Tom Wei-Wu Chen

Bevacizumab Preconditioning Followed by Etoposide and Cisplatin Is Highly Effective in Treating Brain Metastases of Breast Cancer Progressing from Whole-Brain Radiotherapy

Purpose: We hypothesized that a window period between bevacizumab and cytotoxic agents may enhance drug delivery into tumor tissue through bevacizumab-induced vascular normalization in patients with brain metastases of breast cancer (BMBC). Experimental Design: A single-arm phase II study was conducted in which BMBC patients refractory to whole-brain radiotherapy (WBRT) were enrolled. In a 21-day cycle, patients received bevacizumab (15 mg/kg) on day 1, which, with a 1-day window period, was followed by etoposide (70 mg/m2/day; days 2–4) and cisplatin (70 mg/m2; day 2; BEEP regimen). The BEEP regimen was administered for a maximum of 6 cycles. The primary endpoint was the central nervous system (CNS)–objective response rate according to volumetric response criteria. Results: A total of 35 patients were enrolled between January 2011 and January 2013. The median age was 54.3 years (range, 33–75); 19 patients (54.3%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. Twenty-seven patients [77.1%; 95% confidence interval (CI), 59.9–89.6] achieved a CNS-objective response, including 13 patients (37.1%) with a ≥80% volumetric reduction of CNS lesions. With a median follow-up of 16.1 months, the median CNS progression-free survival and overall survival times were 7.3 months (95% CI, 6.5–8.1) and 10.5 months (95% CI, 7.8–13.2), respectively. Common grade 3 or 4 toxicities included neutropenia (30.8%) and infection (21.3%). Conclusions: By administering bevacizumab 1 day before etoposide and cisplatin, the BEEP regimen appeared highly effective in BMBC refractory to WBRT. Further study of vascular normalization window concept is warranted. Clin Cancer Res; 21(8); 1851–8. ©2015 AACR.

Association of Hospital Characteristics and Diagnosis With the Repeat Use of CT and MRI: A Nationwide Population-Based Study in an Asian Country

OBJECTIVE The objective of our study was to assess the association of hospital characteristics and diagnosis with repeated utilization of CT and MRI using the nationwide population-based Taiwan National Health Insurance database. MATERIALS AND METHODS All CT and MR examinations for all health care services-including inpatient, outpatient, and emergency services-performed during 2004 and 2005 were identified. Logistic regression using generalized estimating equations was used for multivariate analysis to explore the relationships between hospital characteristics, diagnosis, and the use of CT and MRI repeated within 90 days. RESULTS A total of 2,152,292 patients underwent CT and MR examinations during the study period, and 21.5% of those patients underwent repeat scanning within 90 days. The medical center had the highest rate of repeat scanning (24.9%) followed by the regional hospital (20.4%) and community hospital (13%). Repeat CT or MRI was most commonly performed of patients with a malignancy (31.8%), a neurologic disorder (24.0%), or a brain or spinal injury (25.3%). CONCLUSION Our study shows that repeat use of CT and MRI within 90 days is high and is related to both diagnosis and hospital characteristics. Although the Taiwanese experience might not apply to all countries, this knowledge should aid in the review of health care policies so that guidelines for repeat scanning may be tailored to the different levels of hospitals (medical centers, 25%; regional hospital, 20%; community hospital, 13%) and to different diseases (malignant neoplasms, 32%; neurologic disorders and brain, neck, or spinal injury, 25%; other entities, 20%) to achieve maximum efficiency within a limited health care budget.

Personalized medicine for metastatic breast cancer.

Purpose of review With recent advances in DNA sequencing technology, recurrent genomic alterations can be identified in tumor samples from patients with metastatic breast cancer (MBC) to enrich clinical trials testing targeted therapies. This review provides an overview of clinically relevant genomic alterations in MBC and summarizes the recent clinical data from early phase trials of novel targeted treatments. Recent findings The clinical development of personalized treatment includes targeted agents directed against PI3K/mTOR, fibroblast growth factor receptor (FGFR), human epidermal growth factor receptor 2 (HER2), DNA repair, and cell cycle pathways. PI3K/mTOR pathway drugs are active in endocrine and trastuzumab-resistant disease. Drugs targeted at PI3K/mTOR, FGFR, and poly(ADP-ribose) polymerase show early signs of efficacy in MBC subpopulations enriched with relevant pathway aberrancies. Regimens combining targeted agents with either endocrine, anti-HER2, or chemotherapy treatments are also being studied in hormone receptor-defined and HER2-defined or pathway-enriched subgroups. Summary A new approach to personalized medicine for MBC that involves molecular screening for clinically relevant genomic alterations and genotype-targeted treatments is emerging. Clinical trials are needed to determine whether rare subpopulations of MBC benefit from genotype-targeted treatments.

Delineation of the Watershed between Right and Left Hepatic Arterial Territories with Carbon Dioxide–enhanced Ultrasonography

PURPOSE To delineate the watersheds between hepatic arterial territories and their variations with the use of CO(2)-enhanced ultrasonography (US) and to compare the results with segmental anatomy as described by Couinaud. MATERIALS AND METHODS From March 2004 to January 2005, this study recruited 31 patients (18 men and 13 women; mean age, 63 years; range, 47-77 y) with hepatocellular carcinoma (HCC) who were scheduled to receive transarterial chemoembolization. After serial angiography, CO(2)-enhanced US was performed with catheters superselectively inserted into the hepatic arteries. The territorial divisions between hepatic arteries were compared with the anatomic courses of the middle and left hepatic veins. Data from 17 patients were used to assess the vascular territories of the right and left lobe and data from the remaining 14 patients were used to assess those of the left medial and left lateral segments. RESULTS Mapped arterial territories exactly matched Couinaud segments in 17 of 31 patients (54.8%). They did not coincide with Couinaud segments in 45.2% of patients with HCC. Crossover enhancement was noted over the right and left lobes and over the left medial and lateral segments in seven patients each. Two tumors located exactly in watershed areas showed CO(2) enhancement across the hepatic vein. CONCLUSIONS CO(2)-enhanced US is useful to delineate arterial territories of hepatic segments and show crossover arterial supply compared with Couinaud segments. Awareness of crossover arterial supply is important for chemoembolization, segmental chemoembolization, hepatic arterial infusion, sonography, and surgery.

Systemic therapies for recurrent or metastatic nasopharyngeal carcinoma: a systematic review

Background:The majority of published studies in recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) are single-arm trials. Reliable modelling of progression-free survival (PFS) and overall survival (OS) outcomes, therefore, is difficult. This study aim to analyse existent literature to estimate the relative efficacy of available systemic regimens in RM-NPC, as well as provide estimates of aggregate OS and PFS.Methods:We conducted a systematic search of MEDLINE, EMBASE and the Cochrane Library to March 2015. Clinical trials (in English only) investigating cytotoxic and molecularly targeted agents in adult patients with RM-NPC were included. All relevant studies were assessed for quality using Downs and Blacks (DB) checklist (maximum quality score of 27). Aggregate data analysis and Student’s t-test were performed for all identified studies (model A). For studies that published analysable Kaplan−Meier curves, survival data were extracted and marginal proportional hazards models were constructed (model B).Results:A total of 56 studies were identified and included in model A, 26 of which had analysable Kaplan−Meier curves and were included in model B. The 26 studies in model B had significantly higher mean DB scores than the remaining 30 (17.3 vs 13.7, P=0.002). For patients receiving first line chemotherapy, the estimated median OS was 15.7 months by model A (95% CI, 12.3–19.1), and 19.3 months by model B (95% CI, 17.6–21.1). For patients undergoing second line or higher therapies (2nd+), the estimated median OS was 11.5 months by model A (95% CI 10.1–12.9), and 12.5 months by model B (95% CI 11.9–13.4). PFS estimates for patients undergoing first-line chemotherapy by model A was 7.6 months (95% CI, 6.2–9.0), and 8.0 months by model B (95% CI, 7.6–8.8). For patients undergoing therapy in the 2nd+ setting, the estimated PFS by model A was 5.4 months (95% CI, 3.8–7.0), and 5.2 months by model B (95% CI, 4.7–5.6).Conclusions:We present the first aggregate estimates of OS and PFS for RM-NPC patients receiving first and second-line or higher treatment settings, which could inform the design of future clinical trials in this disease setting.

Phosphatidylinositol-3 Kinase Inhibitors, Buparlisib and Alpelisib, Sensitize Estrogen Receptor-positive Breast Cancer Cells to Tamoxifen

Tamoxifen is the standard first-line hormonal therapy for premenopausal women with estrogen receptor (ER)-positive metastatic breast cancer (BC). One of the crucial mechanisms underlying hormonal therapy resistance is the collateral activation of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We explored whether PI3K inhibitors, buparlisib and alpelisib, enhance the efficacy of tamoxifen against ER-positive BC cells. We have observed a synergism between alpelisib or buparlisib and tamoxifen in the treatment for ER-positive BC cell lines harboring different PI3K alterations. Immunoblotting analysis showed alpelisib, buparlisib, or either drug in combination with tamoxifen downregulated the PI3K downstream targets in the MCF-7 and ZR75-1 cells. In the MCF-7 cells transfected with a constitutive active (myristoylated) AKT1 construct or mutant ER, the synergistic effect between alpelisib and tamoxifen was markedly attenuated, indicating that synergism depends on AKT inhibition or normally functioning ER. Combining alpelisib or buparlisib with tamoxifen also attenuated MCF-7 tumor growth in Balb/c nude mice. Our data suggest that additional PI3K blockade might be effective in enhancing the therapeutic effect of tamoxifen in ER-positive BC and support the rationale combination in clinical trials.

The diameter of the common bile duct in an asymptomatic Taiwanese population: Measurement by magnetic resonance cholangiopancreatography

Background: Magnetic resonance cholangiopancreatography (MRCP) is a popular modality for evaluation of the biliary tract, yet there is no data on the normal common bile duct (CBD) size of the average Taiwanese adult. This study attempts to establish a reference range for CBD diameter for the Taiwanese population. Methods: Over a 2‐year period, all adults who underwent abdominal magnetic resonance imaging for health screening were recruited into the study. Patients with a prior history of hepatobiliary surgery and other significant morbidity were not included. Patients who were found to have abnormal liver function test results or abnormal imaging findings were also excluded from the study. After the patients fasted for a minimum of 8 hours, MR imaging was performed with a 1.5 T MR imager using a phased‐array coil. Breath‐hold thick slab single‐shot turbo spin echo (ssTSE BH) projections were obtained, and these were used for CBD and portal vein diameter (PVD) measurement by workstation software. Initial recruitment included 265 patients, of which 66 were excluded due to abnormal liver function tests, seven more were excluded due to excess imaging artifacts or incomplete CBD visualization, and five were excluded due to other abnormal blood tests. This yielded a final study group of 187 patients between the ages of 21 and 78 years, which comprised 69 women and 118 men. Results: The mean CBD diameter is 4.6 mm, with a range from 1.76 to 10.49 mm. CBD diameters are significantly different in patients both younger and older than 65 years of age (p < 0.05), and are not significantly related to gender, serum glucose level, cholesterol level, hepatitis status and PVD. Conclusion: Our study showed that the average CBD diameter for an asymptomatic Taiwanese adult is 4.6 mm, with an upper limit of 10.49 mm. CBD diameter is only significantly correlated with age. This is a useful reference in todays clinical setting where MRCP are commonly performed for evaluation of suspected biliary tract disease.

A Phase I/II study of the combination of lapatinib and oral vinorelbine in HER2-positive metastatic breast cancer

Background The combination of lapatinib and oral vinorelbine for HER2 positive metastatic breast cancer (MBC) is convenient but with uncertain toxicity profiles. A Phase I/II study was designed to understand the tolerability and efficacy of this combination treatment. Method Female MBC patients with HER2 positive were eligible. Lapatinib was given once daily and oral vinorelbine was given on Days 1 and 8 of a 21-day cycle. A 3 + 3 standard dose-escalation rule was applied in the Phase I study. The primary endpoint of the Phase II study was PFS. In the Phase II part, because no DLT was observed in the first 20 patients, vinorelbine dose-escalation was permitted if no significant toxicities after the first cycle was observed. Result From June 2009 to February 2013, 46 patients were enrolled in Phase I (n = 15) and II (n = 31) studies. Median age was 52.8 (range 34.3-84.0); 28 (60.9%) patients were ER positive. In the Phase I study, two patients had DLTs (neutropenia (n = 2), diarrhea (n = 1)). The MTD was determined at lapatinib 1000 mg plus oral vinorelbine 50 mg/m2. In the Phase II study, 11 patients safely had vinorelbine escalated to 60 mg/m2 on cycle 2. The median PFS was 5.6 months (95% CI 5.2-5.9); 6 (19.4%) patients had PR; the clinical benefit rate was 38.7%. Six patients had disease control over 2 years. Conclusion Lapatinib 1000 mg and oral vinorelbine 50 mg/m2 were tolerable with manageable toxicities. Escalation to vinorelbine 60 mg/m2 is feasible if no significant toxicities after the first cycle. Clinical efficacy was demonstrated with long-term responders observed.

Prognostic factors and treatment outcomes of malignant pleural mesothelioma in Eastern Asian patients – A Taiwanese study

BACKGROUND/PURPOSE There are scarce reports on the prognostic factors and treatment outcomes of patients with malignant pleural mesothelioma (MPM) in Asia. This study aimed to address these matters in a real-world setting. METHODS Medical records of patients with histologically proven MPM diagnosed between 1977 and 2016 at the National Taiwan University Hospital were reviewed. Variables including age, gender, performance status, asbestos exposure, smoking history, histology subtype, staging, and treatment received were recorded. All patients were followed until death or March 1st, 2017. Survival and prognostic factors were analyzed by the Kaplan-Meir method and the Cox proportional hazard model. RESULTS A total of 93 patients was identified, including 65 men and 28 women. An increasing trend of MPM cases diagnosed was observed in the past 40 years. Stage I/II disease (HR 0.24, 95% CI 0.13-0.46) and epithelioid histology (HR 0.42, 95% CI 0.23-0.75) were associated with favorable prognosis, whereas age ≥70 years (HR 2.66, 95% CI 1.36-5.22) and ECOG ≥2 (HR 5.03, 95% CI 2.69-9.4) were poor prognostic factors. After adjustment for prognostic factors, surgery in stage I-III MPM (HR 0.36, 95% CI 0.15-0.83) and systemic therapy in stage III/IV disease (HR 0.42, 95% CI 0.19-0.94) conferred a survival benefit. CONCLUSION This is one of the largest case series of MPM reported in Asia outside of Japan. Prognostic factors in the study population included age, performance status, stage, and histology subtype. Surgery in potentially resectable disease and systemic therapy in advanced MPM confer a survival benefit in Asian patients.

Imaging biomarkers from multiparametric magnetic resonance imaging are associated with survival outcomes in patients with brain metastases from breast cancer

ObjectivesThe aim of this study is to investigate the correlation of survival outcomes with imaging biomarkers from multiparametric magnetic resonance imaging (MRI) in patients with brain metastases from breast cancer (BMBC).MethodsThis study was approved by the institutional review board. Twenty-two patients with BMBC who underwent treatment involving bevacizumab on day 1, etoposide on days 2-4, and cisplatin on day 2 in 21-day cycles were prospectively enrolled for a phase II study. Three brain MRIs were performed: before the treatment, on day 1, and on day 21. Eight imaging biomarkers were derived from dynamic contrast-enhanced MRI (Peak, IAUC60, Ktrans, kep, ve), diffusion-weighted imaging [apparent diffusion coefficient (ADC)], and MR spectroscopy (choline/N-acetylaspartate and choline/creatine ratios). The relative changes (Δ) in these biomarkers were correlated with the central nervous system (CNS)-specific progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier and Cox proportional hazard models.ResultsThere were no significant differences in the survival outcomes as per the changes in the biomarkers on day 1. On day 21, those with a low ΔKtrans (p = 0.024) or ΔADC (p = 0.053) reduction had shorter CNS-specific PFS; further, those with a low ΔPeak (p = 0.012) or ΔIAUC60 (p = 0.04) reduction had shorter OS compared with those with high reductions. In multivariate analyses, ΔKtrans and ΔPeak were independent prognostic factors for CNS-specific PFS and OS, respectively, after controlling for age, size, hormone receptors, and performance status.ConclusionsMultiparametric MRI may help predict the survival outcomes in patients with BMBC.Key Points• Decreased angiogenesis after chemotherapy on day 21 indicated good survival outcome.• ΔKtranswas an independent prognostic factors for CNS-specific PFS.• ΔPeak was an independent prognostic factors for OS.• Multiparametric MRI helps clinicians to assess patients with BMBC.• High-risk patients may benefit from more intensive follow-up or treatment strategies.