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Cancer-associated thrombosis (CAT) is a common complication of malignancies. Patients with CAT are at risk of venous thromboembolism recurrence, but also at risk of bleeding while anticoagulated. Taiwanese patients are perceived to have a lower incidence of CAT, likely leading to false reassurance for Taiwanese patients with cancer. Because of this, oncologists and cardiologists from multiple medical institutions in Taiwan have set forth to provide clinical consensus guidelines on the management of CAT, based on local clinical practices and guided by predominant international clinical practice guidelines. This paper aims to describe the current disease burden of cancer-associated venous thromboembolism in Taiwanese cancer patients, and discusses the unmet needs and gaps in the management of this medical complication. It also outlines diagnostic and management strategies relevant to the different treatment options available, such as non-vitamin K antagonist oral anticoagulants.

Background: Remarkable progress has been made in immunotherapy, specifically antibodies for programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1), for treating advanced cancers. In this study, we explored whether circulating immune cells can be used as biomarkers of the efficacy of such therapy., Methods: We enrolled patients who received nivolumab, an anti-PD-1 antibody, for advanced hepatocellular carcinoma (HCC) in clinical trials and who consented to the collection of their peripheral blood. Using flow cytometry, we analyzed lymphocyte subclasses and the PD-1 or PD-L1 positivity of immune cells. These results were compared between patients with disease control (complete response, partial response, or stable disease) and those with disease progression., Results: This study included 16 patients. The objective response rate was 19%, and the disease control rate was 75%. The hemogram results and the percentage of total αβ T cells or CD4 T cells did not significantly change after nivolumab treatment; moreover, they were not associated with treatment outcomes. The number of CD8 T cells significantly increased after 4 weeks (p = 0.016); however, this change was not associated with treatment outcomes. Patients with disease control exhibited peripheral B cells with significantly lower pretreatment PD-1 positivity than did patients with disease progression (p = 0.042). Patients with disease progression were more likely to exhibit monocytes with increased PD-L1 positivity after 28 (p = 0.020) or 42 (p = 0.008) days of treatment., Conclusion: The low pretreatment PD-1 positivity of peripheral B cells and the constant posttreatment PD-L1 positivity of monocytes were associated with disease control after nivolumab treatment for advanced HCC., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2020, the Chinese Medical Association.)

Competing Interests: Declaration of competing interest Dr. Chih-Hung Hsu reports receiving honoraria from BMS, MSD, ONO Pharmaceutical Company, and Roche; serving in a consulting role for BMS, MSD, ONO Pharmaceutical Company, and Roche; and receiving research funding from MSD. Dr. Yu-Yun Shao and Dr. Tsung-Hao Liu report no conflicts of interest.

Purpose: We investigated whether low skeletal muscle mass (LSMM) defined according to different muscle groups on computed tomography (CT) scans are predictive factors of survival for advanced hepatocellular carcinoma (HCC)., Methods: In this retrospective study, we analyzed patients who received sorafenib therapy for advanced HCC in a prospective patient cohort between 2007 and 2012. The total skeletal muscle (TSM), paraspinal muscle (PS), psoas muscle (PM), rectus abdominis (RA), and abdominal wall (AW) muscle areas were evaluated using a single CT slice at the third lumbar vertebra before treatment. LSMM was determined according to the TSM, PS, PM, RA and AW indices, which was calculated as the parameters divided by the square of the body height., Results: We enrolled 137 patients. Women had significantly lower TSM index than men did (p < .001). Among men, the optimal cut points of the TSM, PM and RA indices for LSMM diagnosis were 39.1, 8.3 and 2.9 cm 2 /m 2 , respectively. Patients with LSMM defined by TSM (median 5.1 vs. 8.0 months, p = .007), PM (5.8 vs. 11.8 months, p < .001), and RA (7.2 vs. 8.1 months, p = .003) indices exhibited poorer overall survival than patients without LSMM. After adjusting for clinical variables, TSM (hazard ratio [HR]: 2.122, 95% confidence interval [CI]: 1.134-3.971) and PM (HR: 1.730, 95% CI: 1.058-2.828) indices-defined LSMM remained independent predictors for poor OS, but RA index-defined LSMM did not., Conclusion: LSMM defined by TSM and PM indices are independent predictors of poor prognosis for advanced HCC., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: Poor adherence to analgesic drugs is one of the most common barriers to adequate pain management. This prospective, cross-sectional, patient-oriented observational study aimed to explore the adherence rate, clinical factors, and impact of adherence to analgesic drugs on the quality of life (QoL) among cancer outpatients in Taiwan., Methods: Eight hundred ninety-seven consecutive adult outpatients with cancer who had reported tumor pain and received regular analgesic drug treatment were enrolled from 16 medical centers across Taiwan. The Brief Pain Inventory was used to assess pain intensity and QoL. Morisky's four-item medication adherence scale was used to assess adherence to analgesic drugs. Clinical factors possibly associated with good adherence to analgesic drugs were analyzed using multivariate logistic regression analyses., Results: Of the 897 patients, 26.9% met criteria for the good, 35.5% for the moderate, and 37.6% for the poor adherence groups. The good adherence group had significantly better QoL outcomes than the moderate and poor adherence groups (all p < 0.05). Age ≥ 50 years, head and neck or hematological malignancies, cancer-related pain, patients who agreed or strongly agreed that the side effects of analgesic drugs were tolerable, and patients who disagreed or strongly disagreed that the dosing schedule could be flexibly self-adjusted to deal with the actual pain were predictors of good adherence to analgesic drugs., Conclusions: Awareness of the clinical factors associated with adherence to analgesic drugs may help clinicians to identify cancer patients at a greater risk of non-adherence, reinforce optimal pain management, and improve the QoL by enhancing adherence to pain medications.

Purpose: The purpose of this study is to investigate the prevalence of pain, pain management, and impact of recent pain on daily functioning in patients with head and neck cancer (HNC) and patients with other cancers., Methods: This multi-center survey was conducted by using Brief Pain Inventory questionnaire to evaluate pain status and its impact on daily functioning., Results: A total of 3289 patients were analyzed including 708 HNC patients and 2581 patients with other cancers. The overall pain prevalence was 69.17%. A higher percentage of HNC patients had recent pain (60.59 vs. 44.01%, P < 0.001), required pain management (86.29 vs. 72.03%, P < 0.001), and used any analgesics (53.81 vs. 34.52%, P < 0.001). HNC patients with pain management had a higher prevalence of recent pain (85.83 vs. 81.14%, P = 0.044) and a slightly lower satisfaction rate (74.00 vs. 79.70%, P = 0.070). Regarding the impact of pain on daily functioning, HNC patients had a lower mean interference score for general activity such as walking, normal work, sleep, and life enjoyment., Conclusions: The HNC patients may need more intensive pain management to achieve optimal pain control and maintain daily functioning.

Transdermal buprenorphine (TDB) has demonstrated effectiveness in treating a range of chronic pain conditions, including cancer pain, nociceptive pain, and neuropathic pain and has a favorable safety profile. Worldwide, clinical experience of its use is relatively limited. There is considerable misunderstanding about the pharmacology, mechanism of action, and safety of buprenorphine. There is also limited guidance on the appropriate use of TDB for chronic pain management. This article presents an overview of TDB and also provides practical recommendations for its use as part of a multifaceted strategy in chronic cancer and non-cancer pain.

Monoclonal antibody (mAb) drugs have generated much interest in recent years for treating various diseases. Immunoglobulin G (IgG) represents a high percentage of mAb drugs that have been approved by the Food and Drug Administration (FDA). To facilitate therapeutic drug monitoring and pharmacokinetic/pharmacodynamic studies, we developed a general liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify the concentration of IgG-based mAbs in human plasma. Three IgG-based drugs (bevacizumab, nivolumab and pembrolizumab) were selected to demonstrate our method. Protein G beads were used for sample pretreatment due to their universal ability to trap IgG-based drugs. Surrogate peptides that were obtained after trypsin digestion were quantified by using LC-MS/MS. To calibrate sample preparation errors and matrix effects that occur during LC-MS/MS analysis, we used two internal standards (IS) method that include the IgG-based drug-IS tocilizumab and post-column infused IS. Using two internal standards was found to effectively improve quantification accuracy, which was within 15% for all mAb drugs that were tested at three different concentrations. This general method was validated in term of its precision, accuracy, linearity and sensitivity for 3 demonstration mAb drugs. The successful application of the method to clinical samples demonstrated its' applicability in clinical analysis. It is anticipated that this general method could be applied to other mAb-based drugs for use in precision medicine and clinical studies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Although irinotecan and oxaliplatin are both standard treatments for advanced colon cancer, it remains unknown whether either is effective for patients with resectable synchronous colon cancer and liver-confined metastasis (SCCLM) after curative surgery., Patients and Methods: A population-based cohort of patients diagnosed with de novo SCCLM between 2004 and 2009 was established by searching the database of the Taiwan Cancer Registry and the National Health Insurance Research Database of Taiwan. Patients who underwent curative surgery as their first therapy followed by chemotherapy doublets were classified into the irinotecan group or oxaliplatin group accordingly. Patients who received radiotherapy or did not receive chemotherapy doublets were excluded., Results: We included 6,533 patients with de novo stage IV colon cancer. Three hundred and nine of them received chemotherapy doublets after surgery; 77 patients received irinotecan and 232 patients received oxaliplatin as adjuvant chemotherapy. The patients in both groups exhibited similar overall survival (median: not reached vs. 40.8 months, p=0.151) and time to the next line of treatment (median: 16.5 vs. 14.3 months, p=0.349) in both univariate and multivariate analyses. Additionally, patients with resectable SCCLM had significantly shorter median overall survival than patients with stage III colon cancer who underwent curative surgery and subsequent adjuvant chemotherapy, but longer median overall survival than patients with de novo stage IV colon cancer who underwent surgery only at the primary site followed by standard systemic chemotherapy (p<0.001)., Conclusion: Irinotecan and oxaliplatin exhibited similar efficacy in patients who underwent curative surgery for resectable SCCLM., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Antiangiogenic therapy is crucial for advanced hepatocellular carcinoma (HCC) treatment. Interleukin (IL)-6 is an inflammatory response mediator that can promote angiogenesis. We explored its prognostic role in patients with advanced HCC., Methods: We had two patient cohorts, both comprising patients who received sorafenib-containing therapy as the first-line treatment for advanced HCC. We explored the best cut point for pretreatment plasma IL-6 levels in the exploration cohort and then confirmed it in the validation cohort., Results: In total, 55 and 73 patients constituted the exploration and validation cohorts, respectively. In the exploration cohort, a cut point of 4.28 pg/ml was the best for defining high and low IL-6 levels because it could most effectively differentiate overall survival (OS). On application of this cut point to the validation cohort, patients with high plasma IL-6 levels, compared with patients with low IL-6 levels, exhibited significantly poorer OS (median, 8.0 vs 13.9 months, P = 0.031) but similar progression-free survival or treatment response. After adjusting for patient demographics and tumor characteristics, a high plasma IL-6 level remained an independent predictor of poor OS (hazard ratio 2.594, P = 0.005)., Conclusion: High pretreatment plasma IL-6 levels were associated with poor prognosis of patients with advanced HCC., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Context: Undertreatment of cancer pain among outpatient cancer patients needs to be addressed to enhance care and improve patients' quality of life (QoL)., Objectives: This prospective, cross-sectional, patient-focused study aimed to explore the prevalence of pain and undertreatment of cancer pain in outpatients in Taiwan., Methods: A total of 2652 non-selected outpatients with cancer and aged 20 years or older from 16 medical centers across Taiwan were included in this survey. All patients completed a questionnaire based on the Brief Pain Inventory. Pain management index (PMI) was used to evaluate the adequacy of pain management. Possible clinical variables of patients with positive PMI were examined by univariate and multivariate logistic regressions., Results: A total of 1659 (62.6%) outpatients had experienced some degree of pain; among these, 32.4% had negative PMI. Patients with a negative PMI score had significantly poor outcomes of QoL and a significantly higher tendency toward dissatisfaction with pain control by the physician and with the prescribed analgesic drugs. Female gender, primary tumor from breast, non-cancer-related cause of pain, and hospital locations from north Taiwan were independent variables that predicated patients with undertreatment of cancer pain. Most importantly, a forward trend of undertreatment of pain among patients who presented with lower prevalent rate of pain was observed., Conclusion: One-third of Taiwanese outpatients experienced pain because of undertreatment. Awareness of the prevalence of undertreatment of cancer pain and identification of the vulnerable subjects may assist in enhancing patient care and improving patient's QoL., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

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 124 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 max and AUC t of codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed 124 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).

Purpose: Do-not-resuscitate (DNR) consent is crucial in end-of-life (EOL) care for patients with advanced cancer. However, DNR consents signed by patients (DNR-P) and surrogates (DNR-S) reflect differently on patient autonomy and awareness., Methods: This retrospective study enrolled advanced cancer patients treated at National Taiwan University Hospital, Hsin-Chu Branch between 2012 and 2014. Patients who signed DNR consent at other hospitals were excluded; the remaining patients were subsequently classified into DNR-S and DNR-P groups., Results: We enrolled 1495 patients. The most prevalent primary cancers were hepato-biliary-pancreatic (26.9 %), lung (16.3 %), and colorectal (14.0 %) cancers. We classified 965 (64.5 %) and 530 (35.5 %) patients into the DNR-S and DNR-P groups, respectively. Significant differences were observed between both groups regarding gender (p = 0.002), age (p < 0.001), and the Eastern Cooperative Oncology Group performance (p < 0.001) and educational (p < 0.001) status levels. The median survival times after DNR consent signature were 5.0 days (95 % confidence interval [CI] 4.4-5.6 days) and 14.0 days (95 % CI 12.1-15.9 days) in the DNR-S and DNR-P groups, respectively (p < 0.001). The median good death evaluation (GDE) scores were 5.4 (95 % CI 4.9-6.0) and 13.7 (95 % CI 12.7-14.6) in the DNR-S and DNR-P groups, respectively (p < 0.001). Univariate and multivariate analyses revealed that DNR-S was an independent factor for significantly low GDE scores (i.e., poor EOL care quality)., Conclusion: The DNR concept is emerging; however, the DNR-P percentage remains low (35.6 %) in patients with advanced cancer. DNR-P significantly improves the EOL care quality.

Sorafenib, a multikinase inhibitor, is currently the only approved drug for advanced hepatocellular carcinoma (HCC). The current study tested the hypothesis whether inhibition of the Wnt/β-catenin signaling pathway could improve the anti-tumor effects of sorafenib in HCC. ICG-001, a small molecule which blocks the interaction of β-catenin with its transcriptional coactivator CBP, dose-dependently enhanced the growth-suppressive and apoptosis-induction effects of sorafenib in multiple HCC cell lines. Downregulation of β-catenin by RNA interference increased sorafenib sensitivity, whereas overexpression of β-catenin reduced sorafenib sensitivity in Huh7 cells. The sorafenib-sensitization effect of short hairpin RNA (shRNA)-mediated β-catenin downregulation in Huh7 cells was attenuated by β-catenin overexpression. Mechanistically, sorafenib combined with ICG-001 or shRNA-mediated β-catenin downregulation augmented the induction of apoptosis, and resulted in a significant downregulation of Mcl-1 in HCC cells. In Huh7 cell mouse xenograft model, the combination of ICG-001 and sorafenib showed a more significant growth-retarding effect than single agent treatment of sorafenib or ICG-001. Our data indicate that inhibition of the Wnt/β-catenin signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Opioids are crucial in cancer pain management. We examined the nationwide prescription patterns of opioids in Taiwan cancer patients to find the potential concerns., Methods: We reviewed the claims database of the National Health Insurance of Taiwan for patients diagnosed with cancer from 2003 to 2011. The use and cost of analgesics were analyzed. Opioids were classified into recommended strong opioids (morphine and transdermal fentanyl), recommended weak opioids (tramadol, buprenorphine, and codeine), and unrecommended opioids (propoxyphene, nalbuphine, and meperidine)., Results: We enrolled 1,424,048 patients with cancer, and ∼50% of them took analgesics. Among analgesic users, patients who used opioids increased from 48.2% in 2003 to 52.0% in 2010. Approximately 92% of the opioid use came from recommended opioids, either strong (51%) or weak opioids (41%). The ratio of the use of short-acting strong opioids to that of long-acting opioids increased from 0.41 in 2003 to 0.63 in 2011. Transdermal fentanyl accounted for > 50% of the use of strong opioids. Among weak opioids, the use of tramadol gradually increased to 71% in 2011. On average, opioids contributed to 0.79‰ of all medical expenditures and 2.94‰ of all medication costs., Conclusion: The use of short-acting strong opioids increased during the study period. Instead of oral opioids, transdermal fentanyl was the most commonly used opioid among Taiwan cancer patients. The use of weak opioids, particularly tramadol, was high. These concerns should be the focus of pain management education., (Copyright © 2016. Published by Elsevier B.V.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Sorafenib has become the standard therapy for patients with advanced hepatocellular carcinoma (HCC). Unfortunately, most patients eventually develop acquired resistance. Therefore, it is important to identify potential biomarkers that could predict the efficacy of sorafenib. To identify target proteins associated with the development of sorafenib resistance, we applied stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomic approach to analyze differences in protein expression levels between parental HuH-7 and sorafenib-acquired resistance HuH-7 (HuH-7(R)) cells in vitro, combined with an isobaric tags for relative and absolute quantitation (iTRAQ) quantitative analysis of HuH-7 and HuH-7(R) tumors in vivo. In total, 2,450 quantified proteins were identified in common in SILAC and iTRAQ experiments, with 81 showing increased expression (>2.0-fold) with sorafenib resistance and 75 showing decreased expression (<0.5-fold). In silico analyses of these differentially expressed proteins predicted that 10 proteins were related to cancer with involvements in cell adhesion, migration, and invasion. Knockdown of one of these candidate proteins, galectin-1, decreased cell proliferation and metastasis in HuH-7(R) cells and restored sensitivity to sorafenib. We verified galectin-1 as a predictive marker of sorafenib resistance and a downstream target of the AKT/mTOR/HIF-1α signaling pathway. In addition, increased galectin-1 expression in HCC patients' serum was associated with poor tumor control and low response rate. We also found that a high serum galectin-1 level was an independent factor associated with poor progression-free survival and overall survival. In conclusion, these results suggest that galectin-1 is a possible biomarker for predicting the response of HCC patients to treatment with sorafenib. As such, it may assist in the stratification of HCC and help direct personalized therapy., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The approval of sorafenib, a multikinase inhibitor targeting primarily Raf kinase and the vascular endothelial growth factor receptor, in 2007 for treating advanced hepatocellular carcinoma (HCC) has generated considerable enthusiasm in drug development for this difficult-to-treat disease. However, because several randomized Phase III studies testing new multikinase inhibitors failed, sorafenib remains the standard of first-line systemic therapy for patients with advanced HCC. Field practice studies worldwide have suggested that in daily practice, physicians are adopting either a preemptive dose modification or a ramp-up strategy to improve the compliance of their patients. In addition, accumulating data have suggested that patients with Child-Pugh class B liver function can tolerate sorafenib as well as patients with Child-Pugh class A liver function, although the actual benefit of sorafenib in patients with Child-Pugh class B liver function has yet to be confirmed. Whether sorafenib can be used as an adjunctive therapy to improve the outcomes of intermediate-stage HCC patients treated with transcatheter arterial chemoembolization or early-stage HCC patients after curative therapies is being investigated in several ongoing randomized Phase III studies. An increasing number of studies have reported that sorafenib exerts "off-target" effects, including the modulation of signaling pathways other than Raf/MEK/ERK pathway, nonapoptotic cell death mechanisms, and even immune modulation. Finally, although sorafenib in combination with chemotherapy or other targeted therapies has the potential to improve therapeutic efficacy in treating HCC, it also increases toxicity. Additional clinical studies are warranted to determine useful sorafenib-based combinations for the treatment of advanced HCC.

Background: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor despite treatment with sorafenib or other anti-angiogenic targeted-therapies. Patients with advanced HCC with prolonged survival may exhibit unique clinical characteristics., Patients and Methods: We reviewed patients with Barcelona Clinic Liver Cancer stage C HCC, who were enrolled in six clinical trials for first-line anti-angiogenic targeted-therapy between May 2005 and December 2010 in a single Institute. Patients with prolonged survival were identified as those who exhibited overall survival (OS) of more than two years; their clinical variables were analyzed., Results: Of the 189 enrolled patients, 22 (11.6%) patients with prolonged survival were identified. Their median OS was 58.7 (range=24.6-88.4) months, compared to an OS of 7.1 months for the overall patient cohort. A multivariate analysis showed that the patients with prolonged survival were less likely to have chronic hepatitis B virus infection, α-fetoprotein level >400 ng/ml, and liver involvement than were the remaining patients. In addition, the patients with prolonged survival experienced significantly higher response rates (50.0%) and disease control rates (86.4%) to the first-line targeted-therapy, and received more additional therapies than did the other patients. Seven patients remained disease-free for a median of 27.0 (range, 4.5-64.6) months after receiving additional locoregional therapies., Conclusion: Patients with advanced HCC who experienced prolonged survival exhibited certain clinical features and strong treatment responses to first-line anti-angiogenic targeted-therapies. Additional locoregional therapies could contribute to the long-term disease-free status in selected patients.

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., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: The epidermal growth factor receptor inhibitors, gefitinib and erlotinib, are used as standard salvage therapy for advanced non-small-cell lung cancer (NSCLC). The aim of the present study was to compare their efficacies in this population., Patients and Methods: The Taiwan Cancer Registry and the National Health Insurance claim databases were searched for newly diagnosed patients with NSCLC from 2004 to 2007 who received gefitinib or erlotinib as third-line therapy. Overall survival (OS) and time to treatment failure (TTF) were determined from registered parameters. Treatment efficacies were compared by the log-rank test in total population and subsets with different clinical characteristics. The Cox's proportion hazard model was used to estimate the adjusted hazard ratios in multivariate analyses., Results: A total of 984 patients who received gefitinib (67%) or erlotinib (33%) were included. Patients receiving gefitinib or erlotinib had similar OS (median, 10.2 versus 9.9 months, p=0.524) and TTF (median, 5.5 versus 3.4 months, p=0.103). In multivariate analyses, both treatment groups had similar risk of overall mortality (adjusted hazard ratio [HR]=1.04, p=0.629) and treatment failure (adjusted HR=0.94, p=0.417). Comparing the treatments in subgroups based on age, tumour histology and gender also revealed no differences in OS and TTF. For patients who received gefitinib or erlotinib for more than 3 or 6 months, there was no difference in TTF but patients who received erlotinib had longer OS., Conclusions: Gefitinib and erlotinib had similar efficacies as salvage therapy for advanced NSCLC in Taiwan., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background/aim: Biomarker studies using immunohistochemical (IHC) staining have not been successful for advanced hepatocellular carcinoma (HCC). We aimed to examine whether the tissue procurement process influences the protein expression levels detected by IHC., Materials and Methods: Forty-two tissue pairs of HCC that had been both preoperatively biopsied and then surgically resected were included in the study. IHC staining was used to determine expression of target molecules, all of which were graded according to the percentage of positively stained tumor cells. The expression of beta-catenin was analyzed according to the localization of positive staining., Results: Biopsied and surgically resected tissues exhibited dissimilar phosphorylated extracellular signal regulated kinase (p-ERK) and phosphorylated AKT expression levels (kappa=0.025 and 0.153, respectively). On the contrary, p53 exhibited similar expression levels, and beta-catenin exhibited similar staining localization patterns in biopsied and surgically resected tissues (kappa=0.729 and 0.654, respectively)., Conclusion: Biopsied HCC tissues and their corresponding resected HCC tissues have inconsistent IHC-detected ERK and AKT expressions.

Background: The current standard treatment for patients with metastatic gastric cancer (MGC) is systemic chemotherapy. For gastric cancer patients with ovarian metastases, i.e. Krukenberg tumors, it is not known whether metastasectomy is associated with additional benefits., Patients and Methods: All patients who were diagnosed with gastric cancer and ovarian metastases between March 2000 and July 2010 in a medical center were included in the current study. The clinicopathological features and the treatment records were reviewed in detail and their association with overall survival (OS) was analyzed., Results: A total of 85 patients were identified. Thirty five (41.2%) and 50 (58.8%) patients did and did not undergo metastasectomy of Krukenberg tumors, respectively. The performance status and the proportion of patients receiving subsequent systemic therapy were well-matched between the two groups. Regarding disease status, patients who underwent metastasectomy had significantly larger Krukenberg tumors, pronounced bilateral disease and less extensive metastases outside the ovaries than patients who did not undergo metastasectomy. Patients who underwent metastasectomy had a better OS [median=14.1 months; 95% confidence interval (CI)=8.6-19.6 months] than patients who did not undergo metastasectomy (median OS=8 months; 95% CI=5.6-10.4 months, p=0.001). There was no aberrant postoperative morbiditie rate observed, and the median length of hospital stay after metastasectomy alone was 6 days. Based on multivariate analysis, metastasectomy remained an independent predictor of better OS (hazard ratio=0.36, p=0.002). The administration of subsequent systemic therapy, the use of platinum-based chemotherapy, and a better performance status also predict a better OS., Conclusion: Metastasectomy of Krukenberg tumors may be associated with survival benefits in patients with MGC. Further prospective studies are warranted.

Background: Hepatitis B virus (HBV) infection is one of the main etiologies of hepatocellular carcinoma (HCC). We explored the impact of HBV DNA levels on the prognosis of patients with advanced HCC., Patients and Methods: The study was based on patients with advanced HCC and chronic HBV infection enrolled into three phase II trials evaluating first-line antiangiogenic therapy. Pre-treatment HBV DNA levels were measured by real-time quantitative polymerase chain reaction., Results: Seventy-two patients were included. Patients with detectable HBV DNA levels had poorer median overall survival (OS) compared to patients without detectable levels (4.8 vs. 9.3 months, p=0.037). After adjusting for other clinicopathologic variables, the baseline HBV DNA level was an independent predictor of poor OS (p=0.014). Baseline HBV DNA levels were not correlated with progression-free survival or disease control rate., Conclusion: Baseline HBV DNA levels were associated with the prognosis of patients with chronic HBV infection receiving antiangiogenic therapy for advanced HCC.

Once distant metastasis occurs, head and neck squamous cell carcinoma (HNSCC) patients generally have a poor prognosis with limited treatment options. A subgroup of patients who developed pleural metastases after curative treatment of localized HNSCC appeared to have worse outcomes. All patients from National Taiwan University Hospital who were diagnosed with localized HNSCC from January 1, 2000 to December 31, 2007 and developed distant metastases were included in this analysis. Medical records were reviewed. Patients with pleura as the first metastatic sites were compared to those with other first metastases for differences in basic demographics, time to distant metastasis (TTM) and overall survival (OS). A total of 198 patients were included, and 52 (26%) had pleural involvement at first diagnosis of distant metastases. Younger age at diagnosis (P=0.002) and buccal mucosa origin (P=0.006) were risk factors for developing pleural metastases. Patients with pleura as the first metastatic sites, compared to those with other first metastases, had significantly shorter TTM (median 7.5 vs. 11.1 months, P<0.001) and OS (median 9.6 vs. 16.5 months, P<0.001). By multivariate analysis, pleural metastases remained an independent predictor for shorter OS. In conclusion, patients with pleural metastases comprise a unique subgroup of HNSCC which rapidly develop distant metastases with poor prognosis., (Copyright 2010 Elsevier Ltd. All rights reserved.)

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., (Copyright 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Tyrosine kinase inhibitors of the epidermal growth factor receptor, gefitinib and erlotinib, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). Many phase II or III studies have proven the efficacy of gefitinib or erlotinib as the first-line, second-line, or third-line treatment. However, it is not clear whether gefitinib or erlotinib has different activities in advanced NSCLC patients with different clinicopathological features or at different stages. We review the published clinical trials that used gefitinib or erlotinib in NSCLC and compare their efficacy. The selection criteria and efficacy measurement in these trials that might affect the final results of the studies are listed and discussed. The adequate-powered, direct comparisons of gefitinib against erlotinib under the same clinical scenarios are lacking. There is no evidence at present that the efficacy of these two agents in NSCLC is different.

Background/purpose: Hypersensitivity reactions during oxaliplatin infusion are a major problem associated with its use. In this study, we investigated the characteristics and risk factors of these events., Methods: All patients who had received oxaliplatin in outpatient settings from January 2006 to March 2007 in a medical center were enrolled in this retrospective study. All the oxaliplatin infusions were reviewed. Manifestations of hypersensitivity reactions and clinicopathological variables were collected from medical records., Results: Three hundred and eighty-three patients with 3648 oxaliplatin infusions were reviewed. Forty-seven patients (12.7%) developed hypersensitivity reactions, which occurred after a median of 10 infusions. The median time of onset from start of infusion was 40 minutes. Most presentations (90.7%) were mild to moderate, but rechallenge with oxaliplatin led to a high chance of further reactions (71.4%). Cutaneous symptoms were the most prevalent manifestation, followed by respiratory symptoms. With each repeated infusion, the incidence of hypersensitivity reactions increased. Higher oxaliplatin dose per infusion was an independent risk factor for such reactions., Conclusion: Patients treated with oxaliplatin for an extended period have a greater risk of oxaliplatin-related hypersensitivity reactions., (Copyright 2010 Formosan Medical Association & Elsevier. Published by Elsevier B.V. All rights reserved.)

Bowel perforation is a rare but life-threatening complication of bevacizumab, a new anticancer treatment. Patients with bowel perforation usually present with acute abdominal symptoms. Here a case history is presented to highlight a pancreatic cancer patient on bevacizumab chemotherapy who developed empyema as the first manifestation of gastric perforation. This unusual presentation warns physicians that bevacizumab-related bowel perforation can arise as a thoracic complication, without typical gastrointestinal manifestations, in an advanced cancer patient.

Oxaliplatin-related thrombocytopenia is considered rare and mostly self-limited. We present the first reported fatal case due to this complication. A 64-year-old patient with metastatic colon cancer was admitted for his 24th course of chemotherapy with oxaliplatin and 24-hour infusion of fluorouracil and leucovorin. Consciousness changed on the next evening and deteriorated to deep coma within hours. Computed tomography revealed large intracranial hemorrhage with brain herniation. Hemogram showed severe thrombocytopenia, which was considered to be associated with oxaliplatin. The patient died six days later. The incidence of oxaliplatin-related thrombocytopenia may have been underestimated and its severity long neglected. Other hypersensitivity reactions may precede its onset. Early hemogram examination during hypersensitivity reaction to oxaliplatin may provide early diagnosis and the prevention of the possible fatal consequences.