Milind Javle

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (113)453.06 Total impact

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    ABSTRACT: Background and aims. Platelets are believed to promote tumor growth and metastasis but their prognostic role in locally advanced pancreatic cancer (LAPC) remains largely unknown. We assessed whether pretreatment platelet counts independently predict survival outcomes in patients with LAPC treated with chemoradiation (CRT). Methods. We retrospectively reviewed the MD Anderson pancreatic cancer database and identified 199 patients with LAPC treated with CRT between 2006 and 2012. Induction chemotherapy was used prior to consolidative CRT in 177 (89%) patients. Median radiation dose was 50.4 Gy. Concurrent radiosensitizers were gemcitabine-based (13%) or capecitabine-based (84%) regimens. Actuarial univariate and multivariate statistical methods were used to determine significant prognostic factors for overall survival (OS) and progression-free survival (PFS) calculated from the start of treatment. Results. Median follow-up was 9.9 months. Median OS and PFS durations were 17.7 and 10.7 months, respectively. On univariate analysis, platelet count > 300 K/μl, KPS ≤ 80, ≥ 5% weight loss and pretreatment CA19-9 above the median were associated with inferior OS or PFS. Median OS was lower in patients with platelet count > 300 K/μl compared to patients with platelet count ≤ 300 K/μl (10.2 vs. 19 months; p = 0.0002). Corresponding median PFS times were 7.8 months and 11.1 months (p = 0.004), respectively. On multivariate analysis, platelet count > 300 K/μl (p = 0.012), ≥ 5% weight loss (p = 0.002) and elevated pretreatment CA19-9 (p = 0.005) were independent prognostic factors for OS. Platelet count > 300 K/μl (p = 0.03) and KPS ≤ 80 (p = 0.05) independently predicted PFS. Conclusions. Our analysis suggests that pretreatment thrombocytosis independently predicts inferior OS and PFS in LAPC.
    Acta oncologica (Stockholm, Sweden) 01/2015; · 2.27 Impact Factor
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    ABSTRACT: Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics. We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials. There were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors. There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.
    PLoS ONE 12/2014; 9(12):e115383. · 3.53 Impact Factor
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    ABSTRACT: There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of therapeutic outcome.
    Physical Biology 12/2014; 11(6):065002. · 3.14 Impact Factor
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    ABSTRACT: Pancreatic cancer is rapidly fatal with median survival of only 6 months (mo). Quality-of-life (QoL) was analyzed prospectively in a phase 2 study of gemcitabine (G), capecitabine (C) and bevacizumab (B) in APC patients. A total of 50 patients with APC received B 15 mg/kg, C 1,300 mg/m(2) daily for 2 weeks and G 1,000 mg/m(2) weekly 2 times; cycles were repeated every 21 days. Endpoints: progression free survival (PFS), overall survival (OS) and assessment of QoL prior to each cycle using the European organization for research and treatment of cancer (EORTC) PAN-26 QoL questionnaire. An exact 95% confidence interval (CI) (Clopper-Pearson method) was used to assess rate of improved QoL (defined as >5% decrease in two consecutive scores compared with baseline). Patient characteristics- Stage IIB/III/IV: 3/5/42; Sex: 28 M/22 F; Median age: 64 years. QoL in patients- improved: 56%, no improvement: 24%; unevaluable: 20%. Median PFS: 5.8 mo, OS: 9.8 mo. QoL improvement rate: 28/40=0.7 (95% CI: 0.53-0.83) in evaluable patients. Using QoL improvement rate, no significant difference was seen in patients with OS ≥6 mo compared to OS <6 mo. However QoL scores at 3 and 6 weeks from start of treatment correlated strongly with ≥6 mo survival (P value 0.0092 and 0.0081, respectively). Baseline score and change in QoL scores of patients on G, C and B were not predictive of survival ≥6 mo. Post treatment scores at 3 and 6 weeks from start of therapy however, were predictive of survival ≥6 mo suggesting the potential predictive value of this tool for use in future studies.
    Journal of gastrointestinal oncology 12/2014; 5(6):433-439.
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    ABSTRACT: Gemcitabine plus platinum (GEM-P) combination chemotherapy is standard treatment for first-line advanced cholangiocarcinoma (aCC). GEM-P first-line therapy reports a progression-free survival (PFS) of 8 months and overall survival (OS) of 11.7 months. Treatment in the second-line setting is less clear. Five-year survival for aCC remains dismal at 5-10%. The purpose of this study was to describe the outcomes with second-line systemic treatment at our institution. This study was a single institution retrospective chart review of aCC patients who initiated second-line systemic treatment during 1/1/2009 to 12/31/2012. The primary objective was to evaluate PFS with second-line systemic treatment. Secondary objectives were OS and disease control rate. Second-line systemic regimens were classified into four treatment groups: GEM-P, gemcitabine + fluoropyrimidine (GEM-FU), other FU combination (FU-combo), and others. Fifty-six patients were included and the majority had intrahepatic aCC. A total of 80% received first-line gemcitabine-based therapy. Second-line therapy consisted of GEM-P (19.6%), GEM-FU (28.6%), FU-combo (37.5%), and others (14.3%). Median PFS was 2.7-month (95% CI, 2.3-3.8 months) with a median OS of 13.8 months (95% CI, 12-19.3 months) and a disease control rate of 50%. No significant difference in survival was identified between the four treatment groups. This study revealed a 2.7-month PFS, 50% disease control rate, and potential survival benefit with second-line treatment. Options for second-line systemic therapy include GEM-FU, FU-combo, GEM-P if not given in the first-line setting. Targeted therapy with erlotinib or bevacizumab could be considered in addition to chemotherapy.
    Journal of gastrointestinal oncology 12/2014; 5(6):408-413.
  • Javle M, Smyth EC, Chau I
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    ABSTRACT: Gastric cancer is the fourth most common cancer globally and represents the second most common cause of cancer mortality. Early detection, aggressive surgical resection and postoperative adjuvant therapy has led to survival improvement for early stage gastric cancer, particularly in Asian countries. Unfortunately, advanced gastric cancer continues to pose a formidable challenge with few gains being reported recently. Trastuzumab was the first targeted agent to be approved for the treatment of advanced gastric cancer in 2010. The failure of the AVAGAST trial was a setback for anti-angiogenic therapy for this disease. Ramucirumab is a monoclonal antibody that binds to VEGF-R2 and prevents its activation. The recent REGARD trial was a randomized phase III trial of ramucirumab vs. placebo for patients with advanced, pre-treated gastric cancer that met its primary endpoint of increased overall survival. The toxicity of ramucirumab was modest in this setting, with an increased risk of grade 3 or higher hypertension (8% vs. 3%, with ramucirumab and placebo, respectively). The subsequent RAINBOW trial of paclitaxel plus ramucirumab vs. paclitaxel plus placebo for advanced pretreated gastric cancer confirmed the survival advantage of this antiangiogenic agent in gastric cancer. Ramucirumab is the first FDA approved therapy for advanced gastric cancer after prior chemotherapy.
    Clinical Cancer Research 10/2014; · 8.19 Impact Factor
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    ABSTRACT: Pancreatic adenosquamous carcinoma (ASC) is an enigmatic and aggressive tumor that has a worse prognosis and higher metastatic potential than its adenocarcinoma counterpart. Here we report that ASC tumors frequently harbor somatically acquired mutations in the UPF1 gene, which encodes the core component of the nonsense-mediated RNA decay (NMD) pathway. These tumor-specific mutations alter UPF1 RNA splicing and perturb NMD, leading to upregulated levels of NMD substrate mRNAs. UPF1 mutations are, to our knowledge, the first known unique molecular signatures of pancreatic ASC.
    Nature Medicine 05/2014; · 28.05 Impact Factor
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    ABSTRACT: To determine the prognostic impact of tumor location in gallbladder cancer.
    Annals of Surgery 05/2014; · 7.19 Impact Factor
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    ABSTRACT: IGF-1 plays a role in the growth of multiple tumor types, including pancreatic cancer. IGF-1 also serves as a growth factor for muscle. The impact of therapeutic targeting of IGF-1 on muscle mass is unknown. We evaluated muscle mass at L3 in patients enrolled in a randomized phase II study of MK-0646 (M), a monoclonal antibody directed against the IGF-1 protein, in patients with metastatic pancreatic cancer (MPC). Two different doses of M were tested, 5 and 10 mg/kg. We used the Slice-o-matic (ver 4.3) software to segregate CT images into muscle and fat components and measured muscle area (cm(2)) at baseline and after 2 and 4 months of treatment. Patients received either gemcitabine with erlotinib (G + E), G + E + M, or G + M. Differences between the groups were compared using t tests. Fifty-three patients had both baseline and 2-month imaging available for analysis. Of these, 42 received M with their chemo, and 11 had G + E only. After 2 months of treatment, both groups demonstrated decrease in muscle mass. G + E patients lost 5.6 % of muscle mass; M patients lost 9.1 and 8.6 % after treatment with 5 and 10 mg/kg, respectively (p = 0.53). Patients demonstrating a response lost less muscle (median 4.6 %) than those with stable disease (9.6 %) and progressive disease (8.9 %, p = 0.14). Muscle retention from baseline to 2-month imaging, defined as loss of <6 cm(2) of muscle, correlated with better survival than those patients demonstrating a muscle loss (HR 0.51, p = 0.03). MPC patients can be expected to lose muscle mass even while having clinical benefit (PR or SD) from chemotherapy. Muscle loss correlated with a risk of study drop-out and death. There was a non-significant trend toward greater muscle mass loss in patients on anti-IGF-1R therapy. However, it is unclear if this loss translates into functional differences between patients.
    Journal of Cachexia, Sarcopenia and Muscle 04/2014; · 7.41 Impact Factor
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    ABSTRACT: The objective of this study was to evaluate whether building upon multidrug chemotherapy regimens represents a viable strategy in pancreatic cancer clinical trial design. We performed a pooled analysis of all single-arm phase II studies in which a specific targeted agent (the anti-vascular endothelial growth factor monoclonal antibody bevacizumab) was added to gemcitabine-based cytotoxic doublets. The primary end point was overall survival (OS). Secondary end points included objective response rate, CA-19-9 biomarker response rate, and adverse event frequencies. Kaplan-Meier methods estimated time-to-event end points, whereas the Cox proportional hazard model estimated univariate hazard ratios of death. For the 300 patients included in the pooled analysis, median OS was 9.1 months (95% confidence interval, 8.3-10.2). Differences in OS were observed according to patients' baseline performance status (median OS, 10.4 vs 8.6 months for Eastern Cooperative Oncology Group 0 vs 1, respectively). Moreover, bevacizumab-related adverse events were not observed at increased frequency with gemcitabine-based doublets compared with historic data. Recognizing the limitations of cross-study comparisons, these results compare favorably to those from Cancer and Leukemia Group B 80303, a phase III trial testing bevacizumab in combination with gemcitabine alone. This is the largest data set available to demonstrate the feasibility of building upon more intensive chemotherapy backbones in clinical trials of novel targeted agents in pancreatic cancer.
    Pancreas 04/2014; 43(3):343-9. · 3.01 Impact Factor
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    ABSTRACT: Background. The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy. Methods. We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC. Results. Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival. Conclusion. Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints. Trial registration. Clinicaltrials.gov NCT01276613. Funding. Lustgarten Foundation (989161), Department of Defense (W81XWH-09-1-0212), NIH (U54CA151668, KCA088084).
    The Journal of clinical investigation 03/2014; · 15.39 Impact Factor
  • Javle M, Smyth EC, Chau I
    Clinical Cancer Research 03/2014; · 8.19 Impact Factor
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    ABSTRACT: The HER2/neu gene is a proto-oncogene that can predict the response to treatment with trastuzumab, pertuzumab, and lapatinib. This study was conducted to determine the frequency of HER2/neu overexpression and to identify a subgroup of patients with gallbladder cancer who would benefit from targeted therapy. Patients with gallbladder cancer (n = 187; 165 women and 22 men) with a recorded follow-up of at least 5 years were included, along with control subjects (n = 75). An automated immunohistochemical technique was used with an anti-ErbB2 antibody. Scoring was conducted according to the CAP/ASCO (College of American Pathologists/American Society of Clinical Oncology) criteria for breast cancer. Overexpression of HER2/neu was observed in 12.8% of the cases. Of those, 0% were mucosal, 14.3% muscular, 12.8% subserosal, and 10.6% serosal. In 20% of the cases, equivocal staining was observed. Overexpression was more frequent in the advanced cancers and in the better differentiated tumors (13.8% and 17.4%, respectively), but the difference was nonsignificant. The patients with overexpression of HER2/neu had a worse overall survival, when compared with those who had no expression at 5 years (34% vs. 41%). This is the single largest study of HER2/neu expression in gallbladder cancer to use commonly accepted scoring criteria. The results indicate that HER2/neu overexpression occurred in 14% of the advanced gallbladder cancer cases. This subgroup may benefit from inhibitors of the HER2/neu pathway.
    Gastrointestinal cancer research: GCR 03/2014; 7(2):42-8.
  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):B132-B132. · 6.11 Impact Factor
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    ABSTRACT: Transforming growth factor (TGF)-β signaling pathway, may act both as a tumor suppressor and as a tumor promoter in pancreatic cancer, depending on tumor stage and cellular context. TGF-β pathway has been under intensive investigation as a potential therapeutic target in the treatment of cancer. We hypothesized a correlation between TGF-βR2/SMAD4 expression in the tumor, plasma TGF-β1 ligand level, genetic variation in TGF-B pathway and prognosis of pancreatic cancer. We examined TGF-βR2 and SMAD4 protein expression in biopsy or surgical samples from 91 patients with pancreatic ductal adenocarcinoma (PDAC) using immunohistochemistry. Plasma level of TGF-β1 was measured in 644 patients with PDAC using ELISA. Twenty-eight single nucleotide polymorphisms (SNP) of the TGF-β1, TGF-β2, TGF-β3, TGF-βR1, TGF-βR2, and SMAD4 genes were determined in 1636 patients with PDAC using the Sequenom method. Correlation between protein expression in the tumor, plasma TGF-β1 level, and genotypes with overall survival (OS) was evaluated with Cox proportional regression models. The expression level of TGF-βR2 and SMAD4 as an independent marker was not associated with OS. However, patients with both low nuclear staining of TGF-βR2 and high nuclear staining of SMAD4 may have better survival (P = 0.06). The mean and median level of TGF-β1 was 15.44 (SD: 10.99) and 12.61 (interquartile range: 8.31 to 19.04) ng/ml respectively. Patients with advanced disease and in the upper quartile range of TGF-β1 level had significantly reduced survival than those with low levels (P = 0.02). A significant association of SMAD4 SNP rs113545983 with overall survival was observed (P<0.0001). Our data provides valuable baseline information regarding the TGF-β pathway in pancreatic cancer, which can be utilized in targeted therapy clinical trials. High TGF-β1 plasma level, SMAD4 SNP or TGF-βR2/SMAD4 tumor protein expression may suggest a dependence on this pathway in patients with advanced pancreatic cancer.
    PLoS ONE 01/2014; 9(1):e85942. · 3.53 Impact Factor
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    ABSTRACT: Gallbladder cancer is relatively uncommon, with a high incidence in certain geographic locations, including Latin America, East and South Asia, and Eastern Europe. Molecular characterization of this disease has been limited, and targeted therapy options for advanced disease remain an open area of investigation. In the present study, surgical pathology obtained from resected gallbladder cancer cases (n = 72) was examined for the presence of targetable, somatic mutations. All cases were formalin fixed and paraffin embedded (FFPE). Two approaches were used: (a) mass spectroscopy-based profiling for 159 point ("hot spot") mutations in 33 genes commonly involved in solid tumors and (b) next-generation sequencing (NGS) platform that examined the complete coding sequence of in 182 cancer-related genes. Fifty-seven cases were analyzed for hot spot mutations; and 15, for NGS. Fourteen hot spot mutations were identified in 9 cases. Of these, KRAS mutation was significantly associated with poor survival on multivariate analysis. Other targetable mutations included PIK3CA (n = 2) and ALK (n = 1). On NGS, 26 mutations were noted in 15 cases. TP53 and PI3 kinase pathway (STK11, RICTOR, TSC2) mutations were common. One case had FGF10 amplification, whereas another had FGF3-TACC gene fusion, not previously described in gallbladder cancer. In conclusion, somatic mutation profiling using archival FFPE samples from gallbladder cancer is feasible. NGS, in particular, may be a useful platform for identifying novel mutations for targeted therapy.
    Human pathology 11/2013; · 2.81 Impact Factor
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    ABSTRACT: Cancer patients are a high-risk population for venous thromboembolism (VTE); the natural history of gonadal vein thrombosis (GVT) occurring in cancer patients is not well described in the medical literature. Utilizing a software program the computerized tomographic scan reports of patients at a single cancer center from January 1, 2004 to June 30, 2011 were searched for the term GVT. Patients included in this analysis had a diagnosis of cancer, an isolated GVT (i.e. no evidence of thrombosis at another site), no symptoms referable to the GVT, and at least six months of follow-up information. All subsequent recurrent VTE events were confirmed by imaging studies. 196 cancer patients with GVT were identified. The majority of patients in this analysis had metastatic disease (118, 61.2%) as well as active cancer (167, 85.2%). Twenty patients (10.8%) developed recurrent VTE (median follow-up 14.5months); median time to recurrent VTEs was 5.5months (range 0-19months). When considering only patients with without a recent history of gynecologic surgery, VTE recurrence rates were 14.3%. Active cancer was the only risk factor significantly associated with recurrent VTE (P=0.047). Based upon the patient's risk factors for VTE, treatment of an incidentally detected GVT in cancer patients with anticoagulation, as per guidelines for other VTE sites, may be indicated in certain high risk subgroups, especially those patients with active cancer who have not had prior pelvic surgery.
    Thrombosis Research 10/2013; · 2.43 Impact Factor
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    ABSTRACT: The goal of this study was to determine the incidence and risk factors associated with gastric bleeding in patients treated with radiation therapy for intrahepatic cholangiocarcinoma. Between November 2002 and December 2008, 33 patients with intrahepatic cholangiocarcinoma were treated with radiation therapy to the primary site. Twenty-nine (88%) patients were previously treated with chemotherapy, including gemcitabine and cisplatin in 19 patients. The median dose of radiation therapy was 50.4 Gy (range, 35-70 Gy). Twenty-seven (82%) patients received concurrent therapy, with capecitabine in 26 and bevacizumab in 1 patient. Nine of the 33 patients developed gastric bleeding, with a 1-year actuarial rate of 36%. Of these 9 patients, 7 presented with bleeding symptoms and 2 presented with anemia. All 9 patients were documented to have gastritis on endoscopy. The absolute and percent volumes of stomach receiving 40 and 50 Gy were significantly associated with the risk of gastric bleeding. Patients with intrahepatic cholangiocarcinoma have a significant risk of developing gastric bleeding after radiation therapy. Hence, the volume of stomach exposed to radiation therapy should be minimized in patients receiving radiation therapy for intrahepatic cholangiocarcinoma.
    Practical radiation oncology. 10/2013; 3(4):344-8.
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    ABSTRACT: Metastatic pancreatic cancer carries a poor prognosis, with median survival on the order of several months. There is evidence that combining gemcitabine with either erlotinib or cisplatin may be superior to single agent gemcitabine in patients with good performance (PS 0-1). We retrospectively compared outcomes of patients treated with either the three drug regimen of gemcitabine, cisplatin, and erlotinib (GCE) or the doublet of gemcitabine and cisplatin (GC) in order to assess the potential benefit of erlotinib. We also evaluated the role of erlotinib among smokers and non-smokers. We retrospectively analyzed 145 patients who presented between 2006 and 2009 with previously untreated metastatic pancreatic cancer initially treated at the M.D. Anderson cancer center with either GC or GCE. Information on tumor characteristics and overall survival time (OS) was collected by medical record review. Kaplan-Meier curves were used to estimate OS. Log rank tests were used to compare OS between groups. The Cox proportional hazards regression model was used to evaluate the ability of patient prognostic variables or treatment group to predict OS. A total of 71 patients were treated with GC, while 74 were treated with GCE. Cox analyses found no significant difference in overall survival (median 5.5 vs. 8.0 months, respectively, p-value = 0.1). Small sampling numbers may have contributed to this result. One year survival was 23 % in the GCE group and 13 % in the GC group. Patients with poor performance status (PS = 2-3) had worse survival as compared to patients with better performance status (PS = 0-1, p = 0.001). As in earlier studies, patients treated with more lines of therapy tended to have better survival (p <0.0001), and CA19-9 was found to be a significant predictor for OS (p = 0.001). No statistical evidence of a survival difference was found between smokers and non-smokers in both treatment groups (p = 0.72). In conclusion, though there was a trend towards improved survival with the addition of erlotinib to gemcitabine and cisplatin, this does not reach statistical significance.
    Investigational New Drugs 05/2013; 31(5). · 3.50 Impact Factor
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    ABSTRACT: Patients with advanced cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few therapeutic options for relapsed disease. Given the overall poor prognosis in this population and the availability of novel targeted therapies, we systematically analyzed the characteristics and outcomes for GC and CC patients treated on phase I trials with an emphasis on targeted agents and locoregional therapies. Of 40 treated patients (GC=6; CC=34; median age, 60 years), 8 (20%) had stable disease (SD) > 6 months, 3 (8%) partial response (PR), on protocols with hepatic arterial drug infusion and anti-angiogenic, anti-HER-2/neu or novel MAPK/ERK kinase (MEK) inhibitors. Median progression-free survival (PFS) on phase I trials was 2.0 months (95% CI 1.7, 2.8) versus 3.0 months (95% CI 2.4, 5.0), 3.0 months (95% CI 2.3, 4.6), and 3.0 months (95% CI 2.4, 3.9) for their first-, second-, and last-line FDA-approved therapy. In univariate analysis, >3 metastatic sites, elevated alanine aminotransferase (ALT) (>56IU/L), serum creatinine (>1.6mg/dL), and CA19-9 (>35U/mL) were associated with a shorter PFS. Mutational analysis revealed mutation in the KRAS oncogene in 2 of 11 patients (18%). The SD >6 months/PR rate of 28% was seen with hepatic arterial infusion of oxaliplatin, and inhibitors of angiogenesis, HER-2/neu or MEK. The PFS in phase I trials was similar to that of the first, second, and last-line therapy (P=0.95, 0.98, 0.76, respectively) with FDA-approved agents given in the advanced setting, emphasizing a role for targeted agents in a clinical trials setting as potentially valuable therapeutic options for these patients.
    Oncotarget 01/2013; 4(1):153-162. · 6.63 Impact Factor

Publication Stats

1k Citations
453.06 Total Impact Points

Institutions

  • 2007–2014
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 2010
    • Loma Linda University
      • Division of Hematology/Oncology
      Loma Linda, CA, United States
  • 2003–2010
    • Roswell Park Cancer Institute
      • • Department of Medicine
      • • Roswell Park Cancer Institute, Elm and Carlton Streets
      Buffalo, New York, United States
  • 2005–2009
    • University at Buffalo, The State University of New York
      • Department of Medicine
      Buffalo, NY, United States
    • Erie County Medical Center
      New York City, New York, United States
  • 2004
    • State University of New York
      New York City, New York, United States