Andrew X Zhu

Harvard University, Cambridge, Massachusetts, United States

Are you Andrew X Zhu?

Claim your profile

Publications (200)1388.41 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: More effective therapy is needed for intrahepatic cholangiocarcinoma (ICC). The encouraging clinical results obtained with checkpoint molecule-specific monoclonal antibodies (mAbs) have prompted us to investigate whether this type of immunotherapy may be applicable to ICC. The aims of this study were to determine whether 1) patients mount a T-cell immune response to their ICC, 2) checkpoint molecules are expressed on both T-cells and tumor cells, and 3) tumor cells are susceptible to recognition by cognate T-cells. Experimental design: Twenty-seven ICC tumors were analyzed for i) lymphocyte infiltrate ii) HLA class I and HLA class II expression, and iii) PD-1 and PD-L1 expression by T-cells and ICC cells, respectively. The results of this analysis were correlated with the clinicopathological characteristics of the patients investigated. Results: Lymphocyte infiltrates were identified in all tumors. PD-L1 expression and HLA class I antigen expression by ICC cells was observed in 8 and 11, respectively, of the 27 tumors analyzed. HLA class I antigen expression correlated with CD8+ T cell infiltrate. Furthermore, positive HLA class I antigen expression in combination with negative/rare PD-L1 expression was associated with favorable clinical course of the disease. Conclusions: ICC patients are likely to mount a T cell immune response against their own tumors. Defects in HLA class I antigen expression in combination with PD-L1 expression by ICC cells provide them with an immune escape mechanism. This mechanism justifies the implementation of immunotherapy with checkpoint molecule-specific mAbs in patients bearing ICC tumors without defects in HLA class I antigen expression.
    Clinical Cancer Research 09/2015; DOI:10.1158/1078-0432.CCR-15-0715 · 8.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: To find prognostic biomarkers in pretreatment dynamic contrast-enhanced MRI (DCE-MRI) water-exchange-modified (WX) kinetic parameters for advanced hepatocellular carcinoma (HCC) treated with antiangiogenic monotherapy. Methods: Twenty patients with advanced HCC underwent DCE-MRI and were subsequently treated with sunitinib. Pretreatment DCE-MRI data on advanced HCC were analyzed using five different WX kinetic models: the Tofts-Kety (WX-TK), extended TK (WX-ETK), two compartment exchange, adiabatic approximation to tissue homogeneity (WX-AATH), and distributed parameter (WX-DP) models. The total hepatic blood flow, arterial flow fraction (γ), arterial blood flow (BFA), portal blood flow, blood volume, mean transit time, permeability-surface area product, fractional interstitial volume (vI), extraction fraction, mean intracellular water molecule lifetime (τC), and fractional intracellular volume (vC) were calculated. After receiver operating characteristic analysis with leave-one-out cross-validation, individual parameters for each model were assessed in terms of 1-year-survival (1YS) discrimination using Kaplan-Meier analysis, and association with overall survival (OS) using univariate Cox regression analysis with permutation testing. Results: The WX-TK-model-derived γ (P = 0.022) and vI (P = 0.010), and WX-ETK-model-derived τC (P = 0.023) and vC (P = 0.042) were statistically significant prognostic biomarkers for 1YS. Increase in the WX-DP-model-derived BFA (P = 0.025) and decrease in the WX-TK, WX-ETK, WX-AATH, and WX-DP-model-derived vC (P = 0.034, P = 0.038, P = 0.028, P = 0.041, respectively) were significantly associated with an increase in OS. Conclusions: The WX-ETK-model-derived vC was an effective prognostic biomarker for advanced HCC treated with sunitinib.
    PLoS ONE 09/2015; 10(9):e0136725. DOI:10.1371/journal.pone.0136725 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Conflicting data exist regarding the prognostic impact of the isocitrate dehydrogenase (IDH) mutation in intrahepatic cholangiocarcinoma (ICC), and limited data exist in patients with advanced-stage disease. Similarly, the clinical phenotype of patients with advanced IDH mutant (IDHm) ICC has not been characterized. In this study, we report the correlation of IDH mutation status with prognosis and clinicopathologic features in patients with advanced ICC. Patients with histologically confirmed advanced ICC who underwent tumor mutational profiling as a routine part of their care between 2009 and 2014 were evaluated. Clinical and pathological data were collected by retrospective chart review for patients with IDHm versus IDH wild-type (IDHwt) ICC. Pretreatment tumor volume was calculated on computed tomography or magnetic resonance imaging. Of the 104 patients with ICC who were evaluated, 30 (28.8%) had an IDH mutation (25.0% IDH1, 3.8% IDH2). The median overall survival did not differ significantly between IDHm and IDHwt patients (15.0 vs. 20.1 months, respectively; p = .17). The pretreatment serum carbohydrate antigen 19-9 (CA19-9) level in IDHm and IDHwt patients was 34.5 and 118.0 U/mL, respectively (p = .04). Age at diagnosis, sex, histologic grade, and pattern of metastasis did not differ significantly by IDH mutation status. The IDH mutation was not associated with prognosis in patients with advanced ICC. The clinical phenotypes of advanced IDHm and IDHwt ICC were similar, but patients with IDHm ICC had a lower median serum CA19-9 level at presentation. Previous studies assessing the prognostic impact of the isocitrate dehydrogenase (IDH) gene mutation in intrahepatic cholangiocarcinoma (ICC) mainly focused on patients with early-stage disease who have undergone resection. These studies offer conflicting results. The target population for clinical trials of IDH inhibitors is patients with unresectable or metastatic disease, and the current study is the first to focus on the prognosis and clinical phenotype of this population and reports on the largest cohort of patients with advanced IDH mutant ICC to date. The finding that the IDH mutation lacks prognostic significance in advanced ICC is preliminary and needs to be confirmed prospectively in a larger study. ©AlphaMed Press.
    The Oncologist 08/2015; 20(9). DOI:10.1634/theoncologist.2015-0210 · 4.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Subcutaneous xenografts have been used for decades to study hepatocellular carcinoma (HCC). These models do not reproduce the specific pathophysiological features of HCCs, which occur in cirrhotic livers that show pronounced necroinflammation, abnormal angiogenesis and extensive fibrosis. As these features are crucial for studying the role of the pathologic host microenvironment in tumor initiation, progression and treatment response, alternative HCC models are desirable. Here we describe a syngeneic orthotopic HCC model in immunocompetent mice with liver cirrhosis induced by carbon tetrachloride (CCl4) that recapitulates key features of human HCC. Induction of substantial hepatic fibrosis requires 12 weeks of CCl4 administration. Intrahepatic implantation of mouse HCC cell lines requires 30 min per mouse. Tumor growth varies by tumor cell line and mouse strain used. Alternatively, tumors can be induced in a genetically engineered mouse model. In this setting, CCl4 is administered for 12 weeks after tail-vein injection of Cre-expressing adenovirus (adeno-Cre) in Stk4(-/-)Stk3(F/-) (also known as Mst1(-/-)Mst2(F/-); F indicates a floxed allele) mice, and it results in the development of HCC tumors (hepatocarcinogenesis) concomitantly with liver cirrhosis.
    Nature Protocol 08/2015; 10(8):1264-1274. DOI:10.1038/nprot.2015.080 · 9.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to find prognostic biomarkers in perfusion computed tomography (PCT)-based kinetic parameters for advanced hepatocellular carcinoma (HCC) treated with antiangiogenic chemotherapy. Twenty-two patients with advanced HCC underwent PCT imaging and subsequently received bevacizumab in combination with gemcitabine and oxaliplatin. Pretreatment PCT data within advanced HCC were analyzed using the Tofts-Kety, 2-compartment exchange, adiabatic approximation to the tissue homogeneity (AATH), and distributed parameter models. Blood flow, blood volume, extraction fraction (E), and other 3 parameters were calculated. Kinetic parameters in each model were evaluated with 1-year survival discrimination using Kaplan-Meier analysis and with overall survival using univariate Cox regression analysis. Only the AATH model-derived E was statistically significantly prognostic for 1-year survival. The increased AATH model-derived E was significantly associated with longer overall survival (P = 0.005). The AATH model-derived E was an effective prognostic biomarker for advanced HCC.
    Journal of computer assisted tomography 07/2015; DOI:10.1097/RCT.0000000000000288 · 1.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tracer kinetic model selection for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data analysis influences its use as a prognostic biomarker. Our aim was to find DCE-MRI parameters that predict 1-year survival (1YS) and overall survival (OS) among patients with advanced hepatocellular carcinoma (HCC) treated with antiangiogenic monotherapy by conducting a proof-of-concept comparative study of five different kinetic models. Twenty patients with advanced HCC underwent DCE-MRI and subsequently received sunitinib. Pretreatment DCE-MRI data were analyzed retrospectively by using the Tofts-Kety (TK), extended TK, two compartment exchange, adiabatic approximation to the tissue homogeneity (AATH), and distributed parameter (DP) models. Arterial flow fraction (γ), arterial blood flow (BFA), permeability-surface area product (PS), fractional interstitial volume (vI), and other five parameters were calculated for each model. Individual parameters were evaluated for 1YS prediction using cross-validated Kaplan-Meier analysis, and for association with OS using univariate Cox regression analysis, with additional permutation testing. For 1YS prediction, the TK model-derived γ (P = .007) and vI (P = .029) and the AATH model-derived PS (P = .005) were significant; all these parameters were lower in the high-risk group. Increase in the AATH model-derived PS and the DP model-derived BFA was associated with significant increase in OS with hazard ratios of 0.766 (P = .023) and 0.809 (P = .025), respectively. The AATH model-derived PS was an effective prognostic biomarker for both 1YS and OS. Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.
    Academic radiology 07/2015; DOI:10.1016/j.acra.2015.05.012 · 1.75 Impact Factor
  • Lipika Goyal · Dawn Q Chong · Dan G Duda · Andrew X Zhu
    The Lancet Oncology 07/2015; 16(8). DOI:10.1016/S1470-2045(15)00093-5 · 24.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with, number NCT01140347. Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. Eli Lilly and Co. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 06/2015; 16(7). DOI:10.1016/S1470-2045(15)00050-9 · 24.69 Impact Factor
  • Annals of Oncology 06/2015; 26(suppl 4):iv109-iv109. DOI:10.1093/annonc/mdv235.04 · 7.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Many patients with primary hepatic malignancies present with advanced disease that is not suitable for surgical resection, orthotopic liver transplantation, or radiofrequency ablation. Outcomes are particularly dismal in patients with large, unresectable tumors and/or tumor venous thrombosis. Liver-directed radiotherapy, including stereotactic body radiotherapy (SBRT), is able to treat a variety of tumor sizes and tumors with venous involvement and has demonstrated excellent safety and control outcomes. SBRT should be considered a standard option in patients with early-stage hepatocellular carcinoma who are not candidates for surgical resection, orthotopic liver transplantation or radiofrequency ablation. SBRT should be strongly considered in patients with larger tumors and/or tumors with tumor venous thrombosis who have adequate liver function. Radiotherapy should remain a focus of hepatocellular carcinoma research.
    04/2015; 2(2). DOI:10.2217/HEP.15.7
  • Journal of Hepatology 04/2015; 62:S416. DOI:10.1016/S0168-8278(15)30504-3 · 11.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this study was to evaluate the response of biliary tract cancer treated with multidrug chemotherapy using FDG PET in comparison with morphologic and density changes. In this phase II clinical trial, 28 patients with unresectable or metastatic biliary tract cancers treated with gemcitabine and oxaliplatin combined with bevacizumab (GEMOX-B) underwent FDG PET and contrast-enhanced CT at baseline and after the second cycle of the therapy (8 weeks). A single reviewer recorded tumor maximum standardized uptake value (SUVmax) along with size, volume (3D-sphere), and density. The percentage changes of the parameters were compared with progression-free survival at 7 months. Overall survival was compared with the percentage change of SUVmax. After 8 weeks, measurable reductions (± SD) in size (7.05 ± 4.19 to 5.52 ± 3.28 cm, -21.70%), volume (411.38 ± 540.08 to 212.41 ± 293.45 cm(3), -48.36%), and density (60.76 ± 20.65 to 50.68 ± 16.89 HU, -15.59%) were noted along with a substantial drop in SUVmax (5.95 ± 1.95 to 3.36 ± 1.28, -43.52%). The SUVmax change showed positive correlations with tumor size change (R(2) = 0.39, p = 0.0004) and volumetric change (R(2) = 0.34, p = 0.001). Patients who showed a larger drop in SUVmax at 8 weeks correlated with favorable progression-free survival (p = 0.02). ROC analysis showed that a 45% reduction in SUVmax was the best cutoff value to detect favorable progression-free survival patients. When we used this cutoff value, Kaplan-Meier analysis showed that patients with tumors showing greater reduction in SUVmax had favorable progression-free survival and overall survival (p = 0.0009, p = 0.03). In biliary tract cancers treated with GEMOX-B, the reduction of SUVmax after therapy is a better predictor for survival than morphologic and density changes.
    American Journal of Roentgenology 04/2015; 204(4):776-781. DOI:10.2214/AJR.14.13223 · 2.73 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. YAP functions as a rheostat in maintaining metabolic specialization, differentiation, and quiescence within the hepatocyte compartment. Increased or decreased YAP activity reprograms subsets of hepatocytes to different fates associated with deregulation of the HNF4A, CTNNB1, and E2F transcriptional programs that control hepatocyte quiescence and differentiation. Importantly, treatment with small interfering RNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model. Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of the positional identity of hepatocytes, supports targeting of YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype that is potentially responsive to this approach. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(10). DOI:10.1016/j.celrep.2015.02.027 · 8.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyper-activation of mammalian target of rapamycin (mTOR) signaling plays a pivotal role in HCC tumorigenesis. Tuberous Sclerosis Complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the present study, we discovered that TSC2 loss of function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV+ HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. Copyright © 2015, American Association for Cancer Research.
    Molecular Cancer Therapeutics 02/2015; 14(5). DOI:10.1158/1535-7163.MCT-14-0768 · 5.68 Impact Factor
  • Dr. Andrew X. Zhu
    [Show abstract] [Hide abstract]
    ABSTRACT: Cholangiocarcinoma (CCA) comprises a heterogeneous group of cancers with pathologic features of biliary tract differentiation, and is best classified anatomically as intrahepatic CCA (ICC), perihilar (pCCA), or distal (dCCA) CCA. They represent a clinically and genetically diverse collection of cancers. Surgical resection represents the only curative modality for CCA, although there are encouraging data with liver transplantation for early stage pCCA. There is no established adjuvant therapy for CCA. Unfortunately, most patients with CCA will present with unresectable or metastatic disease with poor prognosis. Currently the combination of gemcitabine and cisplatin remains the standard therapy for advanced CCA. No second line therapy has definitely demonstrated improved survival benefits. Development of molecularly targeted therapies in advanced CCA remains challenging. However, recent efforts with targeted and whole exome sequencing have defined the landscape of mutations underlying CCA, particularly ICC. The identification of novel molecular signatures in CCA coupled with molecularly targeted therapy development provides the potential for developing novel therapeutic options in this intractable disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Best practice & research. Clinical gastroenterology 02/2015; 29(2). DOI:10.1016/j.bpg.2015.02.010 · 3.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To compare the safety and efficacy of using 70-150 μm drug-eluting beads (DEBs) (LC BeadM1; Biocompatibles UK Ltd, Farnham, Surrey, United Kingdom) in addition to 100-300 μm DEBs with 100-300 μm DEBs alone in transarterial chemoembolization for treatment of hepatocellular carcinoma (HCC). A cohort of patients with HCC who underwent transarterial chemoembolization with two vials of 100-300 μm DEBs (group 1, 55 procedures among 42 patients, 33 men, average Model for End-Stage Liver Disease score 10 ± 0.6, 67% Child-Pugh A, 33% Child-Pugh B) was retrospectively compared with a cohort of patients who underwent transarterial chemoembolization with one vial of 70-150 μm DEBs followed by one vial of 100-300 μm DEBs (group 2, 51 procedures among 42 patients, 29 men, average Model for End-Stage Liver Disease score 9 ± 0.6, 73% Child-Pugh A, 27% Child-Pugh B) in regard to adverse events and response on 1-month follow-up imaging using modified Response Evaluation Criteria In Solid Tumors criteria. There was no difference in 1-month imaging response (P = .3). Patients in group 2 were readmitted more often within 1 month for hepatobiliary adverse events (group 2, 25%; group 1, 9%; P < .0001), including ascites, gastrointestinal hemorrhage, biliary dilatation, and cholecystitis. Despite similar efficacy based on short-term follow-up imaging, transarterial chemoembolization with smaller DEBs (70-150 μm) followed by larger DEBs (100-300 μm) may cause more hepatobiliary adverse events. Copyright © 2015 SIR. Published by Elsevier Inc. All rights reserved.
    Journal of Vascular and Interventional Radiology 02/2015; 26(4). DOI:10.1016/j.jvir.2014.12.020 · 2.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The genetic abnormalities involved in the pathogenesis of gallbladder carcinoma (GBC) remain unclear. Microsatellite instability (MSI) has been described in many carcinomas, but little is known about the significance of mismatch repair in gallbladder carcinogenesis. Additionally, methylation status of long interspersed element-1 (LINE-1), a surrogate marker of global DNA methylation, has defined distinct subsets of other cancer types but has not been explored in GBC. Immunohistochemical expression of MSH2, MSH6, MLH1, and PMS2 and LINE-1 mRNA in situ hybridization was evaluated in 67 primary and 15 metastatic GBCs from 77 patients. Amplification of human epidermal growth factor receptor 2 (HER2) was evaluated by fluorescence in situ hybridization. Genotyping for 24 genes involved in carcinogenesis was performed using a multiplex PCR-based platform. MSI was present in 6 of 77 GBCs (7.8 %). Loss of MSH2/MSH6 was detected in five cases and loss of MLH1/PMS2 in one case. MSI status was not associated with Lynch syndrome, tumor grade, extracellular mucin, or tumor-infiltrating lymphocytes. There was no significant difference in mean overall survival of patients with and without MSI. Strong LINE-1 staining was identified in none of the GBC with MSI and in 36 of 69 (52 %) of those without MSI (p = 0.005), suggesting that LINE-1 in the former cohort was hypermethylated. All MSI tumors were negative for HER2 amplification, and TP53 and NRAS mutations were only found in GBC without MSI. MSI was identified in a minority of GBC cases. The strong correlation between global DNA methylation as measured by LINE-1 and loss of mismatch repair proteins suggests that methylation may account for the loss of these proteins. These hypermethylated tumors appear to represent a genetically unique cohort of gallbladder neoplasms, and the data suggests that demethylating agents may have a therapeutic value in this class of tumors.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 02/2015; 466(4). DOI:10.1007/s00428-015-1720-0 · 2.65 Impact Factor
  • Journal of Vascular and Interventional Radiology 02/2015; 26(2):S106. DOI:10.1016/j.jvir.2014.12.285 · 2.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: On the basis of the ACCORD trial, FOLFIRINOX is effective in metastatic pancreatic adenocarcinoma (PDAC), making it a rational choice for locally advanced PDAC (LA). Aims of this study are to evaluate the accuracy of imaging in determining the resectability of PDAC and to determine the surgical and clinicopathologic outcomes of pancreatic resections after neoadjuvant FOLFIRINOX therapy. Clinicopathologic data were retrospectively collected for surgical PDAC patients receiving neoadjuvant FOLFIRINOX or no neoadjuvant therapy between April 2011 and February 2014. Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus guidelines defined LA and borderline. Imaging was reviewed by a blinded senior pancreatic surgeon. Of 188 patients undergoing resection for PDAC, 40 LA/borderline received FOLFIRINOX and 87 received no neoadjuvant therapy. FOLFIRINOX resulted in a significant decrease in tumor size, yet 19 patients were still classified as LA and 9 as borderline. Despite post-FOLFIRINOX imaging suggesting continued unresectability, 92% had an R0 resection. When compared with no neoadjuvant therapy, FOLFIRINOX resulted in significantly longer operative times (393 vs 300 minutes) and blood loss (600 vs 400 mL), but significantly lower operative morbidity (36% vs 63%) and no postoperative pancreatic fistulas. Length of stay (6 vs 7 days), readmissions (20% vs 30%), and mortality were equivalent (1% vs 0%). On final pathology, the FOLFIRINOX group had a significant decrease in lymph node positivity (35% vs 79%) and perineural invasion (72% vs 95%). Median follow-up was 11 months with a significant increase in overall survival with FOLFIRINOX. After neoadjuvant FOLFIRINOX imaging no longer predicts unresectability. Traditional pathologic predictors of survival are improved, and morbidity is decreased in comparison to patients with clearly resectable cancers at the time of presentation.
    Annals of Surgery 01/2015; 261(1):12-7. DOI:10.1097/SLA.0000000000000867 · 8.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To compare the clinical outcomes of sorafenib plus either erlotinib or placebo in patients with advanced hepatocellular carcinoma (HCC) in a multicenter, multinational, randomized, phase III trial. Patients with advanced HCC and underlying Child-Pugh class A cirrhosis, who were naive to systemic treatment (N = 720), were randomly assigned to sorafenib plus either erlotinib (n = 362) or placebo (n = 358). The primary end point was overall survival (OS). Median OS was similar in the sorafenib plus erlotinib and sorafenib plus placebo groups (9.5 v 8.5 months, respectively; hazard ratio [HR], 0.929; P = .408), as was median time to progression (3.2 v 4.0 months, respectively; HR, 1.135; P = .18). In the sorafenib/erlotinib arm versus the sorafenib/placebo arm, the overall response rate trended higher (6.6% v 3.9%, respectively; P = .102), whereas the disease control rate was significantly lower (43.9% v 52.5%, respectively; P = .021). The median durations of treatment with sorafenib were 86 days in the sorafenib/erlotinib arm and 123 days in the sorafenib/placebo arm. In the sorafenib/erlotinib and sorafenib/placebo arms, the rates of treatment-emergent serious AEs (58.0% v 54.6%, respectively) and drug-related serious AEs (21.0% v 22.8%, respectively) were similar. AEs matched the known safety profiles of both agents, but rates of rash/desquamation, anorexia, and diarrhea were higher in the sorafenib/erlotinib arm, whereas rates of alopecia and hand-foot skin reaction were higher in the sorafenib/placebo arm. Withdrawal rates for AEs during cycles 1 to 3 were higher in the sorafenib/erlotinib arm. Adding erlotinib to sorafenib did not improve survival in patients with advanced HCC. © 2014 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 12/2014; 33(6). DOI:10.1200/JCO.2013.53.7746 · 18.43 Impact Factor

Publication Stats

8k Citations
1,388.41 Total Impact Points


  • 2004–2015
    • Harvard University
      Cambridge, Massachusetts, United States
    • Massachusetts General Hospital
      • • Division of Hematology and Medical Oncology
      • • Department of Radiology
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2003–2015
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2014
    • University of Toronto
      • Department of Radiation Oncology
      Toronto, Ontario, Canada
  • 2010
    • The University of Calgary
      • Department of Medicine
      Calgary, Alberta, Canada
  • 2006–2010
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
    • Rutgers, The State University of New Jersey
      Нью-Брансуик, New Jersey, United States
  • 2009
    • University of California, Los Angeles
      • Department of Medicine
      Los Angeles, CA, United States