatment had an impact on OS.

Implications For Practice: The finding that chronic hepatitis C virus (HCV) infection might predict poor overall survival (OS) in epidermal growth factor receptor mutation-positive advanced non-small cell lung cancer (NSCLC) patients treated with first-line gefitinib may raise awareness of benefit from anti-HCV treatment in this patient population. Brain metastasis in the initial diagnosis or intracranial progression during gefitinib treatment is not a prognostic factor for OS. This study, which enrolled a real-world population of NSCLC patients, including sicker patients who were not eligible for a clinical trial, may have impact on guiding usual clinical practice.
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http://dx.doi.org/10.1634/theoncologist.2016-0331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599189PMC
September 2017

Phase Ib study of codrituzumab in combination with sorafenib in patients with non-curable advanced hepatocellular carcinoma (HCC).

Cancer Chemother Pharmacol 2017 Feb 24;79(2):421-429. Epub 2017 Jan 24.

Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Purpose: Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC.

Patients And Methods: In a 3 + 3 design, codrituzumab was given intravenously in various doses with sorafenib 400 mg twice daily to patients with advanced HCC, age ≥18, ECOG 0-1, Child-Pugh A and B7, adequate organ functions, and no prior systemic therapy, with tumor assessment by RECIST 1.0 and safety by CTCAE 3.0. PK and pre, during, and post-therapy I radiolabeled codrituzumab PET scan imaging were performed.

Results: 41 patients were enrolled: 2.5 mg/kg weekly (qw) (12), 5 mg/kg qw (12), 10 mg/kg qw (3), 1600 mg every 2 weeks (q2w) (6), and 1600 mg qw (7). Two drug limiting toxicities occurred: grade 3 hyponatremia at 5 mg/kg and grade 3 hyponatremia and hyperglycemia at 1600 mg q2w. Adverse events occurred in 80% of patients, including at least one ≥grade 3: ten (25%) increased AST, three (7.5%) increased ALT, and ten (25%) increased lipase. There were no responses and nine (25.7%) had stable disease. PK C and AUC of codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed I radiolabeled codrituzumab uptake in tumor. In all three patients who underwent a post-progression PET, glypican-3 remained expressed.

Conclusion: Codrituzumab plus sorafenib were tolerated at 1600 mg q2w and 400 mg bid, respectively, with no responses. Codrituzumab exerts selective distribution to HCC cells, and GPC3 does not show any down-regulation post-progression (NCT00976170).
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http://dx.doi.org/10.1007/s00280-017-3241-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548107PMC
February 2017

Primary tumor site is a useful predictor of cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 non-mutant) metastatic colorectal cancer: a nationwide cohort study.

BMC Cancer 2016 05 24;16:327. Epub 2016 May 24.

Department of Oncology, National Taiwan University Hospital, 7, Chun-Shan S Rd, Taipei, 10002, Taiwan.

Background: Previous studies have shown left-sided colorectal cancer (LCRC) and right-sided colorectal cancer (RCRC) exhibit different molecular and clinicopathological features. We explored the association between the primary tumor site and cetuximab efficacy in KRAS wild-type colorectal cancer (CRC).

Methods: This study enrolled a cohort of patients, who had received cetuximab treatment after two or more lines of chemotherapy for KRAS wild-type (exon 2 nonmutant) metastatic CRC, from the databases of Taiwan Cancer Registry (2004-2010) and National Health Insurance (2004-2011). Survival data were obtained from the National Death Registry. Time to treatment discontinuation (TTD) and overall survival (OS) after the start of cetuximab treatment were compared between patients with LCRC (splenic flexure to rectum) and RCRC (cecum to hepatic flexure).

Results: A total of 969 CRC patients were enrolled. Among them, 765 (78.9 %) and 136 (14.0 %) patients had LCRC and RCRC, respectively. Patients with LCRC, compared to patients with RCRC, had longer TTD (median, 4.59 vs. 2.75 months, P = .0005) and OS (median, 12.62 vs. 8.07 months, P < .0001) after the start of cetuximab treatment. Multivariate analysis revealed a right-sided primary tumor site was an independent predictor of shorter TTD (adjusted hazard ratio [HR] = 1.32, using the LCRC group as a reference, 95 % confidence interval: 1.08-1.61, P = .0072) and OS (adjusted HR = 1.45, 95 % CI: 1.18-1.78, P = .0003).

Conclusion: Our findings demonstrate that a left-sided primary tumor site is a useful predictor of improved cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 nonmutant) metastatic CRC.
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http://dx.doi.org/10.1186/s12885-016-2358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879738PMC
May 2016

The Response, Outcome and Toxicity of Aggressive Palliative Thoracic Radiotherapy for Metastatic Non-Small Cell Lung Cancer Patients with Controlled Extrathoracic Diseases.

PLoS One 2015 31;10(12):e0145936. Epub 2015 Dec 31.

Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Background And Purpose: For metastatic non-small cell lung cancer (NSCLC) patients with controlled extrathoracic disease after systemic treatment, stable or progressive primary lung lesions may cause respiratory symptoms and increase comorbidities. In the present study, we sought to investigate whether aggressive palliative thoracic radiotherapy (RT) can enhance local control and improve the survival for this subgroup of patients.

Materials And Methods: Between March 2006 and December 2014, 56 patients with metastatic NSCLC who had responsive or stable extrathoracic diseases after chemotherapy and/or molecular targets, and received thoracic RT for stable and progressive primary lung lesions were included. RT with a median dose of 55 Gy (range, 40-62 Gy) was administered in 1.8-2.5 Gy fractions to primary lung tumor and regional mediastinal lymph nodes using modern RT technique. Overall survival (OS) from diagnosis, and locoregional progression-free survival (LRPFS), and survival calculated from radiotherapy (OS-RT) were estimated using the Kaplan-Meier method.

Results: There were 37 men and 19 women with a median age of 60 years at diagnosis. The median interval from the diagnosis of metastatic disease to thoracic RT was 8 months. Following thoracic RT, 26 patients (46%) achieved complete or partial response (overall response rate, ORR). Patients with squamous cell carcinoma or poorly-differentiated carcinoma had a higher ORR than those with adenocarcinoma (63% vs. 34%, P = 0.034). EGFR mutations was closely associated with a better ORR (45% vs. 29%, P = 0.284). At a median follow-up time of 44 months, the median OS, LRPFS after RT, and OS-RT were 50 months, 15 months, and 18 months.

Conclusion: Radical palliative throractic RT is safe and might be beneficial for primary lung lesions of metastatic NSCLC patients with controlled extrathoracic diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145936PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697816PMC
June 2016

Young patients with colorectal cancer have increased risk of second primary cancers.

Jpn J Clin Oncol 2015 Nov 18;45(11):1029-35. Epub 2015 Sep 18.

Center for Comparative Effectiveness Research, National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei City Taiwan Cancer Registry, Taipei City Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei City, Taiwan, ROC

Objective: Because the number of long-term survivors of colorectal cancer has increased, second primary cancer has become an important issue. However, previous studies were heterogeneous in design, and few data for Asia-Pacific area were available.

Methods: This was a retrospective population-based study conducted using the national database of the Taiwan Cancer Registry. Patients who have histology-proven primary colon cancer and rectal cancer from 1995 to 2005 were enrolled in this study. All second primary cancer events had to be histology proven. The standardized incidence ratio of second primary cancer was used as an indicator. Standardized incidence ratio was counted as the number of observed second primary cancer divided by the expected number of cancer cases in the general population.

Results: A total of 65 648 eligible index patients were enrolled, and 3810 second primary cancer events were identified. The standardized incidence ratio for all of the patients was 1.03 (95% confidence interval: 0.99-1.06), which implied that the risk of second primary cancer was not significantly elevated in the index patients compared with that of the general population. The standardized incidence ratio for the patients aged <50, 50-70 and >70 years was 2.52 (95% confidence interval: 2.28-2.78), 1.18 (95% confidence interval: 1.12-1.23) and 0.80 (95% confidence interval: 0.76-0.84), respectively. In young patients (aged <50 years), the standardized incidence ratio increase was statistically significant and persisted for over 10 years and this significantly increased across all subgroups. The small intestine, the large intestine, the female genital organs and the lungs were the most common sites of second primary cancer in young patients.

Conclusions: Young patients with colorectal cancer have an increased risk of developing second primary cancer.
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http://dx.doi.org/10.1093/jjco/hyv137DOI Listing
November 2015

The Prognostic Impact of Type 2 Diabetes Mellitus on Early Cervical Cancer in Asia.

Oncologist 2015 Sep 3;20(9):1051-7. Epub 2015 Aug 3.

Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan, Republic of China; Departments of Oncology, Internal Medicine, and Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Graduate Institute of Oncology, College of Medicine, and Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan, Republic of China; Center for Comparative Effectiveness Research, National Center of Excellence for Clinical Trial and Research, Taipei, Taiwan, Republic of China; Division of Health Technology Assessment, Center for Drug Evaluation, Taipei, Taiwan, Republic of China; Taiwan Cancer Registry, Taipei, Taiwan, Republic of China

Background: Many studies have shown that type 2 diabetes mellitus (DM) increases the risk for several types of cancer but not cervical cancer (CC). Although DM and insulin-like growth factor 1 have preclinical and clinical implications for CC, less is known about the prognostic impact of DM on patients with early stage CC.

Patients And Methods: We used the nationwide Taiwan Cancer Registry database to collect the characteristics of stage I-IIA cervical cancer patients diagnosed between 2004 and 2008. DM and other comorbidities were retrieved from the National Health Insurance database. Cervical cancer-specific survival (CSS) and overall survival (OS) times of patients according to DM status were estimated using the Kaplan-Meier method. We used a Cox proportional hazards model to calculate adjusted hazard ratios (HRs) for the effects of DM and other risk factors on mortality.

Results: A total of 2,946 patients had primary stage I-IIA CC and received curative treatments, and 284 (9.6%) had DM. The 5-year CSS and OS rates for patients with DM were significantly lower than those without DM (CSS: 85.4% vs. 91.5%; OS: 73.9% vs. 87.9%). After adjusting for clinicopathologic variables and comorbidities, DM remained an independent unfavorable prognostic factor for CSS (adjusted HR: 1.46) and OS (adjusted HR: 1.55).

Conclusion: In Asian patients with early cervical cancer, DM is an independent unfavorable prognostic factor influencing both OS and CSS, even after curative treatments.

Implications For Practice: Type 2 diabetes mellitus (DM) increases the incidence of several types of cancer but not cervical cancer (CC); however, less is known about the impact of DM on patients who already have CC. This study suggests that DM may increase the risk of cancer recurrence and death for early stage CC patients, even after curative treatments. Incorporating DM control should be considered part of the continuum of care for early stage CC patients, and close surveillance during routine follow-up in this population is recommended.
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http://dx.doi.org/10.1634/theoncologist.2015-0111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571799PMC
September 2015

Statin Use Is Associated With Improved Prognosis of Colorectal Cancer in Taiwan.

Clin Colorectal Cancer 2015 Sep 21;14(3):177-184.e4. Epub 2015 Feb 21.

Center for Comparative Effectiveness Research, National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Taiwan Cancer Registry, Taipei, Taiwan. Electronic address:

Background: Statins are widely used for hyperlipidemia control and might also exhibit anticancer properties. This study explored whether statin use is associated with the prognosis of curatively resected colorectal cancer (CRC).

Materials And Methods: Using data from the Taiwan Cancer Registry, we established a population-based cohort of patients who received curative surgery for stage I, II, or III CRC. Data related to prescription medications and comorbidities were retrieved from the database of the National Health Insurance program of Taiwan. Statin users were defined as patients who had used statins within 1 year before their cancer diagnosis. Univariate and multivariate analyses were used to compare cancer-specific survival (CSS) and overall survival (OS) between statin users and patients who had never used statins (never users). In the multivariate analysis, we used propensity scores to adjust for age, sex, diagnosis year, physician visits, hospitalization, conjunctive medications, and comorbidities.

Results: A total of 17,115 patients were enrolled; 2145 (13%) of these patients were statin users, and 14,970 (87%) were never users. After adjusting for other potential prognostic factors, statin use was an independent predictor for longer CSS (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.68-0.88; P < .001) and OS (HR, 0.82; 95% CI, 0.74-0.92; P < .001). These associations were consistent across subgroups, including sexes, tumor stages, and age cohorts, and in CRC patients who suffered from diabetes and hypertension.

Conclusion: Statin use is associated with an improved prognosis of curatively resected CRC.
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http://dx.doi.org/10.1016/j.clcc.2015.02.003DOI Listing
September 2015

Comparative effectiveness of first-line platinum-based chemotherapy regimens for advanced lung squamous cell carcinoma.

Clin Lung Cancer 2015 Mar 30;16(2):137-43. Epub 2014 Sep 30.

Center for Comparative Effectiveness Research, National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan; Taiwan Cancer Registry, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.

Background: Platinum-based chemotherapy is the standard first-line therapy for patients with advanced lung squamous cell carcinoma (SCC). We compared the effectiveness of first-line chemotherapy regimens.

Methods: We searched the database of the Taiwan Cancer Registry for patients with newly diagnosed advanced lung SCC from 2004 to 2007. Medication prescription data were retrieved from the database of National Health Insurance, Taiwan. We identified patients who received standard first-line platinum-based chemotherapy, which was defined as chemotherapy with a platinum (P) compound (cisplatin or carboplatin) in addition to 1 of the 4 chemotherapy agents, including gemcitabine (G), docetaxel (D), paclitaxel (T), and vinorelbine (V). Deaths were identified by searching the National Death Registry. Overall survival (OS) was compared between patients who underwent different therapies.

Results: In total, 2790 patients were identified; 983 patients (35.2%) received standard first-line chemotherapy with P and G (58.1%), D (14.5%), T (11.6%), or V (15.8%). Older patients (age ≥ 70 years) were less likely to receive P + D than P + G, P + T, or P + V (P = .018). Patients who received P + G, P + D, P + T, or P + V had similar OS (median, 8.9, 7.9, 9.5, and 8.2 months; P = .816). In multivariate analyses adjusting for age, sex, and stage, the first-line chemotherapy regimen was not a predictor for OS. With P + G as the reference group, the adjusted hazard ratios of P + D, P + T, and P + V were 1.03, 0.90, and 1.02, respectively (P = .710).

Conclusions: In patients with advanced lung SCC, various regimens did not have a significant effect on survival outcomes.
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http://dx.doi.org/10.1016/j.cllc.2014.09.004DOI Listing
March 2015

Potential synergistic anti-tumor activity between lenalidomide and sorafenib in hepatocellular carcinoma.

J Gastroenterol Hepatol 2014 Dec;29(12):2021-31

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.

Background And Aim: The immune modulatory drug lenalidomide has shown promising anti-tumor activity in a clinical trial of patients with advanced hepatocellular carcinoma (HCC). The present study explored whether lenalidomide can enhance the anti-tumor activity of sorafenib, the standard molecular targeted therapy for HCC.

Methods: The anti-tumor efficacy of single-agent or combination treatment was measured by change in tumor volume and animal survival using an orthotopic liver cancer model. Distribution of T-cell subpopulations in tumor-infiltrating lymphocytes (TILs) and splenocytes derived from tumor-implanted mice was measured by flow cytometry. Depletion of relevant T-cell subpopulations or cytokines was done by co-administration of relevant antibodies with study drug treatment. Tumor cell apoptosis and tumor angiogenesis were measured by transferase deoxytidyl uridine end labeling assay and immunohistochemical study, respectively.

Results: Combination of sorafenib and lenalidomide produced significant synergistic anti-tumor efficacy in terms of tumor growth delay and animal survival. This synergistic effect was associated with a significant increase in interferon-γ expressing CD8(+) lymphocytes in TILs and a significantly higher number of granzyme- or perforin-expressing CD8(+) T cells, compared with vehicle- or single-agent treatment groups. Combination treatment significantly increased apoptotic tumor cells and vascular normalization in tumor tissue. The synergistic anti-tumor effect was abolished after CD8 depletion.

Conclusions: Lenalidomide can enhance the anti-tumor effects of sorafenib in HCC through its immune modulatory effects, and CD8(+) TILs play an important role in the anti-tumor synergism.
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http://dx.doi.org/10.1111/jgh.12708DOI Listing
December 2014

Type 2 diabetes mellitus is associated with increased mortality in Chinese patients receiving curative surgery for colon cancer.

Oncologist 2014 Sep 24;19(9):951-8. Epub 2014 Jul 24.

Department of Oncology, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan, Republic of China; Department of Oncology and Center for Comparative Effectiveness Research, National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Graduate Institutes of Oncology and Clinical Medicine and Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China; Institutes of Health Policy and Management and Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan, Republic of China

Background: We investigated the association between diabetes mellitus (DM) and the prognosis of patients with early colon cancer who had undergone curative surgery.

Methods: From three national databases of patients in Taiwan, we selected a cohort of colon cancer patients who had been newly diagnosed with stage I or stage II colon cancer between January 1, 2004 and December 31, 2008 and had undergone curative surgery. We collected information regarding DM (type 2 DM only), the use of antidiabetic medications, other comorbidities, and survival outcomes. The colon cancer-specific survival (CSS) and the overall survival (OS) were compared between patients with and without DM.

Results: We selected 6,937 colon cancer patients, among whom 1,371 (19.8%) had DM. The colon cancer patients with DM were older and less likely to receive adjuvant chemotherapy but had a similar tumor stage and grade, compared with colon cancer patients without DM. Compared with colon cancer patients without DM, patients with DM had significantly shorter OS (5-year OS: 71.0% vs. 81.7%) and CSS (5-year CSS: 86.7% vs. 89.2%). After adjusting for age, sex, stage, adjuvant chemotherapy, and comorbidities in our multivariate analysis, DM remained an independent prognostic factor for overall mortality (adjusted hazards ratio: 1.32, 95% confidence interval: 1.18-1.49), but not for cancer-specific mortality. Among the colon cancer patients who had received antidiabetic drug therapy, patients who had used insulin had significantly shorter CSS and OS than patients who had not.

Conclusion: Among patients who receive curative surgery for early colon cancer, DM is a predictor of increased overall mortality.
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http://dx.doi.org/10.1634/theoncologist.2013-0423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153450PMC
September 2014

Phase II multicentered study of low-dose everolimus plus cisplatin and weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin as first-line treatment for patients with advanced gastric cancer.

Oncology 2014 4;87(2):104-13. Epub 2014 Jul 4.

National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan, ROC.

Objective: This phase II trial investigates the efficacy and safety of low-dose everolimus in combination with cisplatin-fluorouracil chemotherapy in patients with advanced gastric cancer.

Methods: Eligible patients with chemotherapy-naïve advanced gastric cancer received low-dose everolimus (10 mg p.o. on days 1, 8 and 15) plus cisplatin and a weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin (HDFL) chemotherapy (cisplatin 35 mg/m(2) intravenous infusion for 24 h on days 1 and 8, 5-fluorouracil 2,000 mg/m(2) and leucovorin 300 mg/m(2) intravenous infusion for 24 h on days 1, 8 and 15) every 28 days. The primary endpoint was objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.0.

Results: Forty patients (19 men; 21 women; median age, 54.1 years; range, 33.7-73.3 years) received a median of 6 (range, 1-30; 95% CI, 4.9-8.0) cycles of study treatment. The ORR was 52.5% (21 confirmed partial response). The median progression-free survival and overall survival were 6.9 (95% CI, 4.9-8.4) and 10.5 (95% CI, 8.6-12.3) months, respectively. Most adverse events were mild.

Conclusion: Adding low-dose everolimus to cisplatin-HDFL chemotherapy failed to increase the ORR as in a preplanned statistical assumption but may prolong progression-free survival in treatment-naïve advanced gastric cancer patients.
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http://dx.doi.org/10.1159/000362671DOI Listing
September 2014

Clinical trials in hepatocellular carcinoma: an update.

Liver Cancer 2013 Aug;2(3-4):345-64

Department of Oncology, National Taiwan University Hospital, Taiwan (ROC) ; Department of Internal Medicine, National Taiwan University Hospital, Taiwan (ROC) ; Graduate Institute of Oncology, School of Medicine, National Taiwan University, Taiwan (ROC).

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.
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http://dx.doi.org/10.1159/000343850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881316PMC
August 2013

Radiosensitization by combining an aurora kinase inhibitor with radiotherapy in hepatocellular carcinoma through cell cycle interruption.

Int J Cancer 2014 Jul 10;135(2):492-501. Epub 2014 Jan 10.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.

Radiotherapy has been integrated into the multimodal treatment of hepatocellular carcinoma (HCC), especially of localized hepatic tumor(s) refractory to conventional treatment. However, tumor control remains unsatisfactory mainly because of insufficient dose, and sublethally irradiated tumor may associate with metastasis. Our aim was to assess the effect of combining a molecularly targeted Aurora kinase inhibitor, VE-465, with radiotherapy in in vitro and in vivo models of human HCC. Human HCC cell lines (Huh7 and PLC-5) were used to evaluate the in vitro synergism of combining VE-465 with irradiation. Flow cytometry analyzed the cell cycle changes, while western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with VE-465 and/or radiotherapy for the in vivo response. VE-465 significantly enhanced radiation-induced death in HCC cells by a mechanism involving the enhanced inhibition of histone H3 phosphorylation and interruption of cell cycle change. In SCID, mice bearing ectopic HCC xenografts, pretreatment with VE-465 (20 mg/kg/day × 9 days) significantly enhanced the tumor-suppressive effect of radiotherapy (5 Gy/day × 5 days) by 54.0%. A similar combinatorial effect of VE-465 and radiotherapy was observed in an orthotopic model of Huh7 tumor growth by 17.2%. In the orthotopic Huh7 xenografts, VE-465 significantly enhanced radiation-induced tumor growth suppression by a mechanism involving the increased apoptosis. VE-465 is a potent inhibitor of Aurora kinase with therapeutic value as a radiosensitizer of HCC.
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http://dx.doi.org/10.1002/ijc.28682DOI Listing
July 2014

Radiofrequency ablation is superior to ethanol injection in early-stage hepatocellular carcinoma irrespective of tumor size.

PLoS One 2013 11;8(11):e80276. Epub 2013 Nov 11.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan ; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

Background: Randomized trials suggest that radiofrequency ablation (RFA) may be more effective than percutaneous ethanol injection (PEI) in the treatment of hepatocellular carcinoma (HCC). However, the survival advantage of RFA needs confirmation in daily practice.

Methods: We conducted a population-based cohort study using the Taiwan Cancer Registry, National Health Insurance claim database and National Death Registry data from 2004 through 2009. Patients receiving PEI or RFA as first-line treatment for newly-diagnosed stage I-II HCC were enrolled.

Results: A total of 658 patients receiving RFA and 378 patients receiving PEI treatment were included for final analysis. The overall survival (OS) rates of patients in the RFA and PEI groups at 5-year were 55% and 42%, respectively (p < 0.01). Compared to patients that received PEI, those that received RFA had lower risks of overall mortality and first-line treatment failure (FTF), with adjusted hazard ratios (HRs) [95% confidence interval (CI)] of 0.60 (0.50-0.73) for OS and 0.54 (0.46-0.64) for FTF. The favorable outcomes for the RFA group were consistently significant for patients with tumors > 2 cm as well as for those with tumors < 2 cm. Consistent results were also observed in other subgroup analyses defined by gender, age, tumor stage, and co-morbidity status.

Conclusion: RFA provides better survival benefits than PEI for patients with unresectable stage I-II HCC, irrespective of tumors > 2 cm or ≤ 2 cm, in contemporary clinical practice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080276PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823653PMC
February 2015

A pilot study of hepatic arterial infusion of chemotherapy for patients with advanced hepatocellular carcinoma who have failed anti-angiogenic therapy.

Liver Int 2013 Oct 28;33(9):1413-9. Epub 2013 May 28.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.

Background & Aims: For patients with advanced hepatocellular carcinoma (HCC) who have failed first-line anti-angiogenic therapy, there is no salvage treatment. Hepatic arterial infusion of chemotherapy (HAIC) has been reported to achieve substantial treatment responses in HCC patients. We aimed to explore the feasibility of using HAIC as second-line therapy for advanced HCC.

Methods: We retrospectively reviewed all consecutive patients who received HAIC for advanced HCC after failure of first-line anti-angiogenic therapy at a single institute. Patients received HAIC with 60 mg/m(2) cisplatin on Day 2, and 500 mg/m(2) /d dose of 5-fluorouracil on Days 1-3. The treatment was repeated every 21 days and continued until disease progression or the occurrence of intolerable toxicities. Tumour assessment was performed after every 3 cycles of HAIC following RECIST criteria, version 1.0.

Results: A total of 23 patients were included. Eleven (48%) patients had main portal vein thrombosis. Liver reserve was classified as Child-Pugh A in 19 (83%) patients and B in 4 (17%) patients. No complete response was observed, although 6 (26%) patients showed partial responses. The median progression-free survival was 4.4 months, and the median overall survival was 7.5 months. Common toxicities included bone marrow suppression, elevated transaminase levels, neutropenia, nausea and malaise. Only 7 (30%) patients experienced grade 3 or 4 toxicities, and no patients withdrew from the therapy because of intolerable or life-threatening toxicities.

Conclusion: HAIC is a feasible second-line therapy for patients with advanced HCC who have failed anti-angiogenic therapy.
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http://dx.doi.org/10.1111/liv.12207DOI Listing
October 2013

Modern prospection for hepatic arterial infusion chemotherapy in malignancies with liver metastases.

Int J Hepatol 2013 17;2013:141590. Epub 2013 Apr 17.

Department of Hemato-Oncology, E-Da Hospital, No. 1, Yi-da Road, Jiaosu Village, Yanchao, Kaohsiung 82445, Taiwan ; Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei City 10002, Taiwan.

Malignancy with liver metastasis plays an important role in daily oncology practice, especially for primary cancers of the gastrointestinal tract and hepatopancreatobiliary system. On account of the dual vascular supply system and the fact that most metastatic liver tumors are supplied by the hepatic artery, hepatic artery infusion chemotherapy (HAIC) is an appealing method for the treatment of liver metastases. Herein, we summarize recent study results reported in the literature regarding the use of HAIC for metastatic liver tumors, with special focus on colorectal cancer.
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http://dx.doi.org/10.1155/2013/141590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652147PMC
May 2013

The Aurora kinases inhibitor VE-465 is a novel treatment for glioblastoma multiforme.

Oncology 2013 27;84(6):326-35. Epub 2013 Apr 27.

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, ROC. lpyalexandra @ gmail.com

Glioblastoma multiforme (GBM) is one of the most common and aggressive types of primary brain tumor. After complete surgical resection combined with radiation and chemotherapy, approximately 10% of patients survive for more than 5 years. Therefore, a novel therapy for GBM is needed. Aurora-A (AURKA) plays important roles in cell cycle regulation, such as centrosome maturation, chromatic separation, bipolar spindle assembly, and mitotic entry. To investigate the effects of AURKA inhibition, three GBM cell lines, including GBM 8401, GBM 8901, and U87-MG cells, were treated with the AURKA inhibitor VE-465. Sensitivities to VE-465, as indicated by 50% inhibitory concentration values for GBM 8401, GBM 8901, and U87-MG cells, were 6, 25, and 19 nM, respectively. Additionally, colony formation of GBM 8401 and GBM 8901 cells was decreased after treatment with the VE-465. VE-465 treatment increased polyploidy and p53 protein expression, and inhibited cell growth in a caspase-independent manner. Taken together, these results suggest that the inhibition of AURKA by a small-molecule inhibitor may have potential to serve as a novel therapeutic approach for GBM.
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http://dx.doi.org/10.1159/000347021DOI Listing
August 2013

Hospital volume of percutaneous radiofrequency ablation is closely associated with treatment outcomes for patients with hepatocellular carcinoma.

Cancer 2013 Mar 4;119(6):1210-6. Epub 2012 Dec 4.

Department of Oncology, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan.

Background: Hospital volume for several major operations is associated with treatment outcomes. In this study, the authors explored the influence of hospital radiofrequency ablation (RFA) volume on the prognosis of patients who received RFA for hepatocellular carcinoma (HCC).

Methods: The authors searched for all patients who were diagnosed with stage I or stage II HCC from 2004 to 2006 and who received RFA as first-line therapy in a population-based cohort. Overall survival (OS) and liver cancer-specific survival (CSS) were compared according to hospital volume. A Cox proportional hazards model was used for multivariate analysis.

Results: In total, 661 patients received first-line RFA for stage I and II HCC in 28 hospitals. Among these, there were 480 patients (72.6%) in the high-volume group (those who received RFA at hospitals that treated >10 first-line patients per year), and there were 181 patients (27.4%) in the low-volume group (those who received RFA at hospitals that treated ≤ 10 first-line patients per year). The sex, age, stage, tumor size, and year of diagnosis for patients in the 2 groups did not differ significantly. Patients in the high-volume group demonstrated significantly longer OS and CSS than those in the low-volume group (5-year OS rate, 58.7% vs 47.2%; P = .001; 5-year CSS rate, 67.1% vs 57.1%; P = .009). After adjusting for covariates, high-volume hospitals remained an independent predictor of longer OS (hazard ratio, 0.57; P < .001) and CSS (hazard ratio, 0.57; P = .003).

Conclusions: Patients who received first-line RFA for HCC in high-volume hospitals demonstrated better survival outcomes.
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http://dx.doi.org/10.1002/cncr.27800DOI Listing
March 2013