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Hurwitz, Herbert Ira

Overview:

Particular Clinical Interests and Skills: Phase I clinical trials involving new anti cancer drugs; drug combinations; and combinations of new drugs with radiation; cancers of the GI system

Positions:

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1988

M.D. — Thomas Jefferson University

Medical Resident, Medicine

Michael Reese Hospital & Medical Center

Clinical Oncology Fellow, Medicine

Johns Hopkins University

Grants:

A first in human study of repeat dosing with REGN2810 a fully human antibody to programmed death - 1 (PD-1) as single therapy and in combination with selected

Administered By
Duke Cancer Institute
AwardedBy
Regeneron Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
January 01, 2016
End Date
December 31, 2021

A platform study exploring the safety tolerability effects on the tumor microenvironment and efficacy of Pembroliumab (MK-3475) + INCB combination

Administered By
Duke Cancer Institute
AwardedBy
Incyte Corporation
Role
Principal Investigator
Start Date
May 01, 2016
End Date
May 01, 2021

A Companion study for patient who completed participation in a REGN2810 study

Administered By
Duke Cancer Institute
AwardedBy
Regeneron Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2021

An open label multicenter dose escalation and expansion phase IB study to evaluste the safety pharmacokinetics and therapeutic activity

Administered By
Duke Cancer Institute
AwardedBy
F. Hoffmann-La Roche Ltd
Role
Principal Investigator
Start Date
March 01, 2016
End Date
February 28, 2021

A Phase 2 randomized proff of concept study of Nab-Paclitaxel/Gemcitabine alone and in combination with ACP-196 in subjects with previously untreated metastatic pancreatic cancer.

Administered By
Duke Cancer Institute
AwardedBy
Acerta Pharma
Role
Principal Investigator
Start Date
November 01, 2015
End Date
October 31, 2020

BACCI - RU021416 Phase II Study

Administered By
Duke Cancer Institute
AwardedBy
Academic and Community Cancer Research United
Role
Principal Investigator
Start Date
June 16, 2017
End Date
May 31, 2020

A phase 1 first in human open labe dose escalation study of MGD007 a humanized gpA33 x CD3 dual affinity retargeted

Administered By
Duke Cancer Institute
AwardedBy
MacroGenics, Inc.
Role
Principal Investigator
Start Date
November 01, 2014
End Date
October 31, 2019

A randomized double blind studyh of Ruxolitinib or placebo in combination with Regorafenib in subjects with relapsed or

Administered By
Duke Cancer Institute
AwardedBy
Incyte Corporation
Role
Principal Investigator
Start Date
October 01, 2014
End Date
September 30, 2019

Preclinical and Human Correlative Studies of a Novel Bruton Tyronsine Kinase Inhibitor in Pancreatic Cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 30, 2016
End Date
September 29, 2019

First-in-human dose escalation of TEW-7197 monotherapy in subjects with advanced stage solid tumors

Administered By
Duke Cancer Institute
AwardedBy
MedPacto, Inc
Role
Principal Investigator
Start Date
August 01, 2014
End Date
July 30, 2019

Duke-UNC-Wash U Partnership for Early Phase Clinical Trials in Cancer

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 04, 2014
End Date
February 28, 2019

A phase Ib study of combination Regorafenib with PF-03446962 in patient with refactory metastatic colorectal cancer or G

Administered By
Duke Cancer Institute
AwardedBy
Pfizer, Inc.
Role
Principal Investigator
Start Date
January 01, 2013
End Date
December 31, 2018

A Phase I/II open label multicenter study of the safety and efficacy of LAG525 single agent in combination with PDR001 adminitered to patients

Administered By
Duke Cancer Institute
AwardedBy
Novartis Pharmaceuticals Corporation
Role
Principal Investigator
Start Date
April 13, 2015
End Date
November 13, 2018

Phase Ib study of Atezolizumab in combination with Bevacizumab in solid tumor patients

Administered By
Duke Cancer Institute
AwardedBy
Genentech, Inc.
Role
Principal Investigator
Start Date
January 25, 2017
End Date
September 15, 2018

Blood-based Angiome Profiling to Direct Bevacizumab Therapy in Ovarian Cancer

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
May 01, 2014
End Date
April 30, 2017

A randomized double bline phase 3 study of the JAK 1/2 inhibitor Ruxotinib or placebo in conbination with capecitbine

Administered By
Duke Cancer Institute
AwardedBy
Incyte Corporation
Role
Principal Investigator
Start Date
September 01, 2014
End Date
April 19, 2017

The prevalence of MET gene amplification in metastatic colorectal cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Amgen, Inc.
Role
Investigator
Start Date
November 25, 2014
End Date
November 24, 2016

Cancer Biology Training Grant

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Cancer Institute
Role
Mentor
Start Date
July 01, 1993
End Date
March 31, 2016

Clinical Oncology Research Career Development Program

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 29, 2009
End Date
July 31, 2015

Anti-VEGF in Tumors & Wounds: Efficacy vs Toxicity

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 16, 2006
End Date
February 28, 2012

Wound Angiogenesis as a Biomarker for Tumor Angiogenesis

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2006
End Date
June 30, 2011

Biomarker Studies for Novel Anti-Cancer Agents

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
May 28, 2003
End Date
February 29, 2008

Partner-Assisted Emotional Disclosure for GI Cancer

Administered By
Psychiatry & Behavioral Sciences, Behavioral Medicine
AwardedBy
National Institutes of Health
Role
Physician
Start Date
March 02, 2004
End Date
February 28, 2008

Does NO mediate clinical anti-VEGF vascular effects

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 26, 2003
End Date
August 31, 2006

New Clinical Biomarker for Cancer--Wound Angiogenesis

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2000
End Date
January 31, 2006
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Publications:

Clinical Calculator for Early Mortality in Metastatic Colorectal Cancer: An Analysis of Patients From 28 Clinical Trials in the Aide et Recherche en Cancérologie Digestive Database

Authors
Renfro, LA; Goldberg, RM; Grothey, A; Sobrero, A; Adams, R; Seymour, MT; Heinemann, V; Schmoll, H-J; Douillard, J-Y; Hurwitz, H; Fuchs, CS; Diaz-Rubio, E; Porschen, R; Tournigand, C; Chibaudel, B; Hoff, PM; Kabbinavar, FF; Falcone, A; Tebbutt, NC; Punt, CJA; Hecht, JR; Souglakos, J; Bokemeyer, C; Van Cutsem, E; Saltz, L; de Gramont, A; Sargent, DJ
MLA Citation
Renfro, LA, Goldberg, RM, Grothey, A, Sobrero, A, Adams, R, Seymour, MT, Heinemann, V, Schmoll, H-J, Douillard, J-Y, Hurwitz, H, Fuchs, CS, Diaz-Rubio, E, Porschen, R, Tournigand, C, Chibaudel, B, Hoff, PM, Kabbinavar, FF, Falcone, A, Tebbutt, NC, Punt, CJA, Hecht, JR, Souglakos, J, Bokemeyer, C, Van Cutsem, E, Saltz, L, de Gramont, A, and Sargent, DJ. "Clinical Calculator for Early Mortality in Metastatic Colorectal Cancer: An Analysis of Patients From 28 Clinical Trials in the Aide et Recherche en Cancérologie Digestive Database." Journal of Clinical Oncology 35.17 (June 10, 2017): 1929-1937.
Source
crossref
Published In
Journal of Clinical Oncology
Volume
35
Issue
17
Publish Date
2017
Start Page
1929
End Page
1937
DOI
10.1200/JCO.2016.71.5771

Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First-Line Metastatic Colorectal Cancer.

These negative phase II results for parsatuzumab highlight the challenges of developing an agent intended to enhance the efficacy of vascular endothelial growth factor inhibition without the benefit of validated pharmacodynamic biomarkers or strong predictive biomarker hypotheses.Any further clinical development of anti-EGFL7 is likely to require new mechanistic insights and biomarker development for antiangiogenic agents.EGFL7 (epidermal growth factor-like domain 7) is a tumor-enriched vascular extracellular matrix protein that supports endothelial cell survival. This phase II trial evaluated the efficacy of parsatuzumab (also known as MEGF0444A), a humanized anti-EGFL7 IgG1 monoclonal antibody, in combination with modified FOLFOX6 (mFOLFOX6) (folinic acid, 5-fluorouracil, and oxaliplatin) bevacizumab in patients with previously untreated metastatic colorectal cancer (mCRC).One-hundred twenty-seven patients were randomly assigned to parsatuzumab, 400 mg, or placebo, in combination with mFOLFOX6 plus bevacizumab, 5 mg/kg. Treatment cycles were repeated every 2 weeks until disease progression or unacceptable toxicity for a maximum of 24 months, with the exception of oxaliplatin, which was administered for up to 8 cycles.The progression-free survival (PFS) hazard ratio was 1.17 (95% confidence interval [CI], 0.71-1.93; p = .548). The median PFS was 12 months for the experimental arm versus 11.9 months for the control arm. The hazard ratio for overall survival was 0.97 (95% CI, 0.46-2.1; p = .943). The overall response rate was 59% in the parsatuzumab arm and 64% in the placebo arm. The adverse event profile was similar in both arms.There was no evidence of efficacy for the addition of parsatuzumab to the combination of bevacizumab and chemotherapy for first-line mCRC. The Oncologist 2017;22:375-e30.

Authors
García-Carbonero, R; van Cutsem, E; Rivera, F; Jassem, J; Gore, I; Tebbutt, N; Braiteh, F; Argiles, G; Wainberg, ZA; Funke, R; Anderson, M; McCall, B; Stroh, M; Wakshull, E; Hegde, P; Ye, W; Chen, D; Chang, I; Rhee, I; Hurwitz, H
MLA Citation
García-Carbonero, R, van Cutsem, E, Rivera, F, Jassem, J, Gore, I, Tebbutt, N, Braiteh, F, Argiles, G, Wainberg, ZA, Funke, R, Anderson, M, McCall, B, Stroh, M, Wakshull, E, Hegde, P, Ye, W, Chen, D, Chang, I, Rhee, I, and Hurwitz, H. "Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First-Line Metastatic Colorectal Cancer." The oncologist 22.4 (April 2017): 375-e30.
PMID
28275117
Source
epmc
Published In
The oncologist
Volume
22
Issue
4
Publish Date
2017
Start Page
375
End Page
e30
DOI
10.1634/theoncologist.2016-0133

Phase I study of pazopanib plus TH-302 in advanced solid tumors.

To define the maximum tolerated dose (MTD), recommended phase II dose (RPTD), and assess safety and tolerability for the combination of pazopanib plus TH-302, an investigational hypoxia-activated prodrug (HAP), in adult patients with advanced solid tumors.This was an open-label, non-randomized, single-center, phase I trial consisting 2 stages. Stage 1 was a standard "3 + 3" dose escalation design to determine safety and the RPTD for TH-302 plus pazopanib combination. Stage 2 was an expanded cohort to better describe the tolerability and toxicity profile at the MTD. Pazopanib was orally dosed at 800 mg daily on days 1-28 for all cohorts. TH-302 was administered intravenously on days 1, 8 and 15 of a 28-day cycle at doses of 340 mg/m2 (cohort 1) or 480 mg/m2 (cohort 2). Dose limiting toxicity (DLT) was assessed in the first 28-day cycle. Efficacy was assessed every 2 cycles.Thirty patients were enrolled between December 2011 and September 2013. In the dose escalation stage, 7 patients were enrolled in the 340 mg/m2 TH-302 cohort and 6 patients in the 480 mg/m2 TH-302 cohort. Ten patients were evaluable for DLT. DLTs included grade 2 intolerable esophagitis (n = 1) in the 340 mg/m2 TH-302 cohort, and grade 3 vaginal inflammation (n = 1) and grade 3 neutropenia with grade 3 thrombocytopenia (n = 1, same patient) in the 480 mg/m2 TH-302 cohort. The 340 mg/m2 TH-302 cohort was determined to be MTD and RPTD. The most common treatment-related adverse events were hematologic (anemia, neutropenia, and thrombocytopenia), nausea/vomiting, palmar-plantar erythrodysesthesia syndrome, constipation, fatigue, mucositis, anorexia, pain, and hypertension. Partial response (PR) was observed in 10% (n = 3) of patients, stable disease (SD) in 57% (n = 17), and progressive disease (PD) in 23% (n = 7). Due to toxicity, 3 patients were discontinued from study drug prior to first radiographic assessment but were included in these calculations. Disease control ≥6 months was observed in 37% of patients (n = 11).The RPTD for this novel combination is pazopanib 800 mg daily on days 1-28 plus TH-302 340 mg/m2 on days 1, 8 and 15 of each 28-day cycle. Preliminary activity was seen in treatment-refractory cancers and supports potential value of co-targeting tumor angiogenesis and tumor hypoxia.

Authors
Riedel, RF; Meadows, KL; Lee, PH; Morse, MA; Uronis, HE; Blobe, GC; George, DJ; Crawford, J; Niedzwiecki, D; Rushing, CN; Arrowood, CC; Hurwitz, HI
MLA Citation
Riedel, RF, Meadows, KL, Lee, PH, Morse, MA, Uronis, HE, Blobe, GC, George, DJ, Crawford, J, Niedzwiecki, D, Rushing, CN, Arrowood, CC, and Hurwitz, HI. "Phase I study of pazopanib plus TH-302 in advanced solid tumors." Cancer chemotherapy and pharmacology 79.3 (March 2017): 611-619.
PMID
28238078
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
79
Issue
3
Publish Date
2017
Start Page
611
End Page
619
DOI
10.1007/s00280-017-3256-2

Percutaneous biliary drainage catheter insertion in patients with extensive hepatic metastatic tumor burden.

Patients with metastatic disease of the liver can have hyperbilirubinemia due to a number of reasons, including biliary obstruction. The purpose of this study was to analyze patient outcomes after percutaneous biliary drainage (PBD) catheter insertion in patients with extensive hepatic metastatic tumor burden.Out of 746 PBD insertions, 44 patients (24 males, 20 females, mean age 57.4 years, range, 34-80 years) had metastatic malignancy with a hepatic tumor burden of greater than 20% parenchymal volume based on pre-procedure computed tomography (CT) or magnetic resonance imaging (MRI). Laboratory data before and after PBD insertion were compared. Survival and outcomes analysis performed. A subanalysis was performed on patients with CT-demonstrated catheter traversal of tumoral tissue.A PBD catheter was successfully inserted in all patients. The mean serum bilirubin level decreased significantly from 10.9±6.4 mg/dL immediately prior to PBD insertion to 7.1±5.6 mg/dL (P<0.001) within one month post PBD insertion. Four patients (11%) demonstrated normalization of bilirubin levels to less than 1.6 mg/dL. Of the 14 patients with a post-procedure CT or MRI, the PBD catheter traversed a tumor in 11 (79%). One of these patients required a transfusion after the procedure and one had recurrent catheter exchanges due to pericatheter leakage. The 30-day overall survival was 41% with a median survival of 19 days. The percentage decrease in serum bilirubin after PBD insertion and pre-procedure international normalized ratio (INR) were correlated with improved survival (OR =3.7, P=0.010 and OR =4.9, P=0.028 respectively). The PBD-associated major complication rate was 16%.In patients with hyperbilirubinemia and extensive hepatic metastatic disease burden, survival was dismal after PBD catheter insertion. Serum bilirubin level normalization occurred rarely.

Authors
Langman, EL; Suhocki, PV; Hurwitz, HI; Morse, MA; Burbridge, RA; Smith, TP; Kim, CY
MLA Citation
Langman, EL, Suhocki, PV, Hurwitz, HI, Morse, MA, Burbridge, RA, Smith, TP, and Kim, CY. "Percutaneous biliary drainage catheter insertion in patients with extensive hepatic metastatic tumor burden." Journal of gastrointestinal oncology 7.6 (December 2016): 875-881.
PMID
28078111
Source
epmc
Published In
Journal of Gastrointestinal Oncology
Volume
7
Issue
6
Publish Date
2016
Start Page
875
End Page
881
DOI
10.21037/jgo.2016.06.13

Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance).

Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin-binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment-by-marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild-type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild-type (WT) patients (chemo HR = 0.98, 95% CI = 0.74-1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05-2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02-2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67-1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68-13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31-2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88-1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32-1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab.

Authors
Hatch, AJ; Sibley, AB; Starr, MD; Brady, JC; Jiang, C; Jia, J; Bowers, DL; Pang, H; Owzar, K; Niedzwiecki, D; Innocenti, F; Venook, AP; Hurwitz, HI; Nixon, AB; Alliance for Clinical Trials in Oncology,
MLA Citation
Hatch, AJ, Sibley, AB, Starr, MD, Brady, JC, Jiang, C, Jia, J, Bowers, DL, Pang, H, Owzar, K, Niedzwiecki, D, Innocenti, F, Venook, AP, Hurwitz, HI, Nixon, AB, and Alliance for Clinical Trials in Oncology, . "Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance)." Cancer medicine 5.9 (September 2016): 2249-2260.
PMID
27465221
Source
epmc
Published In
Cancer Medicine
Volume
5
Issue
9
Publish Date
2016
Start Page
2249
End Page
2260
DOI
10.1002/cam4.806

Development of a Novel c-MET-Based CTC Detection Platform.

Amplification of the MET oncogene is associated with poor prognosis, metastatic dissemination, and drug resistance in many malignancies. We developed a method to capture and characterize circulating tumor cells (CTC) expressing c-MET using a ferromagnetic antibody. Immunofluorescence was used to characterize cells for c-MET, DAPI, and pan-CK, excluding CD45(+) leukocytes. The assay was validated using appropriate cell line controls spiked into peripheral blood collected from healthy volunteers (HV). In addition, peripheral blood was analyzed from patients with metastatic gastric, pancreatic, colorectal, bladder, renal, or prostate cancers. CTCs captured by c-MET were enumerated, and DNA FISH for MET amplification was performed. The approach was highly sensitive (80%) for MET-amplified cells, sensitive (40%-80%) for c-MET-overexpressed cells, and specific (100%) for both c-MET-negative cells and in 20 HVs. Of 52 patients with metastatic carcinomas tested, c-MET CTCs were captured in replicate samples from 3 patients [gastric, colorectal, and renal cell carcinoma (RCC)] with 6% prevalence. CTC FISH demonstrated that MET amplification in both gastric and colorectal cancer patients and trisomy 7 with gain of MET gene copies in the RCC patient. The c-MET CTC assay is a rapid, noninvasive, sensitive, and specific method for detecting MET-amplified tumor cells. CTCs with MET amplification can be detected in patients with gastric, colorectal, and renal cancers.This study developed a novel c-MET CTC assay for detecting c-MET CTCs in patients with MET amplification and warrants further investigation to determine its clinical applicability. Mol Cancer Res; 14(6); 539-47. ©2016 AACR.

Authors
Zhang, T; Boominathan, R; Foulk, B; Rao, C; Kemeny, G; Strickler, JH; Abbruzzese, JL; Harrison, MR; Hsu, DS; Healy, P; Li, J; Pi, C; Prendergast, KM; Hobbs, C; Gemberling, S; George, DJ; Hurwitz, HI; Connelly, M; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Zhang, T, Boominathan, R, Foulk, B, Rao, C, Kemeny, G, Strickler, JH, Abbruzzese, JL, Harrison, MR, Hsu, DS, Healy, P, Li, J, Pi, C, Prendergast, KM, Hobbs, C, Gemberling, S, George, DJ, Hurwitz, HI, Connelly, M, Garcia-Blanco, MA, and Armstrong, AJ. "Development of a Novel c-MET-Based CTC Detection Platform." Molecular cancer research : MCR 14.6 (June 2016): 539-547.
Website
http://hdl.handle.net/10161/11944
PMID
26951228
Source
epmc
Published In
Molecular cancer research : MCR
Volume
14
Issue
6
Publish Date
2016
Start Page
539
End Page
547
DOI
10.1158/1541-7786.mcr-16-0011

HER2 testing in metastatic colorectal cancer: ready for prime time?

Authors
Hurwitz, HI
MLA Citation
Hurwitz, HI. "HER2 testing in metastatic colorectal cancer: ready for prime time?." Clinical advances in hematology & oncology : H&O 14.4 (April 2016): 235-237. (Interview)
PMID
27166605
Source
epmc
Published In
Clinical advances in hematology & oncology : H&O
Volume
14
Issue
4
Publish Date
2016
Start Page
235
End Page
237

Body Mass Index Is Prognostic in Metastatic Colorectal Cancer: Pooled Analysis of Patients From First-Line Clinical Trials in the ARCAD Database.

In recent retrospective analyses of early-stage colorectal cancer (CRC), low and high body mass index (BMI) scores were associated with worsened outcomes. Whether BMI is a prognostic or predictive factor in metastatic CRC (mCRC) is unclear.Individual data from 21,149 patients enrolled onto 25 first-line mCRC trials during 1997 to 2012 were pooled. We assessed both prognostic and predictive effects of BMI on overall survival and progression-free survival, and we accounted for patient and tumor characteristics and therapy type (targeted v nontargeted).BMI was prognostic for overall survival (P < .001) and progression-free survival (P < .001), with an L-shaped pattern. That is, risk of progression and/or death was greatest for low BMI; risk decreased as BMI increased to approximately 28 kg/m(2), and then it plateaued. Relative to obese patients, patients with a BMI of 18.5 kg/m(2) had a 27% increased risk of having a PFS event (95% CI, 20% to 34%) and a 50% increased risk of death (95% CI, 43% to 56%). Low BMI was associated with poorer survival for men than women (interaction P < .001). BMI was not predictive of treatment effect.Low BMI is associated with an increased risk of progression and death among the patients enrolled on the mCRC trials, with no increased risk for elevated BMI, in contrast to the adjuvant setting. Possible explanations include negative effects related to cancer cachexia in patients with low BMI, increased drug delivery or selection bias in patients with high BMI, and potential for an interaction between BMI and molecular signaling pathways.

Authors
Renfro, LA; Loupakis, F; Adams, RA; Seymour, MT; Heinemann, V; Schmoll, H-J; Douillard, J-Y; Hurwitz, H; Fuchs, CS; Diaz-Rubio, E; Porschen, R; Tournigand, C; Chibaudel, B; Falcone, A; Tebbutt, NC; Punt, CJA; Hecht, JR; Bokemeyer, C; Van Cutsem, E; Goldberg, RM; Saltz, LB; de Gramont, A; Sargent, DJ; Lenz, H-J
MLA Citation
Renfro, LA, Loupakis, F, Adams, RA, Seymour, MT, Heinemann, V, Schmoll, H-J, Douillard, J-Y, Hurwitz, H, Fuchs, CS, Diaz-Rubio, E, Porschen, R, Tournigand, C, Chibaudel, B, Falcone, A, Tebbutt, NC, Punt, CJA, Hecht, JR, Bokemeyer, C, Van Cutsem, E, Goldberg, RM, Saltz, LB, de Gramont, A, Sargent, DJ, and Lenz, H-J. "Body Mass Index Is Prognostic in Metastatic Colorectal Cancer: Pooled Analysis of Patients From First-Line Clinical Trials in the ARCAD Database." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34.2 (January 2016): 144-150.
PMID
26503203
Source
epmc
Published In
Journal of Clinical Oncology
Volume
34
Issue
2
Publish Date
2016
Start Page
144
End Page
150
DOI
10.1200/jco.2015.61.6441

Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed.

Patients with advanced pancreatic adenocarcinoma have a poor prognosis and limited second-line treatment options. Evidence suggests a role for the Janus kinase (JAK)/signal transducer and activator of transcription pathway in the pathogenesis and clinical course of pancreatic cancer.In this double-blind, phase II study, patients with metastatic pancreatic cancer who had experienced treatment failure with gemcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000 mg/m(2) twice daily) or placebo plus capecitabine. The primary end point was overall survival (OS); secondary end points included progression-free survival, clinical benefit response, objective response rate, and safety. Prespecified subgroup analyses evaluated treatment heterogeneity and efficacy in patients with evidence of inflammation.In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio was 0.79 (95% CI, 0.53 to 1.18; P = .25) for OS and was 0.75 (95% CI, 0.52 to 1.10; P = .14) for progression-free survival. In a prespecified subgroup analysis of patients with inflammation, defined by serum C-reactive protein levels greater than the study population median (ie, 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% CI, 0.26 to 0.85; P = .011). Prolonged survival in this subgroup was supported by post hoc analyses of OS that categorized patients by the modified Glasgow Prognostic Score, a systemic inflammation-based prognostic system. Grade 3 or greater adverse events were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups. Grade 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%).Ruxolitinib plus capecitabine was generally well tolerated and may improve survival in patients with metastatic pancreatic cancer and evidence of systemic inflammation.

Authors
Hurwitz, HI; Uppal, N; Wagner, SA; Bendell, JC; Beck, JT; Wade, SM; Nemunaitis, JJ; Stella, PJ; Pipas, JM; Wainberg, ZA; Manges, R; Garrett, WM; Hunter, DS; Clark, J; Leopold, L; Sandor, V; Levy, RS
MLA Citation
Hurwitz, HI, Uppal, N, Wagner, SA, Bendell, JC, Beck, JT, Wade, SM, Nemunaitis, JJ, Stella, PJ, Pipas, JM, Wainberg, ZA, Manges, R, Garrett, WM, Hunter, DS, Clark, J, Leopold, L, Sandor, V, and Levy, RS. "Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.34 (December 2015): 4039-4047.
PMID
26351344
Source
epmc
Published In
Journal of Clinical Oncology
Volume
33
Issue
34
Publish Date
2015
Start Page
4039
End Page
4047
DOI
10.1200/jco.2015.61.4578

Direct Evidence of Target Inhibition with Anti-VEGF, EGFR, and mTOR Therapies in a Clinical Model of Wound Healing.

In early clinical testing, most novel targeted anticancer therapies have limited toxicities and limited efficacy, which complicates dose and schedule selection for these agents. Confirmation of target inhibition is critical for rational drug development; however, repeated tumor biopsies are often impractical and peripheral blood mononuclear cells and normal skin are often inadequate surrogates for tumor tissue. Based upon the similarities of tumor and wound stroma, we have developed a clinical dermal granulation tissue model to evaluate novel targeted therapies.A 4-mm skin punch biopsy was used to stimulate wound healing and a repeat 5-mm punch biopsy was used to harvest the resulting granulation tissue. This assay was performed at pretreatment and on-treatment evaluating four targeted therapies, bevacizumab, everolimus, erlotinib, and panitumumab, in the context of three different clinical trials. Total and phosphorylated levels VEGFR2, S6RP, and EGFR were evaluated using ELISA-based methodologies.Significant and consistent inhibition of the VEGF pathway (using VEGFR2 as the readout) was observed in granulation tissue biopsies from patients treated with bevacizumab and everolimus. In addition, significant and consistent inhibition of the mTOR pathway (using S6RP as the readout) was observed in patients treated with everolimus. Finally, significant inhibition of the EGFR pathway (using EGFR as the readout) was observed in patients treated with panitumumab, but this was not observed in patients treated with erlotinib.Molecular analyses of dermal granulation tissue can be used as a convenient and quantitative pharmacodynamic biomarker platform for multiple classes of targeted therapies.

Authors
Jia, J; Dellinger, AE; Weiss, ES; Bulusu, A; Rushing, C; Li, H; Howard, LA; Kaplan, N; Pang, H; Hurwitz, HI; Nixon, AB
MLA Citation
Jia, J, Dellinger, AE, Weiss, ES, Bulusu, A, Rushing, C, Li, H, Howard, LA, Kaplan, N, Pang, H, Hurwitz, HI, and Nixon, AB. "Direct Evidence of Target Inhibition with Anti-VEGF, EGFR, and mTOR Therapies in a Clinical Model of Wound Healing." Clinical cancer research : an official journal of the American Association for Cancer Research 21.15 (August 2015): 3442-3452.
PMID
25878330
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
15
Publish Date
2015
Start Page
3442
End Page
3452
DOI
10.1158/1078-0432.ccr-14-2819

Identifying Blood-Based Protein Biomarkers for Antiangiogenic Agents in the Clinic: A Decade of Progress.

Agents that inhibit tumor angiogenesis are widely used and have provided meaningful survival benefits to patients in multiple disease settings. However, these agents differ significantly in their mechanisms of action and potential toxicities, and there are currently no prospectively validated biomarkers to guide the selection of agents for individual patients. Blood-based protein biomarkers are well suited for trials investigating antiangiogenic agents for multiple reasons. Many elements of the molecular pathways that antiangiogenic agents target are present and detectable in the circulation, sample collection is minimally invasive, and samples can be collected throughout the course of treatment. Blood-based biomarkers for antiangiogenic therapies are urgently needed to guide the development of therapeutic strategies. This review provides a brief summary of the current blood-based protein biomarkers for antiangiogenic therapies.

Authors
Hatch, AJ; Clarke, JM; Nixon, AB; Hurwitz, HI
MLA Citation
Hatch, AJ, Clarke, JM, Nixon, AB, and Hurwitz, HI. "Identifying Blood-Based Protein Biomarkers for Antiangiogenic Agents in the Clinic: A Decade of Progress." Cancer journal (Sudbury, Mass.) 21.4 (July 2015): 322-326. (Review)
PMID
26222085
Source
epmc
Published In
Cancer Journal
Volume
21
Issue
4
Publish Date
2015
Start Page
322
End Page
326
DOI
10.1097/ppo.0000000000000129

Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors.

Ramucirumab is a fully human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2). An initial phase I study evaluated ramucirumab administered weekly in advanced cancer patients. This phase I study of ramucirumab [administered every 2 or 3 weeks (Q2W or Q3W)] examined safety, maximum tolerated dose, pharmacokinetics, immunogenicity, antitumor activity, and pharmacodynamics.Patients with advanced solid malignancies were treated with escalating doses of ramucirumab i.v. over 1 h. Blood was sampled for pharmacokinetics studies throughout treatment; levels of circulating vascular endothelial growth factor-A (VEGF-A) and soluble VEGF receptors (R)-1 and -2 were assessed.Twenty-five patients were treated with ramucirumab: 13 with 6, 8, or 10 mg/kg Q2W, and 12 with 15 or 20 mg/kg Q3W. The median treatment duration was 12 weeks (range 2-81). No dose-limiting toxicities were observed. The most frequently reported adverse events (AEs) included proteinuria and hypertension (n = 6 each), and diarrhea, fatigue and headache (n = 4 each). Treatment-related grade 3/4 AEs were: two grade 3 hypertension (10 and 20 mg/kg), one each grade 3 vomiting, fatigue (20 mg/kg), atrial flutter (15 mg/kg), and one each grade 4 duodenal ulcer hemorrhage (6 mg/kg) and grade 4 pneumothorax (20 mg/kg). Pharmacokinetic analysis revealed low clearance and half-life of ∼110-160 h. Analysis of serum biomarkers indicated considerable patient-to-patient variability, but trends toward elevated VEGF-A and a transient decline in soluble VEGFR-2. Fifteen patients (60%) had best response of stable disease, with a median duration of 13 months (range 2-18 months) in tumor types including colorectal, renal, liver, and neuroendocrine cancers.Ramucirumab was well tolerated. Study results led to recommended phase II doses of 8 mg/kg Q2W and 10 mg/kg Q3W. Prolonged stable disease was observed, suggesting ramucirumab efficacy in various solid tumors.NCT00786383.

Authors
Chiorean, EG; Hurwitz, HI; Cohen, RB; Schwartz, JD; Dalal, RP; Fox, FE; Gao, L; Sweeney, CJ
MLA Citation
Chiorean, EG, Hurwitz, HI, Cohen, RB, Schwartz, JD, Dalal, RP, Fox, FE, Gao, L, and Sweeney, CJ. "Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors." Annals of oncology : official journal of the European Society for Medical Oncology 26.6 (June 2015): 1230-1237.
PMID
25787923
Source
epmc
Published In
Annals of Oncology
Volume
26
Issue
6
Publish Date
2015
Start Page
1230
End Page
1237
DOI
10.1093/annonc/mdv144

Treatment of palmar-plantar erythrodysesthesia (PPE) with topical sildenafil: a pilot study.

Palmar-plantar erythrodysesthesia (PPE) is a common chemotherapy and anti-VEGF multi-kinase inhibitor class-related toxicity that often results in debilitating skin changes and often limits the use of active anti-cancer regimens. Mechanistic and anecdotal clinical evidence suggested that topical application of sildenafil cream may help reduce the severity of PPE. Therefore, we conducted a randomized, double-blind, placebo-controlled pilot study to evaluate the feasibility, safety and efficacy of topical sildenafil cream for the treatment of PPE.Eligible subjects were required to have grade 1-3 PPE associated with either capecitabine or sunitinib. Subjects were randomized to receive 1 % topical sildenafil cream to the left extremities or right extremities and placebo cream on the opposite extremity. Two times per day, 0.5 mL of cream was applied to each affected hand/foot. The primary endpoint was improvement in PPE grading at any point on study. Clinical assessments were evaluated by NCI-CTC 4.0 grading and patient self-reported pain.Ten subjects were enrolled, nine were evaluable for safety and efficacy. Five of nine subjects reported some improvement in foot pain and three of eight subjects for hand pain improvement. One of these subjects noted specific improvement in tactile function. No treatment-related toxicities were observed.In this limited, single-center study, topical cream containing 1 % sildenafil is feasible to administer, is well-tolerated, and may mitigate PPE-related symptoms due to anti-cancer therapeutic agents. Further validation is necessary.

Authors
Meadows, KL; Rushing, C; Honeycutt, W; Latta, K; Howard, L; Arrowood, CA; Niedzwiecki, D; Hurwitz, HI
MLA Citation
Meadows, KL, Rushing, C, Honeycutt, W, Latta, K, Howard, L, Arrowood, CA, Niedzwiecki, D, and Hurwitz, HI. "Treatment of palmar-plantar erythrodysesthesia (PPE) with topical sildenafil: a pilot study." Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 23.5 (May 2015): 1311-1319.
PMID
25341548
Source
epmc
Published In
Supportive Care in Cancer
Volume
23
Issue
5
Publish Date
2015
Start Page
1311
End Page
1319
DOI
10.1007/s00520-014-2465-z

Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib.

The objectives of this study were to provide sunitinib to patients with gastrointestinal stromal tumor (GIST) who were otherwise unable to obtain it and to collect broad safety and efficacy data from a large population of patients with advanced GIST after imatinib failure.Imatinib-resistant/intolerant patients with advanced GIST received sunitinib on an initial dosing schedule of 50 mg daily in 6-week cycles (4 weeks on treatment, 2 weeks off treatment). Tumor assessment frequency was according to local practice, and response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.0. Overall survival (OS) and safety were assessed regularly. Post hoc analyses evaluated different patterns of treatment management.At final data cutoff, 1124 patients comprised the intent-to-treat population, and 15% of these patients had a baseline Eastern Cooperative Oncology Group performance status ≥2. The median treatment duration was 7.0 months. The median time to tumor progression was 8.3 months (95% confidence interval [CI], 8.0-9.4 months), the median OS was 16.6 months (95% CI, 14.9-18.0 months), and 36% of patients were alive at the time of analysis. Patients for whom the initial dosing schedule was modified exhibited longer median OS (23.5 months) than those who were treated strictly according to the initial dosing schedule (11.1 months). The most common treatment-related grade 3 and 4 adverse events were hand-foot syndrome (11%), fatigue (9%), neutropenia (8%), hypertension (7%), and thrombocytopenia (6%). Treatment-related adverse events associated with cardiac function (eg, congestive heart failure and myocardial infarction) were reported at frequencies of ≤1% each.This treatment-use study confirms the long-term safety and efficacy of sunitinib in a large international population of patients with advanced GIST after imatinib failure.

Authors
Reichardt, P; Kang, Y-K; Rutkowski, P; Schuette, J; Rosen, LS; Seddon, B; Yalcin, S; Gelderblom, H; Williams, CC; Fumagalli, E; Biasco, G; Hurwitz, HI; Kaiser, PE; Fly, K; Matczak, E; Chen, L; Lechuga, MJ; Demetri, GD
MLA Citation
Reichardt, P, Kang, Y-K, Rutkowski, P, Schuette, J, Rosen, LS, Seddon, B, Yalcin, S, Gelderblom, H, Williams, CC, Fumagalli, E, Biasco, G, Hurwitz, HI, Kaiser, PE, Fly, K, Matczak, E, Chen, L, Lechuga, MJ, and Demetri, GD. "Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib." Cancer 121.9 (May 2015): 1405-1413.
PMID
25641662
Source
epmc
Published In
Cancer
Volume
121
Issue
9
Publish Date
2015
Start Page
1405
End Page
1413
DOI
10.1002/cncr.29220

Motesanib with or without panitumumab plus FOLFIRI or FOLFOX for the treatment of metastatic colorectal cancer.

This study assessed the safety, efficacy, and pharmacokinetics of motesanib, a multitargeted small molecule angiogenesis inhibitor, with and without panitumumab, in combination with FOLFIRI or FOLFOX in patients with metastatic colorectal cancer (mCRC).This open-label, phase 1b, two-part, multicenter study in patients with mCRC and ≤1 prior treatment evaluated escalating doses (50, 75, 100, or 125 mg QD, 75 mg BID) of motesanib with panitumumab and chemotherapy (Part 1) and the target dose of motesanib with chemotherapy (Part 2).At 17 sites in the USA and Australia, 119 patients were enrolled between December 2004 and February 2010. In Part 1 [motesanib plus panitumumab/FOLFIRI (n = 36) or plus panitumumab/FOLFOX (n = 17)], all motesanib doses tested were tolerated and 125 mg QD was deemed the target dose. Following toxicity results for combination therapy in other trials, panitumumab was withdrawn from the study. Part 2 evaluated motesanib 125 mg with chemotherapy [FOLFIRI (n = 37); FOLFOX (n = 29)]. The primary endpoint, objective response rate in patients with measurable disease by RECIST, was 20 % overall and was higher among patients receiving first-line (27 % overall; FOLFOX, 24 %; FOLFIRI, 27 %) compared with second-line therapy (14 % overall; FOLFOX, 0 %; FOLFIRI, 20 %). The most common adverse events were diarrhea, nausea, fatigue, and hypertension. We observed a low rate of cholecystitis [3 of 119 (2.5 %)], a known adverse event of motesanib and other small molecule VEGF inhibitors.Motesanib 125 mg QD in combination with FOLFIRI or FOLFOX chemotherapy was tolerated and demonstrated modest efficacy in first-/second-line mCRC.

Authors
Tebbutt, N; Kotasek, D; Burris, HA; Schwartzberg, LS; Hurwitz, H; Stephenson, J; Warner, DJ; Chen, L; Hsu, C-P; Goldstein, D
MLA Citation
Tebbutt, N, Kotasek, D, Burris, HA, Schwartzberg, LS, Hurwitz, H, Stephenson, J, Warner, DJ, Chen, L, Hsu, C-P, and Goldstein, D. "Motesanib with or without panitumumab plus FOLFIRI or FOLFOX for the treatment of metastatic colorectal cancer." Cancer chemotherapy and pharmacology 75.5 (May 2015): 993-1004.
PMID
25772756
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
75
Issue
5
Publish Date
2015
Start Page
993
End Page
1004
DOI
10.1007/s00280-015-2694-y

Biomarker signatures correlate with clinical outcome in refractory metastatic colorectal cancer patients receiving bevacizumab and everolimus.

A novel combination of bevacizumab and everolimus was evaluated in refractory colorectal cancer patients in a phase II trial. In this retrospective analysis, plasma samples from 49 patients were tested for over 40 biomarkers at baseline and after one or two cycles of drug administration. Analyte levels at baseline and change on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) using univariate Cox proportional hazard modeling. Multivariable analyses were conducted using Cox modeling. Significant changes in multiple markers were observed following bevacizumab and everolimus treatment. Baseline levels of six markers significantly correlated with PFS and OS, including CRP, Gro-α, IGFBP-1, TF, ICAM-1, and TSP-2 (P < 0.05). At C2D1, changes of IGFBP-3, TGFβ-R3, and IGFBP-2 correlated with PFS and OS. Prognostic models were developed for OS and PFS (P = 0.0002 and 0.004, respectively). The baseline model for OS consisted of CRP, Gro-α, and TF, while the on-treatment model at C2D1 included IGFBP-2, IGFBP-3, and TGFβ-R3. These data demonstrated that multiple biomarkers were significantly modulated in response to bevacizumab and everolimus. Several markers correlated with both PFS and OS. Interestingly, these markers are known to be associated with inflammation and IGF signaling, key modulators of mTOR biology.

Authors
Liu, Y; Starr, MD; Brady, JC; Rushing, C; Bulusu, A; Pang, H; Honeycutt, W; Amara, A; Altomare, I; Uronis, HE; Hurwitz, HI; Nixon, AB
MLA Citation
Liu, Y, Starr, MD, Brady, JC, Rushing, C, Bulusu, A, Pang, H, Honeycutt, W, Amara, A, Altomare, I, Uronis, HE, Hurwitz, HI, and Nixon, AB. "Biomarker signatures correlate with clinical outcome in refractory metastatic colorectal cancer patients receiving bevacizumab and everolimus." Molecular cancer therapeutics 14.4 (April 2015): 1048-1056.
PMID
25695956
Source
epmc
Published In
Molecular cancer therapeutics
Volume
14
Issue
4
Publish Date
2015
Start Page
1048
End Page
1056
DOI
10.1158/1535-7163.mct-14-0923-t

Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study.

To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins.This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100% in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50%. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken.Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26%), nausea (23%), and vomiting (13%). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17%) had stable disease as the best treatment response.DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.

Authors
Hurwitz, HI; Smith, DC; Pitot, HC; Brill, JM; Chugh, R; Rouits, E; Rubin, J; Strickler, J; Vuagniaux, G; Sorensen, JM; Zanna, C
MLA Citation
Hurwitz, HI, Smith, DC, Pitot, HC, Brill, JM, Chugh, R, Rouits, E, Rubin, J, Strickler, J, Vuagniaux, G, Sorensen, JM, and Zanna, C. "Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study." Cancer chemotherapy and pharmacology 75.4 (April 2015): 851-859.
PMID
25716544
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
75
Issue
4
Publish Date
2015
Start Page
851
End Page
859
DOI
10.1007/s00280-015-2709-8

Gene expression markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance).

Formalin-fixed, paraffin-embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis-related genes to identify prognostic or predictive biomarkers for cetuximab treatment.Patients (238 total) with first-line metastatic colorectal cancer (mCRC) were randomized to FOLFOX or FOLFIRI chemotherapy ± cetuximab. qRT-PCR analyses were conducted on tissues from 103 patients at baseline to measure gene expression levels of HER-related genes, including amphiregulin (AREG), betacellulin (BTC), NT5E (CD73), DUSP4, EGF, EGFR, epigen (EPGN), epiregulin (EREG), HBEGF, ERBB2 (HER2), ERBB3 (HER3), ERBB4 (HER4), PHLDA1, and TGFA. The interactions between expression levels and treatment with respect to progression-free survival (PFS) and overall survival (OS) were modeled using multiplicative Cox proportional hazards models.High tumor mRNA levels of HER2 [hazard ratio (HR), 0.64; P = 0.002] and EREG (HR, 0.89; P = 0.016) were prognostic markers associated with longer PFS across all patients. HER3 and CD73 expression levels were identified as potential predictive markers of benefit from cetuximab. In KRAS wild-type (WT) tumors, low HER3 expression was associated with longer OS from cetuximab treatment, whereas high HER3 expression was associated with shorter OS from cetuximab treatment (chemo + cetuximab: HR, 1.15; chemo-only: HR, 0.48; Pinteraction = 0.029). High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT (chemo + cetuximab: HR, 0.91; chemo-only: HR, 1.57; Pinteraction = 0.026) and KRAS-mutant (Mut) tumors (chemo + cetuximab: HR, 0.80; chemo-only: HR, 1.29; P = 0.025).Gene expression of HER3 and CD73 was identified as a potential predictive marker for cetuximab. These data implicate HER axis signaling and immune modulation as potential mechanisms of cetuximab action and sensitivity.

Authors
Cushman, SM; Jiang, C; Hatch, AJ; Shterev, I; Sibley, AB; Niedzwiecki, D; Venook, AP; Owzar, K; Hurwitz, HI; Nixon, AB
MLA Citation
Cushman, SM, Jiang, C, Hatch, AJ, Shterev, I, Sibley, AB, Niedzwiecki, D, Venook, AP, Owzar, K, Hurwitz, HI, and Nixon, AB. "Gene expression markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance)." Clinical cancer research : an official journal of the American Association for Cancer Research 21.5 (March 2015): 1078-1086.
PMID
25520391
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
5
Publish Date
2015
Start Page
1078
End Page
1086
DOI
10.1158/1078-0432.ccr-14-2313

Primary tumor location as a prognostic factor in metastatic colorectal cancer.

We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC).We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided.Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location.These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.

Authors
Loupakis, F; Yang, D; Yau, L; Feng, S; Cremolini, C; Zhang, W; Maus, MKH; Antoniotti, C; Langer, C; Scherer, SJ; Müller, T; Hurwitz, HI; Saltz, L; Falcone, A; Lenz, H-J
MLA Citation
Loupakis, F, Yang, D, Yau, L, Feng, S, Cremolini, C, Zhang, W, Maus, MKH, Antoniotti, C, Langer, C, Scherer, SJ, Müller, T, Hurwitz, HI, Saltz, L, Falcone, A, and Lenz, H-J. "Primary tumor location as a prognostic factor in metastatic colorectal cancer." Journal of the National Cancer Institute 107.3 (March 2015).
PMID
25713148
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
107
Issue
3
Publish Date
2015
DOI
10.1093/jnci/dju427

A Phase I/biomarker study of bevacizumab in combination with CNTO 95 in patients with advanced solid tumors.

PURPOSE: Inhibition of tumor angiogenesis is an effective mechanism to limit tumor growth; dual inhibition may result in additional benefit. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF), and intetumumab is a fully humanized monoclonal antibody that blocks αv integrins when complexed with β integrins. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus intetumumab in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. METHODS: Patients with refractory solid tumors, Karnofsky performance status ≥70%, and adequate organ function were eligible. Plasma samples and wound biopsies were obtained at baseline and on-treatment. RESULTS: Twelve patients were enrolled and received study drug. No tumor responses were noted. Observed toxicities included three cases of transient uveitis likely related to intetumumab and one case of reversible posterior leukoencephalopathy syndrome likely related to bevacizumab. Biomarker analysis revealed changes in soluble endoglin, soluble E-cadherin, and soluble E-selectin as well as PlGF and VEGF-D while on treatment. There was no observed impact of bevacizumab plus intetumumab on the phosphorylated or total levels of paxillin in wound tissue; however, an increase in the ratio of phospho/total paxillin levels was noted. CONCLUSIONS: Bevacizumab and intetumumab can be administered safely in combination. Bevacizumab plus intetumumab treatment resulted in changes in the plasma levels of several extracellular matrix interacting proteins and angiogenic factors.

Authors
Uronis, HE; Jia, J; Bendell, JC; Howard, L; Ready, NA; Lee, PH; Starr, MD; Dellinger, A; Pang, H; Nixon, AB; Hurwitz, HI
MLA Citation
Uronis, HE, Jia, J, Bendell, JC, Howard, L, Ready, NA, Lee, PH, Starr, MD, Dellinger, A, Pang, H, Nixon, AB, and Hurwitz, HI. "A Phase I/biomarker study of bevacizumab in combination with CNTO 95 in patients with advanced solid tumors." Cancer chemotherapy and pharmacology 75.2 (February 2015): 343-352.
PMID
25527204
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
75
Issue
2
Publish Date
2015
Start Page
343
End Page
352
DOI
10.1007/s00280-014-2647-x

A leave-one-out cross-validation SAS macro for the identification of markers associated with survival.

A proper internal validation is necessary for the development of a reliable and reproducible prognostic model for external validation. Variable selection is an important step for building prognostic models. However, not many existing approaches couple the ability to specify the number of covariates in the model with a cross-validation algorithm. We describe a user-friendly SAS macro that implements a score selection method and a leave-one-out cross-validation approach. We discuss the method and applications behind this algorithm, as well as details of the SAS macro.

Authors
Rushing, C; Bulusu, A; Hurwitz, HI; Nixon, AB; Pang, H
MLA Citation
Rushing, C, Bulusu, A, Hurwitz, HI, Nixon, AB, and Pang, H. "A leave-one-out cross-validation SAS macro for the identification of markers associated with survival." Computers in biology and medicine 57 (February 2015): 123-129.
PMID
25553357
Source
epmc
Published In
Computers in Biology and Medicine
Volume
57
Publish Date
2015
Start Page
123
End Page
129
DOI
10.1016/j.compbiomed.2014.11.015

A Phase I/biomarker study of bevacizumab in combination with CNTO 95 in patients with advanced solid tumors

© Springer-Verlag 2014. Purpose: Inhibition of tumor angiogenesis is an effective mechanism to limit tumor growth; dual inhibition may result in additional benefit. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF), and intetumumab is a fully humanized monoclonal antibody that blocks αv integrins when complexed with β integrins. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus intetumumab in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. Methods: Patients with refractory solid tumors, Karnofsky performance status ≥70 %, and adequate organ function were eligible. Plasma samples and wound biopsies were obtained at baseline and on-treatment. Results: Twelve patients were enrolled and received study drug. No tumor responses were noted. Observed toxicities included three cases of transient uveitis likely related to intetumumab and one case of reversible posterior leukoencephalopathy syndrome likely related to bevacizumab. Biomarker analysis revealed changes in soluble endoglin, soluble E-cadherin, and soluble E-selectin as well as PlGF and VEGF-D while on treatment. There was no observed impact of bevacizumab plus intetumumab on the phosphorylated or total levels of paxillin in wound tissue; however, an increase in the ratio of phospho/total paxillin levels was noted. Conclusions: Bevacizumab and intetumumab can be administered safely in combination. Bevacizumab plus intetumumab treatment resulted in changes in the plasma levels of several extracellular matrix interacting proteins and angiogenic factors.

Authors
Uronis, HE; Jia, J; Bendell, JC; Howard, L; Ready, NA; Lee, PH; Starr, MD; Dellinger, A; Pang, H; Nixon, AB; Hurwitz, HI
MLA Citation
Uronis, HE, Jia, J, Bendell, JC, Howard, L, Ready, NA, Lee, PH, Starr, MD, Dellinger, A, Pang, H, Nixon, AB, and Hurwitz, HI. "A Phase I/biomarker study of bevacizumab in combination with CNTO 95 in patients with advanced solid tumors." Cancer Chemotherapy and Pharmacology 75.2 (January 1, 2015): 343-352.
Source
scopus
Published In
Cancer Chemotherapy and Pharmacology
Volume
75
Issue
2
Publish Date
2015
Start Page
343
End Page
352
DOI
10.1007/s00280-014-2647-x

Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: Results of a first-in-man study

© 2015 The Author(s). Purpose: To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins. Methods: This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100 % in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50 %. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken. Results: Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26 %), nausea (23 %), and vomiting (13 %). Average t < inf > max < /inf > and T < inf > 1/2 < /inf > was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses > 80 mg. Five patients (17 %) had stable disease as the best treatment response. Conclusion: DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.

Authors
Hurwitz, HI; Smith, DC; Pitot, HC; Brill, JM; Chugh, R; Rouits, E; Rubin, J; Strickler, J; Vuagniaux, G; Sorensen, JM; Zanna, C
MLA Citation
Hurwitz, HI, Smith, DC, Pitot, HC, Brill, JM, Chugh, R, Rouits, E, Rubin, J, Strickler, J, Vuagniaux, G, Sorensen, JM, and Zanna, C. "Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: Results of a first-in-man study." Cancer Chemotherapy and Pharmacology 75.4 (January 1, 2015): 851-859.
Source
scopus
Published In
Cancer Chemotherapy and Pharmacology
Volume
75
Issue
4
Publish Date
2015
Start Page
851
End Page
859
DOI
10.1007/s00280-015-2709-8

Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the digestive system database.

Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination.Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti-epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R(2) statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models.Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R(2), 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy.In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.

Authors
Shi, Q; de Gramont, A; Grothey, A; Zalcberg, J; Chibaudel, B; Schmoll, H-J; Seymour, MT; Adams, R; Saltz, L; Goldberg, RM; Punt, CJA; Douillard, J-Y; Hoff, PM; Hecht, JR; Hurwitz, H; Díaz-Rubio, E; Porschen, R; Tebbutt, NC; Fuchs, C; Souglakos, J; Falcone, A; Tournigand, C; Kabbinavar, FF; Heinemann, V; Van Cutsem, E; Bokemeyer, C; Buyse, M; Sargent, DJ
MLA Citation
Shi, Q, de Gramont, A, Grothey, A, Zalcberg, J, Chibaudel, B, Schmoll, H-J, Seymour, MT, Adams, R, Saltz, L, Goldberg, RM, Punt, CJA, Douillard, J-Y, Hoff, PM, Hecht, JR, Hurwitz, H, Díaz-Rubio, E, Porschen, R, Tebbutt, NC, Fuchs, C, Souglakos, J, Falcone, A, Tournigand, C, Kabbinavar, FF, Heinemann, V, Van Cutsem, E, Bokemeyer, C, Buyse, M, and Sargent, DJ. "Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the digestive system database." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.1 (January 2015): 22-28.
PMID
25385741
Source
epmc
Published In
Journal of Clinical Oncology
Volume
33
Issue
1
Publish Date
2015
Start Page
22
End Page
28
DOI
10.1200/jco.2014.56.5887

Treatment of palmar-plantar erythrodysesthesia (PPE) with topical sildenafil: a pilot study

© 2014, Springer-Verlag Berlin Heidelberg.Purpose: Palmar-plantar erythrodysesthesia (PPE) is a common chemotherapy and anti-VEGF multi-kinase inhibitor class-related toxicity that often results in debilitating skin changes and often limits the use of active anti-cancer regimens. Mechanistic and anecdotal clinical evidence suggested that topical application of sildenafil cream may help reduce the severity of PPE. Therefore, we conducted a randomized, double-blind, placebo-controlled pilot study to evaluate the feasibility, safety and efficacy of topical sildenafil cream for the treatment of PPE. Methods: Eligible subjects were required to have grade 1–3 PPE associated with either capecitabine or sunitinib. Subjects were randomized to receive 1 % topical sildenafil cream to the left extremities or right extremities and placebo cream on the opposite extremity. Two times per day, 0.5 mL of cream was applied to each affected hand/foot. The primary endpoint was improvement in PPE grading at any point on study. Clinical assessments were evaluated by NCI-CTC 4.0 grading and patient self-reported pain. Results: Ten subjects were enrolled, nine were evaluable for safety and efficacy. Five of nine subjects reported some improvement in foot pain and three of eight subjects for hand pain improvement. One of these subjects noted specific improvement in tactile function. No treatment-related toxicities were observed. Conclusions: In this limited, single-center study, topical cream containing 1 % sildenafil is feasible to administer, is well-tolerated, and may mitigate PPE-related symptoms due to anti-cancer therapeutic agents. Further validation is necessary.

Authors
Meadows, KL; Rushing, C; Honeycutt, W; Latta, K; Howard, L; Arrowood, CA; Niedzwiecki, D; Hurwitz, HI
MLA Citation
Meadows, KL, Rushing, C, Honeycutt, W, Latta, K, Howard, L, Arrowood, CA, Niedzwiecki, D, and Hurwitz, HI. "Treatment of palmar-plantar erythrodysesthesia (PPE) with topical sildenafil: a pilot study." Supportive Care in Cancer 23.5 (2015): 1311-1319.
Source
scival
Published In
Supportive Care in Cancer
Volume
23
Issue
5
Publish Date
2015
Start Page
1311
End Page
1319
DOI
10.1007/s00520-014-2465-z

An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer.

This phase I study evaluated the pharmacokinetics and pharmacodynamics of CEP-11981, an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, in patients with advanced, relapsed, or refractory solid tumors.Oral CEP-11981 dose escalations followed a modified Fibonacci sequence (from 3.0 to 4.2, 5.9, 11.8, 19.7, 29.6, 41.4, 55.0, 73.0, 97.4, and 126.6 mg/m(2)). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated.CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m(2). The MTD of CEP-11981 was determined to be 97.4 mg/m(2), with DLTs observed at the 126.6 mg/m(2) dose. The DLTs were grade 4 neutropenia in 1 patient and grade 3 T-wave inversion with chest heaviness and fatigue in 1 patient. All 3 events resolved on stopping CEP-11981. The most frequently reported adverse events of any grade were fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, constipation, headache, dizziness, and dyspnea. Treatment-related grade 3/4 neutropenia was observed in the highest-dose cohorts (2 patients at 97.4 mg/m(2) and 1 patient at 126.6 mg/m(2)), indicating some off-target inhibition. VEGF inhibition was greatest in the higher-dose groups. Although no patient experienced complete or partial response, 44% patients achieved stable disease when measured at ≥ 6 weeks, which occurred more frequently in cohorts receiving ≥ 73.0 mg/m(2).In patients with recurrent or refractory solid tumors, disease stabilization was achieved. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased.

Authors
Pili, R; Carducci, M; Brown, P; Hurwitz, H
MLA Citation
Pili, R, Carducci, M, Brown, P, and Hurwitz, H. "An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer." Investigational new drugs 32.6 (December 2014): 1258-1268.
PMID
25152243
Source
epmc
Published In
Investigational New Drugs
Volume
32
Issue
6
Publish Date
2014
Start Page
1258
End Page
1268
DOI
10.1007/s10637-014-0147-9

The search for biomarkers to direct antiangiogenic treatment in epithelial ovarian cancer.

Antiangiogenic agents have demonstrated improved progression-free survival in women with primary and recurrent epithelial ovarian cancer (EOC). Biomarkers that predict outcomes in patients treated with antiangiogenic agents are being investigated to rationally direct therapy for women most likely to benefit from these agents. Among the most promising plasma-based biomarkers are vascular endothelial growth factor (VEGF)-A, fibroblast growth factor, platelet-derived growth factor, angiopoietin-2, and VEGF receptor-2. While these biomarkers have been correlated with prognosis, they have not been shown to predict benefit, specifically from anti-VEGF therapy, highlighting the need for alternative biomarkers, including molecular and clinical factors, which may be predictive of outcome in women with ovarian cancer treated with antiangiogenic agents. Biomarkers are currently being investigated as secondary outcomes in several ongoing phase II and phase III clinical trials of antiangiogenic agents in patients with EOC. Molecular techniques, such as microarray analyses, and imaging techniques, such as dynamic contrast-enhanced magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography, are also being explored in this field. In this review, we provide a comprehensive overview of current biomarker research, with an emphasis on angiogenic biomarkers associated with EOC.

Authors
Secord, AA; Nixon, AB; Hurwitz, HI
MLA Citation
Secord, AA, Nixon, AB, and Hurwitz, HI. "The search for biomarkers to direct antiangiogenic treatment in epithelial ovarian cancer." Gynecologic oncology 135.2 (November 2014): 349-358. (Review)
PMID
25178997
Source
epmc
Published In
Gynecologic Oncology
Volume
135
Issue
2
Publish Date
2014
Start Page
349
End Page
358
DOI
10.1016/j.ygyno.2014.08.033

A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors.

PURPOSE: To investigate the safety, optimal dosing, pharmacokinetics and clinical activity of a regimen of navitoclax (ABT-263) combined with gemcitabine in patients with solid tumors. EXPERIMENTAL DESIGN: Patients with solid tumors for which gemcitabine was deemed an appropriate therapy were enrolled into one of two different dosing schedules (21-day dosing schedule: navitoclax administered orally on days 1-3 and 8-10,; and gemcitabine 1,000 mg/m(2) on days 1 and 8; 28-day dosing schedule: navitoclax administrated orally on days 1-3, 8-10, and 15-17; and gemcitabine 1,000 mg/m(2) on days 1, 8 and 15). Navitoclax doses were escalated from 150 to 425 mg. An expanded safety cohort was conducted for the 21-day dosing schedule at the maximum tolerated dose (MTD) of navitoclax. RESULTS: Forty-six patients were enrolled at three U.S. centers. The most common adverse events included: hematologic abnormalities (thrombocytopenia, neutropenia, and anemia), liver enzyme elevations (ALT and AST), and gastrointestinal disturbances (diarrhea, nausea, and vomiting). Dose-limiting toxicities (DLTs) observed in cycle 1 were grade 4 thrombocytopenia (2 patients), grade 4 neutropenia (1 patient), and grade 3 AST elevation (2 patients). The MTD of navitoclax was 325 mg co-administered with gemcitabine 1,000 mg/m(2) for the 21-day schedule. No clinically significant pharmacokinetic drug-drug interactions were observed. There were no objective responses. Stable disease, reported at the end of cycle 2, was the best response in 54 % of evaluable patients (n = 39). CONCLUSIONS: The combination of navitoclax 325 mg with gemcitabine 1,000 mg/m(2) was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors.

Authors
Cleary, JM; Lima, CMSR; Hurwitz, HI; Montero, AJ; Franklin, C; Yang, J; Graham, A; Busman, T; Mabry, M; Holen, K; Shapiro, GI; Uronis, H
MLA Citation
Cleary, JM, Lima, CMSR, Hurwitz, HI, Montero, AJ, Franklin, C, Yang, J, Graham, A, Busman, T, Mabry, M, Holen, K, Shapiro, GI, and Uronis, H. "A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors." Investigational new drugs 32.5 (October 2014): 937-945.
PMID
24916770
Source
epmc
Published In
Investigational New Drugs
Volume
32
Issue
5
Publish Date
2014
Start Page
937
End Page
945
DOI
10.1007/s10637-014-0110-9

Effects of the combination of TRC105 and bevacizumab on endothelial cell biology.

Endoglin, or CD105, is a cell membrane glycoprotein that is overexpressed on proliferating endothelial cells (EC), including those found in malignancies and choroidal neovascularization. Endoglin mediates the transition from quiescent endothelium, characterized by the relatively dominant state of Smad 2/3 phosphorylation, to active angiogenesis by preferentially phosphorylating Smad 1/5/8. The monoclonal antibody TRC105 binds endoglin with high avidity and is currently being tested in phase 1b and phase 2 clinical trials. In this report, we evaluated the effects of TRC105 on primary human umbilical vascular endothelial cells (HUVEC) as a single agent and in combination with bevacizumab. As single agents, both TRC105 and bevacizumab efficiently blocked HUVEC tube formation, and the combination of both agents achieved even greater levels of inhibition. We further assessed the effects of each drug on various aspects of HUVEC function. While bevacizumab was observed to inhibit HUVEC viability in nutrient-limited medium, TRC105 had little effect on HUVEC viability, either alone or in combination with bevacizumab. Additionally, both drugs inhibited HUVEC migration and induced apoptosis. At the molecular level, TRC105 treatment of HUVEC lead to decreased Smad 1/5/8 phosphorylation in response to BMP-9, a primary ligand for endoglin. Together, these results indicate that TRC105 acts as an effective anti-angiogenic agent alone and in combination with bevacizumab.

Authors
Liu, Y; Tian, H; Blobe, GC; Theuer, CP; Hurwitz, HI; Nixon, AB
MLA Citation
Liu, Y, Tian, H, Blobe, GC, Theuer, CP, Hurwitz, HI, and Nixon, AB. "Effects of the combination of TRC105 and bevacizumab on endothelial cell biology." Investigational new drugs 32.5 (October 2014): 851-859.
PMID
24994097
Source
epmc
Published In
Investigational New Drugs
Volume
32
Issue
5
Publish Date
2014
Start Page
851
End Page
859
DOI
10.1007/s10637-014-0129-y

Understanding the mechanisms of action of antiangiogenic agents in metastatic colorectal cancer: a clinician's perspective.

Multiple clinical trials using bevacizumab, ziv-aflibercept, and regorafenib have recently demonstrated efficacy for patients with metastatic colorectal cancer. While the net clinical benefit of each of these therapies in the second-line and refractory disease setting appears to be similar, important distinctions exist between the agents at the pharmacodynamic, tumor microenvironment, and clinical levels. The purpose of this review is to survey the preclinical evidence regarding the mechanisms of action of these novel antiangiogenic agents and provide an overview of their respective clinical activity, while highlighting distinctions between therapies. Fundamental understanding of these distinctions may aid in clinical decisions and choice of antiangiogenic therapies.

Authors
Clarke, JM; Hurwitz, HI; Rangwala, F
MLA Citation
Clarke, JM, Hurwitz, HI, and Rangwala, F. "Understanding the mechanisms of action of antiangiogenic agents in metastatic colorectal cancer: a clinician's perspective." Cancer treatment reviews 40.9 (October 2014): 1065-1072. (Review)
PMID
25047778
Source
epmc
Published In
Cancer Treatment Reviews
Volume
40
Issue
9
Publish Date
2014
Start Page
1065
End Page
1072
DOI
10.1016/j.ctrv.2014.07.001

A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma.

Vatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC).A phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC.We evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability (> 1 year) was demonstrated in 19% of patients.Relevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC.

Authors
Bitting, RL; Healy, P; Creel, PA; Turnbull, J; Morris, K; Wood, SY; Hurwitz, HI; Starr, MD; Nixon, AB; Armstrong, AJ; George, DJ
MLA Citation
Bitting, RL, Healy, P, Creel, PA, Turnbull, J, Morris, K, Wood, SY, Hurwitz, HI, Starr, MD, Nixon, AB, Armstrong, AJ, and George, DJ. "A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma." Clinical genitourinary cancer 12.4 (August 2014): 241-250.
PMID
24685058
Source
epmc
Published In
Clinical genitourinary cancer
Volume
12
Issue
4
Publish Date
2014
Start Page
241
End Page
250
DOI
10.1016/j.clgc.2013.11.020

Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors.

To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients.This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms.Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival.Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m(2) BID days 1-14; oxaliplatin 100 mg/m(2) and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC.

Authors
Rangwala, F; Bendell, JC; Kozloff, MF; Arrowood, CC; Dellinger, A; Meadows, J; Tourt-Uhlig, S; Murphy, J; Meadows, KL; Starr, A; Broderick, S; Brady, JC; Cushman, SM; Morse, MA; Uronis, HE; Hsu, SD; Zafar, SY; Wallace, J; Starodub, AN; Strickler, JH; Pang, H; Nixon, AB; Hurwitz, HI
MLA Citation
Rangwala, F, Bendell, JC, Kozloff, MF, Arrowood, CC, Dellinger, A, Meadows, J, Tourt-Uhlig, S, Murphy, J, Meadows, KL, Starr, A, Broderick, S, Brady, JC, Cushman, SM, Morse, MA, Uronis, HE, Hsu, SD, Zafar, SY, Wallace, J, Starodub, AN, Strickler, JH, Pang, H, Nixon, AB, and Hurwitz, HI. "Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors." Investigational new drugs 32.4 (August 2014): 700-709.
PMID
24711126
Source
epmc
Published In
Investigational New Drugs
Volume
32
Issue
4
Publish Date
2014
Start Page
700
End Page
709
DOI
10.1007/s10637-014-0089-2

Bevacizumab exposure beyond first disease progression in patients with metastatic colorectal cancer: analyses of the ARIES observational cohort study.

PURPOSE: This analysis from Avastin® Registries: Investigation of Effectiveness and Safety (ARIES) examined the association between exposure to bevacizumab after disease progression (PD) and postprogression survival (PPS) in bevacizumab-exposed metastatic colorectal cancer (mCRC) through the application of time-dependent and time-fixed analytical methods. METHODS: Patients with mCRC who were treated with first-line bevacizumab and who survived first PD (PD1) were included. A time-dependent Cox regression model was fitted to assess the effect of cumulative bevacizumab exposure on PPS, while controlling for potential confounders. In addition to support findings from previous studies, a modified intent-to-treat (mITT) analysis compared PPS in patients who received bevacizumab beyond disease progression (BBP) with those who did not (No-BBP). RESULTS: Of 1550 patients, 1199 survived PD1 and had a median PPS of 13.4 months. Cumulative bevacizumab exposure was associated with improved PPS (p = 0.0040). After adjusting for confounders, the hazard ratios (HRs) for PPS decreased, on average, by 1.2% (range, 1.1-1.3%) with each additional dose of bevacizumab. In the mITT analysis, the median PPS for BBP (n = 438) was 14.4 months vs 10.6 months with for No-BBP (n = 667). BBP was found to be independently associated with longer PPS in a multivariable Cox regression analysis (HR, 0.84; 95% confidence interval, 0.73-0.97). Protocol-specified adverse events suspected to be associated with bevacizumab occurred in 13.0% of patients with BBP. CONCLUSION: This analysis supports the observation that bevacizumab exposure after PD1 is associated with longer PPS in mCRC.

Authors
Grothey, A; Flick, ED; Cohn, AL; Bekaii-Saab, TS; Bendell, JC; Kozloff, M; Roach, N; Mun, Y; Fish, S; Hurwitz, HI
MLA Citation
Grothey, A, Flick, ED, Cohn, AL, Bekaii-Saab, TS, Bendell, JC, Kozloff, M, Roach, N, Mun, Y, Fish, S, and Hurwitz, HI. "Bevacizumab exposure beyond first disease progression in patients with metastatic colorectal cancer: analyses of the ARIES observational cohort study." Pharmacoepidemiology and drug safety 23.7 (July 2014): 726-734.
PMID
24830357
Source
epmc
Published In
Pharmacoepidemiology and Drug Safety
Volume
23
Issue
7
Publish Date
2014
Start Page
726
End Page
734
DOI
10.1002/pds.3633

Modulation of circulating protein biomarkers following TRC105 (anti-endoglin antibody) treatment in patients with advanced cancer.

TRC105 is an endoglin-targeting drug that possesses anti-angiogenic and antitumor potential. Analysis of the initial phase I trial of TRC105 demonstrated good tolerability and efficacy in cancer patients. In this report, we analyzed multiple circulating biomarkers at baseline, cycle 2 day 1 (C2D1), and end of study (EOS) for each patient. The baseline level and the fold change from baseline to both C2D1 and EOS for each marker were statistically analyzed. At C2D1, seven markers were significantly downregulated (angiopoietin-2 [Ang-2], insulin-like growth factor-binding protein-3 [IGFBP-3], plasminogen activator inhibitor-1 [PAI-1] total, platelet-derived growth factor [PDGF]-AA, PDGF-BB, thrombospondin-1 [TSP-1], and vascular endothelial growth factor [VEGF]-D). Meanwhile, seven markers were upregulated by C2D1 (E-Cadherin, soluble Endoglin [sEnd], E-Selectin, interleukin-6 [IL-6], osteopontin [OPN], TSP-2, and von Willebrand factor [vWF]). At EOS, seven markers were upregulated including Ang-2, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), IGFBP-1, IL-6, TSP-2, and vascular cell adhesion molecule-1 (VCAM-1). A statistical trend was also seen for increases of VEGF-A and placenta growth factor (PlGF) at EOS. Throughout treatment, sEnd levels significantly increased, an observation that was recapitulated in cultured endothelial cells. This is the first report of plasma-based biomarkers in patients receiving TRC105. TRC105 treatment by C2D1 was associated with decreases in several angiogenic factors, including Ang-2, PDGF isoforms, and VEGF isoforms, offering insight into the mechanisms underlying TRC105's anti-angiogenic, antitumor function. Increases in sEnd were the most significant of all observed biomarker changes and may reflect direct drug effects. Additionally, biomarker changes in response to TRC105 are distinct from those seen in patients treated with VEGF-targeting drugs, suggesting the possible utility of combining these two classes of angiogenesis inhibitors in patients.

Authors
Liu, Y; Starr, MD; Brady, JC; Dellinger, A; Pang, H; Adams, B; Theuer, CP; Lee, NY; Hurwitz, HI; Nixon, AB
MLA Citation
Liu, Y, Starr, MD, Brady, JC, Dellinger, A, Pang, H, Adams, B, Theuer, CP, Lee, NY, Hurwitz, HI, and Nixon, AB. "Modulation of circulating protein biomarkers following TRC105 (anti-endoglin antibody) treatment in patients with advanced cancer." Cancer medicine 3.3 (June 2014): 580-591.
PMID
24574330
Source
epmc
Published In
Cancer Medicine
Volume
3
Issue
3
Publish Date
2014
Start Page
580
End Page
591
DOI
10.1002/cam4.207

Safety and effectiveness of bevacizumab treatment for metastatic colorectal cancer: final results from the Avastin(®) Registry - Investigation of Effectiveness and Safety (ARIES) observational cohort study.

AIMS: The Avastin(®) Registry - Investigation of Effectiveness and Safety (ARIES) observational cohort study (OCS) was designed to prospectively examine outcomes associated with bevacizumab-containing treatment for metastatic colorectal cancer (mCRC) in a community-based setting, where patient populations are less restricted than those in randomised trials. MATERIALS AND METHODS: Patients with mCRC who were eligible for bevacizumab in combination with chemotherapy in first- or second-line treatment were enrolled from November 2006 to September 2008. There were no protocol-specified treatment regimens; the dose and schedule of bevacizumab and chemotherapy were at the treating physician's discretion. The objectives in the ARIES OCS included analyses of progression-free survival (PFS), overall survival, treatment patterns and safety in each of the first- and second-line treatment cohorts. RESULTS: ARIES enrolled 1550 patients with mCRC receiving first-line therapy with bevacizumab. The median follow-up time was 20.6 months. The median PFS in this cohort was 10.2 months (95% confidence interval 9.8-10.6) and the median overall survival was 23.2 months (95% confidence interval 21.2-24.8). In a separate cohort of 482 patients with second-line mCRC, the median follow-up time was 16.9 months, the median PFS and overall survival from the start of second-line treatment to the end of follow-up was 7.9 months (95% confidence interval 7.2-8.3) and 17.8 months (95% confidence interval 16.5-20.7), respectively. Incidences of known bevacizumab-associated adverse events in ARIES were generally consistent with those previously reported in OCSs and randomised trials. CONCLUSION: Results from the prospective ARIES OCS add further evidence to support the effectiveness and safety of bevacizumab when added to first- and second-line treatment regimens for patients with mCRC in community treatment settings.

Authors
Hurwitz, HI; Bekaii-Saab, TS; Bendell, JC; Cohn, AL; Kozloff, M; Roach, N; Mun, Y; Fish, S; Flick, ED; Grothey, A; ARIES Study Investigators,
MLA Citation
Hurwitz, HI, Bekaii-Saab, TS, Bendell, JC, Cohn, AL, Kozloff, M, Roach, N, Mun, Y, Fish, S, Flick, ED, Grothey, A, and ARIES Study Investigators, . "Safety and effectiveness of bevacizumab treatment for metastatic colorectal cancer: final results from the Avastin(®) Registry - Investigation of Effectiveness and Safety (ARIES) observational cohort study." Clinical oncology (Royal College of Radiologists (Great Britain)) 26.6 (June 2014): 323-332.
PMID
24686090
Source
epmc
Published In
Clinical Oncology
Volume
26
Issue
6
Publish Date
2014
Start Page
323
End Page
332
DOI
10.1016/j.clon.2014.03.001

Metastatic ampullary adenocarcinoma presenting as a hydrocele: a case report.

CONTEXT: Metastases from ampullary malignancies are common, but spread to the testicle and paratesticular tissue is exceedingly rare with only 2 reported cases in the literature. CASE REPORT: We report a case of a 70 year-old male with a history of ampullary adenocarcinoma status post pancreaticoduodenectomy who presented with a symptomatic right-sided hydrocele. Subsequent pathology revealed metastatic ampullary adenocarcinoma. CONCLUSIONS: Metastasis to the testicle and paratesticular tissue from ampullary malignancies is rare, but must be considered in the evaluation of scrotal masses in patients with a history of ampullary malignancy.

Authors
Lane, WO; Bentley, RC; Hurwitz, HI; Howard, LA; Polascik, TJ; Anderson, MR; Blazer, DG
MLA Citation
Lane, WO, Bentley, RC, Hurwitz, HI, Howard, LA, Polascik, TJ, Anderson, MR, and Blazer, DG. "Metastatic ampullary adenocarcinoma presenting as a hydrocele: a case report." JOP : Journal of the pancreas 15.3 (May 27, 2014): 266-268.
PMID
24865540
Source
epmc
Published In
JOP : Journal of the pancreas
Volume
15
Issue
3
Publish Date
2014
Start Page
266
End Page
268
DOI
10.6092/1590-8577/2407

Metastatic ampullary adenocarcinoma presenting as a hydrocele: a case report

CONTEXT: Metastases from ampullary malignancies are common, but spread to the testicle and paratesticular tissue is exceedingly rare with only 2 reported cases in the literature. CASE REPORT: We report a case of a 70 year-old male with a history of ampullary adenocarcinoma status post pancreaticoduodenectomy who presented with a symptomatic right-sided hydrocele. Subsequent pathology revealed metastatic ampullary adenocarcinoma. CONCLUSIONS: Metastasis to the testicle and paratesticular tissue from ampullary malignancies is rare, but must be considered in the evaluation of scrotal masses in patients with a history of ampullary malignancy.

Authors
Lane, WO; Bentley, RC; Hurwitz, HI; Howard, LA; Polascik, TJ; Anderson, MR; Blazer, DG
MLA Citation
Lane, WO, Bentley, RC, Hurwitz, HI, Howard, LA, Polascik, TJ, Anderson, MR, and Blazer, DG. "Metastatic ampullary adenocarcinoma presenting as a hydrocele: a case report." JOP : Journal of the pancreas 15.3 (May 1, 2014): 266-268.
Source
scopus
Published In
JOP : Journal of the pancreas
Volume
15
Issue
3
Publish Date
2014
Start Page
266
End Page
268
DOI
10.6092/1590-8577/2407

Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer.

This study was conducted to evaluate potential pharmacokinetic interactions between docetaxel and atrasentan as part of a phase I/II clinical trial.Patients with prostate cancer were treated with intravenous docetaxel (60-75 mg/m(2)) every 3 weeks and oral atrasentan (10 mg) daily starting on day 3 of cycle 1 and then given continuously. The pharmacokinetics of both drugs were evaluated individually (cycle 1, day 1 for docetaxel; day 21 for atrasentan) and in combination (cycle 2, day 1 for both drugs). Pharmacogenomics of alpha-1-acid glycoprotein (AAG) were also explored.Paired pharmacokinetic data sets for both drugs were evaluable in 21 patients. Atrasentan was rapidly absorbed and plasma concentrations varied over a fourfold range at steady state within a typical patient. The median apparent oral clearance of atrasentan was 17.4 L/h in cycle 1 and was not affected by docetaxel administration (p = 0.9). Median systemic clearance of docetaxel was 51.1 L/h on the first cycle and significantly slower (p = 0.01) compared with that obtained during co-administration of atrasentan, 61.6 L/h. Docetaxel systemic clearance in cycle 1 was 70.0 L/h in patients homozygous for a variant allele in AAG compared with 44.5 L/h in those with at least one wild-type allele (p = 0.03).Genetic polymorphism in AAG may explain some inter-patient variability in docetaxel pharmacokinetics. The systemic clearance of docetaxel is increased by approximately 21 % when given concomitantly with atrasentan; however, atrasentan pharmacokinetics does not appear to be influenced by docetaxel administration.

Authors
Younis, IR; George, DJ; McManus, TJ; Hurwitz, H; Creel, P; Armstrong, AJ; Yu, JJ; Bacon, K; Hobbs, G; Peer, CJ; Petros, WP
MLA Citation
Younis, IR, George, DJ, McManus, TJ, Hurwitz, H, Creel, P, Armstrong, AJ, Yu, JJ, Bacon, K, Hobbs, G, Peer, CJ, and Petros, WP. "Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer." Cancer chemotherapy and pharmacology 73.5 (May 2014): 991-997.
PMID
24619498
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
73
Issue
5
Publish Date
2014
Start Page
991
End Page
997
DOI
10.1007/s00280-014-2432-x

Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer.

PURPOSE: Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). METHODS: Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m(2) twice daily, days 1-14), oxaliplatin (130 mg/m(2) on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (src(act)) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). RESULTS: Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of src(act) expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src(act) expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). CONCLUSIONS: The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib.

Authors
Strickler, JH; McCall, S; Nixon, AB; Brady, JC; Pang, H; Rushing, C; Cohn, A; Starodub, A; Arrowood, C; Haley, S; Meadows, KL; Morse, MA; Uronis, HE; Blobe, GC; Hsu, SD; Zafar, SY; Hurwitz, HI
MLA Citation
Strickler, JH, McCall, S, Nixon, AB, Brady, JC, Pang, H, Rushing, C, Cohn, A, Starodub, A, Arrowood, C, Haley, S, Meadows, KL, Morse, MA, Uronis, HE, Blobe, GC, Hsu, SD, Zafar, SY, and Hurwitz, HI. "Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer." Invest New Drugs 32.2 (April 2014): 330-339.
PMID
24173967
Source
pubmed
Published In
Investigational New Drugs
Volume
32
Issue
2
Publish Date
2014
Start Page
330
End Page
339
DOI
10.1007/s10637-013-0042-9

Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with advanced cancer.

PURPOSE: The angiogenesis inhibitor dalantercept (formerly ACE-041) is a soluble form of activin receptor-like kinase-1 (ALK1) that prevents activation of endogenous ALK1 by bone morphogenetic protein-9 (BMP9) and BMP10 and exhibits antitumor activity in preclinical models. This first-in-human study of dalantercept evaluated its safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in adults with advanced solid tumors. EXPERIMENTAL DESIGN: Patients in dose-escalating cohorts received dalantercept subcutaneously at one of seven dose levels (0.1-4.8 mg/kg) every 3 weeks until disease progression. Patients in an expansion cohort received dalantercept at 0.8 or 1.6 mg/kg every 3 weeks until disease progression. RESULTS: In 37 patients receiving dalantercept, the most common treatment-related adverse events were peripheral edema, fatigue, and anemia. Edema and fluid retention were dose-limiting toxicities and responded to diuretic therapy. No clinically significant, treatment-related hypertension, proteinuria, gross hemorrhage, or gastrointestinal perforations were observed. One patient with refractory squamous cell cancer of the head and neck had a partial response, and 13 patients had stable disease according to RECISTv1.1, eight of whom had prolonged periods (≥12 weeks) of stable disease. Correlative pharmacodynamic markers included tumor metabolic activity and tumor blood flow, which decreased from baseline in 63% and 82% of evaluable patients, respectively, and telangiectasia in eight patients. CONCLUSION: Dalantercept was well-tolerated at doses up to 1.6 mg/kg, with a safety profile distinct from inhibitors of the VEGF pathway. Dalantercept displayed promising antitumor activity in patients with advanced refractory cancer, and multiple phase II studies are underway.

Authors
Bendell, JC; Gordon, MS; Hurwitz, HI; Jones, SF; Mendelson, DS; Blobe, GC; Agarwal, N; Condon, CH; Wilson, D; Pearsall, AE; Yang, Y; McClure, T; Attie, KM; Sherman, ML; Sharma, S
MLA Citation
Bendell, JC, Gordon, MS, Hurwitz, HI, Jones, SF, Mendelson, DS, Blobe, GC, Agarwal, N, Condon, CH, Wilson, D, Pearsall, AE, Yang, Y, McClure, T, Attie, KM, Sherman, ML, and Sharma, S. "Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with advanced cancer." Clin Cancer Res 20.2 (January 15, 2014): 480-489.
PMID
24173543
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
20
Issue
2
Publish Date
2014
Start Page
480
End Page
489
DOI
10.1158/1078-0432.CCR-13-1840

Palliative treatment of metastatic colorectal cancer: What is the optimal approach? Topical collection on gastrointestinal cancers

Worldwide, colorectal cancer (CRC) is responsible for over 600,000 deaths annually and remains a significant public health concern. Because of therapeutic advancements over the past two decades, patients with metastatic CRC are living longer with an improved quality of life. This review will highlight recent trial evidence that improves outcomes for patients with metastatic disease. Topics will include the optimal use of first-line combination chemotherapy, bevacizumab in patients with advanced age or comorbidities, maintenance chemotherapy, first-line use of anti-EGFR therapies, first-line cetuximab versus bevacizumab, anti-angiogenic therapies past progression, and management of treatment-refractory disease. Clinical trial evidence will be presented, along with guidance on how to integrate recent evidence into clinical practice. Finally, this review will examine innovative drug development strategies, and will discuss potentially actionable targets identified by molecular testing. © 2013 Springer Science+Business Media New York.

Authors
Strickler, JH; Hurwitz, HI
MLA Citation
Strickler, JH, and Hurwitz, HI. "Palliative treatment of metastatic colorectal cancer: What is the optimal approach? Topical collection on gastrointestinal cancers." Current Oncology Reports 16.1 (January 1, 2014).
Source
scopus
Published In
Current Oncology Reports
Volume
16
Issue
1
Publish Date
2014
DOI
10.1007/s11912-013-0363-z

Phase i study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer

Purpose Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). Methods Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m 2 twice daily, days 1-14), oxaliplatin (130 mg/m 2 on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (src act ) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). Results Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of src act expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src act expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low src act expression (IHC 0 or 1); (p = 0.007). Conclusions The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of src act expression may predict those patients most likely to benefit from dasatinib. © 2013 Springer Science+Business Media New York.

Authors
Strickler, JH; McCall, S; Nixon, AB; Brady, JC; Pang, H; Rushing, C; Cohn, A; Starodub, A; Arrowood, C; Haley, S; Meadows, KL; Morse, MA; Uronis, HE; Blobe, GC; Hsu, SD; Zafar, SY; Hurwitz, HI
MLA Citation
Strickler, JH, McCall, S, Nixon, AB, Brady, JC, Pang, H, Rushing, C, Cohn, A, Starodub, A, Arrowood, C, Haley, S, Meadows, KL, Morse, MA, Uronis, HE, Blobe, GC, Hsu, SD, Zafar, SY, and Hurwitz, HI. "Phase i study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer." Investigational New Drugs 32.2 (January 1, 2014): 330-339.
Source
scopus
Published In
Investigational New Drugs
Volume
32
Issue
2
Publish Date
2014
Start Page
330
End Page
339
DOI
10.1007/s10637-013-0042-9

Safety and effectiveness of bevacizumab treatment for metastatic colorectal cancer: Final results from the Avastin® Registry - Investigation of Effectiveness and Safety (ARIES) observational cohort study

Aims: The Avastin ® Registry - Investigation of Effectiveness and Safety (ARIES) observational cohort study (OCS) was designed to prospectively examine outcomes associated with bevacizumab-containing treatment for metastatic colorectal cancer (mCRC) in a community-based setting, where patient populations are less restricted than those in randomised trials. Materials and Methods: Patients with mCRC who were eligible for bevacizumab in combination with chemotherapy in first- or second-line treatment were enrolled from November 2006 to September 2008. There were no protocol-specified treatment regimens; the dose and schedule of bevacizumab and chemotherapy were at the treating physician's discretion. The objectives in the ARIES OCS included analyses of progression-free survival (PFS), overall survival, treatment patterns and safety in each of the first- and second-line treatment cohorts. Results: ARIES enrolled 1550 patients with mCRC receiving first-line therapy with bevacizumab. The median follow-up time was 20.6 months. The median PFS in this cohort was 10.2 months (95% confidence interval 9.8-10.6) and the median overall survival was 23.2 months (95% confidence interval 21.2-24.8). In a separate cohort of 482 patients with second-line mCRC, the median follow-up time was 16.9 months, the median PFS and overall survival from the start of second-line treatment to the end of follow-up was 7.9 months (95% confidence interval 7.2-8.3) and 17.8 months (95% confidence interval 16.5-20.7), respectively. Incidences of known bevacizumab-associated adverse events in ARIES were generally consistent with those previously reported in OCSs and randomised trials. Conclusion: Results from the prospective ARIES OCS add further evidence to support the effectiveness and safety of bevacizumab when added to first- and second-line treatment regimens for patients with mCRC in community treatment settings. © 2014 The Royal College of Radiologists.

Authors
Hurwitz, HI; Bekaii-Saab, TS; Bendell, JC; Cohn, AL; Kozloff, M; Roach, N; Mun, Y; Fish, S; Flick, ED; Grothey, A
MLA Citation
Hurwitz, HI, Bekaii-Saab, TS, Bendell, JC, Cohn, AL, Kozloff, M, Roach, N, Mun, Y, Fish, S, Flick, ED, and Grothey, A. "Safety and effectiveness of bevacizumab treatment for metastatic colorectal cancer: Final results from the Avastin® Registry - Investigation of Effectiveness and Safety (ARIES) observational cohort study." Clinical Oncology 26.6 (January 1, 2014): 323-332.
Source
scopus
Published In
Clinical Oncology
Volume
26
Issue
6
Publish Date
2014
Start Page
323
End Page
332
DOI
10.1016/j.clon.2014.03.001

Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer

Purpose: This study was conducted to evaluate potential pharmacokinetic interactions between docetaxel and atrasentan as part of a phase I/II clinical trial. Methods: Patients with prostate cancer were treated with intravenous docetaxel (60-75 mg/m 2 ) every 3 weeks and oral atrasentan (10 mg) daily starting on day 3 of cycle 1 and then given continuously. The pharmacokinetics of both drugs were evaluated individually (cycle 1, day 1 for docetaxel; day 21 for atrasentan) and in combination (cycle 2, day 1 for both drugs). Pharmacogenomics of alpha-1-acid glycoprotein (AAG) were also explored. Results: Paired pharmacokinetic data sets for both drugs were evaluable in 21 patients. Atrasentan was rapidly absorbed and plasma concentrations varied over a fourfold range at steady state within a typical patient. The median apparent oral clearance of atrasentan was 17.4 L/h in cycle 1 and was not affected by docetaxel administration (p = 0.9). Median systemic clearance of docetaxel was 51.1 L/h on the first cycle and significantly slower (p = 0.01) compared with that obtained during co-administration of atrasentan, 61.6 L/h. Docetaxel systemic clearance in cycle 1 was 70.0 L/h in patients homozygous for a variant allele in AAG compared with 44.5 L/h in those with at least one wild-type allele (p = 0.03). Conclusion: Genetic polymorphism in AAG may explain some inter-patient variability in docetaxel pharmacokinetics. The systemic clearance of docetaxel is increased by approximately 21 % when given concomitantly with atrasentan; however, atrasentan pharmacokinetics does not appear to be influenced by docetaxel administration. © 2014 Springer-Verlag.

Authors
Younis, IR; George, DJ; McManus, TJ; Hurwitz, H; Creel, P; Armstrong, AJ; Yu, JJ; Bacon, K; Hobbs, G; Peer, CJ; Petros, WP
MLA Citation
Younis, IR, George, DJ, McManus, TJ, Hurwitz, H, Creel, P, Armstrong, AJ, Yu, JJ, Bacon, K, Hobbs, G, Peer, CJ, and Petros, WP. "Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer." Cancer Chemotherapy and Pharmacology 73.5 (January 1, 2014): 991-997.
Source
scopus
Published In
Cancer Chemotherapy and Pharmacology
Volume
73
Issue
5
Publish Date
2014
Start Page
991
End Page
997
DOI
10.1007/s00280-014-2432-x

Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors

Purpose: To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. Design: This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. Results: Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF 165 levels significantly correlated with longer progression free survival. Conclusions: Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m 2 BID days 1-14; oxaliplatin 100 mg/m 2 and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC. © 2014 Springer Science+Business Media.

Authors
Rangwala, F; Bendell, JC; Kozloff, MF; Arrowood, CC; Dellinger, A; Meadows, J; Tourt-Uhlig, S; Murphy, J; Meadows, KL; Starr, A; Broderick, S; Brady, JC; Cushman, SM; Morse, MA; Uronis, HE; Hsu, SD; Zafar, SY; Wallace, J; Starodub, AN; Strickler, JH; Pang, H; Nixon, AB; Hurwitz, HI
MLA Citation
Rangwala, F, Bendell, JC, Kozloff, MF, Arrowood, CC, Dellinger, A, Meadows, J, Tourt-Uhlig, S, Murphy, J, Meadows, KL, Starr, A, Broderick, S, Brady, JC, Cushman, SM, Morse, MA, Uronis, HE, Hsu, SD, Zafar, SY, Wallace, J, Starodub, AN, Strickler, JH, Pang, H, Nixon, AB, and Hurwitz, HI. "Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors." Investigational New Drugs 32.4 (January 1, 2014): 700-709.
Source
scopus
Published In
Investigational New Drugs
Volume
32
Issue
4
Publish Date
2014
Start Page
700
End Page
709
DOI
10.1007/s10637-014-0089-2

Bevacizumab exposure beyond first disease progression in patients with metastatic colorectal cancer: Analyses of the ARIES observational cohort study

Purpose: This analysis from Avastin® Registries: Investigation of Effectiveness and Safety (ARIES) examined the association between exposure to bevacizumab after disease progression (PD) and postprogression survival (PPS) in bevacizumab-exposed metastatic colorectal cancer (mCRC) through the application of time-dependent and time-fixed analytical methods. Methods: Patients with mCRC who were treated with first-line bevacizumab and who survived first PD (PD1) were included. A time-dependent Cox regression model was fitted to assess the effect of cumulative bevacizumab exposure on PPS, while controlling for potential confounders. In addition to support findings from previous studies, a modified intent-to-treat (mITT) analysis compared PPS in patients who received bevacizumab beyond disease progression (BBP) with those who did not (No-BBP). Results: Of 1550 patients, 1199 survived PD1 and had a median PPS of 13.4months. Cumulative bevacizumab exposure was associated with improved PPS (p=0.0040). After adjusting for confounders, the hazard ratios (HRs) for PPS decreased, on average, by 1.2% (range, 1.1-1.3%) with each additional dose of bevacizumab. In the mITT analysis, the median PPS for BBP (n=438) was 14.4months vs 10.6months with for No-BBP (n=667). BBP was found to be independently associated with longer PPS in a multivariable Cox regression analysis (HR, 0.84; 95% confidence interval, 0.73-0.97). Protocol-specified adverse events suspected to be associated with bevacizumab occurred in 13.0% of patients with BBP. Conclusion: This analysis supports the observation that bevacizumab exposure after PD1 is associated with longer PPS in mCRC. © 2014 John Wiley & Sons, Ltd.

Authors
Grothey, A; Flick, ED; Cohn, AL; Bekaii-Saab, TS; Bendell, JC; Kozloff, M; Roach, N; Mun, Y; Fish, S; Hurwitz, HI
MLA Citation
Grothey, A, Flick, ED, Cohn, AL, Bekaii-Saab, TS, Bendell, JC, Kozloff, M, Roach, N, Mun, Y, Fish, S, and Hurwitz, HI. "Bevacizumab exposure beyond first disease progression in patients with metastatic colorectal cancer: Analyses of the ARIES observational cohort study." Pharmacoepidemiology and Drug Safety 23.7 (January 1, 2014): 726-734.
Source
scopus
Published In
Pharmacoepidemiology and Drug Safety
Volume
23
Issue
7
Publish Date
2014
Start Page
726
End Page
734
DOI
10.1002/pds.3633

A phase Ib study of combined VEGFR and mTOR inhibition with Vatalanib and everolimus in patients with advanced renal cell carcinoma

Background Vatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC). Patients and Methods A phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC. Results We evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability ( > 1 year) was demonstrated in 19% of patients. Conclusion Relevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC. © 2014 Elsevier Inc. All rights reserved.

Authors
Bitting, RL; Healy, P; Creel, PA; Turnbull, J; Morris, K; Wood, SY; Hurwitz, HI; Starr, MD; Nixon, AB; Armstrong, AJ; George, DJ
MLA Citation
Bitting, RL, Healy, P, Creel, PA, Turnbull, J, Morris, K, Wood, SY, Hurwitz, HI, Starr, MD, Nixon, AB, Armstrong, AJ, and George, DJ. "A phase Ib study of combined VEGFR and mTOR inhibition with Vatalanib and everolimus in patients with advanced renal cell carcinoma." Clinical Genitourinary Cancer 12.4 (January 1, 2014): 241-250.
Source
scopus
Published In
Clinical genitourinary cancer
Volume
12
Issue
4
Publish Date
2014
Start Page
241
End Page
250
DOI
10.1016/j.clgc.2013.11.020

Palliative Treatment of Metastatic Colorectal Cancer: What is the Optimal Approach?

Authors
Strickler, JH; Hurwitz, HI
MLA Citation
Strickler, JH, and Hurwitz, HI. "Palliative Treatment of Metastatic Colorectal Cancer: What is the Optimal Approach?." Current Oncology Reports 16.1 (2014): 1-8.
Source
scopus
Published In
Current Oncology Reports
Volume
16
Issue
1
Publish Date
2014
Start Page
1
End Page
8

Palliative treatment of metastatic colorectal cancer: what is the optimal approach?

Worldwide, colorectal cancer (CRC) is responsible for over 600,000 deaths annually and remains a significant public health concern. Because of therapeutic advancements over the past two decades, patients with metastatic CRC are living longer with an improved quality of life. This review will highlight recent trial evidence that improves outcomes for patients with metastatic disease. Topics will include the optimal use of first-line combination chemotherapy, bevacizumab in patients with advanced age or comorbidities, maintenance chemotherapy, first-line use of anti-EGFR therapies, first-line cetuximab versus bevacizumab, anti-angiogenic therapies past progression, and management of treatment-refractory disease. Clinical trial evidence will be presented, along with guidance on how to integrate recent evidence into clinical practice. Finally, this review will examine innovative drug development strategies, and will discuss potentially actionable targets identified by molecular testing.

Authors
Strickler, JH; Hurwitz, HI
MLA Citation
Strickler, JH, and Hurwitz, HI. "Palliative treatment of metastatic colorectal cancer: what is the optimal approach?." Curr Oncol Rep 16.1 (2014): 363-. (Review)
PMID
24293074
Source
pubmed
Published In
Current Oncology Reports
Volume
16
Issue
1
Publish Date
2014
Start Page
363
DOI
10.1007/s11912-013-0363-z

Palliative treatment of metastatic colorectal cancer: what is the optimal approach?

Worldwide, colorectal cancer (CRC) is responsible for over 600,000 deaths annually and remains a significant public health concern. Because of therapeutic advancements over the past two decades, patients with metastatic CRC are living longer with an improved quality of life. This review will highlight recent trial evidence that improves outcomes for patients with metastatic disease. Topics will include the optimal use of first-line combination chemotherapy, bevacizumab in patients with advanced age or comorbidities, maintenance chemotherapy, first-line use of anti-EGFR therapies, first-line cetuximab versus bevacizumab, anti-angiogenic therapies past progression, and management of treatment-refractory disease. Clinical trial evidence will be presented, along with guidance on how to integrate recent evidence into clinical practice. Finally, this review will examine innovative drug development strategies, and will discuss potentially actionable targets identified by molecular testing.

Authors
Strickler, JH; Hurwitz, HI
MLA Citation
Strickler, JH, and Hurwitz, HI. "Palliative treatment of metastatic colorectal cancer: what is the optimal approach?." Current oncology reports 16.1 (2014): 363--.
Source
scival
Published In
Current Oncology Reports
Volume
16
Issue
1
Publish Date
2014
Start Page
363-
DOI
10.1007/s11912-013-0363-z

A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors

© Springer Science+Business Media 2014.Summary Purpose: To investigate the safety, optimal dosing, pharmacokinetics and clinical activity of a regimen of navitoclax (ABT-263) combined with gemcitabine in patients with solid tumors. Experimental Design: Patients with solid tumors for which gemcitabine was deemed an appropriate therapy were enrolled into one of two different dosing schedules (21-day dosing schedule: navitoclax administered orally on days 1-3 and 8-10,; and gemcitabine 1,000 mg/m<sup>2</sup> on days 1 and 8; 28-day dosing schedule: navitoclax administrated orally on days 1-3, 8-10, and 15-17; and gemcitabine 1,000 mg/m<sup>2</sup> on days 1, 8 and 15). Navitoclax doses were escalated from 150 to 425 mg. An expanded safety cohort was conducted for the 21-day dosing schedule at the maximum tolerated dose (MTD) of navitoclax. Results: Forty-six patients were enrolled at three U.S. centers. The most common adverse events included: hematologic abnormalities (thrombocytopenia, neutropenia, and anemia), liver enzyme elevations (ALT and AST), and gastrointestinal disturbances (diarrhea, nausea, and vomiting). Dose-limiting toxicities (DLTs) observed in cycle 1 were grade 4 thrombocytopenia (2 patients), grade 4 neutropenia (1 patient), and grade 3 AST elevation (2 patients). The MTD of navitoclax was 325 mg co-administered with gemcitabine 1,000 mg/m<sup>2</sup> for the 21-day schedule. No clinically significant pharmacokinetic drug- drug interactions were observed. There were no objective responses. Stable disease, reported at the end of cycle 2, was the best response in 54 % of evaluable patients (n = 39). Conclusions: The combination of navitoclax 325 mg with gemcitabine 1,000 mg/m<sup>2</sup> was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors.

Authors
Cleary, JM; Lima, CMSR; Hurwitz, HI; Montero, AJ; Franklin, C; Yang, J; Graham, A; Busman, T; Mabry, M; Holen, K; Shapiro, GI; Uronis, H
MLA Citation
Cleary, JM, Lima, CMSR, Hurwitz, HI, Montero, AJ, Franklin, C, Yang, J, Graham, A, Busman, T, Mabry, M, Holen, K, Shapiro, GI, and Uronis, H. "A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors." Investigational New Drugs 32.5 (2014): 937-945.
Source
scival
Published In
Investigational New Drugs
Volume
32
Issue
5
Publish Date
2014
Start Page
937
End Page
945
DOI
10.1007/s10637-014-0110-9

An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer

© 2014 The Author(s).Background This phase I study evaluated the pharmacokinetics and pharmacodynamics of CEP-11981, an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, in patients with advanced, relapsed, or refractory solid tumors. Methods Oral CEP-11981 dose escalations followed a modified Fibonacci sequence (from 3.0 to 4.2, 5.9, 11.8, 19.7, 29.6, 41.4, 55.0, 73.0, 97.4, and 126.6 mg/m<sup>2</sup>). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated. Results CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m<sup>2</sup>. The MTD of CEP-11981 was determined to be 97.4 mg/m<sup>2</sup>, with DLTs observed at the 126.6 mg/m<sup>2</sup> dose. The DLTs were grade 4 neutropenia in 1 patient and grade 3 T-wave inversion with chest heaviness and fatigue in 1 patient. All 3 events resolved on stopping CEP-11981. The most frequently reported adverse events of any grade were fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, constipation, headache, dizziness, and dyspnea. Treatment-related grade 3/4 neutropenia was observed in the highest-dose cohorts (2 patients at 97.4 mg/m<sup>2</sup> and 1 patient at 126.6 mg/m<sup>2</sup>), indicating some off-target inhibition. VEGF inhibition was greatest in the higher-dose groups. Although no patient experienced complete or partial response, 44 % patients achieved stable disease when measured at ≥ 6 weeks, which occurred more frequently in cohorts receiving ≥ 73.0 mg/m<sup>2</sup>. Conclusions In patients with recurrent or refractory solid tumors, disease stabilization was achieved. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased.

Authors
Pili, R; Carducci, M; Brown, P; Hurwitz, H
MLA Citation
Pili, R, Carducci, M, Brown, P, and Hurwitz, H. "An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer." Investigational New Drugs 32.6 (2014): 1258-1268.
Source
scival
Published In
Investigational New Drugs
Volume
32
Issue
6
Publish Date
2014
Start Page
1258
End Page
1268
DOI
10.1007/s10637-014-0147-9

Understanding the mechanisms of action of antiangiogenic agents in metastatic colorectal cancer: A clinician's perspective

© 2014 Elsevier Ltd.Multiple clinical trials using bevacizumab, ziv-aflibercept, and regorafenib have recently demonstrated efficacy for patients with metastatic colorectal cancer. While the net clinical benefit of each of these therapies in the second-line and refractory disease setting appears to be similar, important distinctions exist between the agents at the pharmacodynamic, tumor microenvironment, and clinical levels. The purpose of this review is to survey the preclinical evidence regarding the mechanisms of action of these novel antiangiogenic agents and provide an overview of their respective clinical activity, while highlighting distinctions between therapies. Fundamental understanding of these distinctions may aid in clinical decisions and choice of antiangiogenic therapies.

Authors
Clarke, JM; Hurwitz, HI; Rangwala, F
MLA Citation
Clarke, JM, Hurwitz, HI, and Rangwala, F. "Understanding the mechanisms of action of antiangiogenic agents in metastatic colorectal cancer: A clinician's perspective." Cancer Treatment Reviews 40.9 (2014): 1065-1072.
Source
scival
Published In
Cancer Treatment Reviews
Volume
40
Issue
9
Publish Date
2014
Start Page
1065
End Page
1072
DOI
10.1016/j.ctrv.2014.07.001

Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance).

PURPOSE: CALGB80303 was a phase III trial of 602 patients with locally advanced or metastatic pancreatic cancer comparing gemcitabine/bevacizumab versus gemcitabine/placebo. The study found no benefit in any outcome from the addition of bevacizumab to gemcitabine. Blood samples were collected and multiple angiogenic factors were evaluated and then correlated with clinical outcome in general (prognostic markers) and with benefit specifically from bevacizumab treatment (predictive markers). EXPERIMENTAL DESIGN: Plasma samples were analyzed via a novel multiplex ELISA platform for 31 factors related to tumor growth, angiogenesis, and inflammation. Baseline values for these factors were correlated with overall survival (OS) using univariate Cox proportional hazard regression models and multivariable Cox regression models with leave-one-out cross validation. Predictive markers were identified using a treatment by marker interaction term in the Cox model. RESULTS: Baseline plasma was available from 328 patients. Univariate prognostic markers for OS were identified including: Ang2, CRP, ICAM-1, IGFBP-1, TSP-2 (all P < 0.001). These prognostic factors were found to be highly significant, even after adjustment for known clinical factors. Additional modeling approaches yielded prognostic signatures from multivariable Cox regression. The gemcitabine/bevacizumab signature consisted of IGFBP-1, interleukin-6, PDGF-AA, PDGF-BB, TSP-2; whereas the gemcitabine/placebo signature consisted of CRP, IGFBP-1, PAI-1, PDGF-AA, P-selectin (both P < 0.0001). Finally, three potential predictive markers of bevacizumab efficacy were identified: VEGF-D (P < 0.01), SDF1 (P < 0.05), and Ang2 (P < 0.05). CONCLUSION: This study identified strong prognostic markers for pancreatic cancer patients. Predictive marker analysis indicated that plasma levels of VEGF-D, Ang2, and SDF1 significantly predicted for benefit or lack of benefit from bevacizumab in this population.

Authors
Nixon, AB; Pang, H; Starr, MD; Friedman, PN; Bertagnolli, MM; Kindler, HL; Goldberg, RM; Venook, AP; Hurwitz, HI; Alliance for Clinical Trials In Oncology,
MLA Citation
Nixon, AB, Pang, H, Starr, MD, Friedman, PN, Bertagnolli, MM, Kindler, HL, Goldberg, RM, Venook, AP, Hurwitz, HI, and Alliance for Clinical Trials In Oncology, . "Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance)." Clin Cancer Res 19.24 (December 15, 2013): 6957-6966.
PMID
24097873
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
19
Issue
24
Publish Date
2013
Start Page
6957
End Page
6966
DOI
10.1158/1078-0432.CCR-13-0926

Modulation of immune system inhibitory checkpoints in colorectal cancer

T cell infiltration of colorectal cancer is associated with improved clinical outcome, underlining the importance of the immune system in cancer control; however, immune checkpoints, including the inhibitory T cell molecules CTLA-4 and PD-1 that temper the native immune response, mitigating autoimmunity, are coopted by tumors to facilitate escape from immune surveillance. Blockade of CTLA-4 and PD-1 and its ligand PD-L1, expressed by many tumors, have shown impressive activity in melanoma, renal cell carcinoma, and lung cancer. Immune checkpoint inhibition has been less well studied in colorectal cancer, but preclinical and clinical investigations are in progress. © Springer Science+Business Media New York 2013.

Authors
Patel, SP; Osada, T; Osada, K; Hurwitz, H; Lyerly, HK; Morse, MA
MLA Citation
Patel, SP, Osada, T, Osada, K, Hurwitz, H, Lyerly, HK, and Morse, MA. "Modulation of immune system inhibitory checkpoints in colorectal cancer." Current Colorectal Cancer Reports 9.4 (December 1, 2013): 391-397.
Source
scopus
Published In
Current Colorectal Cancer Reports
Volume
9
Issue
4
Publish Date
2013
Start Page
391
End Page
397
DOI
10.1007/s11888-013-0184-3

Understanding and targeting resistance to anti-angiogenic therapies.

Therapies targeting tumor angiogenesis are used in a variety of malignancies, however not all patients benefit from treatment and impact on tumor control may be transient and modest. Mechanisms of resistance to anti-angiogenic therapies can be broadly categorized into VEGF-axis dependent alterations, non-VEGF pathways, and stromal cell interactions. Complimentary combinations of agents that inhibit alternative mechanisms of blood vessel formation may optimize inhibition of angiogenesis and improve clinical benefit for patients. The purpose of this review is to detail the preclinical evidence for mechanisms of angiogenic resistance and provide an overview of novel therapeutic approaches exploiting these pathways.

Authors
Clarke, JM; Hurwitz, HI
MLA Citation
Clarke, JM, and Hurwitz, HI. "Understanding and targeting resistance to anti-angiogenic therapies." J Gastrointest Oncol 4.3 (September 2013): 253-263.
PMID
23997938
Source
pubmed
Published In
Journal of Gastrointestinal Oncology
Volume
4
Issue
3
Publish Date
2013
Start Page
253
End Page
263
DOI
10.3978/j.issn.2078-6891.2013.036

Use of molecular biomarkers to inform adjuvant therapy for colon cancer.

The decision about who may derive benefit from adjuvant chemotherapy in colon cancer is often a difficult one for clinicians. While multiple trials have demonstrated that adjuvant chemotherapy reduces the risk of recurrence and improves overall survival in patients with stage III disease, the data supporting the use of adjuvant chemotherapy in patients with stage II disease are not as compelling. Because adjuvant therapy can have significant toxicity, tools to help clinicians determine who may derive a benefit from therapy are of the utmost importance. Recent advances in high throughput technologies have led to the identification of molecular biomarkers-including microsatellite instability (MSI), loss of heterozygosity (LOH), p53, Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), thymidylate synthase (TS), and excision repair cross-complementation group 1 (ERCC1)--as well as various multigene assays that are being studied for their ability to offer both prognostic and predictive information to clinicians. Here we review the current knowledge about molecular biomarkers that may aid the clinician in offering personalized cancer therapy based on the genetic landscape of an individual patient's tumor.

Authors
Mettu, NB; Hurwitz, H; Hsu, DS
MLA Citation
Mettu, NB, Hurwitz, H, and Hsu, DS. "Use of molecular biomarkers to inform adjuvant therapy for colon cancer." Oncology (Williston Park, N.Y.) 27.8 (August 2013): 746-754. (Review)
PMID
24133820
Source
epmc
Published In
Oncology
Volume
27
Issue
8
Publish Date
2013
Start Page
746
End Page
754

Targeted inhibition of VEGF receptor 2: an update on ramucirumab.

INTRODUCTION: Ramucirumab (IMC-1121B) is a fully humanized IgG1 monoclonal antibody, targeting the extracellular domain of VEGF receptor 2 (VEGFR2). Numerous Phase I - II trials in various malignancies have shown promising clinical antitumor efficacy and tolerability. Most recently, the large Phase III REGARD trial evaluated ramucirumab in patients with refractory metastatic gastric cancer. Patients receiving ramucirumab experienced a median overall survival of 5.2 months compared to 3.8 months on placebo. AREAS COVERED: The purpose of this article is to review the preclinical motivation for VEGFR2-targeted therapies and survey recent data from clinical trials involving ramucirumab, as well as highlight ongoing studies. EXPERT OPINION: Rational multi-target approaches to angiogenesis are needed to overcome resistance mechanisms. Predictive angiogenic biomarkers are also needed to optimize patient selection for novel anti-angiogenic agents.

Authors
Clarke, JM; Hurwitz, HI
MLA Citation
Clarke, JM, and Hurwitz, HI. "Targeted inhibition of VEGF receptor 2: an update on ramucirumab." Expert Opin Biol Ther 13.8 (August 2013): 1187-1196. (Review)
PMID
23803182
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
13
Issue
8
Publish Date
2013
Start Page
1187
End Page
1196
DOI
10.1517/14712598.2013.810717

Dual inhibition of αV integrins and Src kinase activity as a combination therapy strategy for colorectal cancer.

Both Src and αV integrins are important for tumor growth and angiogenesis. They are interconnected and responsible for important features of the tumor phenotype including invasiveness, metastasis, angiogenesis, and resistance to apoptosis. This study examines whether combinational inhibition of both integrin and Src pathways would exert greater antiangiogenesis and antitumor effects than either pathway alone. Using in-vitro cell culture systems, the activity of CNTO95 (Intetumumab), an αV integrin inhibitor, and dasatinib, an Src inhibitor, on proliferation, adhesion, and migration was evaluated in colon cancer cell lines, HCT-116 and RKO, as well as HUVEC cells. The antiangiogenic effect of this combinatory regimen was also tested using an in-vitro tubular network formation assay. The effects of CNTO95 and dasatinib on the activation of Src and integrin pathway signal transduction were also determined by western blotting. The combination of CNTO95 plus dasatinib inhibited adhesion, migration, and paxillin phosphorylation in both HCT-116 and RKO cells. CNTO95 and dasatinib also led to increased apoptosis of HCT-116 cells; however, similar effects were not observed in RKO cells. In addition, dual treatment of CNTO95 and dasatinib exerted enhanced effects on HUVEC cell proliferation, invasion, tubular network formation, and paxillin phosphorylation. In conclusion, our results suggest that concurrent inhibition of both the integrin and the Src pathways exert more pronounced antiangiogenic and antitumor effects than with either pathway being inhibited alone.

Authors
Jia, J; Starodub, A; Cushman, I; Liu, Y; Marshall, DJ; Hurwitz, HI; Nixon, AB
MLA Citation
Jia, J, Starodub, A, Cushman, I, Liu, Y, Marshall, DJ, Hurwitz, HI, and Nixon, AB. "Dual inhibition of αV integrins and Src kinase activity as a combination therapy strategy for colorectal cancer." Anticancer Drugs 24.3 (March 2013): 237-250.
PMID
23275294
Source
pubmed
Published In
Anti-Cancer Drugs
Volume
24
Issue
3
Publish Date
2013
Start Page
237
End Page
250
DOI
10.1097/CAD.0b013e32835d29fd

Ziv-aflibercept: binding to more than VEGF-A--does more matter?

The VELOUR and VITAL studies recently demonstrated ziv-aflibercept improved overall survival in patients with metastatic colorectal cancer (mCRC), including those previously treated with bevacizumab, but did not improve overall survival in non-small-cell lung cancer. Thus, VEGF-directed agents might be useful throughout the continuum of care in mCRC, but biomarkers are needed to identify patients likely to benefit.

Authors
Clarke, JM; Hurwitz, HI
MLA Citation
Clarke, JM, and Hurwitz, HI. "Ziv-aflibercept: binding to more than VEGF-A--does more matter?." Nat Rev Clin Oncol 10.1 (January 2013): 10-11.
PMID
23149898
Source
pubmed
Published In
Nature Reviews Clinical Oncology
Volume
10
Issue
1
Publish Date
2013
Start Page
10
End Page
11
DOI
10.1038/nrclinonc.2012.197

A phase II study of capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas.

BACKGROUND: Esophageal and gastric cancers often present at an advanced stage. Systemic chemotherapy is the mainstay of treatment, but survival with current regimens remains poor. We evaluated the safety, tolerability, and efficacy of the combination capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas. METHODS: Thirty-seven patients with metastatic or unresectable gastric/gastroesophageal junction tumors were enrolled and treated with capecitabine 850 mg/m(2) BID on days 1-14, and oxaliplatin 130 mg/m(2) with bevacizumab 15 mg/kg on day 1 of a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Neuropilin-1 (NRP1) and -2 (NRP2) mRNA expression was evaluated in archived tumor. RESULTS: Thirty-five patients were evaluable for efficacy. Median PFS was 7.2 months; median OS was 10.8 months. RR was estimated at 51.4%. The regimen was tolerable with expected drug class-related toxicities. NRP2 mRNA levels significantly correlated with PFS (p = 0.042) and showed a trend toward significance with OS (p = 0.051). Nonsignificant trends for NRP1 were noted for higher expression levels and worse outcome. CONCLUSIONS: Bevacizumab can be given safely with chemotherapy in patients with metastatic esophagogastric adenocarcinomas. The combination of capecitabine, oxaliplatin, plus bevacizumab has activity comparable to other bevacizumab-containing regimens in metastatic gastroesophageal cancer.

Authors
Uronis, HE; Bendell, JC; Altomare, I; Blobe, GC; Hsu, SD; Morse, MA; Pang, H; Zafar, SY; Conkling, P; Favaro, J; Arrowood, CC; Cushman, SM; Meadows, KL; Brady, JC; Nixon, AB; Hurwitz, HI
MLA Citation
Uronis, HE, Bendell, JC, Altomare, I, Blobe, GC, Hsu, SD, Morse, MA, Pang, H, Zafar, SY, Conkling, P, Favaro, J, Arrowood, CC, Cushman, SM, Meadows, KL, Brady, JC, Nixon, AB, and Hurwitz, HI. "A phase II study of capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas." Oncologist 18.3 (2013): 271-272.
PMID
23485624
Source
pubmed
Published In
The oncologist
Volume
18
Issue
3
Publish Date
2013
Start Page
271
End Page
272
DOI
10.1634/theoncologist.2012-0404

Everolimus in colorectal cancer

Introduction: There has been a strong preclinical rationale for studying mammalian target of rapamycin (mTOR) inhibitors as single agents or in combination, in multiple malignancies and colorectal cancer in particular. Areas covered: The authors summarize the complete clinical experience to date of all trials, both published and in abstract form, of everolimus in colorectal cancer. While initial Phase I trials showed promise, further studies have confirmed that single agent everolimus is not active in advanced metastatic colorectal carcinoma with trials showing single agent tolerability, but without significant hints of efficacy in terms of either objective tumor responses or prolonged stable disease. Combination regimens, including combinations with cytotoxic chemotherapy, and inhibitors of VEGF, EGFR and HDAC have been tested specifically in the colorectal setting in Phase I and Phase II clinical trials. The authors discuss the potential reasons for mixed results and suggest future directions for the development of everolimus in colorectal malignancies. Expert opinion: Studies demonstrate limited clinical activity of everolimus for the treatment of advanced colorectal cancer and have been complicated by increases in toxicity. However, the central role of the PI3K/mTOR pathway in cancer biology suggests that other drug combinations with mTOR inhibition may still merit evaluation. © 2013 Informa UK, Ltd.

Authors
Altomare, I; Hurwitz, H
MLA Citation
Altomare, I, and Hurwitz, H. "Everolimus in colorectal cancer." Expert Opinion on Pharmacotherapy 14.4 (2013): 505-513.
PMID
23406528
Source
scival
Published In
Expert Opinion on Pharmacotherapy
Volume
14
Issue
4
Publish Date
2013
Start Page
505
End Page
513
DOI
10.1517/14656566.2013.770473

Analysis of early hypertension and clinical outcome with bevacizumab: Results from seven phase III studies

Background. Hypertension is associated with antivascular endothelial growth factor treatment, but the clinical implications of hypertension are uncertain. To assess the prognostic and predictive value of bevacizumab-related hypertension, a comprehensive analysis of whether hypertension and efficacy outcomes are associated was conducted on seven companysponsored placebo-controlled phase III studies of bevacizumab. Methods. Patient-specific data were available from 6,486 patients with metastatic colorectal, breast, non-small cell lung, pancreatic, and renal cell cancers. Primary hypertension endpoint was a blood pressure (BP) increase of >20 mmHg systolic or >10 mmHg diastolic within the first 60 days of treatment. Additional endpoints included other predefined thresholds of change in BP and severity of hypertension graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. To analyze the general prognostic importance of an early BP increase, multivariate Cox regression models were used to assess the correlation between BP changes and progression-free (PFS) and overall survival (OS) outcomes in the control groups. To analyze whether early BP increases could predict for benefit from bevacizumab, similar analyses were conducted in the bevacizumabtreated and control groups. Results. In six of seven studies, early BP increase was neither predictive of clinical benefit from bevacizumab nor prognostic for the course of the disease. For study AVF2107g, early increased BP was associated with longer PFS and OS times in the bevacizumab group but shorter OS time in the control group. Conclusions. Early treatment-related BP increases do not predict clinical benefit from bevacizumab based on PFS or OS outcomes. BP increases do not appear to have general prognostic importance for patients with advanced cancer. © AlphaMed Press 2013.

Authors
Hurwitz, HI; Douglas, PS; Middleton, JP; Sledge, GW; Johnson, DH; Reardon, DA; Chen, D; Rosen, O
MLA Citation
Hurwitz, HI, Douglas, PS, Middleton, JP, Sledge, GW, Johnson, DH, Reardon, DA, Chen, D, and Rosen, O. "Analysis of early hypertension and clinical outcome with bevacizumab: Results from seven phase III studies." Oncologist 18.3 (2013): 273-280.
PMID
23485622
Source
scival
Published In
The oncologist
Volume
18
Issue
3
Publish Date
2013
Start Page
273
End Page
280
DOI
10.1634/theoncologist.2012-0339

Phase i and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors

This phase I, open-label, dose-escalation study assessed the maximum-tolerated dose, safety, pharmacokinetics, and preliminary antitumor activity of pazopanib plus lapatinib combination therapy in patients with solid tumors. Patients were to take pazopanib and lapatinib orally once daily in a fasting condition. During the escalation phase, pazopanib and lapatinib doses were escalated in serial patient cohorts, and a limited blood sampling scheme was applied for pharmacokinetic evaluation. In the expansion phase, potential pharmacokinetic interaction between pazopanib and lapatinib was evaluated more extensively. Seventy-five patients were treated. Multiple dosing levels were studied, combining pazopanib up to 800 mg/day with lapatinib up to 1,500 mg/day. Dose-limiting toxicities observed included grade 3 neutropenia, fatigue, asymptomatic decline in left ventricular ejection fraction, diarrhea, and liver enzyme elevations. The most common drug-related adverse events were diarrhea, nausea, anorexia, fatigue, vomiting, rash, hair depigmentation, and hypertension. The dose recommended for further evaluation was pazopanib 800 mg plus lapatinib 1,500 mg (paz-800/lap-1500). No clinically significant drug-drug interaction was observed at the paz-400/lap-1000 level. However, at paz-800/lap-1500, an increase in both the AUC0-t and Cmax of pazopanib was observed. Four partial responses were observed in patients with renal cancer (n = 2), giant-cell tumor of the bone (n = 1), and thyroid cancer (n = 1). Stable disease for ≥18 weeks was seen in 12 patients. Pazopanib and lapatinib can be administered in combination at their respective single-agent doses with an acceptable safety profile. Further evaluation of the combination will be pursued, exploring both paz-800/lap-1500 and paz-400/lap-1000. © 2012 Springer Science+Business Media New York.

Authors
Jonge, MJAD; Hamberg, P; Verweij, J; Savage, S; Suttle, AB; Hodge, J; Arumugham, T; Pandite, LN; Hurwitz, HI
MLA Citation
Jonge, MJAD, Hamberg, P, Verweij, J, Savage, S, Suttle, AB, Hodge, J, Arumugham, T, Pandite, LN, and Hurwitz, HI. "Phase i and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors." Investigational New Drugs 31.3 (2013): 751-759.
Source
scival
Published In
Investigational New Drugs
Volume
31
Issue
3
Publish Date
2013
Start Page
751
End Page
759
DOI
10.1007/s10637-012-9885-8

The effect of different dosing regimens of motesanib on the gallbladder: A randomized phase 1b study in patients with advanced solid tumors

Background: Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function.Methods: Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment).Results: Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary " sludge" in Arms A/B/C was 39%/36%/27%.Conclusions: Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis.Trial registration: ClinicalTrials.gov NCT00448786. © 2013 Rosen et al.; licensee BioMed Central Ltd.

Authors
Rosen, LS; Lipton, L; Price, TJ; Belman, ND; Boccia, RV; Hurwitz, HI; Stephenson, JJ; Wirth, LJ; McCoy, S; Hei, Y-J; Hsu, C-P; Tebbutt, NC
MLA Citation
Rosen, LS, Lipton, L, Price, TJ, Belman, ND, Boccia, RV, Hurwitz, HI, Stephenson, JJ, Wirth, LJ, McCoy, S, Hei, Y-J, Hsu, C-P, and Tebbutt, NC. "The effect of different dosing regimens of motesanib on the gallbladder: A randomized phase 1b study in patients with advanced solid tumors." BMC Cancer 13 (2013).
PMID
23679351
Source
scival
Published In
BMC Cancer
Volume
13
Publish Date
2013
DOI
10.1186/1471-2407-13-242

Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials.

PURPOSE: his analysis pooled individual patient data from randomized controlled trials (RCTs) to more thoroughly examine clinical outcomes when adding bevacizumab to chemotherapy for patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patient data were pooled from the first-line AVF2107, NO16966, ARTIST, AVF0780, AVF2192, and AGITG MAX RCTs and the second-line E3200 RCT. All analyses were based on the intent-to-treat population. To assess differences in time-to-event variables by treatment (chemotherapy with or without placebo vs. chemotherapy plus bevacizumab), stratified random-effects (overall) and fixed-effects (subgroup comparisons) models were used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The analysis population comprised 3,763 patients (1,773 chemotherapy with or without placebo; 1,990 chemotherapy plus bevacizumab). The addition of bevacizumab to chemotherapy was associated with statistically significant increases in overall survival (OS; HR, 0.80; 95% CI, 0.71-0.90) and progression-free survival (PFS; HR, 0.57; 95% CI, 0.46-0.71). The effects on OS and PFS across subgroups defined by chemotherapy backbone (oxaliplatin-based, irinotecan-based), extent of disease (liver metastases only, extensive disease), age (<65, ≥65 years), Eastern Cooperative Oncology Group performance status (0, ≥1), and KRAS status (wild-type, mutant) were consistent with the overall analysis. Incidence rates of grade ≥3 hypertension, proteinuria, bleeding, wound-healing complications, gastrointestinal perforations, and thromboembolic events were increased with bevacizumab treatment. CONCLUSION: The use of bevacizumab with chemotherapy resulted in statistically significant increases in OS and PFS for patients with mCRC. The PFS benefit extended across the clinically relevant subgroups examined. The observed safety profile of bevacizumab was consistent with that reported in individual trials.

Authors
Hurwitz, HI; Tebbutt, NC; Kabbinavar, F; Giantonio, BJ; Guan, Z-Z; Mitchell, L; Waterkamp, D; Tabernero, J
MLA Citation
Hurwitz, HI, Tebbutt, NC, Kabbinavar, F, Giantonio, BJ, Guan, Z-Z, Mitchell, L, Waterkamp, D, and Tabernero, J. "Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials." Oncologist 18.9 (2013): 1004-1012.
PMID
23881988
Source
pubmed
Published In
The oncologist
Volume
18
Issue
9
Publish Date
2013
Start Page
1004
End Page
1012
DOI
10.1634/theoncologist.2013-0107

Modulation of Immune System Inhibitory Checkpoints in Colorectal Cancer

T cell infiltration of colorectal cancer is associated with improved clinical outcome, underlining the importance of the immune system in cancer control; however, immune checkpoints, including the inhibitory T cell molecules CTLA-4 and PD-1 that temper the native immune response, mitigating autoimmunity, are coopted by tumors to facilitate escape from immune surveillance. Blockade of CTLA-4 and PD-1 and its ligand PD-L1, expressed by many tumors, have shown impressive activity in melanoma, renal cell carcinoma, and lung cancer. Immune checkpoint inhibition has been less well studied in colorectal cancer, but preclinical and clinical investigations are in progress. © 2013 Springer Science+Business Media New York.

Authors
Patel, SP; Osada, T; Osada, K; Hurwitz, H; Lyerly, HK; Morse, MA
MLA Citation
Patel, SP, Osada, T, Osada, K, Hurwitz, H, Lyerly, HK, and Morse, MA. "Modulation of Immune System Inhibitory Checkpoints in Colorectal Cancer." Current Colorectal Cancer Reports (2013): 1-7.
Source
scival
Published In
Current Colorectal Cancer Reports
Publish Date
2013
Start Page
1
End Page
7
DOI
10.1007/s11888-013-0184-3

Use of molecular biomarkers to inform adjuvant therapy for colon cancer

The decision about who may derive benefit from adjuvant chemotherapy in colon cancer is often a difficult one for clinicians. While multiple trials have demonstrated that adjuvant chemotherapy reduces the risk of recurrence and improves overall survival in patients with stage III disease, the data supporting the use of adjuvant chemotherapy in patients with stage II disease are not as compelling. Because adjuvant therapy can have significant toxicity, tools to help clinicians determine who may derive a benefit from therapy are of the utmost importance. Recent advances in high throughput technologies have led to the identification of molecular biomarkers-including microsatellite instability (MSI), loss of heterozygosity (LOH), p53, Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), thymidylate synthase (TS), and excision repair cross-complementation group 1 (ERCC1)-as well as various multigene assays that are being studied for their ability to offer both prognostic and predictive information to clinicians. Here we review the current knowledge about molecular biomarkers that may aid the clinician in offering personalized cancer therapy based on the genetic landscape of an individual patient's tumor.

Authors
Mettu, NB; Hurwitz, H; Hsu, DS
MLA Citation
Mettu, NB, Hurwitz, H, and Hsu, DS. "Use of molecular biomarkers to inform adjuvant therapy for colon cancer." ONCOLOGY (United States) 27.8 (2013).
Source
scival
Published In
Oncology
Volume
27
Issue
8
Publish Date
2013

Research participants' high expectations of benefit in early-phase oncology trials: are we asking the right question?

PURPOSE: To determine whether patients' expectations of benefit in early-phase oncology trials depend on how patients are queried and to explore whether expectations are associated with patient characteristics. PATIENTS AND METHODS: Participants were 171 patients in phase I or II oncology trials in the United States. After providing informed consent for a trial but before receiving the investigational therapy, participants answered questions about expectations of benefit. We randomly assigned participants to one of three groups corresponding to three queries about expectations: frequency type, belief type, or both. Main outcomes were differences in expectations by question type and the extent to which expectations were associated with demographic characteristics, numeracy, dispositional optimism, religiousness/spirituality, understanding of research, and other measures. RESULTS: The belief-type group had a higher mean expectation of benefit (64.4 of 100) than the combination group (51.6; P = .01) and the frequency-type group (43.1; P < .001). Mean expectations in the combination and frequency groups were not significantly different (P = .06). Belief-type expectations were associated with a preference for nonquantitative information (r = -0.19; 95% CI, -0.19 to -0.36), knowledge about research (r = -0.21; 95% CI, -0.38 to -0.03), dispositional optimism (r = 0.20; 95% CI, 0.01 to 0.37), and spirituality (r = 0.22; 95% CI, 0.03 to 0.38). Frequency-type expectations were associated with knowledge about clinical research (r = -0.27; 95% CI, -0.27 to -0.51). CONCLUSION: In early-phase oncology trials, patients' reported expectations of benefit differed according to how patients were queried and were associated with patient characteristics. These findings have implications for how informed consent is obtained and assessed.

Authors
Weinfurt, KP; Seils, DM; Lin, L; Sulmasy, DP; Astrow, AB; Hurwitz, HI; Cohen, RB; Meropol, NJ
MLA Citation
Weinfurt, KP, Seils, DM, Lin, L, Sulmasy, DP, Astrow, AB, Hurwitz, HI, Cohen, RB, and Meropol, NJ. "Research participants' high expectations of benefit in early-phase oncology trials: are we asking the right question?." J Clin Oncol 30.35 (December 10, 2012): 4396-4400.
PMID
23091107
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
35
Publish Date
2012
Start Page
4396
End Page
4400
DOI
10.1200/JCO.2011.40.6587

Anti-VEGF therapies in the clinic.

The development and use of antiangiogenesis agents, particularly those targeting vascular endothelial growth factor (VEGF), has become an integral component of anticancer regimens for many tumor types. This review is intended to highlight some of the most important clinical successes and failures of anti-VEGF therapies, and where possible, to suggest important lessons that have been learned. This review emphasizes data from agents that have been FDA approved and/or have completed phase III studies.

Authors
Meadows, KL; Hurwitz, HI
MLA Citation
Meadows, KL, and Hurwitz, HI. "Anti-VEGF therapies in the clinic. (Published online)" Cold Spring Harb Perspect Med 2.10 (October 1, 2012). (Review)
PMID
23028128
Source
pubmed
Published In
Cold Spring Harbor perspectives in medicine
Volume
2
Issue
10
Publish Date
2012
DOI
10.1101/cshperspect.a006577

Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors.

PURPOSE: To define the maximum tolerated dose, clinical toxicities, and pharmacodynamics of bevacizumab, everolimus, and panobinostat (LBH-589) when administered in combination to patients with advanced solid tumor malignancies. EXPERIMENT DESIGN: Subjects received 10 mg of panobinostat three times weekly, 5 or 10 mg everolimus daily, and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Protein acetylation was assessed in peripheral blood mononuclear cells (PBMC) both at baseline and on treatment. RESULTS: Twelve subjects were evaluable for toxicity and nine subjects for response. DLTs in cohort 1 included grade 2 esophagitis and grade 3 oral mucositis; DLTs in cohort -1 were grade 2 ventricular arrhythmia and grade 2 intolerable skin rash. Common adverse events were diarrhea (50 %), headache (33 %), mucositis/stomatitis (25 %), hyperlipidemia (25 %), and thrombocytopenia (25 %). There was 1 partial response; an additional 2 subjects had stable disease as best response. No consistent changes in protein acetylation in PBMC were observed in samples available from eight patients on treatment compared with baseline. CONCLUSIONS: Bevacizumab, everolimus, and panobinostat in combination at the lowest proposed doses did not have an acceptable safety and tolerability profile and did not consistently inhibit HDAC activity; therefore, we do not recommend further evaluation.

Authors
Strickler, JH; Starodub, AN; Jia, J; Meadows, KL; Nixon, AB; Dellinger, A; Morse, MA; Uronis, HE; Marcom, PK; Zafar, SY; Haley, ST; Hurwitz, HI
MLA Citation
Strickler, JH, Starodub, AN, Jia, J, Meadows, KL, Nixon, AB, Dellinger, A, Morse, MA, Uronis, HE, Marcom, PK, Zafar, SY, Haley, ST, and Hurwitz, HI. "Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors." Cancer Chemother Pharmacol 70.2 (August 2012): 251-258.
PMID
22744359
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
70
Issue
2
Publish Date
2012
Start Page
251
End Page
258
DOI
10.1007/s00280-012-1911-1

Partner-assisted emotional disclosure for patients with GI cancer: 8-week follow-up and processes associated with change.

PURPOSE: We recently reported that a partner-assisted emotional disclosure intervention for gastrointestinal cancer led to improvements in relationship quality and intimacy for couples in which the patient initially reported higher levels of holding back from discussing cancer-related concerns. The purposes of the present study were to examine outcomes at 8-week follow-up and process variables that may influence treatment effects. METHODS: One hundred thirty couples were randomly assigned to either partner-assisted emotional disclosure or an education/support control condition. Participants completed measures of relationship quality, intimacy, and psychological distress before randomization, post-treatment, and 8 weeks later. Patients in the disclosure intervention completed measures of negative affect immediately following each treatment session, and their level of expressiveness during the sessions was rated by trained observers. Data were analyzed using multilevel modeling. RESULTS: Among couples in which the patient initially reported higher levels of holding back, the disclosure intervention led to improvements in relationship quality and intimacy that were maintained at 8-weeks follow-up. High levels of patient expressiveness during the disclosure sessions were associated with improvements in relationship quality and intimacy, and high levels of patient negative affect immediately following the sessions were associated with reductions in psychological distress at the post-test assessment. CONCLUSIONS: For couples in which the patient tends to hold back from discussing concerns, partner-assisted emotional disclosure is a beneficial intervention leading to improvements in relationship functioning that maintain over time. Future research is needed to examine methods of enhancing intervention effects, including encouraging patient expressiveness and negative affect during the sessions.

Authors
Porter, LS; Keefe, FJ; Baucom, DH; Hurwitz, H; Moser, B; Patterson, E; Kim, HJ
MLA Citation
Porter, LS, Keefe, FJ, Baucom, DH, Hurwitz, H, Moser, B, Patterson, E, and Kim, HJ. "Partner-assisted emotional disclosure for patients with GI cancer: 8-week follow-up and processes associated with change." Support Care Cancer 20.8 (August 2012): 1755-1762.
PMID
21947440
Source
pubmed
Published In
Supportive Care in Cancer
Volume
20
Issue
8
Publish Date
2012
Start Page
1755
End Page
1762
DOI
10.1007/s00520-011-1272-z

Does preoperative therapy optimize outcomes in patients with resectable pancreatic cancer?

The objective of this study was to compare survival between all patients with radiographically resectable adenocarcinoma of the proximal pancreas who underwent preoperative chemoradiation therapy (PRE-OP CRT) or surgical exploration first (SURGERY) with "intention to resect." Pancreatic cancer patients who undergo resection after PREOP CRT live longer than patients who undergo resection without PREOP CRT, a difference that may be attributable to patient selection. We retrospectively identified 236 patients with pancreatic head adenocarcinoma seen between 1999 and 2007 with sufficient data to be confirmed medically and radiographically resectable. The outcomes of 144 patients who underwent PREOP CRT were compared to those of 92 patients who proceeded straight to SURGERY. The groups were similar in age and gender. Tumors were slightly larger in the PREOP CRT group (mean 2.5 cm vs. 2.1 cm, P < 0.01), and there were trends toward more venous abutment (54% vs. 39%, P = 0.06) and a higher Charlson comorbidity index (P = 0.1). In the PREOP CRT group, 76 patients (53%) underwent resection, 28 (19%) had metastatic and 17 (12%) locally unresectable disease after PREOP CRT, and 23 (16%) were not explored due to performance status or loss to follow-up. In the SURGERY group, 68 patients (74%) underwent resection. Sixteen patients (17%) had metastatic and eight patients (9%) locally unresectable disease at exploration. In patients who underwent resection, the PREOP CRT group had smaller pathologic tumor size and lower incidence of positive lymph nodes than the SURGERY group but no difference in positive margins or need for vascular resection. Median overall survival (OS) in patients undergoing resection was 27 months in the PREOP CRT group and 17 months in the SURGERY group (P = 0.04). Median OS in all patients treated with PREOP CRT or surgically explored with intention to resect was 15 and 13 months, respectively, with superimposable survival curves. Despite a lower resection rate, the PREOP CRT group as a whole had a similar OS to the SURGERY group as a whole. For patients who underwent resection, those in the PREOP CRT had longer survival than those in the SURGERY group, suggesting that PREOP CRT allows better patient selection for resection. PREOP CRT should be considered an acceptable alternative for most patients with resectable pancreatic cancer.

Authors
Papalezova, KT; Tyler, DS; Blazer, DG; Clary, BM; Czito, BG; Hurwitz, HI; Uronis, HE; Pappas, TN; Willett, CG; White, RR
MLA Citation
Papalezova, KT, Tyler, DS, Blazer, DG, Clary, BM, Czito, BG, Hurwitz, HI, Uronis, HE, Pappas, TN, Willett, CG, and White, RR. "Does preoperative therapy optimize outcomes in patients with resectable pancreatic cancer?." J Surg Oncol 106.1 (July 1, 2012): 111-118.
PMID
22311829
Source
pubmed
Published In
Journal of Surgical Oncology
Volume
106
Issue
1
Publish Date
2012
Start Page
111
End Page
118
DOI
10.1002/jso.23044

A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors.

PURPOSE: Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination. METHODS: Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. RESULTS: Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5 mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5 mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91 %), mucositis/stomatitis (75 %), hypomagnesemia (72 %), hypocalcemia (56 %) and hypokalemia (50 %). There were 3 partial responses; an additional 10 subjects had stable disease ≥6 months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40 months. CONCLUSIONS: The recommended phase II dose is everolimus at 5 mg three times weekly plus panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors.

Authors
Vlahovic, G; Meadows, KL; Uronis, HE; Morse, MA; Blobe, GC; Riedel, RF; Zafar, SY; Alvarez-Secord, A; Gockerman, J; Starodub, AN; Ready, NE; Anderson, EL; Bendell, JC; Hurwitz, HI
MLA Citation
Vlahovic, G, Meadows, KL, Uronis, HE, Morse, MA, Blobe, GC, Riedel, RF, Zafar, SY, Alvarez-Secord, A, Gockerman, J, Starodub, AN, Ready, NE, Anderson, EL, Bendell, JC, and Hurwitz, HI. "A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors." Cancer Chemother Pharmacol 70.1 (July 2012): 95-102.
PMID
22638798
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
70
Issue
1
Publish Date
2012
Start Page
95
End Page
102
DOI
10.1007/s00280-012-1889-8

Development and utilization of a combined LC-UV and LC-MS/MS method for the simultaneous analysis of tegafur and 5-fluorouracil in human plasma to support a phase I clinical study of oral UFT®/leucovorin.

Tegafur is a 5-fluorouracil (5-FU) prodrug widely used outside the United States to treat colorectal cancer as well as cancers of the head and neck. The resulting plasma concentrations of tegafur are much higher than those of 5-FU; thus, analytical methods are needed that are sensitive enough to detect low plasma concentrations of 5-FU and robust enough to simultaneously analyze tegafur. Previous LC-MS/MS methods have either failed to demonstrate the ability to simultaneously measure low 5-FU and high tegafur plasma levels, or failed to be applicable in clinical studies. Our goal was to develop a method capable of measuring low concentrations of 5-FU (8-200 ng/ml) and high concentrations of tegafur (800-20,000 ng/ml) in human plasma and to subsequently evaluate the utility of the method in patient samples collected during a phase I clinical study where oral doses of either 200mg or 300 mg UF®/LV (uracil and tegafur in a 4:1 molar ratio plus leucovorin) were administered. A combined LC-MS/MS and LC-UV method was developed utilizing negative ion atmospheric pressure ionization (API). The method provides an accuracy and precision of <10% and <6%, respectively, for both analytes. Material recoveries from the liquid-liquid extraction technique were 97-110% and 86-91% for tegafur and 5-FU, respectively. Utilization of this method to determine tegafur and 5-FU plasma concentrations followed by noncompartmental pharmacokinetic analyses successfully estimated pharmacokinetic parameters (C(MAX), t(MAX) and AUC(0-10h)) in the clinical study patients. Overall, this method is ideal for the simultaneous bioanalysis of low levels of 5-FU and relatively higher levels of its prodrug, tegafur, in human plasma for clinical pharmacokinetic analysis.

Authors
Peer, CJ; McManus, TJ; Hurwitz, HI; Petros, WP
MLA Citation
Peer, CJ, McManus, TJ, Hurwitz, HI, and Petros, WP. "Development and utilization of a combined LC-UV and LC-MS/MS method for the simultaneous analysis of tegafur and 5-fluorouracil in human plasma to support a phase I clinical study of oral UFT®/leucovorin." J Chromatogr B Analyt Technol Biomed Life Sci 898 (June 1, 2012): 32-37.
PMID
22565063
Source
pubmed
Published In
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Volume
898
Publish Date
2012
Start Page
32
End Page
37
DOI
10.1016/j.jchromb.2012.04.010

Carcinoma of the ampulla of Vater: patterns of failure following resection and benefit of chemoradiotherapy.

BACKGROUND: Ampullary carcinoma is a rare malignancy. Despite radical resection, survival rates remain low with high rates of local failure. We performed a single-institution outcomes analysis to define the role of concurrent chemoradiotherapy (CRT) in addition to surgery. METHODS: A retrospective analysis was performed of all patients undergoing potentially curative pancreaticoduodenectomy for adenocarcinoma of the ampulla of Vater at Duke University Hospitals between 1976 and 2009. Time-to-event analysis was performed comparing all patients who underwent surgery alone to the cohort of patients receiving CRT in addition to surgery. Local control (LC), disease-free survival (DFS), overall survival (OS), and metastases-free survival (MFS) were estimated using the Kaplan-Meier method. RESULTS: A total of 137 patients with ampullary carcinoma underwent Whipple procedure. Of these, 61 patients undergoing resection received adjuvant (n = 43) or neoadjuvant (n = 18) CRT. Patients receiving chemoradiotherapy were more likely to have poorly differentiated tumors (P = .03). Of 18 patients receiving neoadjuvant therapy, 67% were downstaged on final pathology with 28% achieving pathologic complete response (pCR). With a median follow-up of 8.8 years, 3-year local control was improved in patients receiving CRT (88% vs 55%, P = .001) with trend toward 3-year DFS (66% vs 48%, P = .09) and OS (62% vs 46%, P = .074) benefit in patients receiving CRT. CONCLUSIONS: Long-term survival rates are low and local failure rates high following radical resection alone. Given patterns of relapse with surgery alone and local control benefit in patients receiving CRT, the use of chemoradiotherapy in selected patients should be considered.

Authors
Palta, M; Patel, P; Broadwater, G; Willett, C; Pepek, J; Tyler, D; Zafar, SY; Uronis, H; Hurwitz, H; White, R; Czito, B
MLA Citation
Palta, M, Patel, P, Broadwater, G, Willett, C, Pepek, J, Tyler, D, Zafar, SY, Uronis, H, Hurwitz, H, White, R, and Czito, B. "Carcinoma of the ampulla of Vater: patterns of failure following resection and benefit of chemoradiotherapy." Ann Surg Oncol 19.5 (May 2012): 1535-1540.
PMID
22045467
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
19
Issue
5
Publish Date
2012
Start Page
1535
End Page
1540
DOI
10.1245/s10434-011-2117-1

Registries and randomized trials in assessing the effects of bevacizumab in colorectal cancer: is there a common theme?

Authors
Hurwitz, HI; Lyman, GH
MLA Citation
Hurwitz, HI, and Lyman, GH. "Registries and randomized trials in assessing the effects of bevacizumab in colorectal cancer: is there a common theme?." J Clin Oncol 30.6 (February 20, 2012): 580-581.
PMID
22253468
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
6
Publish Date
2012
Start Page
580
End Page
581
DOI
10.1200/JCO.2011.40.7031

A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303.

BACKGROUND AND AIMS: Cancer and Leukemia Group B 80303 was a randomized, phase III study in patients with advanced pancreatic cancer treated with gemcitabine plus either bevacizumab or placebo. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS) using overall survival (OS) as the endpoint. EXPERIMENTAL DESIGN: DNA from 351 patients was genotyped for more than 550,000 single-nucleotide polymorphisms (SNP). Associations between OS and SNPs were investigated using the log-linear 2-way multiplicative Cox proportional hazards model. The subset of 294 genetically European patients was used for the primary analysis. RESULTS: A nonsynonymous SNP in interleukin (IL)17F (rs763780, H161R) and an intronic SNP in strong linkage disequilibrium (rs7771466) were associated with OS using genome-wide criteria (P ≤ 10(-7)). Median OS was significantly shorter (P = 2.61 × 10(-8)) for the rs763780 heterozygotes [3.1 months; 95% confidence interval (CI), 2.3-4.3] than for the patients without this variant (6.8 months; 95% CI, 5.8-7.3). After adjustment by stratification factors, the P value for the association was 9.51 × 10(-7). CONCLUSIONS: The variant 161R form of IL-17F is a natural antagonist of the antiangiogenic effects of wild-type 161H IL-17F, and angiogenesis may play an important role in the metastatic spread of pancreatic cancer. In this preliminary study, we hypothesize that the angiogenetic potential of pancreatic cancers in patients with variant IL-17F is higher than that of tumors in patients with wild-type IL-17F, conferring worse prognosis. This exploratory GWAS may provide the foundation for testing the biology and clinical effects of novel genes and their heritable variants through mechanistic and confirmatory studies in pancreatic cancer.

Authors
Innocenti, F; Owzar, K; Cox, NL; Evans, P; Kubo, M; Zembutsu, H; Jiang, C; Hollis, D; Mushiroda, T; Li, L; Friedman, P; Wang, L; Glubb, D; Hurwitz, H; Giacomini, KM; McLeod, HL; Goldberg, RM; Schilsky, RL; Kindler, HL; Nakamura, Y; Ratain, MJ
MLA Citation
Innocenti, F, Owzar, K, Cox, NL, Evans, P, Kubo, M, Zembutsu, H, Jiang, C, Hollis, D, Mushiroda, T, Li, L, Friedman, P, Wang, L, Glubb, D, Hurwitz, H, Giacomini, KM, McLeod, HL, Goldberg, RM, Schilsky, RL, Kindler, HL, Nakamura, Y, and Ratain, MJ. "A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303." Clin Cancer Res 18.2 (January 15, 2012): 577-584.
PMID
22142827
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
18
Issue
2
Publish Date
2012
Start Page
577
End Page
584
DOI
10.1158/1078-0432.CCR-11-1387

Anti-VEGF therapies in the clinic

The development and use of antiangiogenesis agents, particularly those targeting vascular endothelial growth factor (VEGF), has become an integral component of anticancer regimens for many tumor types. This review is intended to highlight some of the most important clinical successes and failures of anti-VEGF therapies, and where possible, to suggest important lessons that have been learned. This review emphasizes data from agents that have been FDA approved and/or have completed phase III studies. © 2012 Cold Spring Harbor Laboratory Press.

Authors
Meadows, KL; Hurwitz, HI
MLA Citation
Meadows, KL, and Hurwitz, HI. "Anti-VEGF therapies in the clinic." Cold Spring Harbor Perspectives in Medicine 2.10 (January 1, 2012).
Source
scopus
Published In
Cold Spring Harbor perspectives in medicine
Volume
2
Issue
10
Publish Date
2012
DOI
10.1101/cshperspect.a006577

Anti-VEGF therapies in the clinic

The development and use of antiangiogenesis agents, particularly those targeting vascular endothelial growth factor (VEGF), has become an integral component of anticancer regimens for many tumor types. This reviewis intended to highlight some of the most important clinical successes and failures of anti-VEGF therapies, and where possible, to suggest important lessons that have been learned. This review emphasizes data from agents that have been FDA approved and/or have completed phase III studies. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.

Authors
Meadows, KL; Hurwitz, HI
MLA Citation
Meadows, KL, and Hurwitz, HI. "Anti-VEGF therapies in the clinic." Cold Spring Harbor Perspectives in Biology 4.11 (2012).
Source
scival
Published In
Cold Spring Harbor perspectives in biology
Volume
4
Issue
11
Publish Date
2012

A phase I first-in-human study of TRC105 (anti-endoglin antibody) in patients with advanced cancer

Purpose: TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors. Patients and Methods: Patients received escalating doses of intravenous TRC105 until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. Results: Fifty patients were treated with escalating doses of TRC105. The maximum tolerated dose (MTD) was exceeded at 15 mg/kg every week because of dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concentrations that saturate CD105 receptors were maintained at 10 mg/kg weekly (the MTD) and 15 mg/kg every 2 weeks. Common adverse events including anemia, telangiectasias, and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase Ib and phase II studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%), including two ongoing responses at 48 and 18 months. Conclusion: TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 weeks, with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clinical activity was seen in a refractory patient population. Ongoing clinical trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, breast, and hepatocellular cancer. ©2012 AACR.

Authors
Rosen, LS; Hurwitz, HI; Wong, MK; Goldman, J; Mendelson, DS; Figg, WD; Spencer, S; Adams, BJ; Alvarez, D; Seon, BK; Theuer, CP; Leigh, BR; Gordon, MS
MLA Citation
Rosen, LS, Hurwitz, HI, Wong, MK, Goldman, J, Mendelson, DS, Figg, WD, Spencer, S, Adams, BJ, Alvarez, D, Seon, BK, Theuer, CP, Leigh, BR, and Gordon, MS. "A phase I first-in-human study of TRC105 (anti-endoglin antibody) in patients with advanced cancer." Clinical Cancer Research 18.17 (2012): 4820-4829.
PMID
22767667
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
18
Issue
17
Publish Date
2012
Start Page
4820
End Page
4829
DOI
10.1158/1078-0432.CCR-12-0098

A Randomized, phase II trial of standard triweekly compared with dose-dense biweekly capecitabine plus oxaliplatin plus bevacizumab as first-line treatment for metastatic colorectal cancer: XELOX-A-DVS (dense versus standard)

Background. Capecitabine administered for 7 days biweekly with oxaliplatin (XELOX) biweekly has been reported to have activity and safety profiles similar to those of standard capecitabine given for 14 days triweekly. Multiple studies have shown that the addition of bevacizumab to 5-fluorouracil- based chemotherapy is active and well tolerated. Methods. Patients with metastatic colorectal cancer (mCRC) were randomized to XELOX plus bevacizumab using a standard triweekly cycle (Q3W) or a dose-dense biweekly cycle (Q2W) schedule. The primary endpoint was the progression-free survival (PFS) interval. This trial is registered on ClinicalTrials.gov (identifier, NCT00159432). Results. In total, 435 U.S. patients were randomized. The median PFS intervals were 9.6 months in the Q3W group and 9.1 months in theQ2Wgroup. The median overall survival times were 28.4 months and 22.1 months and the median times to treatment failure were 5.5 months and 3.4 months, respectively. Overall, gastrointestinal disorders were the most common (93%) adverse event (AE). Grade 3 or 4 AEs occurred in 75% and 81% of patients in the Q3W and Q2W groups, respectively. Treatment discontinuation as a result of diarrhea (5% versus 10%) and hand-foot syndrome (2% versus 9%) was less common in the Q3W group than in the Q2W group, respectively. Conclusions. Based on these results, the first-line treatment of U.S. patients with mCRC using a biweekly combination of XELOX and bevacizumab at the doses studied cannot be recommended. XELOX Q3W remains the preferred schedule for the management of mCRC. ©AlphaMed Press.

Authors
Hurwitz, H; Mitchell, EP; Cartwright, T; Kwok, A; Hu, S; Mckenna, E; Patt, YZ
MLA Citation
Hurwitz, H, Mitchell, EP, Cartwright, T, Kwok, A, Hu, S, Mckenna, E, and Patt, YZ. "A Randomized, phase II trial of standard triweekly compared with dose-dense biweekly capecitabine plus oxaliplatin plus bevacizumab as first-line treatment for metastatic colorectal cancer: XELOX-A-DVS (dense versus standard)." Oncologist 17.7 (2012): 937-946.
PMID
22622147
Source
scival
Published In
The oncologist
Volume
17
Issue
7
Publish Date
2012
Start Page
937
End Page
946
DOI
10.1634/theoncologist.2012-0071

Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure

Purpose: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. Experimental Design: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. Results: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P=0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. Conclusions: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events. ©2012 AACR.

Authors
Demetri, GD; Garrett, CR; Schöffski, P; Shah, MH; Verweij, J; Leyvraz, S; Hurwitz, HI; Pousa, AL; Cesne, AL; Goldstein, D; Paz-Ares, L; Blay, J-Y; McArthur, GA; Xu, Q; Huang, X; Harmon, CS; Tassell, V; Cohen, DP; Casali, PG
MLA Citation
Demetri, GD, Garrett, CR, Schöffski, P, Shah, MH, Verweij, J, Leyvraz, S, Hurwitz, HI, Pousa, AL, Cesne, AL, Goldstein, D, Paz-Ares, L, Blay, J-Y, McArthur, GA, Xu, Q, Huang, X, Harmon, CS, Tassell, V, Cohen, DP, and Casali, PG. "Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure." Clinical Cancer Research 18.11 (2012): 3170-3179.
PMID
22661587
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
18
Issue
11
Publish Date
2012
Start Page
3170
End Page
3179
DOI
10.1158/1078-0432.CCR-11-3005

Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors

This phase I, open-label, dose-escalation study assessed the maximum-tolerated dose, safety, pharmacokinetics, and preliminary antitumor activity of pazopanib plus lapatinib combination therapy in patients with solid tumors. Patients were to take pazopanib and lapatinib orally once daily in a fasting condition. During the escalation phase, pazopanib and lapatinib doses were escalated in serial patient cohorts, and a limited blood sampling scheme was applied for pharmacokinetic evaluation. In the expansion phase, potential pharmacokinetic interaction between pazopanib and lapatinib was evaluated more extensively. Seventy-five patients were treated. Multiple dosing levels were studied, combining pazopanib up to 800 mg/day with lapatinib up to 1,500 mg/day. Dose-limiting toxicities observed included grade 3 neutropenia, fatigue, asymptomatic decline in left ventricular ejection fraction, diarrhea, and liver enzyme elevations. The most common drug-related adverse events were diarrhea, nausea, anorexia, fatigue, vomiting, rash, hair depigmentation, and hypertension. The dose recommended for further evaluation was pazopanib 800 mg plus lapatinib 1,500 mg (paz-800/lap-1500). No clinically significant drug-drug interaction was observed at the paz-400/lap-1000 level. However, at paz-800/lap-1500, an increase in both the AUC 0-t and C max of pazopanib was observed. Four partial responses were observed in patients with renal cancer (n = 2), giant-cell tumor of the bone (n = 1), and thyroid cancer (n = 1). Stable disease for ≥18 weeks was seen in 12 patients. Pazopanib and lapatinib can be administered in combination at their respective single-agent doses with an acceptable safety profile. Further evaluation of the combination will be pursued, exploring both paz-800/lap-1500 and paz-400/lap-1000. © 2012 Springer Science+Business Media New York.

Authors
Jonge, MJAD; Hamberg, P; Verweij, J; Savage, S; Suttle, AB; Hodge, J; Arumugham, T; Pandite, LN; Hurwitz, HI
MLA Citation
Jonge, MJAD, Hamberg, P, Verweij, J, Savage, S, Suttle, AB, Hodge, J, Arumugham, T, Pandite, LN, and Hurwitz, HI. "Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors." Investigational New Drugs (2012): 1-9.
PMID
23054212
Source
scival
Published In
Investigational New Drugs
Publish Date
2012
Start Page
1
End Page
9
DOI
10.1007/s10637-012-9885-8

Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-Bevacizumab or FOLFIRI-bevacizumab: Results from ARIES, a bevacizumab observational cohort study

Background. The Avastin® Registry: Investigation of Effectiveness and Safety (ARIES) study is a prospective, community- based observational cohort study that evaluated the effectiveness and safety of first-line treatment patterns, assessing the impact of chemotherapy choice and treatment duration. Methods. The ARIES study enrolled patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy with bevacizumab and followed them longitudinally. The protocol did not specify treatment regimens or assessments. Analyses included all patients who initiated bevacizumab in combination with either first-line oxaliplatin with infusional 5-fluorouracil and leucovorin (FOLFOX) or irinotecan with infusional 5-fluorouracil and leucovorin (FOLFIRI). Progression-free survival (PFS) and overall survival (OS) times were estimated using Kaplan-Meier methods. Hazard ratios (HRs) were estimated with multivariate Cox regression analysis, adjusting for potential confounding factors. Results. In total, 1,550 patients with first-line mCRC were enrolled (median follow-up, 21 months) and most received FOLFOX-bevacizumab (n = 968) or FOLFIRI- bevacizumab (n = 243) as first-line therapy. The baseline characteristics and median treatment duration were generally similar between subgroups. There were no significant differences in the median PFS (10.3 months vs. 10.2 months) or OS (23.7 months vs. 25.5 months) time between the FOLFOX-bevacizumab and FOLFIRI-bevacizumab subgroups, respectively, by unadjusted analyses. Multivariate analyses showed FOLFIRI-bevacizumab resulted in a similar PFS (HR, 1.03; 95% confidence interval [CI], 0.88 -1.21) and OS (HR, 0.95; 95% CI, 0.78 -1.16) outcome as with FOLFOX-bevacizumab. The incidence proportions of bevacizumab-associated adverse events were similar for FOLFOX- and FOLFIRI-based therapies. Conclusions. In first-linemCRCpatients, the FOLFOX- bevacizumab and FOLFIRI-bevacizumab regimens were associated with similar treatment patterns and clinical outcomes. © AlphaMed Press.

Authors
Bendell, JC; Bekaii-Saab, TS; Cohn, AL; Hurwitz, HI; Kozloff, M; Tezcan, H; Roach, N; Mun, Y; Fish, S; Flick, ED; Dalal, D; Grothey, A
MLA Citation
Bendell, JC, Bekaii-Saab, TS, Cohn, AL, Hurwitz, HI, Kozloff, M, Tezcan, H, Roach, N, Mun, Y, Fish, S, Flick, ED, Dalal, D, and Grothey, A. "Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-Bevacizumab or FOLFIRI-bevacizumab: Results from ARIES, a bevacizumab observational cohort study." Oncologist 17.12 (2012): 1486-1495.
PMID
23015662
Source
scival
Published In
The oncologist
Volume
17
Issue
12
Publish Date
2012
Start Page
1486
End Page
1495
DOI
10.1634/theoncologist.2012-0190

Maintenance therapy for first-line metastatic colorectal cancer: activity and sustainability.

Authors
Strickler, JH; Hurwitz, HI
MLA Citation
Strickler, JH, and Hurwitz, HI. "Maintenance therapy for first-line metastatic colorectal cancer: activity and sustainability." Oncologist 17.1 (2012): 9-10.
PMID
22234629
Source
pubmed
Published In
The oncologist
Volume
17
Issue
1
Publish Date
2012
Start Page
9
End Page
10
DOI
10.1634/theoncologist.2011-0358

Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer.

Since its approval for the first-line treatment of metastatic colorectal cancer (mCRC), bevacizumab has become a standard treatment option in combination with chemotherapy for patients with mCRC. Bevacizumab has demonstrated efficacy in combination with a number of different backbone chemotherapy regimens, and its widespread use has introduced several important questions regarding the selection and optimization of bevacizumab-based treatment regimens, its use in various patient populations, and the identification of associated adverse events. This review discusses the results of several phase II and phase III clinical trials, as well as large observational studies, to address the use of bevacizumab in the treatment of patients with mCRC in the first-line setting.

Authors
Strickler, JH; Hurwitz, HI
MLA Citation
Strickler, JH, and Hurwitz, HI. "Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer." Oncologist 17.4 (2012): 513-524. (Review)
PMID
22477726
Source
pubmed
Published In
The oncologist
Volume
17
Issue
4
Publish Date
2012
Start Page
513
End Page
524
DOI
10.1634/theoncologist.2012-0003

Anti-VEGF therapies in the clinic.

The development and use of antiangiogenesis agents, particularly those targeting vascular endothelial growth factor (VEGF), has become an integral component of anticancer regimens for many tumor types. This review is intended to highlight some of the most important clinical successes and failures of anti-VEGF therapies, and where possible, to suggest important lessons that have been learned. This review emphasizes data from agents that have been FDA approved and/or have completed phase III studies.

Authors
Meadows, KL; Hurwitz, HI
MLA Citation
Meadows, KL, and Hurwitz, HI. "Anti-VEGF therapies in the clinic." Cold Spring Harbor perspectives in medicine 2.10 (2012).
Source
scival
Published In
Cold Spring Harbor perspectives in medicine
Volume
2
Issue
10
Publish Date
2012
DOI
10.1101/cshperspect.a006577

Radiotherapy in the treatment of patients with unresectable extrahepatic cholangiocarcinoma.

PURPOSE: Extrahepatic cholangiocarcinoma is an uncommon but lethal malignancy. We analyzed the role of definitive chemoradiotherapy for patients with nonmetastatic, locally advanced extrahepatic cholangiocarcinoma treated at a single institution. METHODS AND MATERIALS: This retrospective analysis included 37 patients who underwent external beam radiation therapy (EBRT) with concurrent chemotherapy and/or brachytherapy (BT) for locally advanced extrahepatic cholangiocarcinoma. Local control (LC) and overall survival (OS) were assessed, and univariate regression analysis was used to evaluate the effects of patient- and treatment-related factors on clinical outcomes. RESULTS: Twenty-three patients received EBRT alone, 8 patients received EBRT plus BT, and 6 patients received BT alone (median follow-up of 14 months). Two patients were alive without evidence of recurrence at the time of analysis. Actuarial OS and LC rates at 1 year were 59% and 90%, respectively, and 22% and 71%, respectively, at 2 years. Two patients lived beyond 5 years without evidence of recurrence. On univariate analysis, EBRT with or without BT improved LC compared to BT alone (97% vs. 56% at 1 year; 75% vs. 56% at 2 years; p = 0.096). Patients who received EBRT alone vs. BT alone also had improved LC (96% vs. 56% at 1 year; 80% vs. 56% at 2 years; p = 0.113). Age, gender, tumor location (proximal vs. distal), histologic differentiation, EBRT dose (≤ or >50 Gy), EBRT planning method (two-dimensional vs. three-dimensional), and chemotherapy were not associated with patient outcomes. CONCLUSIONS: Patients with locally advanced extrahepatic cholangiocarcinoma have poor survival. Long-term survival is rare. The majority of patients treated with EBRT had local control at the time of death, suggesting that symptoms due to the local tumor effect might be effectively controlled with radiation therapy, and EBRT is an important element of treatment. Novel treatment approaches are indicated in the therapy for this disease.

Authors
Ghafoori, AP; Nelson, JW; Willett, CG; Chino, J; Tyler, DS; Hurwitz, HI; Uronis, HE; Morse, MA; Clough, RW; Czito, BG
MLA Citation
Ghafoori, AP, Nelson, JW, Willett, CG, Chino, J, Tyler, DS, Hurwitz, HI, Uronis, HE, Morse, MA, Clough, RW, and Czito, BG. "Radiotherapy in the treatment of patients with unresectable extrahepatic cholangiocarcinoma." Int J Radiat Oncol Biol Phys 81.3 (November 1, 2011): 654-659.
PMID
20864265
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
81
Issue
3
Publish Date
2011
Start Page
654
End Page
659
DOI
10.1016/j.ijrobp.2010.06.018

A phase I multicenter study of continuous oral administration of lonafarnib (SCH 66336) and intravenous gemcitabine in patients with advanced cancer.

We conducted a phase I study to assess safety, pharmacokinetics, pharmacodynamics, and activity of lonafarnib plus gemcitabine. Subjects received oral lonafarnib twice daily and gemcitabine on days 1, 8, and 15 every 28 days; multiple dose levels were explored. Lonafarnib had no apparent effect on gemcitabine PK. Mean lonafarnib half-life ranged from 4 to 7 hr; median T(max) values ranged from 4 to 8 hr. Two patients had partial response; seven patients had stable disease at least 6 months. Oral lonafarnib at 150 mg a.m./100 mg p.m. plus gemcitabine at 1,000 mg/m(2) is the maximum tolerated dose with acceptable safety and tolerability.

Authors
Wong, NS; Meadows, KL; Rosen, LS; Adjei, AA; Kaufmann, SH; Morse, MA; Petros, WP; Zhu, Y; Statkevich, P; Cutler, DL; Meyers, ML; Hurwitz, HI
MLA Citation
Wong, NS, Meadows, KL, Rosen, LS, Adjei, AA, Kaufmann, SH, Morse, MA, Petros, WP, Zhu, Y, Statkevich, P, Cutler, DL, Meyers, ML, and Hurwitz, HI. "A phase I multicenter study of continuous oral administration of lonafarnib (SCH 66336) and intravenous gemcitabine in patients with advanced cancer." Cancer Invest 29.9 (November 2011): 617-625.
PMID
22011284
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
29
Issue
9
Publish Date
2011
Start Page
617
End Page
625
DOI
10.3109/07357907.2011.621912

A phase II study of oxaliplatin, dose-intense capecitabine, and high-dose bevacizumab in the treatment of metastatic colorectal cancer.

BACKGROUND: This study was designed to determine the efficacy and tolerability of a novel 2-week regimen of capecitabine, oxaliplatin (OHP), and bevacizumab in patients with chemo-naive advanced colorectal cancer. PATIENTS AND METHODS: Nineteen patients with previously untreated advanced colorectal cancer received capecitabine at 1000 mg/m(2) twice a day on days 1-5 and days 8-12 of a 14-day cycle, and OHP at 85 mg/m(2) and bevacizumab at 10 mg/kg every 2 weeks. Because of unacceptable toxicities, the capecitabine dose was reduced to 850 mg/m(2). Thirty-one additional patients were treated at the lower capecitabine dose. Treatment continued until disease progression, persistent intolerable toxicity, or physician and/or patient discretion. RESULTS: Overall, toxicities were better managed and tolerated at the 850 mg/-m(2) capecitabine dose. The most common treatment-related grade ≥ 3 toxicities were diarrhea and sensory neuropathy. In the first 19 subjects, the response rate was 63% (95% confidence interval [CI], 38%-84%) and 5 patients had stable disease; median progression-free survival (PFS) was 10.1 months (95% CI, 5.7-19.5 months). In the subsequent 31 patients, the response was 42% (95% CI, 25%-61%); 11 patients had stable disease and median PFS was 10.4 months (95% CI, 6.9-15.4); median overall survival was 24.8 months (95% CI, 12.9-39.7). CONCLUSIONS: This novel regimen of capecitabine at 850 mg/m(2) twice a day on days 1-5 and days 8-12 and OHP at 85 mg/m(2)and bevacizumab at 10 mg/kg every 14 days is clinically active in advanced colorectal cancer. The toxicity profile of this regimen is consistent with the standard every-3-week dosing schedule.

Authors
Wong, NS; Fernando, NH; Bendell, JC; Morse, MA; Blobe, GC; Honeycutt, W; Pang, H; Hurwitz, HI
MLA Citation
Wong, NS, Fernando, NH, Bendell, JC, Morse, MA, Blobe, GC, Honeycutt, W, Pang, H, and Hurwitz, HI. "A phase II study of oxaliplatin, dose-intense capecitabine, and high-dose bevacizumab in the treatment of metastatic colorectal cancer." Clin Colorectal Cancer 10.3 (September 2011): 210-216.
PMID
21855046
Source
pubmed
Published In
Clinical colorectal cancer
Volume
10
Issue
3
Publish Date
2011
Start Page
210
End Page
216
DOI
10.1016/j.clcc.2011.03.018

Highlights in metastatic colorectal cancer from the American Society of Clinical Oncology Annual Meeting, June 3-7, 2011, Chicago, Illinois

Authors
Hurwitz, HI
MLA Citation
Hurwitz, HI. "Highlights in metastatic colorectal cancer from the American Society of Clinical Oncology Annual Meeting, June 3-7, 2011, Chicago, Illinois." July 1, 2011.
Source
scopus
Published In
Clinical advances in hematology & oncology : H&O
Volume
9
Issue
7
Publish Date
2011
Start Page
1
End Page
24

Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies.

PURPOSE: Thromboembolism is a major source of morbidity and mortality in patients with cancer. The contribution of anti-vascular endothelial growth factor therapy to these events remains controversial. PATIENTS AND METHODS: Individual patient data were available for 6,055 patients in 10 randomized studies. Unadjusted and exposure-adjusted incidence of venous thromboembolisms (VTEs) was estimated for the overall population and by tumor type. Multivariate analysis was performed to identify risk factors for development of VTE. The safety of anticoagulant therapy in patients undergoing bevacizumab treatment was also examined. RESULTS: There were no statistically significant increases in the unadjusted or exposure-adjusted incidences of all-grade VTEs for bevacizumab versus controls in the overall population or by tumor type. The unadjusted incidence in the overall population was 10.9% with bevacizumab versus 9.8% with controls (odds ratio, 1.14; 95% CI, 0.96 to 1.35; P = .13); the rate per 100 patient-years was 18.5 for bevacizumab and 20.3 for controls (rate ratio, 0.91; 95% CI, 0.77 to 1.06; P =.23). Incidences of grade 3 to 5 events were similar in both groups. Several risk factors for VTEs were identified, including tumor type, older age, poorer performance status, VTE history, and baseline oral anticoagulant use. No interactions between bevacizumab treatment and these factors were observed. For patients who had a VTE and received full-dose anticoagulation therapy, the risk of severe bleeding was low (< 1%) and unaffected by bevacizumab treatment. CONCLUSION: The addition of bevacizumab to chemotherapy did not statistically significantly increase the risk of VTEs versus chemotherapy alone. The risk for VTEs is driven predominantly by tumor and host factors.

Authors
Hurwitz, HI; Saltz, LB; Van Cutsem, E; Cassidy, J; Wiedemann, J; Sirzén, F; Lyman, GH; Rohr, U-P
MLA Citation
Hurwitz, HI, Saltz, LB, Van Cutsem, E, Cassidy, J, Wiedemann, J, Sirzén, F, Lyman, GH, and Rohr, U-P. "Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies." J Clin Oncol 29.13 (May 1, 2011): 1757-1764.
PMID
21422411
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
13
Publish Date
2011
Start Page
1757
End Page
1764
DOI
10.1200/JCO.2010.32.3220

Phase I and pharmacokinetic study of lonafarnib, SCH 66336, using a 2-week on, 2-week off schedule in patients with advanced solid tumors.

PURPOSE: This phase I study was performed to determine the safety profile, maximum tolerated dose (MTD) and biological activity of lonafarnib (SCH 66336). Single-dose and multi-dose pharmacokinetics were conducted. METHODS: Twenty-one patients with advanced solid tumors were enrolled. Each patient received single-dose administration on day 1, cycle 1 then switched to a twice daily (BID) dosing regimen on days 2-14 of a 28-day cycle; subsequent cycles continued BID dosing on days 1-14. Dose-limiting toxicity (DLT) was assessed during the cycle one; toxicity evaluation was closely monitored throughout the treatment. Radiographic scans were completed to assess tumor response. Blood and urine pharmacokinetics were evaluated on days 1 and 14 in cycle 1. SCH 66336- induced farnesylation inhibition was assessed via conversion of prelamin A to lamin in buccal mucosa. RESULTS: DLT and most common adverse events were diarrhea, fatigue, nausea and anorexia. No grade 3 or 4 hematological toxicities were observed. Nineteen of 21 patients were evaluable for response; short-term stable disease was observed in 5 patients. SCH 66336 systemic exposure increased with dose; however, drug accumulation was higher than projected. Renal excretion of parent drug was negligible. Farnesyl transferase inhibition was detected at the 200 and 300 mg BID doses. CONCLUSION: The MTD and recommended phase II dose is 200 mg BID on days 1-14 of a 28-day dosing regimen. The plasma concentration profile suggests the pharmacokinetics of SCH 66336 is dose and time dependent. Farnesyl transferase target inhibition was observed at doses of lonafarnib recommended for further study.

Authors
Castaneda, C; Meadows, KL; Truax, R; Morse, MA; Kaufmann, SH; Petros, WP; Zhu, Y; Statkevich, P; Cutler, DL; Hurwitz, HI
MLA Citation
Castaneda, C, Meadows, KL, Truax, R, Morse, MA, Kaufmann, SH, Petros, WP, Zhu, Y, Statkevich, P, Cutler, DL, and Hurwitz, HI. "Phase I and pharmacokinetic study of lonafarnib, SCH 66336, using a 2-week on, 2-week off schedule in patients with advanced solid tumors." Cancer Chemother Pharmacol 67.2 (February 2011): 455-463.
PMID
20972873
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
67
Issue
2
Publish Date
2011
Start Page
455
End Page
463
DOI
10.1007/s00280-010-1488-5

A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE).

PURPOSE: VEGF, mTOR, and EGFR inhibitors have demonstrated anti-tumor and anti-angiogenic effects alone and in combination with each other. This study evaluated the safety, tolerability, and pharmacokinetics of bevacizumab, everolimus, and erlotinib combination. METHODS: Doublet therapy consisted of bevacizumab at 10 mg/kg every 14 days and everolimus 5 mg daily which escalated to 10 mg daily. Erlotinib 75 mg daily was added to the phase II dose recommended phase II dose (RPTD) of bevacizumab and everolimus. Dose-limiting toxicity (DLT) was assessed in cycle 1. RESULTS: Forty-eight patients with advanced solid malignancies were evaluable for DLT and efficacy. No DLTs were observed in the doublet dose escalation. Two DLTs (grade 3 mucositis and grade 3 rash) were observed with the addition of erlotinib 75 mg daily. Consequently, triplet doses were adjusted and were better tolerated. Four patients had a partial response. Median progression-free survival (PFS) for the doublet therapy was 6.0 months (0.5 to 32+ months) and 5.5 months (0.8 to 27+ months) for the triplet therapy. Systemic exposure of everolimus was significantly higher in combination with erlotinib (476 ± 161 ng h/mL) compared to when given alone (393 ± 156 ng h/mL; P = 0.020). CONCLUSIONS: The RPTD for the doublet therapy is bevacizumab 10 mg/kg every 14 days and everolimus 10 mg daily, and the RPTD for the triplet therapy is bevacizumab 5 mg/kg every 14 days, everolimus 5 mg and erlotinib 75 mg daily. Prolonged disease stability was demonstrated in tumors known to respond to mTOR inhibition and potentially resistant to VEGF blockade.

Authors
Bullock, KE; Petros, WP; Younis, I; Uronis, HE; Morse, MA; Blobe, GC; Zafar, SY; Gockerman, JP; Lager, JJ; Truax, R; Meadows, KL; Howard, LA; O'Neill, MM; Broadwater, G; Hurwitz, HI; Bendell, JC
MLA Citation
Bullock, KE, Petros, WP, Younis, I, Uronis, HE, Morse, MA, Blobe, GC, Zafar, SY, Gockerman, JP, Lager, JJ, Truax, R, Meadows, KL, Howard, LA, O'Neill, MM, Broadwater, G, Hurwitz, HI, and Bendell, JC. "A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE)." Cancer Chemother Pharmacol 67.2 (February 2011): 465-474.
PMID
21079958
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
67
Issue
2
Publish Date
2011
Start Page
465
End Page
474
DOI
10.1007/s00280-010-1507-6

A phase II study of capecitabine, oxaliplatin, bevacizumab and cetuximab in the treatment of metastatic colorectal cancer.

AIM: This study was designed to determine the efficacy and tolerability of capecitabine, oxaliplatin and bevacizumab in combination with cetuximab as first-line therapy for advanced colorectal cancer. PATIENTS AND METHODS: Patients with previously untreated advanced colorectal cancer received oxaliplatin 130 mg/m² and bevacizumab 7.5 mg/kg every three weeks, capecitabine 850 mg/m² twice daily on days 1-14, and cetuximab at 400 mg/m² load and 250 mg/m² weekly. KRAS, BRAF and PI3K mutation status from paraffin-embedded tumor samples were assessed using real-time polymerase chain reaction. RESULTS: Thirty patients were evaluable for safety and efficacy. One patient had a complete response and 12 patients had a partial response, giving an overall response rate of 43% (95% confidence interval (CI) 25%-63%). Fifteen patients had stable disease. The median time to progression was 10.3 months (95% CI, 6.8-16.3 months). The median overall survival was 18.8 months (95% CI, 14.2-23.7 months). Common grade ≥ 3 non-hematological toxicities were skin rash (37%), sensory neuropathy (27%) and diarrhea (17%). Grade ≥ 3 hematological toxicities were uncommon. Mutations in KRAS, BRAF and PI3K occurred in 34.5%, 10.3% and 10.3% of patients respectively, but did not correlate with treatment outcome. CONCLUSION: The addition of cetuximab to capecitabine, oxaliplatin and bevacizumab did not improve the three-drug regimen activity compared to published data and was associated with significant toxicities requiring frequent dose modifications. KRAS, BRAF, and PI3K mutation status were consistent with published literature, but did not affect outcome in this small study.

Authors
Wong, NS; Fernando, NH; Nixon, AB; Cushman, S; Aklilu, M; Bendell, JC; Morse, MA; Blobe, GC; Ashton, J; Pang, H; Hurwitz, HI
MLA Citation
Wong, NS, Fernando, NH, Nixon, AB, Cushman, S, Aklilu, M, Bendell, JC, Morse, MA, Blobe, GC, Ashton, J, Pang, H, and Hurwitz, HI. "A phase II study of capecitabine, oxaliplatin, bevacizumab and cetuximab in the treatment of metastatic colorectal cancer." Anticancer Res 31.1 (January 2011): 255-261.
PMID
21273607
Source
pubmed
Published In
Anticancer research
Volume
31
Issue
1
Publish Date
2011
Start Page
255
End Page
261

A phase II trial of bevacizumab plus everolimus for patients with refractory metastatic colorectal cancer.

PURPOSE: For patients with metastatic colorectal cancer (mCRC), no standard therapy exists after progression on 5-fluorouracil, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab. Preclinical data demonstrated that combined vascular endothelial growth factor and mammalian target of rapamycin inhibition has greater antiangiogenic and antitumor activity than either monotherapy. A phase I study of bevacizumab plus everolimus demonstrated that the combination is safe; activity was seen in several patients with refractory mCRC. METHODS: Fifty patients with refractory mCRC were enrolled and received bevacizumab at 10 mg/kg every 2 weeks and everolimus at 10 mg orally daily. RESULTS: Of the 50 patients enrolled, the median age was 56 years and the median number of prior regimens was four. Forty-seven patients (96%) had prior bevacizumab exposure and 42 patients (84%) had documented progression on prior bevacizumab-based therapy. Forty-nine patients were evaluable for response; eight patients had minor responses (16%) and an additional 15 patients (30%) had stable disease (SD). No complete or partial responses were seen. The median progression-free survival interval was 2.3 months; however, 26% of patients achieved prolonged SD for ≥6 months, and three patients (6%) were on study for >1 year. The median overall survival duration was 8.1 months. The most common grade 1-2 toxicities were mucositis (68%) and hyperlipidemia (64%). Clinically significant grade ≥3 toxicities included hypertension (14%), fistula/abscess/perforation (8%), mucositis (6%), and hemorrhage (2%). CONCLUSIONS: Bevacizumab plus everolimus is generally tolerable but may have risks related to mucosal damage and/or wound healing. Bevacizumab plus everolimus appears to have modest activity in refractory mCRC in patients.

Authors
Altomare, I; Bendell, JC; Bullock, KE; Uronis, HE; Morse, MA; Hsu, SD; Zafar, SY; Blobe, GC; Pang, H; Honeycutt, W; Sutton, L; Hurwitz, HI
MLA Citation
Altomare, I, Bendell, JC, Bullock, KE, Uronis, HE, Morse, MA, Hsu, SD, Zafar, SY, Blobe, GC, Pang, H, Honeycutt, W, Sutton, L, and Hurwitz, HI. "A phase II trial of bevacizumab plus everolimus for patients with refractory metastatic colorectal cancer." Oncologist 16.8 (2011): 1131-1137.
PMID
21795432
Source
pubmed
Published In
The oncologist
Volume
16
Issue
8
Publish Date
2011
Start Page
1131
End Page
1137
DOI
10.1634/theoncologist.2011-0078

Lack of food effect on single-dose pharmacokinetics of brivanib, and safety and efficacy following multiple doses in subjects with advanced or metastatic solid tumors

Purpose: Brivanib alaninate, an orally available prodrug of brivanib, is currently under evaluation for the treatment of several malignancies. This study aimed to (1) investigate effects of a high-fat meal on single-dose pharmacokinetics of brivanib in subjects with advanced/metastatic solid tumors and (2) assess the safety and preliminary efficacy of single and multiple doses of brivanib alaninate in this population. Methods: A two-part study was conducted consisting of a single-dose phase (Part A) and a multiple-dose phase (Part B). In Part A, subjects received a single dose of brivanib alaninate (800 mg) either in a fasting state or following ingestion of a high-fat meal (approximately 951 kcal [15% protein, 33% carbohydrate, 52% fat]); serial blood samples were collected for pharmacokinetic analysis up to 48 h post-dosing. In Part B, subjects received brivanib alaninate (800 mg) once daily until discontinuation. Throughout both phases, subjects were evaluated for adverse events (AEs) and best clinical response. Results: No clinically significant differences in brivanib exposure were observed between fed and fasting subjects in Part A; C max was unchanged and AUC INF decreased marginally when administered in a fed versus fasted state. In Part A, the incidence of treatment-emergent AEs was broadly similar in a fed or fasted state. Brivanib alaninate was generally well tolerated throughout the study and showed preliminary evidence of antitumor activity. Conclusions: Consumption of a high-fat meal had no significant effect on brivanib pharmacokinetics. The study further demonstrates the acceptable safety/tolerability profile and antitumor potential of brivanib in patients with advanced malignancies. © 2011 Springer-Verlag.

Authors
Lorusso, P; Shapiro, GI; Hurwitz, H; Pilat, MJ; Chemidlin, J; Kollia, G; Syed, S; Fischer, B; Masson, E
MLA Citation
Lorusso, P, Shapiro, GI, Hurwitz, H, Pilat, MJ, Chemidlin, J, Kollia, G, Syed, S, Fischer, B, and Masson, E. "Lack of food effect on single-dose pharmacokinetics of brivanib, and safety and efficacy following multiple doses in subjects with advanced or metastatic solid tumors." Cancer Chemotherapy and Pharmacology 68.6 (2011): 1377-1385.
PMID
21461891
Source
scival
Published In
Cancer Chemotherapy and Pharmacology
Volume
68
Issue
6
Publish Date
2011
Start Page
1377
End Page
1385
DOI
10.1007/s00280-011-1603-2

Reply to S. Hapani et al

Authors
Lyman, GH; Hurwitz, HI; Sirzén, F; Rohr, U-P
MLA Citation
Lyman, GH, Hurwitz, HI, Sirzén, F, and Rohr, U-P. "Reply to S. Hapani et al." Journal of Clinical Oncology 29.25 (2011): 3490-3491.
Source
scival
Published In
Journal of Clinical Oncology
Volume
29
Issue
25
Publish Date
2011
Start Page
3490
End Page
3491
DOI
10.1200/JCO.2011.36.5692

Disease course patterns after discontinuation of bevacizumab: Pooled analysis of randomized phase III trials

Purpose: Preclinical studies have suggested accelerated tumor growth, local invasion, and distant metastasis after withdrawal of treatment with some antiangiogenic agents. To investigate whether discontinuation of bevacizumab treatment is associated with accelerated disease progression or increased mortality, we retrospectively analyzed five randomized, placebo-controlled phase III studies in 4,205 patients with breast, colorectal, renal, and pancreatic cancer. Methods: Time from treatment discontinuation to progressive disease or death was analyzed in patients discontinuing bevacizumab/placebo as a result of adverse events (AEs). Mortality rates were assessed at 30, 60, 90, 120, 150, 180, and 210 days after the last bevacizumab/placebo dose in the following two groups: patients discontinuing bevacizumab/placebo as a result of AEs and patients discontinuing bevacizumab/placebo for any reason. In the same groups, time from treatment discontinuation to death was analyzed. Data on disease progression pattern were available and analyzed in four of the five studies. Results: In the pooled analysis, median time from discontinuation as a result of AEs to progression/death was 3.0 months (95% CI, 2.6 to 3.8 months) for placebo and 4.0 months (95% CI, 3.4 to 4.6 months) for bevacizumab (hazard ratio, 0.93; 95% CI, 0.79 to 1.10). Mortality rates from 30 days to 210 days after treatment discontinuation and time from discontinuation to death were similar in bevacizumab- and placebo-treated patients. In addition, similar patterns of disease progression were seen in bevacizumab- and placebo-treated patients. Conclusion: This retrospective analysis of five placebo-controlled clinical trials does not support a decreased time to disease progression, increased mortality, or altered disease progression pattern after cessation of bevacizumab therapy. © 2010 by American Society of Clinical Oncology.

Authors
Miles, D; Harbeck, N; Escudier, B; Hurwitz, H; Saltz, L; Cutsem, EV; Cassidy, J; Mueller, B; Sirzén, F
MLA Citation
Miles, D, Harbeck, N, Escudier, B, Hurwitz, H, Saltz, L, Cutsem, EV, Cassidy, J, Mueller, B, and Sirzén, F. "Disease course patterns after discontinuation of bevacizumab: Pooled analysis of randomized phase III trials." Journal of Clinical Oncology 29.1 (2011): 83-88.
PMID
21098326
Source
scival
Published In
Journal of Clinical Oncology
Volume
29
Issue
1
Publish Date
2011
Start Page
83
End Page
88
DOI
10.1200/JCO.2010.30.2794

Bleeding events in bevacizumab-treated cancer patients who received full-dose anticoagulation and remained on study

Background: Bevacizumab provides clinical benefit in multiple solid tumours, but is associated with some increase in bleeding risk. Thrombotic events necessitating therapeutic anticoagulation (TA) are common in cancer. This report describes the safety of concurrent bevacizumab and TA in three large placebo-controlled clinical studies. Methods: Study 1 (metastatic colorectal cancer (mCRC)), study 2 (mCRC), and study 3 (advanced non-small cell lung cancer) were blinded phase III studies. Eligibility criteria excluded patients on TA. Patients on protocol treatment who developed thrombotic events requiring TA were permitted to continue bevacizumab or placebo under specified conditions. Adverse events in patients who received bevacizumab and TA concurrently were assessed using the NCI-CTCAE scale. Results: While experience is limited, venous thrombotic events were the most common reason for TA initiation in the three studies. Severe bleeding event rates for patients receiving TA in the bevacizumab-treated groups were similar in frequency to the placebo groups, ranging from 0 to 8% or 0 to 67 events per 100 patient-years. No severe pulmonary bleeding was reported in any of the TA-treated populations. Conclusions: These data suggest that bevacizumab did not increase the risk of severe bleeding in cancer patients who received TA. © 2011 Cancer Research UK All rights reserved.

Authors
Leighl, NB; Bennouna, J; Yi, J; Moore, N; Hambleton, J; Hurwitz, H
MLA Citation
Leighl, NB, Bennouna, J, Yi, J, Moore, N, Hambleton, J, and Hurwitz, H. "Bleeding events in bevacizumab-treated cancer patients who received full-dose anticoagulation and remained on study." British Journal of Cancer 104.3 (2011): 413-418.
PMID
21245868
Source
scival
Published In
British Journal of Cancer
Volume
104
Issue
3
Publish Date
2011
Start Page
413
End Page
418
DOI
10.1038/sj.bjc.6606074

A phase I dose-escalation study of imatinib mesylate (Gleevec/STI571) plus capecitabine (Xeloda) in advanced solid tumors.

UNLABELLED: The aim of this study was to determine the maximally tolerated dose, recommended phase II dose and toxicity profile of capecitabine plus imatinib mesylate combination. PATIENTS AND METHODS: Twenty-four patients with advanced solid tumors were treated with capecitabine twice daily on days 1-14 and imatinib mesylate once daily on a 21-day cycle. Dose-limiting toxicity was assessed during the first cycle. Treatment continued until disease progression or undesirable toxicity. RESULTS: Six patients were treated with capecitabine at 1000 mg/m(2) and imatinib mesylate 300 mg; unacceptable toxicity due to grade 2 intolerable hand-foot syndrome and/or grade > or = 2 diarrhea was observed. Doses were subsequently reduced to capecitabine at 750 mg/m(2) and imatinib mesylate at 300 mg; toxicities were better tolerated at the lower dose. Dose-limiting toxicities consisted of grade 3 diarrhea, anorexia and fatigue lasting > or = 4 days. Treatment-related adverse events greater than or equal to grade 3 included anemia, diarrhea, dysuria, hypophosphatemia and vertigo. Minor responses were observed in two patients: stable disease > or = 6 months was observed in two out of twenty-one evaluable patients. CONCLUSION: Full doses of capecitabine and imatinib mesylate were not tolerable. The maximum tolerated dose and the recommended phase II dose for this drug combination is capecitabine at 750 mg/m(2) twice daily for 1-14 days and imatinib at 300 mg once daily on a 21-day cycle.

Authors
Dugan, E; Truax, R; Meadows, KL; Nixon, AB; Petros, WP; Favaro, J; Fernando, NH; Morse, MA; Blobe, GC; Hurwitz, HI
MLA Citation
Dugan, E, Truax, R, Meadows, KL, Nixon, AB, Petros, WP, Favaro, J, Fernando, NH, Morse, MA, Blobe, GC, and Hurwitz, HI. "A phase I dose-escalation study of imatinib mesylate (Gleevec/STI571) plus capecitabine (Xeloda) in advanced solid tumors." Anticancer Res 30.4 (April 2010): 1251-1256.
PMID
20530436
Source
pubmed
Published In
Anticancer research
Volume
30
Issue
4
Publish Date
2010
Start Page
1251
End Page
1256

Phase I safety, pharmacokinetics, and inhibition of src activity study of saracatinib in patients with solid tumors

Purpose: This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of the oral Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors. Experimental Design: Part A of the study followed a multiple-ascending dose design to establish the maximum tolerated dose (MTD) of saracatinib. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing. Results: In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and Cmax of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ∼40 hours. Conclusions: Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d. ©2010 AACR.

Authors
Baselga, J; Cervantes, A; Martinelli, E; Chirivella, I; Hoekman, K; Hurwitz, HI; Jodrell, DI; Hamberg, P; Casado, E; Elvin, P; Swaisland, A; Iacona, R; Tabernero, J
MLA Citation
Baselga, J, Cervantes, A, Martinelli, E, Chirivella, I, Hoekman, K, Hurwitz, HI, Jodrell, DI, Hamberg, P, Casado, E, Elvin, P, Swaisland, A, Iacona, R, and Tabernero, J. "Phase I safety, pharmacokinetics, and inhibition of src activity study of saracatinib in patients with solid tumors." Clinical Cancer Research 16.19 (2010): 4876-4883.
PMID
20805299
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
16
Issue
19
Publish Date
2010
Start Page
4876
End Page
4883
DOI
10.1158/1078-0432.CCR-10-0748

Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: Phase III trial of the Cancer and Leukemia Group B (CALGB 80303)

Purpose: The combination of gemcitabine plus bevacizumab produced a 21% response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer. These encouraging data led Cancer and Leukemia Group B (CALGB) to conduct a double-blind, placebo-controlled, randomized phase III trial of gemcitabine/bevacizumab versus gemcitabine/ placebo in advanced pancreatic cancer patients. Patients and Methods: Eligible patients had no prior therapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, no tumor invasion of adjacent organs, and no increased bleeding risk. The primary end point was overall survival. Patients were stratified by performance status, extent of disease, and prior radiotherapy. Patients received gemcitabine at 1,000 mg/m2 over 30 minutes on days 1, 8, and 15 every 28 days and bevacizumab at 10 mg/kg or placebo on days 1 and 15 every 28 days. Results: Between June 2004 and April 2006, 602 patients were enrolled onto the study and 535 were treated. Median overall survival was 5.8 months for gemcitabine/bevacizumab and 5.9 months for gemcitabine/placebo (P = .95). Median progression-free survival was 3.8 and 2.9 months, respectively (P = .07). Overall response rates were 13% and 10%, respectively. Patients with a performance status of 0, 1, and 2 survived a median of 7.9, 4.8, and 2.4 months, respectively. The only statistically significant differences in grades 3 and 4 toxicity occurred for hypertension (10% v 3%; P <.001) and proteinuria (5% v 1%; P =.002); venous thrombosis grade ≥ 3 was equivalent in both arms (14% and 15%, respectively). Conclusion: The addition of bevacizumab to gemcitabine does not improve survival in advanced pancreatic cancer patients. © 2010 by American Society of Clinical Oncology.

Authors
Kindler, HL; Niedzwiecki, D; Hollis, D; Sutherland, S; Schrag, D; Hurwitz, H; Innocenti, F; Mulcahy, MF; O'Reilly, E; Wozniak, TF; Picus, J; Bhargava, P; Mayer, RJ; Schilsky, RL; Goldberg, RM
MLA Citation
Kindler, HL, Niedzwiecki, D, Hollis, D, Sutherland, S, Schrag, D, Hurwitz, H, Innocenti, F, Mulcahy, MF, O'Reilly, E, Wozniak, TF, Picus, J, Bhargava, P, Mayer, RJ, Schilsky, RL, and Goldberg, RM. "Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: Phase III trial of the Cancer and Leukemia Group B (CALGB 80303)." Journal of Clinical Oncology 28.22 (2010): 3617-3622.
PMID
20606091
Source
scival
Published In
Journal of Clinical Oncology
Volume
28
Issue
22
Publish Date
2010
Start Page
3617
End Page
3622
DOI
10.1200/JCO.2010.28.1386

Effect of bevacizumab in older patients with metastatic colorectal cancer: Pooled analysis of four randomized studies

Background Bevacizumab is frequently combined with 5-Xuorouracil-based chemotherapy for patients with metastatic colorectal cancer (mCRC). The relative beneffit of bevacizumab in older patients has not been widely studied and is of interest. Patients and methods This retrospective analysis used data from three first-line randomized controlled studies and one second-line randomized controlled study of bevacizumab plus chemotherapy in medically Wt (Eastern Cooperative Oncology Group performance status 0 or 1) patients with mCRC. Overall survival (OS) and on-treatment progression-free survival (PFS) were assessed in patients aged <65, ≥65, and ≥70 years. Results were compared using unstratiWed hazard ratios (HRs). Grade 3-5 adverse events were also assessed. Results Bevacizumab statistically signiWcantly improved PFS [HR 0.58; 95% confidence interval (CI) 0.49-0.68] and OS (HR 0.85; 95% CI 0.74-0.97) in patients aged ≥65 years; patients aged ≥70 years had similar improvements. BeneWts were consistent across the studies, irrespective of setting, bevacizumab dose, or chemotherapy regimen. Increases in thromboembolic events were observed in patients aged ≥65 and ≥70 years in the bevacizumab group compared with the control group, mainly as a result of increases in arterial thromboembolic events. No other substantial age-related increases in grade 3-5 adverse events were observed. Conclusions In medically Wt older patients, bevacizumab provides similar PFS and OS beneWts as in younger patients.

Authors
Cassidy, J; Saltz, LB; Giantonio, BJ; Kabbinavar, FF; Hurwitz, HI; Rohr, U-P
MLA Citation
Cassidy, J, Saltz, LB, Giantonio, BJ, Kabbinavar, FF, Hurwitz, HI, and Rohr, U-P. "Effect of bevacizumab in older patients with metastatic colorectal cancer: Pooled analysis of four randomized studies." Journal of Cancer Research and Clinical Oncology 136.5 (2010): 737-743.
PMID
19904559
Source
scival
Published In
Journal of Cancer Research and Clinical Oncology
Volume
136
Issue
5
Publish Date
2010
Start Page
737
End Page
743
DOI
10.1007/s00432-009-0712-3

Voreloxin, a first-in-class anticancer quinolone derivative, in relapsed/refractory solid tumors: A report on two dosing schedules

Purpose: Voreloxin, a novel replication-dependent DNA-damaging agent, intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks and apoptosis. We report the phase 1 experience of voreloxin in patients with relapsed/refractory solid tumors, including dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, and clinical activity. Experimental Design: Two dose-escalation studies evaluated voreloxin administered i.v. every 3 weeks (SPO-0001) or weekly for 3 weeks every 28 days (SPO-0002). In SPO-0001, patients were classified as heavily pretreated (HP) or minimally pretreated (MP) based on therapeutic history. Results: In the SPO-0001 study, 41 patients (24 HP/17 MP) were treated in eight dose cohorts (3-75 mg/m2). At 60 mg/m2, four HP patients experienced DLTs: grade 4 neutropenia (n = 3, one with fever) and grade 3 febrile neutropenia/pneumonia (n = 1). At 75 mg/m2, two MP patients experienced DLTs: grade 4 neutropenia/thrombocytopenia (n = 1) or grade 2 oral thrush for >29 days (n = 1). Therefore, the MTD was 48 mg/m2 (HP patients) and 60 mg/m2 (MP patients). In the SPO-0002 study, 21 patients were treated in six dose cohorts (3-24 mg/m2). At 18 mg/m2, two patients experienced DLTs: grade 3 neutropenia, one with pleural effusion (>14 days each). The MTD was 15 mg/m2. Voreloxin exhibited low clearance (2 L/h/m2), a long terminal half-life (22 hours), and dose-proportional exposure. Overall, 31 of 62 patients had stable disease and 1 patient (ovarian cancer) had a partial response per Rustin criteria. Conclusions: Voreloxin showed an acceptable safety profile with clinical activity in patients with relapsed/refractory solid tumors. The MTD was schedule-dependent. Voreloxin is currently in clinical studies of ovarian cancer and acute myeloid leukemia. ©2010 AACR.

Authors
Advani, RH; Hurwitz, HI; Gordon, MS; Ebbinghaus, SW; Mendelson, DS; Wakelee, HA; Hoch, U; Silverman, JA; Havrilla, NA; Berman, CJ; Fox, JA; Allen, RS; Adelman, DC
MLA Citation
Advani, RH, Hurwitz, HI, Gordon, MS, Ebbinghaus, SW, Mendelson, DS, Wakelee, HA, Hoch, U, Silverman, JA, Havrilla, NA, Berman, CJ, Fox, JA, Allen, RS, and Adelman, DC. "Voreloxin, a first-in-class anticancer quinolone derivative, in relapsed/refractory solid tumors: A report on two dosing schedules." Clinical Cancer Research 16.7 (2010): 2167-2175.
PMID
20233886
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
16
Issue
7
Publish Date
2010
Start Page
2167
End Page
2175
DOI
10.1158/1078-0432.CCR-09-2236

Phase I dose escalation study of gemcitabine plus irinotecan in advanced solid tumors.

AIM: To determine the maximally tolerated dose (MTD), recommended phase II dose (RPTD) and toxicity profile of gemcitabine plus irinotecan combination. PATIENTS AND METHODS: Thirty-nine evaluable patients with advanced solid tumors were treated with gemcitabine (Gem) and irinotecan (Iri) on days 1, 8 and 15 of a 28-day cycle. Dose levels included Gem/Iri 700/50, 900/50, 900/75, 500/50 mg/m(2) respectively. Dose-limiting toxicity (DLT) was assessed during cycle one; toxicity evaluation was closely monitored throughout the course of treatment. Treatment continued until disease progression or unacceptable toxicity. RESULTS: DLTs primarily consisted of grade > or = 3 thrombocytopenia lasting > or = 4 days often accompanied by grade > or = 3 neutropenia. Other grade > or = 3 toxicities included vomiting, diarrhea, fatigue and elevated alkaline phosphatase. Three patients had a partial response. Stable disease as best response was seen in 16 patients, ranging from 2-18 months. CONCLUSION: The MTD/RPTD is gemcitabine 500 mg/m(2) plus irinotecan 50 mg/m(2) on days 1, 8 and 15 of a 28-day cycle. Given the toxicity profile and negative results of phase III studies, no further testing of this treatment combination is recommended.

Authors
Dugan, E; Truax, R; Meadows, KL; Blobe, GC; Morse, MA; Fernando, NH; Gockerman, JP; Petros, WP; Hurwitz, HI
MLA Citation
Dugan, E, Truax, R, Meadows, KL, Blobe, GC, Morse, MA, Fernando, NH, Gockerman, JP, Petros, WP, and Hurwitz, HI. "Phase I dose escalation study of gemcitabine plus irinotecan in advanced solid tumors." Anticancer Res 29.12 (December 2009): 5149-5153.
PMID
20044630
Source
pubmed
Published In
Anticancer research
Volume
29
Issue
12
Publish Date
2009
Start Page
5149
End Page
5153

Partner-assisted emotional disclosure for patients with gastrointestinal cancer: results from a randomized controlled trial.

BACKGROUND: For patients with cancer who are married or in an intimate relationship, their relationships with their partners play a critical role in their adaptation to illness. However, cancer patients and their partners often have difficulty in talking with each other about their cancer-related concerns. Difficulties in communication ultimately may compromise both the patient-partner relationship and the patient's psychological adjustment. The current study tested the efficacy of a novel partner-assisted emotional disclosure intervention in a sample of patients with gastrointestinal (GI) cancer. METHODS: One hundred thirty patients with GI cancer and their partners were assigned randomly to receive 4 sessions of either partner-assisted emotional disclosure or a couples cancer education/support intervention. Patients and partners completed measures of relationship quality, intimacy with their partner, and psychological distress before randomization and at the end of the intervention sessions. Data were analyzed using multilevel modeling. RESULTS: Compared with an education/support condition, the partner-assisted emotional disclosure condition led to improvements in relationship quality and intimacy for couples in which the patient initially reported higher levels of holding back from discussing cancer-related concerns. CONCLUSIONS: Partner-assisted emotional disclosure is a novel intervention that builds on both the private emotional disclosure and the cognitive-behavioral marital literature. The results of this study suggested that this intervention may be beneficial for couples in which the patient tends to hold back from discussing concerns. The authors concluded that future research on methods of enhancing the effects of partner-assisted emotional disclosure is warranted.

Authors
Porter, LS; Keefe, FJ; Baucom, DH; Hurwitz, H; Moser, B; Patterson, E; Kim, HJ
MLA Citation
Porter, LS, Keefe, FJ, Baucom, DH, Hurwitz, H, Moser, B, Patterson, E, and Kim, HJ. "Partner-assisted emotional disclosure for patients with gastrointestinal cancer: results from a randomized controlled trial." Cancer 115.18 Suppl (September 15, 2009): 4326-4338.
PMID
19731357
Source
pubmed
Published In
Cancer
Volume
115
Issue
18 Suppl
Publish Date
2009
Start Page
4326
End Page
4338
DOI
10.1002/cncr.24578

Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression.

Drugs and antibodies that interrupt vascular endothelial growth factor (VEGF) signaling pathways improve outcomes in patients with a variety of cancers by inhibiting tumor angiogenesis. A major adverse effect of these treatments is hypertension, suggesting a critical role for VEGF in blood pressure (BP) regulation. However, the physiological mechanisms underlying the control of BP by VEGF are unclear. To address this question, we administered a specific antibody against the major VEGF receptor, VEGFR2, to normal mice and assessed the consequences on BP. Compared with vehicle-treated controls, administration of the anti-VEGFR2 antibody caused a rapid and sustained increase in BP of approximately 10 mm Hg. This increase in BP was associated with a significant reduction in renin mRNA expression in the kidney (P=0.019) and in urinary excretion of aldosterone (P<0.05). Treatment with the anti-VEGFR2 antibody also caused a marked reduction in the expression of endothelial and neuronal NO synthases in the kidney. To examine the role of NO in the hypertension caused by blocking VEGFR2, mice were treated with N(omega)-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg per day), an inhibitor of NO production. L-NAME administration abolished the difference in BP between the vehicle- and anti-VEGFR2-treated groups. Our data suggest that VEGF, acting via VEGFR2, plays a critical role in BP control by promoting NO synthase expression and NO activity. Interfering with this pathway is likely to be one mechanism underlying hypertension caused by antiangiogenic agents targeting VEGF.

Authors
Facemire, CS; Nixon, AB; Griffiths, R; Hurwitz, H; Coffman, TM
MLA Citation
Facemire, CS, Nixon, AB, Griffiths, R, Hurwitz, H, and Coffman, TM. "Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression." Hypertension 54.3 (September 2009): 652-658.
PMID
19652084
Source
pubmed
Published In
Hypertension
Volume
54
Issue
3
Publish Date
2009
Start Page
652
End Page
658
DOI
10.1161/HYPERTENSIONAHA.109.129973

Phase I trial of pazopanib in patients with advanced cancer.

PURPOSE: The safety, pharmacokinetics, and clinical activity of pazopanib (GW786034), an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, were evaluated in patients with advanced-stage refractory solid tumors. EXPERIMENTAL DESIGN: Patients were enrolled into sequential dose-escalating cohorts (50 mg three times weekly to 2,000 mg once daily and 300-400 mg twice daily). Escalation or deescalation was based on toxicities observed in the preceding dose cohort. Pharmacokinetic and biomarker samples were obtained. Clinical response was assessed every 9 weeks. RESULTS: Sixty-three patients were treated (dose escalation, n = 43; dose expansion, n = 20). Hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mg once daily. A plateau in steady-state exposure was observed at doses of >or=800 mg once daily. The mean elimination half-life at this dose was 31.1 hours. A mean target trough concentration (C(24)) >or=15 microg/mL (34 micromol/L) was achieved at 800 mg once daily. Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of >or=6 months was observed in 14 patients; clinical benefit was generally observed in patients who received doses of >or=800 mg once daily or 300 mg twice daily. CONCLUSION: Pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.

Authors
Hurwitz, HI; Dowlati, A; Saini, S; Savage, S; Suttle, AB; Gibson, DM; Hodge, JP; Merkle, EM; Pandite, L
MLA Citation
Hurwitz, HI, Dowlati, A, Saini, S, Savage, S, Suttle, AB, Gibson, DM, Hodge, JP, Merkle, EM, and Pandite, L. "Phase I trial of pazopanib in patients with advanced cancer." Clin Cancer Res 15.12 (June 15, 2009): 4220-4227.
PMID
19509175
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
12
Publish Date
2009
Start Page
4220
End Page
4227
DOI
10.1158/1078-0432.CCR-08-2740

Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma.

PURPOSE: Extrahepatic cholangiocarcinoma is a rare malignancy. Despite radical resection, survival remains poor, with high rates of local and distant failure. To clarify the role of radiotherapy with chemotherapy, we performed a retrospective analysis of resected patients who had undergone chemoradiotherapy. METHODS AND MATERIALS: A total of 45 patients (13 with proximal and 32 with distal disease) underwent resection plus radiotherapy (median dose, 50.4 Gy). All but 1 patient received concurrent fluoropyrimidine-based chemotherapy. The median follow-up was 30 months for all patients and 40 months for survivors. RESULTS: Of the 45 patients, 33 underwent adjuvant radiotherapy, and 12 were treated neoadjuvantly. The 5-year actuarial overall survival, disease-free survival, metastasis-free survival, and locoregional control rates were 33%, 37%, 42%, and 78%, respectively. The median survival was 34 months. No patient died perioperatively. Patient age

Authors
Nelson, JW; Ghafoori, AP; Willett, CG; Tyler, DS; Pappas, TN; Clary, BM; Hurwitz, HI; Bendell, JC; Morse, MA; Clough, RW; Czito, BG
MLA Citation
Nelson, JW, Ghafoori, AP, Willett, CG, Tyler, DS, Pappas, TN, Clary, BM, Hurwitz, HI, Bendell, JC, Morse, MA, Clough, RW, and Czito, BG. "Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma." Int J Radiat Oncol Biol Phys 73.1 (January 1, 2009): 148-153.
PMID
18805651
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
73
Issue
1
Publish Date
2009
Start Page
148
End Page
153
DOI
10.1016/j.ijrobp.2008.07.008

Multiagent chemotherapy for isolated colorectal liver metastases: a single-centered retrospective study.

Few studies identifying variables associated with prognosis after resection of colorectal liver metastases (CLM) account for treatment with multiagent chemotherapy (fluoropyrmidines with irinotecan, oxaliplatin, bevacizumab, and/or cetuximab). The objective of this retrospective study was to determine the effect of multiagent chemotherapy on long-term survival after resection of CLM.Demographics, clinicopathologic tumor characteristics, treatments, and long-term outcomes were reviewed.From 1996 to 2006, 230 patients underwent resection of CLM. Treatment strategies before and after resection included fluoropyrimidine monotherapy (n = 34 and n = 39), multiagent chemotherapy (n = 81 and n = 73), and observation (n = 115 and n = 118). Prehepatectomy treatment strategy was not associated with overall survival. Actuarial 4-year survival was 63%, 39%, and 40% for patients treated with multiagent chemotherapy, fluoropyrimidine monotherapy, and observation after hepatectomy, p = 0.06. Posthepatectomy multiagent chemotherapy (p = 0.04, HR 0.52 [0.27-1.03]), duration of posthepatectomy chemotherapy treatment of 2 months or longer (p = 0.05, HR 0.49 [0.25-0.99]), carcino-embryonic antigen level >10 ng/mL (p = 0.03, HR 2.09, 95% CI [1.32-3.32]), and node positive primary tumor (p = 0.002, HR 1.79 [1.06-3.02]) were associated with overall survival in multivariate analysis.The association of posthepatectomy multiagent chemotherapy with overall survival in this retrospective study indicates the need for prospective randomized trials comparing multiagent chemotherapy and fluoropyrimidine monotherapy for CLM.

Authors
Reddy, SK; Broadwater, G; Niedzwiecki, D; Barbas, AS; Hurwitz, HI; Bendell, JC; Morse, MA; Clary, BM
MLA Citation
Reddy, SK, Broadwater, G, Niedzwiecki, D, Barbas, AS, Hurwitz, HI, Bendell, JC, Morse, MA, and Clary, BM. "Multiagent chemotherapy for isolated colorectal liver metastases: a single-centered retrospective study." Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 13.1 (January 2009): 74-84.
PMID
18685900
Source
epmc
Published In
Journal of Gastrointestinal Surgery
Volume
13
Issue
1
Publish Date
2009
Start Page
74
End Page
84
DOI
10.1007/s11605-008-0617-5

The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer.

PURPOSE: Mutations of the K-ras gene were identified as a prognostic marker in metastatic colorectal cancer (mCRC). In addition, emerging data suggest that K-ras mutations are a negative predictor of clinical benefit from anti-epidermal growth factor receptor treatment in mCRC. Previously reported data suggest that the longer overall survival (OS) observed with bevacizumab treatment in mCRC is independent of alterations in the Ras/Raf/Mek/Erk pathway. We conducted additional analyses to better describe the clinical benefit of bevacizumab treatment in mCRC relative to K-ras mutation status. PATIENTS AND METHODS: Additional statistical analyses were done with data from K-ras mutation analyses in 230 patients who were treated with irinotecan, fluorouracil, and leucovorin (IFL) in combination with either bevacizumab or placebo in a randomized phase III study. Following microdissection, tissue was subject to DNA sequencing to identify K-ras mutations in codons 12 and 13. Hazard ratios for the bevacizumab group relative to the control group were estimated from an unstratified Cox regression model. The median progression-free survival (PFS), OS times, and objective response rates were compared. RESULTS: K-ras status was assessed in 230 patients (28.3%). The median PFS was significantly longer in bevacizumab-treated patients with wild-type (wt)- (13.5 versus 7.4 months; hazard ratio 0.44, p < .0001) and mutant (m)-K-ras (9.3 versus 5.5 months; hazard ratio 0.41, p = .0008). A significantly higher response rate for IFL plus bevacizumab was observed only in wt-K-ras patients (60.0% versus 37.3%, p = .006) compared with 43.2% versus 41.2% in the m-K-ras group. CONCLUSION: Bevacizumab provides significant clinical benefit in patients with mCRC expressing either mutant or wild-type K-ras.

Authors
Hurwitz, HI; Yi, J; Ince, W; Novotny, WF; Rosen, O
MLA Citation
Hurwitz, HI, Yi, J, Ince, W, Novotny, WF, and Rosen, O. "The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer." Oncologist 14.1 (January 2009): 22-28.
PMID
19144677
Source
pubmed
Published In
The oncologist
Volume
14
Issue
1
Publish Date
2009
Start Page
22
End Page
28
DOI
10.1634/theoncologist.2008-0213

Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: Pooled analysis of cohorts of older patients from two randomized clinical trials

Purpose: Colorectal cancer (CRC) occurs predominantly in older persons. To provide more statistical power to assess risk/benefit in older patients, we examined the clinical benefit of bevacizumab (BV) plus fluorouracil-based chemotherapy in first-line metastatic CRC (mCRC) treatment in patients aged ≥ 65 years, using data pooled from two placebo-controlled studies. Patients and Methods: Pooled efficacy data for 439 patients ≥ 65 years old randomized to BV plus chemotherapy (n = 218) or placebo plus chemotherapy (n = 221) in study 1 and study 2 were retrospectively analyzed on an intent-to-treat basis for overall survival (OS), progression-free survival (PFS), and objective response. Safety analysis was based on reports of targeted adverse events in treated patients. Results: Median OS with BV plus chemotherapy was 19.3 v 14.3 months with placebo plus chemotherapy (hazard ratio [HR] = 0.70; 95% CI, 0.55 to 0.90; P = .006). Patients treated with BV plus chemotherapy had a median PFS of 9.2 v 6.2 months for placebo plus chemotherapy patients (HR = 0.52; 95% CI, 0.40 to 0.67; P = .0001). The objective response rate was 34.4% with BV plus chemotherapy versus 29.0% with placebo plus chemotherapy (difference not statistically significant). Rates of BV-associated adverse events in the pooled BV plus chemotherapy group were consistent with those reported in the overall populations for the two studies. Conclusion: Analysis of pooled patient cohorts age ≥ 65 years from two similar trials in mCRC indicates that adding bevacizumab to fluorouracil-based chemotherapy improved OS and PFS, similar to the benefits in younger patients. Also, the risks of treatment do not seem to exceed those in younger patients with mCRC. © 2008 by American Society of Clinical Oncology.

Authors
Kabbinavar, FF; Hurwitz, HI; Yi, J; Sarkar, S; Rosen, O
MLA Citation
Kabbinavar, FF, Hurwitz, HI, Yi, J, Sarkar, S, and Rosen, O. "Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: Pooled analysis of cohorts of older patients from two randomized clinical trials." Journal of Clinical Oncology 27.2 (2009): 199-205.
PMID
19064978
Source
scival
Published In
Journal of Clinical Oncology
Volume
27
Issue
2
Publish Date
2009
Start Page
199
End Page
205
DOI
10.1200/JCO.2008.17.7931

An intervention to improve cancer patients' understanding of early-phase clinical trials

Authors
Kass, NE; Sugarman, J; Medley, AM; Fogarty, LA; Taylor, HA; Daugherty, CK; Emerson, MR; Goodman, SN; Hlubocky, FJ; Hurwitz, HI; Carducci, M; Goodwin-Landher, A
MLA Citation
Kass, NE, Sugarman, J, Medley, AM, Fogarty, LA, Taylor, HA, Daugherty, CK, Emerson, MR, Goodman, SN, Hlubocky, FJ, Hurwitz, HI, Carducci, M, and Goodwin-Landher, A. "An intervention to improve cancer patients' understanding of early-phase clinical trials." IRB Ethics and Human Research 31.3 (2009): 1-8.
PMID
19552233
Source
scival
Published In
IRB
Volume
31
Issue
3
Publish Date
2009
Start Page
1
End Page
8

A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer.

PURPOSE: The primary aims of this phase I-II study were to determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary efficacy of the combination of docetaxel and the endothelin A receptor antagonist atrasentan as first-line treatment for men with metastatic castration-resistant prostate cancer. EXPERIMENTAL DESIGN: Patients were treated with docetaxel at doses ranging from 60 to 75 mg/m(2) every 21 days, with daily oral atrasentan 10 mg starting on day 3. Patients were treated until evidence of disease progression or unacceptable toxicity. RESULTS: Thirty-one patients were enrolled over three docetaxel dose levels (8 at 60 mg/m(2), 19 at 70 mg/m(2), and 4 at 75 mg/m(2)) including dose expansion at 70 mg/m(2). The maximum tolerated dose of docetaxel was 70 to 75 mg/m(2). Drug-related grade 3-4 toxicities included neutropenia (50-63%) and febrile neutropenia (16-25%); other grade 1-2 toxicities included fatigue, peripheral edema, diarrhea, headache, rhinitis, anorexia, and nausea. Confirmed prostate-specific antigen (PSA) responses were observed in 23% [95% confidence interval (95% CI), 10-41%]; the rate of >30% declines in PSA was 35% (95% CI, 19-55%). Median overall survival was 17.6 months (95% CI, 13.0-23.2) and median progression-free survival was 4.2 months (95% CI, 2.3-5.8). Significant declines in bone alkaline phosphatase and serum N-telopeptides were observed with therapy. CONCLUSIONS: The maximum tolerated dose of every-3-week docetaxel with 10 mg atrasentan is 70 to 75 mg/m(2). Overall survival and progression-free survival are comparable to that seen with docetaxel and prednisone, whereas the rates of PSA decline are slightly lower than expected. A phase III study of this combination with prednisone has been initiated and is ongoing.

Authors
Armstrong, AJ; Creel, P; Turnbull, J; Moore, C; Jaffe, TA; Haley, S; Petros, W; Yenser, S; Gockerman, JP; Sleep, D; Hurwitz, H; George, DJ
MLA Citation
Armstrong, AJ, Creel, P, Turnbull, J, Moore, C, Jaffe, TA, Haley, S, Petros, W, Yenser, S, Gockerman, JP, Sleep, D, Hurwitz, H, and George, DJ. "A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer." Clin Cancer Res 14.19 (October 1, 2008): 6270-6276.
PMID
18829508
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
19
Publish Date
2008
Start Page
6270
End Page
6276
DOI
10.1158/1078-0432.CCR-08-1085

The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients.

Impairment of dendritic cells (DC), the most effective activators of anticancer immune responses, is one mechanism for defective antitumor immunity, but the causes of DC impairment are incompletely understood. We evaluated the association of impaired DC differentiation with angiogenesis-associated molecules D-dimer, vascular endothelial growth factor (VEGF), urokinase plasminogen activator (uPA), and plasminogen activator inhibitor (PAI-1) in peripheral blood from 41 patients with lung, breast, and colorectal carcinoma. Subsequently, we studied the effect of administration of the anti-VEGF antibody (bevacizumab) on DC maturation and function in vivo. Compared with healthy volunteers, cancer patients had a bias toward the immunoregulatory DC2, had deficits in DC maturation after overnight in vitro culture, and had a significant increase in immature myeloid cell progenitors of DC (0.50 +/- 0.31% vs. 0.32 +/- 0.16% of peripheral blood mononuclear cells, respectively, P = 0.011). A positive correlation was found between the percentage of DC2 and PAI-1 (R = 0.50) and between immature myeloid cells and VEGF (R = 0.52). Bevacizumab administration to cancer patients was associated with a decrease in the accumulation of immature progenitor cells (0.39 +/- 0.30% vs. 0.27 +/- 0.24%, P = 0.012) and induced a modest increase in the DC population in peripheral blood (0.47 +/- 0.23% vs. 0.53 +/- 0.30%). Moreover, anti-VEGF antibody treatment enhanced allo-stimulatory capacity of DC and T cell proliferation against recall antigens. These data suggest that DC differentiation is negatively associated with VEGF levels and may be one explanation for impaired anticancer immunity, especially in patients with advanced malignancies.

Authors
Osada, T; Chong, G; Tansik, R; Hong, T; Spector, N; Kumar, R; Hurwitz, HI; Dev, I; Nixon, AB; Lyerly, HK; Clay, T; Morse, MA
MLA Citation
Osada, T, Chong, G, Tansik, R, Hong, T, Spector, N, Kumar, R, Hurwitz, HI, Dev, I, Nixon, AB, Lyerly, HK, Clay, T, and Morse, MA. "The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients." Cancer Immunol Immunother 57.8 (August 2008): 1115-1124.
PMID
18193223
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
57
Issue
8
Publish Date
2008
Start Page
1115
End Page
1124
DOI
10.1007/s00262-007-0441-x

A phase I study of UFT/leucovorin, carboplatin, and paclitaxel in combination with external beam radiation therapy for advanced esophageal carcinoma.

PURPOSE: Concurrent chemotherapy and radiation therapy (RT) are used to treat patients with esophageal cancer. The optimal combination of chemotherapeutic agents with RT is not well established. We evaluated the safety and preliminary efficacy of a combination of UFT/leucovorin, carboplatin, and paclitaxel with RT in a Phase I study of patients with advanced esophageal cancer. METHODS AND MATERIALS: Patients with squamous cell carcinoma or adenocarcinoma of the esophagus initially received UFT/leucovorin, carboplatin, and paclitaxel with RT (1.8 Gy daily to 45 Gy). After completion, the disease was restaged and patients were evaluated for surgery. Primary end points included determination of dose-limiting toxicities (DLTs) and a recommended Phase II dose. Secondary objectives included determination of non-DLTs, as well as preliminary radiographic and pathologic response rates. RESULTS: Twelve patients were enrolled (11 men, 1 woman). All were assessable for toxicity and efficacy. One of 6 patients at Dose Level 1 (UFT/leucovorin, 200/30 mg twice daily on RT days; carboplatin, area under the curve [AUC] 5, Weeks 1 and 4; paclitaxel, 175 mg/m2 Weeks 1 and 4) had a DLT (febrile neutropenia). Of these 6 patients, 4 underwent esophagectomy and none achieved a pathologic complete response. Six patients were then enrolled at Dose Level 2 (UFT/leucovorin, 300/30 mg in the morning and 200/30 mg in the evening on RT days; carboplatin, AUC 5, Weeks 1 and 4; paclitaxel, 175 mg/m2 Weeks 1 and 4). Two of 6 patients at Dose Level 2 developed DLTs (febrile neutropenia in both). Esophagectomy was performed in 3 patients, with 2 achieving a pathologic complete response. CONCLUSIONS: Maximum tolerated doses in this study were UFT/leucovorin, 200/30 mg twice daily on RT days; carboplatin, AUC 5, Weeks 1 and 4; and paclitaxel, 175 mg/m2 Weeks 1 and 4 when delivered with external RT. In this small study, this regimen appears active, but toxic.

Authors
Czito, BG; Cohen, DP; Kelsey, CR; Lockhart, AC; Bendell, JC; Willett, CG; Petros, WP; D'Amico, TA; Truax, R; Hurwitz, HI
MLA Citation
Czito, BG, Cohen, DP, Kelsey, CR, Lockhart, AC, Bendell, JC, Willett, CG, Petros, WP, D'Amico, TA, Truax, R, and Hurwitz, HI. "A phase I study of UFT/leucovorin, carboplatin, and paclitaxel in combination with external beam radiation therapy for advanced esophageal carcinoma." Int J Radiat Oncol Biol Phys 70.4 (March 15, 2008): 1066-1072.
PMID
17881149
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
70
Issue
4
Publish Date
2008
Start Page
1066
End Page
1072
DOI
10.1016/j.ijrobp.2007.07.2347

Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases.

BACKGROUND: Although commonly used in combination with irinotecan or oxaliplatin (iri/oxal) for treatment of colorectal liver metastases before extirpation, the effects of preoperative bevacizumab on surgical outcomes are not established. The objective of this retrospective study was to determine if addition of bevacizumab to iri/oxal preoperative chemotherapy increases morbidity after hepatic resection. STUDY DESIGN: We compared demographics, clinicopathologic data, treatments, and postoperative outcomes between patients given preoperative iri/oxal with and without bevacizumab and patients who underwent hepatic resection within and after 8 weeks from the last dose of bevacizumab. RESULTS: From 1996 to 2006, 96 patients were treated with preoperative iri/oxal; 39 (40.6%) received concurrent bevacizumab. Preoperative bevacizumab treatment was associated with less blood loss (median 425 mL versus 600 mL, p=0.01) and lower RBC transfusion rates (43.9% versus 23.1%, p=0.06) after partial hepatectomy on univariable analysis. Only age>or=70 years (hazard ratio=8.52, 95% CI [2.00 to 36.45]) and concurrent extrahepatic procedures (hazard ratio=4.12, 95% CI [1.49 to 11.39]) independently predicted RBC transfusion and overall complications, respectively. There were no differences in overall (43.6% versus 38.6%), severe (28.2% versus 24.6%), hepatic (17.9% versus 26.3%), wound (10.3% versus 7%), or thromboembolic or bleeding (2.6% versus 5.3%) complications (all p > 0.05). For patients treated with iri/oxal and bevacizumab, overall complications were more common when resection was performed within 8 weeks after the last bevacizumab dose (62.5% versus 30.4%), but this difference was not statistically significant (p=0.06). CONCLUSIONS: If discontinued at least 8 weeks before hepatic resection, addition of bevacizumab to preoperative iri/oxal does not increase morbidity after hepatic resection.

Authors
Reddy, SK; Morse, MA; Hurwitz, HI; Bendell, JC; Gan, TJ; Hill, SE; Clary, BM
MLA Citation
Reddy, SK, Morse, MA, Hurwitz, HI, Bendell, JC, Gan, TJ, Hill, SE, and Clary, BM. "Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases." J Am Coll Surg 206.1 (January 2008): 96-106.
PMID
18155574
Source
pubmed
Published In
Journal of the American College of Surgeons
Volume
206
Issue
1
Publish Date
2008
Start Page
96
End Page
106
DOI
10.1016/j.jamcollsurg.2007.06.290

Bevacizumab improves the overall and progression-free survival of patients with metastatic colorectal cancer treated with 5-fluorouracil-based regimens irrespective of baseline risk

Background: Köhne et al. [Ann Oncol 2002;13:308-317] showed that four prognostic variables can be used to classify patients with metastatic colorectal cancer (CRC) treated with 5-fluorouracil (5-FU)/leucovorin (LV) into three risk groups with different overall survival (OS). This model was applied to data from phase II/III trials of first-line bevacizumab plus 5-FU/LV with/without irinotecan (IFL). Methods: Data on tumor sites, Eastern Cooperative Oncology Group performance status, alkaline phosphatase levels and white blood cell counts were used to classify patients into Köhne prognostic high-, intermediate- and low-risk groups. Median OS and progression-free survival (PFS) were calculated for patients receiving 5-FU/LV plus bevacizumab or placebo (n = 489) and IFL plus bevacizumab or placebo (n = 812). Results: Median OS was longer in 5-FU/LV/bevacizumab (11.2-22.6 months) than in the 5-FU/LV/placebo (5.7-17.5 months), and in the IFL/bevacizumab arm (14.3-22.5 months) than in the IFL/placebo arm (8.4-17.9 months) across the Köhne high-, intermediate- and low-risk groups. The addition of bevacizumab also extended median PFS across the Köhne risk groups compared with placebo. Conclusions: Bevacizumab improves OS and PFS across the Köhne risk classification in patients with metastatic CRC. The Köhne model can be extended to patients treated with 5-FU/LV/bevacizumab, IFL and IFL/bevacizumab and to PFS data. Copyright © 2008 S. Karger AG.

Authors
Kabbinavar, F; Irl, C; Zurlo, A; Hurwitz, H
MLA Citation
Kabbinavar, F, Irl, C, Zurlo, A, and Hurwitz, H. "Bevacizumab improves the overall and progression-free survival of patients with metastatic colorectal cancer treated with 5-fluorouracil-based regimens irrespective of baseline risk." Oncology 75.3-4 (2008): 215-223.
PMID
18852492
Source
scival
Published In
Oncology
Volume
75
Issue
3-4
Publish Date
2008
Start Page
215
End Page
223
DOI
10.1159/000163850

Health-related quality of life impact of bevacizumab when combined with irinotecan, 5-fluorouracil, and leucovorin or 5-fluorouracil and leucovorin for metastatic colorectal cancer

Purpose. To compare the time to deterioration in health-related quality of life (HRQoL) in patients with previously untreated metastatic colorectal cancer receiving a 5-fluorouracil (5-FU)-based chemotherapy regimen with or without the addition of bevacizumab (BV) in two randomized, placebo-controlled studies. Patients and Methods. Prespecified HRQoL endpoints in the phase II (Study 2192) and phase III (Study 2107) studies were time to deterioration in HRQoL, measured by the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) Colorectal Cancer Subscale (CCS), Trial Outcome Index (TOI-C), and FACT-C total score. Time to deterioration in HRQoL was evaluated for patients with baseline and postbaseline assessments, using the stratified log-rank test. Results. In the pivotal phase III trial, HRQoL baseline and postbaseline CCS scores were available for 127 patients receiving irinotecan, 5-FU, and leucovorin (LV) (IFL) and 122 patients receiving IFL plus BV. The time to deterioration in HRQoL did not differ significantly between treatment groups as measured by the CCS, TOI-C, or FACT-C total score. In the phase II study, baseline and postbaseline CCS scores were available for 77 and 89 patients receiving 5-FU and LV and 5-FU and LV plus BV, respectively. In that study, the time to deterioration in HRQoL was similar between groups as measured by the CCS and TOI-C scores, but was significantly longer in the 5-FU and LV plus BV arm than in the 5-FU and LV plus placebo arm for the FACT-C total score. Conclusions. When added to 5-FU chemotherapy, BV significantly prolonged overall survival and progression-free survival without compromising HRQoL. ©AlphaMed Press.

Authors
Kabbinavar, FF; Wallace, JF; Holmgren, E; Yi, J; Cella, D; Yost, KJ; Hurwitz, HI
MLA Citation
Kabbinavar, FF, Wallace, JF, Holmgren, E, Yi, J, Cella, D, Yost, KJ, and Hurwitz, HI. "Health-related quality of life impact of bevacizumab when combined with irinotecan, 5-fluorouracil, and leucovorin or 5-fluorouracil and leucovorin for metastatic colorectal cancer." Oncologist 13.9 (2008): 1021-1029.
PMID
18776057
Source
scival
Published In
The oncologist
Volume
13
Issue
9
Publish Date
2008
Start Page
1021
End Page
1029
DOI
10.1634/theoncologist.2008-0003

Arterial thromboembolic events and patients with metastatic carcinoma treated with chemotherapy and bevacizumab (Journal of the National Cancer Institute (2007) 99 (1232-1239))

Authors
Scappaticci, FA; Skillings, JR; Holden, SN; Gerber, H-P; Miller, K; Kabbinavar, F; Bergsland, E; Ngai, J; Holmgren, E; Wang, J; Hurwitz, H
MLA Citation
Scappaticci, FA, Skillings, JR, Holden, SN, Gerber, H-P, Miller, K, Kabbinavar, F, Bergsland, E, Ngai, J, Holmgren, E, Wang, J, and Hurwitz, H. "Arterial thromboembolic events and patients with metastatic carcinoma treated with chemotherapy and bevacizumab (Journal of the National Cancer Institute (2007) 99 (1232-1239))." Journal of the National Cancer Institute 100.9 (2008): 685--.
Source
scival
Published In
Journal of the National Cancer Institute
Volume
100
Issue
9
Publish Date
2008
Start Page
685-
DOI
10.1093/jnci/djn126

Response-independent survival benefit in metastatic colorectal cancer: A comparative analysis of N9741 and AVF2107

Purpose: In the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response. Patients and Methods: For these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy. Results: Compared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders. Conclusion: In both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient. © 2008 by American Society of Clinical Oncology.

Authors
Grothey, A; Hedrick, EE; Mass, RD; Sarkar, S; Suzuki, S; Ramanathan, RK; Hurwitz, HI; Goldberg, RM; Sargent, DJ
MLA Citation
Grothey, A, Hedrick, EE, Mass, RD, Sarkar, S, Suzuki, S, Ramanathan, RK, Hurwitz, HI, Goldberg, RM, and Sargent, DJ. "Response-independent survival benefit in metastatic colorectal cancer: A comparative analysis of N9741 and AVF2107." Journal of Clinical Oncology 26.2 (2008): 183-189.
PMID
18182660
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
2
Publish Date
2008
Start Page
183
End Page
189
DOI
10.1200/JCO.2007.13.8099

Duodenal adenocarcinoma: patterns of failure after resection and the role of chemoradiotherapy.

PURPOSE: To report patterns of disease recurrence after resection of adenocarcinoma of the duodenum and compare outcomes between patients undergoing surgery only vs. surgery with concurrent chemotherapy and radiation therapy (CT-RT). METHODS AND MATERIALS: This was a retrospective analysis of all patients undergoing potentially curative therapy for adenocarcinoma of the duodenum at Duke University Medical Center and affiliated hospitals between 1975 and 2005. Overall survival (OS), disease-free survival (DFS), and local control (LC) were estimated using the Kaplan-Meier method. Univariate regression analysis evaluated the effect of CT-RT on clinical endpoints. RESULTS: Thirty-two patients were identified (23 M, 9 F). Median age was 60 years (range, 32-77 years). Surgery alone was performed in 16 patients. An additional 16 patients received either preoperative (n = 11) or postoperative (n = 5) CT-RT. Median RT dose was 50.4 Gy (range, 12.6-54 Gy). All patients treated with RT also received concurrent 5-fluorouracil-based CT. Two patients treated preoperatively had a pathologic complete response (18%), and none had involved lymph nodes at resection. Five-year OS, DFS, and LC for the entire group were 48%, 47%, and 55%, respectively. Five-year survival did not differ between patients receiving CT-RT vs. surgery alone (57% vs. 44%, p = 0.42). However, in patients undergoing R0 resection, CT-RT appeared to improve OS (5-year 83% vs. 53%, p = 0.07). CONCLUSIONS: Local failure after surgery alone is high. Given the patterns of relapse with surgery alone and favorable outcomes in patients undergoing complete resection with CT-RT, the use of CT-RT in selected patients should be considered.

Authors
Kelsey, CR; Nelson, JW; Willett, CG; Chino, JP; Clough, RW; Bendell, JC; Tyler, DS; Hurwitz, HI; Morse, MA; Clary, BM; Pappas, TN; Czito, BG
MLA Citation
Kelsey, CR, Nelson, JW, Willett, CG, Chino, JP, Clough, RW, Bendell, JC, Tyler, DS, Hurwitz, HI, Morse, MA, Clary, BM, Pappas, TN, and Czito, BG. "Duodenal adenocarcinoma: patterns of failure after resection and the role of chemoradiotherapy." Int J Radiat Oncol Biol Phys 69.5 (December 1, 2007): 1436-1441.
PMID
17689032
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
69
Issue
5
Publish Date
2007
Start Page
1436
End Page
1441
DOI
10.1016/j.ijrobp.2007.05.006

Paclitaxel-based chemoradiotherapy in the treatment of patients with operable esophageal cancer.

PURPOSE: To compare a neoadjuvant regimen of cisplatin/5-fluorouracil (5-FU) and concurrent radiation therapy (RT) with paclitaxel-based regimens and RT in the management of operable esophageal (EC)/gastroesophageal junction (GEJ) cancer. METHODS AND MATERIALS: All patients receiving neoadjuvant chemotherapy (CT) and RT for EC/GEJ cancer at Duke University between January 1995 and December 2004 were included. Clinical end points were compared for patients receiving paclitaxel-based regimens (TAX) vs. alternative regimens (non-TAX). Local control (LC), disease-free survival (DFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Chi-square analysis was performed to test the effect of TAX on pathologic complete response (pCR) rates and toxicity. RESULTS: A total of 109 patients received CT-RT followed by esophagectomy (95 M; 14 F). Median RT dose was 45 Gy (range, 36-66 Gy). The TAX and non-TAX groups comprised 47% and 53% of patients, respectively. Most (83%) TAX patients received three drug regimens including platinum and a fluoropyrimidine. In the non-TAX group, 89% of the patients received cisplatin and 5-FU. The remainder received 5-FU or capecitabine alone. Grade 3-4 toxicity occurred in 41% of patients receiving TAX vs. 24% of those receiving non-TAX (p = 0.19). Overall pCR rate was 39% (39% with TAX vs. 40% with non-TAX, p = 0.9). Overall LC, DFS, and OS at 3 years were 80%, 34%, and 37%, respectively. At 3 years, there were no differences in LC (75% vs. 85%, p = 0.33) or OS (37% vs. 37%, p = 0.32) between TAX and non-TAX groups. CONCLUSIONS: In this large experience, paclitaxel-containing regimens did not improve pCR rates or clinical end points compared to non-paclitaxel-containing regimens.

Authors
Kelsey, CR; Chino, JP; Willett, CG; Clough, RW; Hurwitz, HI; Morse, MA; Bendell, JC; D'Amico, TA; Czito, BG
MLA Citation
Kelsey, CR, Chino, JP, Willett, CG, Clough, RW, Hurwitz, HI, Morse, MA, Bendell, JC, D'Amico, TA, and Czito, BG. "Paclitaxel-based chemoradiotherapy in the treatment of patients with operable esophageal cancer." Int J Radiat Oncol Biol Phys 69.3 (November 1, 2007): 770-776.
PMID
17889266
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
69
Issue
3
Publish Date
2007
Start Page
770
End Page
776
DOI
10.1016/j.ijrobp.2007.03.035

Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: Phase I trial results.

PURPOSE: The overexpression of vascular endothelial growth factor (VEGF) is associated with poor outcomes in colorectal cancer patients. Bevacizumab, a VEGF inhibitor, enhances the effects of chemotherapy and radiation therapy on tumor cytotoxicity in preclinical models, including colorectal cancer. A Phase I trial was undertaken to evaluate the combination of bevacizumab, capecitabine, oxaliplatin, and radiation therapy in patients with rectal cancer. METHODS AND MATERIALS: Patients with pathologically confirmed adenocarcinoma of the rectum were eligible. Pretreatment staging included computerized tomography, endoscopic ultrasound, and surgical evaluation. Patients received 50.4 Gy of external beam radiation therapy (EBRT) to the tumor in 28 fractions. Capecitabine, oxaliplatin, and bevacizumab were administered concurrently with radiation therapy. After EBRT completion, patients were restaged and evaluated for surgery. Primary endpoints included the determination of dose-limiting toxicity and a recommended Phase II dose, non dose-limiting toxicity, and preliminary radiographic and pathologic response rates. RESULTS: Eleven patients were enrolled. All were evaluable for toxicity and efficacy. Dose level 2 was associated with unacceptable toxicity (primarily diarrhea). Dose level 1 had an acceptable toxicity profile. The recommended Phase II dose in our study was bevacizumab 15 mg/kg Day 1 + 10 mg/kg Days 8 and 22, oxaliplatin 50 mg/m2 weekly, and capecitabine 625 mg/m2 bid during radiation days. Six patients had clinical responses. Two patients had a pathologic complete response, and 3 had microscopic disease only. One patient experienced a postoperative abscess, one a syncopal episode during adjuvant chemotherapy, and one a subclinical myocardial infarction during adjuvant chemotherapy. CONCLUSIONS: The combination of bevacizumab, capecitabine, oxaliplatin, and radiation therapy in rectal cancer was tolerable, with encouraging response rates. Further investigation with this regimen is being pursued in a Phase II setting.

Authors
Czito, BG; Bendell, JC; Willett, CG; Morse, MA; Blobe, GC; Tyler, DS; Thomas, J; Ludwig, KA; Mantyh, CR; Ashton, J; Yu, D; Hurwitz, HI
MLA Citation
Czito, BG, Bendell, JC, Willett, CG, Morse, MA, Blobe, GC, Tyler, DS, Thomas, J, Ludwig, KA, Mantyh, CR, Ashton, J, Yu, D, and Hurwitz, HI. "Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: Phase I trial results." Int J Radiat Oncol Biol Phys 68.2 (June 1, 2007): 472-478.
PMID
17498568
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
68
Issue
2
Publish Date
2007
Start Page
472
End Page
478
DOI
10.1016/j.ijrobp.2007.02.001

Complete pathological response to bevacizumab and chemoradiation in advanced rectal cancer.

Localized rectal cancer responds well to 5-fluorouracil and radiation-based regimens. A phase I-II trial is currently testing the efficacy of adding bevacizumab, a VEGF-specific antibody, to standard chemoradiotherapy. The case presented here is a complete pathological response seen in a patient with extensive and locally invasive carcinoma after receiving this combined treatment.Physical examination, rectal ultrasound, PET-CT scan, laboratory tests, proctoscopic examination, chest radiograph, rectal forcep biopsies with immunohistochemistry, and protein and flow cytometric analyses.Large, invasive, ultrasound stage T4 carcinoma of the rectum, which was positive for survivin.One 2-week cycle of bevacizumab alone, followed by 3 cycles of bevacizumab with continuous 5-fluorouracil infusion, and external-beam radiation therapy given 5 days per week to the pelvis, abdominoperineal resection with posterior vaginectomy, hysterectomy and bilateral salpingo-oophorectomy.

Authors
Willett, CG; Duda, DG; di Tomaso, E; Boucher, Y; Czito, BG; Vujaskovic, Z; Vlahovic, G; Bendell, J; Cohen, KS; Hurwitz, HI; Bentley, R; Lauwers, GY; Poleski, M; Wong, TZ; Paulson, E; Ludwig, KA; Jain, RK
MLA Citation
Willett, CG, Duda, DG, di Tomaso, E, Boucher, Y, Czito, BG, Vujaskovic, Z, Vlahovic, G, Bendell, J, Cohen, KS, Hurwitz, HI, Bentley, R, Lauwers, GY, Poleski, M, Wong, TZ, Paulson, E, Ludwig, KA, and Jain, RK. "Complete pathological response to bevacizumab and chemoradiation in advanced rectal cancer." Nature clinical practice. Oncology 4.5 (May 2007): 316-321.
PMID
17464339
Source
epmc
Published In
Nature Clinical Practice Oncology
Volume
4
Issue
5
Publish Date
2007
Start Page
316
End Page
321
DOI
10.1038/ncponc0813

Is bevacizumab effective and safe in combination with chemotherapy in patients with colorectal cancer?

Authors
Uronis, HE; Hurwitz, HI
MLA Citation
Uronis, HE, and Hurwitz, HI. "Is bevacizumab effective and safe in combination with chemotherapy in patients with colorectal cancer?." Nat Clin Pract Oncol 4.4 (April 2007): 214-215.
PMID
17297504
Source
pubmed
Published In
Nature Clinical Practice Oncology
Volume
4
Issue
4
Publish Date
2007
Start Page
214
End Page
215
DOI
10.1038/ncponc0748

A Phase I study of capecitabine, carboplatin, and paclitaxel with external beam radiation therapy for esophageal carcinoma.

PURPOSE: Concurrent chemotherapy and radiation therapy (RT) are used to treat patients with esophageal cancer. The optimal combination of chemotherapeutic agents with RT is undefined. We evaluated a combination of capecitabine, carboplatin, and paclitaxel with RT in a phase I study. METHODS AND MATERIALS: Patients with squamous cell carcinoma or adenocarcinoma of the esophagus initially received capecitabine, carboplatin, and paclitaxel with RT (1.8 Gy daily to 50.4 Gy). After completion, patients were restaged and evaluated for surgery. Primary endpoints included determination of dose-limiting toxicities (DLT) and a recommended phase II dose, non-DLT, and preliminary radiographic and pathologic response rates. RESULTS: Thirteen patients were enrolled (10 men, 3 women). All were evaluable for toxicity and efficacy. Two of 3 patients at dose level 1 (capecitabine 825 mg/m(2) twice daily on RT days, carboplatin area under the curve (AUC) 2 weekly, paclitaxel 60 mg/m(2) weekly) had DLT (both Grade 4 esophagitis). Of these 3, 2 underwent esophagectomy and had pathologic complete response (pCR). Ten patients were then enrolled at dose level -1 (capecitabine 600 mg/m(2) twice daily, carboplatin AUC 1.5, paclitaxel 45 mg/m(2)). Overall, 3 of 10 patients at dose level -1 developed DLT (2 Grade 3 esophagitis, 1 Grade 3 hypotension). Esophagectomy was performed in 6 of 10 patients. All patients had pathologic downstaging and 2 of 6 had pCR. CONCLUSIONS: The maximally tolerated/recommended phase II doses were capecitabine 600 mg/m(2) twice daily, carboplatin AUC 1.5 weekly, and paclitaxel 45 mg/m(2) weekly with RT to 50.4 Gy. In our small study, this regimen appears active but is accompanied by significant toxicities, primarily esophagitis.

Authors
Czito, BG; Kelsey, CR; Hurwitz, HI; Willett, CG; Morse, MA; Blobe, GC; Fernando, NH; D'Amico, TA; Harpole, DH; Honeycutt, W; Yu, D; Bendell, JC
MLA Citation
Czito, BG, Kelsey, CR, Hurwitz, HI, Willett, CG, Morse, MA, Blobe, GC, Fernando, NH, D'Amico, TA, Harpole, DH, Honeycutt, W, Yu, D, and Bendell, JC. "A Phase I study of capecitabine, carboplatin, and paclitaxel with external beam radiation therapy for esophageal carcinoma." Int J Radiat Oncol Biol Phys 67.4 (March 15, 2007): 1002-1007.
PMID
17197129
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
67
Issue
4
Publish Date
2007
Start Page
1002
End Page
1007
DOI
10.1016/j.ijrobp.2006.10.027

A phase I study of the safety and pharmacokinetics of edotecarin (J-107088), a novel topoisomerase I inhibitor, in patients with advanced solid tumors.

PURPOSE: To assess the maximum tolerated dose, safety, and pharmacokinetic (PK) profile of escalating doses of the novel topoisomerase I (topo I) inhibitor edotecarin (J-107088) given as a 2-h intravenous (IV) infusion once every 21 days in patients with advanced solid tumors who had not responded to standard therapy. PATIENTS AND METHODS: Twenty-nine patients (18M:11F) received a 2-h IV infusion of edotecarin in doses of 6, 8, 11, 13, or 15 mg/m(2) every 21 days (with an additional 1-2 weeks permitted for recovery) and were evaluated for safety, PK, and tumor response. RESULTS: The most common non-hematologic toxicities were grade 1-2 nausea, fatigue, anorexia, vomiting, and fever. The most common hematologic toxicities were grade 1-2 thrombocytopenia and grade 3-4 neutropenia, leukopenia, and anemia. No grade 3-4 diarrhea was reported. Dose-limiting toxicities were observed in four patients at the 15 mg/m(2) dose and one patient at the 13 mg/m(2) dose. These toxicities included grade 3 nausea, vomiting, headache, and fatigue, as well as grade 4 neutropenia and febrile neutropenia. The maximum tolerated dose was declared at 15 mg/m(2). One patient with bladder cancer had a confirmed partial response at a dose of 13 mg/m(2). There was a trend to dose-proportional increases in edotecarin peak plasma concentrations and area under the curve values. Renal excretion of edotecarin was minimal (3-8% of the dose). CONCLUSION: The recommended Phase II dose of edotecarin is 13 mg/m(2) once every 21 days. The toxicities in this study were those typical of cytotoxic chemotherapy and less severe than those associated with other topo I inhibitors. The observed safety profile and preliminary evidence of clinical benefit warrant further investigation of this drug as monotherapy or part of combination therapy in patients with solid tumors.

Authors
Hurwitz, HI; Cohen, RB; McGovren, JP; Hirawat, S; Petros, WP; Natsumeda, Y; Yoshinari, T
MLA Citation
Hurwitz, HI, Cohen, RB, McGovren, JP, Hirawat, S, Petros, WP, Natsumeda, Y, and Yoshinari, T. "A phase I study of the safety and pharmacokinetics of edotecarin (J-107088), a novel topoisomerase I inhibitor, in patients with advanced solid tumors." Cancer Chemother Pharmacol 59.1 (January 2007): 139-147.
PMID
16819636
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
59
Issue
1
Publish Date
2007
Start Page
139
End Page
147
DOI
10.1007/s00280-006-0267-9

Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab

Background: Although combination treatment with bevacizumab (humanized monoclonal antibody against vascular endothelial growth factor) and chemotherapy improves survival of patients with various metastatic carcinomas, an increased risk of arterial thromboembolic events has been observed in some trials. We characterized this risk by performing post hoc analyses of randomized controlled trials that evaluated combination treatment with bevacizumab and chemotherapy versus chemotherapy alone. Low-dose aspirin was permitted in these trials, and its safety was also analyzed. Methods: Data were pooled from five randomized controlled trials that included a total of 1745 patients with metastatic colorectal, breast, or non-small-cell lung carcinoma. The risk of an arterial or venous thromboembolic event was assessed by simple incidence rates, rates per 100 person-years, and/or hazard ratios (HRs). The association between patient characteristics and risk of an arterial thromboembolic event was investigated primarily by Cox proportional hazards regression. The relationship between low-dose aspirin and bleeding was explored by incidence rates and rates per 100 person-years. Results: Combined treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with increased risk for an arterial thromboembolic event (HR = 2.0, 95% confidence interval [CI] = 1.05 to 3.75; P = .031) but not for a venous thromboembolic event (HR = 0.89, 95% CI = 0.66 to 1.20; P = .44). The absolute rate of developing an arterial thromboembolism was 5.5 events per 100 person-years for those receiving combination therapy and 3.1 events per 100 person-years for those receiving chemotherapy alone (ratio = 1.8, 95% CI = 0.94 to 3.33; P = .076). Development of an arterial thromboembolic event was associated with a prior arterial thromboembolic event (P<.001) or age of 65 years or older (P = .01). Baseline or on-study aspirin use was associated with modest increases in grade 3 and 4 bleeding events in both treatment groups, from 3.6% to 4.7% for bevacizumab-treated patients and from 1.7% to 2.2% for control subjects. Conclusions: Combination treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with an increased risk of arterial thromboembolism but not venous thromboembolism. © The Author 2007. Published by Oxford University Press. All rights reserved.

Authors
Scappaticci, FA; Skillings, JR; Holden, SN; Gerber, H-P; Miller, K; Kabbinavar, F; Bergsland, E; Ngai, J; Holmgren, E; Wang, J; Hurwitz, H
MLA Citation
Scappaticci, FA, Skillings, JR, Holden, SN, Gerber, H-P, Miller, K, Kabbinavar, F, Bergsland, E, Ngai, J, Holmgren, E, Wang, J, and Hurwitz, H. "Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab." Journal of the National Cancer Institute 99.16 (2007): 1232-1239.
PMID
17686822
Source
scival
Published In
Journal of the National Cancer Institute
Volume
99
Issue
16
Publish Date
2007
Start Page
1232
End Page
1239
DOI
10.1093/jnci/djm086

Phase II trial of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy

Purpose: Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor receptor and multiple other growth factor receptors. We assessed the safety and efficacy of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy. Patients and Methods: Eighty-four patients were enrolled onto this two-stage phase II trial and were stratified by whether they had received prior bevacizumab (n = 43) or not (n = 41). Treatment comprised sunitinib 50 mg orally daily for 4 weeks, followed by 2 weeks off treatment, in repeated 6-week cycles. Results: By Response Evaluation Criteria in Solid Tumors criteria, one patient, who was in the prior bevacizumab cohort, achieved a partial response, and 13 patients (two in the prior bevacizumab cohort and 11 in the no prior bevacizumab cohort) achieved stable disease lasting ≥ 22 weeks. Median time to progression in the prior bevacizumab and bevacizumab-naïve cohorts was 2.2 months (95% CI, 1.9 to 2.3 months) and 2.5 months (95% CI, 2.3 to 3.1 months), respectively, whereas median overall survival time was 7.1 months (95% CI, 4.9 to 10.6 months) and 10.2 months (95% CI, 8.2 to 15.3 months), respectively. The most common adverse events were fatigue, diarrhea, nausea, vomiting, and anorexia. Twenty-six patients (32%) required dose reduction to 37.5 mg/d, and one patient required dose reduction to 25 mg/d. Conclusion: Sunitinib did not demonstrate a meaningful single-agent objective response rate in colorectal cancer refractory to standard chemotherapy. However, the mechanisms of action and acceptable safety profile of sunitinib warrant further study in combination with standard regimens for metastatic colorectal cancer. © 2007 by American Society of Clinical Oncology.

Authors
Saltz, LB; Rosen, LS; Marshall, JL; Belt, RJ; Hurwitz, HI; Eckhardt, SG; Bergsland, EK; Haller, DG; Lockhart, AC; Lima, CMR; Huang, X; DePrimo, SE; Chow-Maneval, E; Chao, RC; Lenz, HJ
MLA Citation
Saltz, LB, Rosen, LS, Marshall, JL, Belt, RJ, Hurwitz, HI, Eckhardt, SG, Bergsland, EK, Haller, DG, Lockhart, AC, Lima, CMR, Huang, X, DePrimo, SE, Chow-Maneval, E, Chao, RC, and Lenz, HJ. "Phase II trial of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy." Journal of Clinical Oncology 25.30 (2007): 4793-4799.
PMID
17947727
Source
scival
Published In
Journal of Clinical Oncology
Volume
25
Issue
30
Publish Date
2007
Start Page
4793
End Page
4799
DOI
10.1200/JCO.2007.12.8637

Monoclonal antibodies to EGFR: What does the future hold?

Authors
Zafar, Y; Hurwitz, HI
MLA Citation
Zafar, Y, and Hurwitz, HI. "Monoclonal antibodies to EGFR: What does the future hold?." ONCOLOGY 21.8 (2007): 976-977.
Source
scival
Published In
Oncology
Volume
21
Issue
8
Publish Date
2007
Start Page
976
End Page
977

Long-term treatment with bevacizumab for patients with metastatic colorectal cancer: case report.

Bevacizumab is a monoclonal antibody to vascular endothelial growth factor that has demonstrated increased overall survival when added to standard chemotherapy regimens for metastatic colorectal cancer. Herein we report the cases of 2 patients who demonstrated prolonged survival times of almost 5 and 6 years, respectively, on various chemotherapy regimens that also included bevacizumab. Throughout most of their disease course, these patients maintained a good quality of life, with some adjustments of chemotherapy doses because of side effects. Bevacizumab was generally well tolerated in long-term use.

Authors
Hurwitz, HI; Honeycutt, W; Haley, S; Favaro, J
MLA Citation
Hurwitz, HI, Honeycutt, W, Haley, S, and Favaro, J. "Long-term treatment with bevacizumab for patients with metastatic colorectal cancer: case report." Clin Colorectal Cancer 6.1 (May 2006): 66-69.
PMID
16796794
Source
pubmed
Published In
Clinical colorectal cancer
Volume
6
Issue
1
Publish Date
2006
Start Page
66
End Page
69
DOI
10.3816/CCC.2006.n.023

Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results.

PURPOSE: Overexpression of epidermal growth factor receptor (EGFR) has been associated with aggressive tumor phenotypes, chemotherapy, and radiation resistance, as well as poor survival in preclinical and clinical models. The EGFR inhibitor gefitinib potentiates chemotherapy and radiation tumor cytotoxicity in preclinical models, including pancreatic and colorectal cancer. We initiated two phase I trials assessing the combination of gefitinib, capecitabine, and radiation in patients with localized pancreatic and rectal cancer. PATIENTS AND METHODS: Patients with pathologically confirmed adenocarcinoma of the pancreas and rectum were eligible. Pretreatment staging included computed tomography, endoscopic ultrasound, and surgical evaluation. Patients received 50.4 Gy of external-beam radiation therapy to the tumor in 28 fractions. Capecitabine and gefitinib were administered throughout the radiation course. Following completion, patients were restaged and considered for resection. Primary end points included determination of dose-limiting toxicity (DLT) and a phase II dose; secondary end points included determination of non-DLTs and preliminary radiographic and pathologic response rates. RESULTS: Ten patients were entered in the pancreatic study and six in the rectal study. DLT was seen in six of 10 patients in the pancreatic study and two of six patients in the rectal study. The primary DLT in both studies was diarrhea. Two patients developed arterial thrombi. CONCLUSION: The combination of gefitinib, capecitabine, and radiation in pancreatic and rectal cancer patients resulted in significant toxicity. A recommended phase II dose was not determined in either of our studies. Further investigation with this combination should be approached with caution.

Authors
Czito, BG; Willett, CG; Bendell, JC; Morse, MA; Tyler, DS; Fernando, NH; Mantyh, CR; Blobe, GC; Honeycutt, W; Yu, D; Clary, BM; Pappas, TN; Ludwig, KA; Hurwitz, HI
MLA Citation
Czito, BG, Willett, CG, Bendell, JC, Morse, MA, Tyler, DS, Fernando, NH, Mantyh, CR, Blobe, GC, Honeycutt, W, Yu, D, Clary, BM, Pappas, TN, Ludwig, KA, and Hurwitz, HI. "Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results." J Clin Oncol 24.4 (February 1, 2006): 656-662.
PMID
16446337
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
4
Publish Date
2006
Start Page
656
End Page
662
DOI
10.1200/JCO.2005.04.1749

A phase I study of eniluracil/5-FU in combination with radiation therapy for potentially resectable and/or unresectable cancer of the pancreas and distal biliary tract.

PURPOSE: Eniluracil is an effective inactivator of dihydropyrimidine dehydrogenase (DPD). It allows for oral dosing of 5-fluorouracil (5-FU), which may potentially improve the antitumor activity of 5-FU when delivered concurrently with radiotherapy while avoiding the inconvenience and morbidity of continuous infusion (CI) 5-FU. We addressed the safety of oral eniluracil/5-FU combined with radiation therapy and determined the profile of dose-limiting toxicities and recommended Phase II dose (RPTD) in patients with pancreatic and hepatobiliary cancers. METHODS AND MATERIALS: Patients with resectable or locally advanced pancreatic and biliary cancer received eniluracil (starting at 6.0 mg/m(2) q12h)/5-FU (starting at 0.6 mg/m(2) q12h). Eniluracil/5-FU were given concurrently with preoperative radiation to 4500 cGy followed by 540 cGy by reduced fields. Surgery was considered 4 weeks after completion of therapy. RESULTS: Thirteen patients were enrolled. Chemoradiotherapy was completed in all patients. The MTD was not reached and, thus, the RPTD of eniluracil/5-FU was determined to be 10 mg/m(2) q12h/1 mg/m(2) q12h. Two patients with locally advanced disease had a 30-45 percent cross-sectional tumor reduction, one of which underwent margin-negative resection. Two of 5 patients with pancreatic cancer, and 1 of 3 patients with cholangiocarcinoma, with underwent exploratory surgery had margin-negative resections. One patient had a pathologic complete response (pCR). Patient 5-FU plasma exposure increased slightly from Day 8 to Day 31. CONCLUSION: Preoperative chemoradiation with oral eniluracil/5-FU is feasible, well tolerated, and potentially effective in the neoadjuvant setting. Further investigation of oral fluoropyrimidines as radiosensitizers for pancreaticobiliary malignancies is warranted.

Authors
Czito, BG; Hong, TJ; Cohen, DP; Petros, WP; Tyler, DS; Pappas, TN; Yu, D; Lee, CG; Lockhart, AC; Morse, MA; Fernando, N; Hurwitz, HI
MLA Citation
Czito, BG, Hong, TJ, Cohen, DP, Petros, WP, Tyler, DS, Pappas, TN, Yu, D, Lee, CG, Lockhart, AC, Morse, MA, Fernando, N, and Hurwitz, HI. "A phase I study of eniluracil/5-FU in combination with radiation therapy for potentially resectable and/or unresectable cancer of the pancreas and distal biliary tract." Cancer Invest 24.1 (February 2006): 9-17.
PMID
16466986
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
24
Issue
1
Publish Date
2006
Start Page
9
End Page
17
DOI
10.1080/07357900500449454

Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer

Purpose: Exatecan mesylate is a hexacyclic, water-soluble, topoisomerase-1 inhibitor. Exatecan has single-agent and combination activity with gemcitabine in advanced pancreatic cancer. A multicenter, randomized, phase III trial comparing exatecan plus gemcitabine versus gemcitabine alone in advanced pancreatic cancer was conducted. Patients and Methods: Eligibility criteria included Karnofsky performance status ≥ 60%, locally advanced or metastatic pancreatic adenocarcinoma, and no prior chemotherapy. Radiation alone for locally advanced disease was permitted. Patients were randomly assigned on a 1:1 basis. For the exatecan plus gemcitabine arm, exatecan 2.0 mg/m2 and gemcitabine 1,000 mg/m2 were administered on days 1 and 8, every 3 weeks. Gemcitabine alone was dosed at 1,000 mg/m2 up to 7 weeks in the first cycle, then once a week for the first 3 weeks of a 4-week cycle. Tumor assessment was performed every 6 weeks. The primary end point was overall survival. An intent-to-treat analysis was used. Results: From August 2001 to January 2003, 349 patients were randomly assigned, 175 to exatecan plus gemcitabine and 174 to gemcitabine alone. Twenty-four patients (6.9%) were not treated. The median survival time was 6.7 months for exatecan plus gemcitabine and 6.2 months for gemcitabine alone (P = .52). One complete response (CR; < 1%) and 11 partial responses (PRs; 6.3%) were observed in the exatecan plus gemcitabine treatment group, and one CR (< 1%) and eight PRs (4.6%) were observed in the gemcitabine-alone group. Grade 3 and 4 toxicities were higher for the exatecan plus gemcitabine arm versus the gemcitabine alone arm; neutropenia (30% v 15%) and thrombocytopenia (15% v 4%). Conclusion: Exatecan plus gemcitabine was not superior to gemcitabine alone with respect to overall survival in the first-line treatment of advanced pancreatic cancer. © 2006 by American Society of Clinical Oncology.

Authors
Abou-Alfa, GK; Letourneau, R; Harker, G; Modiano, M; Hurwitz, H; Tchekmedyian, NS; Feit, K; Ackerman, J; Jager, RLD; Eckhardt, SG; O'Reilly, EM
MLA Citation
Abou-Alfa, GK, Letourneau, R, Harker, G, Modiano, M, Hurwitz, H, Tchekmedyian, NS, Feit, K, Ackerman, J, Jager, RLD, Eckhardt, SG, and O'Reilly, EM. "Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer." Journal of Clinical Oncology 24.27 (2006): 4441-4447.
PMID
16983112
Source
scival
Published In
Journal of Clinical Oncology
Volume
24
Issue
27
Publish Date
2006
Start Page
4441
End Page
4447
DOI
10.1200/JCO.2006.07.0201

Bevacizumab in the Treatment of Metastatic Colorectal Cancer: Safety Profile and Management of Adverse Events

Bevacizumab is well suited for use in combination with first- or second-line chemotherapy in the treatment of metastatic colorectal cancer because its side effects are predictable and appear not to add to the incidence or severity of the side effects of chemotherapy. Clinical trials of bevacizumab in combination with oxaliplatin-containing and 5-fluorouracil-based regimens have shown that combination therapy is well tolerated and its toxicity is not substantially greater than that of the chemotherapy alone. Preliminary data from community-based and observational studies show that the incidence and severity of adverse events with combinations of bevacizumab and newer chemotherapy regimens are similar to those in the pivotal phase III trial with irinotecan, 5-fluorouracil, and leucovorin plus bevacizumab. Across trials, these side effects include a greater risk of grade 3 hypertension and grade 1 or 2 proteinuria, a slight increase (<2 percentage points) in grade 3 or 4 bleeding, and impaired surgical wound healing in patients who undergo surgery during treatment with bevacizumab. Potentially life-threatening events (arterial thrombotic events and gastrointestinal perforation) have occurred in a small number of patients. Close patient monitoring, especially in patients who are at greater risk of adverse events, is important. © 2006 Elsevier Inc. All rights reserved.

Authors
Hurwitz, H; Saini, S
MLA Citation
Hurwitz, H, and Saini, S. "Bevacizumab in the Treatment of Metastatic Colorectal Cancer: Safety Profile and Management of Adverse Events." Seminars in Oncology 33.SUPPL. 10 (2006): S26-S34.
PMID
17145522
Source
scival
Published In
Seminars in Oncology
Volume
33
Issue
SUPPL. 10
Publish Date
2006
Start Page
S26
End Page
S34
DOI
10.1053/j.seminoncol.2006.08.001

The role of targeted therapy in the treatment of colorectal cancer.

Recent years have brought significant advances in the treatment of metastatic colorectal cancer. Combination regimens with standard chemotherapeutic agents have extended survival to nearly 2 years, and recent studies suggest that chemotherapy-free intervals may be feasible in some patients without compromising survival outcomes. The most significant recent progress has centered on the use of targeted biologic therapies. The first targeted agent to show a significant benefit in metastatic colorectal cancer was bevacizumab. This monoclonal antibody is directed against vascular endothelial growth factor, a molecule known to be involved in the angiogenic process that is central to cancer growth and metastasis. In clinical trials, bevacizumab has improved survival when added to multiple chemotherapy regimens. The second targeted agent to be approved for colorectal cancer is the monoclonal antibody cetuximab, which is directed against the epidermal growth factor receptor, another key mediator of cancer growth. Cetuximab has been shown to increases the efficacy of irinotecan in irinotecan-refractory patients, indicating that cetuximab may make tumors more sensitive to chemotherapeutic agents. Bevacizumab and cetuximab continue to be evaluated alone as maintenance therapy and in combination in different settings to determine their optimal use in colorectal cancer. Additional targeted agents are also being developed and are showing promise in clinical trials.

Authors
Goldberg, RM; Hurwitz, HI; Fuchs, CS
MLA Citation
Goldberg, RM, Hurwitz, HI, and Fuchs, CS. "The role of targeted therapy in the treatment of colorectal cancer." Clinical advances in hematology & oncology : H&O 4.8 Suppl 17 (2006): 1-10.
PMID
17139241
Source
scival
Published In
Clinical advances in hematology & oncology : H&O
Volume
4
Issue
8 Suppl 17
Publish Date
2006
Start Page
1
End Page
10

Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer

Purpose: Bevacizumab is a monoclonal antibody to vascular endothelial growth factor-A (VEGF). In the pivotal trial in metastatic colorectal cancer (mCRC), addition of bevacizumab to first-line irinotecan, fluorouracil, and leucovorin (IFL) significantly prolonged median survival. The aim of these retrospective subset analyses was to evaluate VEGF, thrombospondin-2 (THBS-2), and microvessel density (MVD) as prognostic factors and/or predictors of benefit from bevacizumab. Patients and Methods: In the pivotal trial, 813 patients with untreated mCRC were randomly assigned to receive IFL plus bevacizumab or placebo. Of 312 tissue samples collected (285 primaries, 27 metastases), outcome data were available for 278 (153 bevacizumab, 125 placebo). Epithelial and stromal VEGF expression were assessed by in situ hybridization (ISH) and immunohistochemistry on tissue microarrays and whole sections. Stromal THBS-2 expression was examined by ISH on tissue microarrays. MVD was quantified by Chalkley count. Overall survival was associated with these variables in retrospective subset analyses. Results: In all subgroups, estimated hazard ratios (HRs) for risk of death were < 1 for bevacizumab-treated patients regardless of the level of VEGF or THBS-2 expression or MVD. Patients with a high THBS-2 score showed a nonsignificant improvement in survival following bevacizumab treatment (HR = 0.11; 95% CI, 0.02 to 0.51) compared to patients with a low score (HR = 0.65; 95% CI, 0.41 to 1.02); interaction analysis P = .22. VEGF or THBS-2 expression and MVD were not significant prognostic factors. Conclusion: These exploratory analyses suggest that in patients with mCRC addition of bevacizumab to IFL improves survival regardless of the level of VEGF or THBS-2 expression, or MVD. © 2006 by American Society of Clinical Oncology.

Authors
Jubb, AM; Hurwitz, HI; Bai, W; Holmgren, EB; Tobin, P; Guerrero, AS; Kabbinavar, F; Holden, SN; Novotny, WF; Frantz, GD; Hillan, KJ; Koeppen, H
MLA Citation
Jubb, AM, Hurwitz, HI, Bai, W, Holmgren, EB, Tobin, P, Guerrero, AS, Kabbinavar, F, Holden, SN, Novotny, WF, Frantz, GD, Hillan, KJ, and Koeppen, H. "Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer." Journal of Clinical Oncology 24.2 (2006): 217-227.
PMID
16365183
Source
scival
Published In
Journal of Clinical Oncology
Volume
24
Issue
2
Publish Date
2006
Start Page
217
End Page
227
DOI
10.1200/JCO.2005.01.5388

Disclosure between patients with gastrointestinal cancer and their spouses.

This study examined patterns of disclosure about cancer-related concerns between patients with GI cancer and their spouses, and associations between patient and spouse disclosure and patient adjustment, spouse adjustment, and aspects of relationship functioning. A sample of 47 patients and 45 of their spouses completed a measure of disclosure which included ratings of their level of disclosure and level of holding back from disclosure of cancer-related concerns. Patients completed a measure of quality of life, spouses completed a measure of caregiver strain, and all participants completed measures of psychological distress and relationship functioning (intimacy, empathy, and partner avoidance and criticism). Data analyses revealed that patients and spouses reported moderately high levels of disclosure and low levels of holding back, with patients reporting higher levels of disclosure than spouses. Among patients and spouses, low levels of disclosure and high levels of holding back were associated with poorer relationship functioning. There were also some indications that high levels of holding back, and to a lesser extent low levels of disclosure, were associated with increased psychological distress for both patients and spouses. However, there were no indications that patient or spouse disclosure was harmful for the other person. Considered overall, the results of this study suggest that levels of disclosure between cancer patients and their spouses may be important in understanding how they adjust as a couple to the demands of the patient's illness.

Authors
Porter, LS; Keefe, FJ; Hurwitz, H; Faber, M
MLA Citation
Porter, LS, Keefe, FJ, Hurwitz, H, and Faber, M. "Disclosure between patients with gastrointestinal cancer and their spouses." Psychooncology 14.12 (December 2005): 1030-1042.
PMID
15712247
Source
pubmed
Published In
Psycho-Oncology
Volume
14
Issue
12
Publish Date
2005
Start Page
1030
End Page
1042
DOI
10.1002/pon.915

The effects of ZD6474, an inhibitor of VEGF signaling, on cutaneous wound healing in mice.

BACKGROUND: ZD6474 is an inhibitor of the VEGFR-2 receptor tyrosine kinase with additional activity against EGFR-1 receptor tyrosine kinases that has been shown to inhibit tumor growth and wound-induced neovascularization in pre-clinical studies and phase I clinical trials. The purpose of this study was to determine the effects of ZD6474 on breaking strength in a murine model of cutaneous wound healing. MATERIALS AND METHODS: Balb/C mice were given ZD6474 (50 or 100 mg/kg p.o.) or vehicle starting 7 days before wounding. Two full-thickness incisions were made in each mouse and closed using suture. On post-wounding day 7 or 28, laser Doppler blood flow measurements were made, and the breaking strength of the wounded skin was determined. Microvessel density measurements were performed using computer image analysis of CD31-stained sections. RESULTS: Compared with controls, mice treated with ZD6474 showed a significantly reduced dose-dependent decline in breaking strength, both at POD 7 (P < 0.001) and at POD 28 (P < 0.005). Histologically, the ZD6474-treated mice showed a qualitative reduction in the degree of fibrosis and epithelial proliferation at the wound site, but no significant difference was noted between the 50 mg/kg and 100 mg/kg ZD6474-treated groups. Also, microvessel density measurements demonstrated no significant difference between groups. CONCLUSION: In a murine model of wound healing, ZD6474 treatment did not prevent wound healing, but was associated with a reduced skin breaking strength compared with vehicle-treated controls at both 7 and 28 days post-wounding. These observations may have clinical relevance for the perioperative management of patients treated with inhibitors of angiogenesis.

Authors
Ko, J; Ross, J; Awad, H; Hurwitz, H; Klitzman, B
MLA Citation
Ko, J, Ross, J, Awad, H, Hurwitz, H, and Klitzman, B. "The effects of ZD6474, an inhibitor of VEGF signaling, on cutaneous wound healing in mice." J Surg Res 129.2 (December 2005): 251-259.
PMID
16140331
Source
pubmed
Published In
Journal of Surgical Research
Volume
129
Issue
2
Publish Date
2005
Start Page
251
End Page
259
DOI
10.1016/j.jss.2005.05.006

Ambivalence over emotional expression in patients with gastrointestinal cancer and their caregivers: associations with patient pain and quality of life.

This study examined the role of patient and caregiver ambivalence over emotional expression (AEE) in pain and quality of life (QOL) in a sample of 78 patients with gastrointestinal (GI) cancer. Measures of ambivalence over emotional expression as well as ratings of patient pain and pain behavior were collected from patients and caregivers. Measures of pain catastrophizing, perceptions of social support, and QOL were obtained from patients. Data analyses revealed that patients high in AEE engaged in more catastrophizing and reported higher levels of pain behaviors and poorer QOL. In addition, patients whose caregivers were high in AEE engaged in more catastrophizing, had higher levels of pain and pain behavior, and reported lower emotional well-being. Patient catastrophizing mediated the effects of both patient and caregiver AEE on some patient outcomes. Taken together, these findings suggest that emotional regulation in both patients and their caregivers may be an important factor in understanding cancer patients' experience of and coping with symptoms such as pain.

Authors
Porter, LS; Keefe, FJ; Lipkus, I; Hurwitz, H
MLA Citation
Porter, LS, Keefe, FJ, Lipkus, I, and Hurwitz, H. "Ambivalence over emotional expression in patients with gastrointestinal cancer and their caregivers: associations with patient pain and quality of life." Pain 117.3 (October 2005): 340-348.
PMID
16153771
Source
pubmed
Published In
PAIN
Volume
117
Issue
3
Publish Date
2005
Start Page
340
End Page
348
DOI
10.1016/j.pain.2005.06.021

Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas.

PURPOSE: This study (EGF10004) assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib (GW572016) in patients with ErbB1-expressing and/or ErbB2-overexpressing advanced-stage refractory solid tumors. PATIENTS AND METHODS: Heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were randomly assigned to one of five dose cohorts of lapatinib administered once daily. Pharmacokinetic samples were obtained on days 1 and 20. Clinical response was assessed every 8 weeks. RESULTS: Sixty-seven patients with metastatic solid tumors were treated with lapatinib. The most frequently reported drug-related adverse events were diarrhea (42%) and rash (31%). No grade 4 drug-related adverse events were reported. Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. Drug-related interstitial pneumonitis or cardiac dysfunction associated with other ErbB-targeted therapies was not reported. Four patients with trastuzumab-resistant metastatic breast cancer-two of whom were classified as having inflammatory breast cancer-had partial responses (PRs). Twenty-four patients with various other carcinomas experienced stable disease, of whom 10 received lapatinib for > or = 6 months. The relationships between lapatinib dose or serum concentration and clinical response could not be adequately characterized due to the limited response data. The incidence of diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose. CONCLUSION: Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.

Authors
Burris, HA; Hurwitz, HI; Dees, EC; Dowlati, A; Blackwell, KL; O'Neil, B; Marcom, PK; Ellis, MJ; Overmoyer, B; Jones, SF; Harris, JL; Smith, DA; Koch, KM; Stead, A; Mangum, S; Spector, NL
MLA Citation
Burris, HA, Hurwitz, HI, Dees, EC, Dowlati, A, Blackwell, KL, O'Neil, B, Marcom, PK, Ellis, MJ, Overmoyer, B, Jones, SF, Harris, JL, Smith, DA, Koch, KM, Stead, A, Mangum, S, and Spector, NL. "Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas." J Clin Oncol 23.23 (August 10, 2005): 5305-5313.
PMID
15955900
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
23
Publish Date
2005
Start Page
5305
End Page
5313
DOI
10.1200/JCO.2005.16.584

Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors.

BACKGROUND: ZD6474 selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor and epidermal growth factor receptor. The safety, tolerability and pharmacokinetics of ZD6474 were assessed in a phase I dose-escalation study of patients with advanced solid tumors. PATIENTS AND METHODS: Adult patients with tumors refractory to standard treatments received once-daily oral ZD6474 (50-600 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed. RESULTS: Seventy-seven patients were treated at doses of 50 mg (n=9), 100 mg (n=19), 200 mg (n=8), 300 mg (n=25), 500 mg (n=8), and 600 mg (n=8). Adverse events were generally mild, and the most common dose-limiting toxicities (DLT) were diarrhea (n=4), hypertension (n=4), and rash (n=3). The incidence of most adverse events appeared to be dose-dependant. In the 500 mg/day cohort, 3/8 patients experienced DLT and this dose was therefore considered to exceed the maximum tolerated dose. Pharmacokinetic analysis confirmed that ZD6474 was suitable for once-daily oral dosing. CONCLUSIONS: Once-daily oral dosing of ZD6474 at 300 mg/day is generally well tolerated in patients with advanced solid tumors, and this dose is being investigated in phase II trials.

Authors
Holden, SN; Eckhardt, SG; Basser, R; de Boer, R; Rischin, D; Green, M; Rosenthal, MA; Wheeler, C; Barge, A; Hurwitz, HI
MLA Citation
Holden, SN, Eckhardt, SG, Basser, R, de Boer, R, Rischin, D, Green, M, Rosenthal, MA, Wheeler, C, Barge, A, and Hurwitz, HI. "Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors." Ann Oncol 16.8 (August 2005): 1391-1397.
PMID
15905307
Source
pubmed
Published In
Annals of Oncology
Volume
16
Issue
8
Publish Date
2005
Start Page
1391
End Page
1397
DOI
10.1093/annonc/mdi247

Adjuvant external-beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: a 23-year experience.

PURPOSE: Primary adenocarcinoma of the gallbladder is a rare malignancy. To better define the role of adjuvant radiation therapy and chemotherapy, a retrospective analysis of the outcome of patients undergoing surgery and adjuvant therapy was undertaken. METHODS AND MATERIALS: Twenty-two patients with primary and nonmetastatic gallbladder cancer were treated with radiation therapy after surgical resection. Median radiation dose was 45 Gy. Eighteen patients received concurrent 5-fluorouracil (5-FU) chemotherapy. Median follow-up was 1.7 years in all patients and 3.9 years in survivors. RESULTS: The 5-year actuarial overall survival, disease-free survival, metastases-free survival, and local-regional control of all 22 patients were 37%, 33%, 36%, and 59%, respectively. Median survival for all patients was 1.9 years. CONCLUSION: Our series suggests that an approach of radical resection followed by external-beam radiation therapy with radiosensitizing 5-FU in patients with locally advanced, nonmetastatic carcinoma of the gallbladder may improve survival. This regimen should be considered in patients with resectable gallbladder carcinoma.

Authors
Czito, BG; Hurwitz, HI; Clough, RW; Tyler, DS; Morse, MA; Clary, BM; Pappas, TN; Fernando, NH; Willett, CG
MLA Citation
Czito, BG, Hurwitz, HI, Clough, RW, Tyler, DS, Morse, MA, Clary, BM, Pappas, TN, Fernando, NH, and Willett, CG. "Adjuvant external-beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: a 23-year experience." Int J Radiat Oncol Biol Phys 62.4 (July 15, 2005): 1030-1034.
PMID
15990005
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
62
Issue
4
Publish Date
2005
Start Page
1030
End Page
1034
DOI
10.1016/j.ijrobp.2004.12.059

Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer.

PURPOSE: In a phase III trial, combining bevacizumab (BV)--a recombinant, humanized, monoclonal antibody targeting vascular endothelial growth factor--with irinotecan, bolus fluorouracil (FU), and leucovorin (LV; IFL) increased survival compared with IFL alone in first-line treatment of patients with metastatic colorectal cancer (CRC). Results for the parent study of IFL/BV versus IFL/placebo are reported elsewhere. Here, we describe efficacy and safety results for the third patient cohort in this trial, who received BV combined with FU/LV, and compare them with results for concurrently enrolled patients who received IFL. METHODS: Patients (N = 923) were randomly assigned to receive IFL/placebo (control), IFL/BV, or FU/LV/BV. Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) 5 mg/kg was administered intravenously every 2 weeks. Before an interim analysis confirmed acceptable safety for IFL/BV, 313 patients were concurrently randomly assigned to these three arms; after this analysis, the FU/LV/BV arm was discontinued. RESULTS: Median overall survivals were 18.3 and 15.1 months with FU/LV/BV (n = 110) and IFL/placebo (n = 100), respectively. Median progression-free survivals were 8.8 and 6.8 months, respectively. Overall response rates were 40.0% and 37.0%, and median response durations were 8.5 and 7.2 months, respectively. Adverse events consistent with those expected from FU/leucovorin- or IFL-based regimens were seen, as were modest increases in hypertension and bleeding in the bevacizumab arm, which were generally easily managed. CONCLUSION: The FU/LV/BV regimen seems as effective as IFL and has an acceptable safety profile. FU/LV/BV is an active alternative treatment regimen for patients with previously untreated metastatic CRC.

Authors
Hurwitz, HI; Fehrenbacher, L; Hainsworth, JD; Heim, W; Berlin, J; Holmgren, E; Hambleton, J; Novotny, WF; Kabbinavar, F
MLA Citation
Hurwitz, HI, Fehrenbacher, L, Hainsworth, JD, Heim, W, Berlin, J, Holmgren, E, Hambleton, J, Novotny, WF, and Kabbinavar, F. "Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer." J Clin Oncol 23.15 (May 20, 2005): 3502-3508.
PMID
15908660
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
15
Publish Date
2005
Start Page
3502
End Page
3508
DOI
10.1200/JCO.2005.10.017

Successful desensitization to oxaliplatin.

OBJECTIVE: To report the successful desensitization of a patient to oxaliplatin utilizing an 8-hour desensitization regimen in a controlled environment. CASE SUMMARY: A 53-year-old white woman with metastatic colon cancer was receiving oxaliplatin, bevacizumab, and capecitabine every 2 weeks, with a partial response to therapy. On her fifth cycle of this regimen, she experienced diaphoresis, hypotension, nausea, abdominal cramping, and coryza. According to the Naranjo probability scale, oxaliplatin, and not bevacizumab, was the probable cause of the hypersensitivity reaction. The woman continued therapy with capecitabine and bevacizumab, resulting in stable disease. Due to her initial response to the oxaliplatin-based regimen, it was decided to attempt desensitization to oxaliplatin in a controlled, inpatient environment. An 8-hour desensitization schedule was employed, and the patient successfully completed an additional 3 cycles with full-dose oxaliplatin. DISCUSSION: Hypersensitivity reactions to platinum-containing compounds are well described and potentially life threatening. With expanded use of oxaliplatin in various malignancies, an increased number of hypersensitivity reactions will likely be reported. Patients with previous hypersensitivity reactions to carboplatin are at risk for similar reactions to oxaliplatin. We achieved successful desensitization for oxaliplatin using increased concentrations of the drug over an 8-hour period concomitant with oral and intravenous corticosteroids and histamine blockers. CONCLUSIONS: Hypersensitivity reactions to platinum compounds may result in discontinuation of active therapies in patients with metastatic disease. Desensitization to oxaliplatin is possible utilizing this approach.

Authors
Mis, L; Fernando, NH; Hurwitz, HI; Morse, MA
MLA Citation
Mis, L, Fernando, NH, Hurwitz, HI, and Morse, MA. "Successful desensitization to oxaliplatin." Ann Pharmacother 39.5 (May 2005): 966-969.
PMID
15784807
Source
pubmed
Published In
The Annals of pharmacotherapy
Volume
39
Issue
5
Publish Date
2005
Start Page
966
End Page
969
DOI
10.1345/aph.1E532

Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies.

PURPOSE: This was a pilot study to assess the biologic effects of lapatinib on various tumor growth/survival pathways in patients with advanced ErbB1 and/or ErbB2-overexpressing solid malignancies. PATIENTS AND METHODS: Heavily pretreated patients with metastatic cancers overexpressing ErbB2 and/or expressing ErbB1 were randomly assigned to one of five dose cohorts of lapatinib (GW572016) administered orally once daily continuously. The biologic effects of lapatinib on tumor growth and survival pathways were assessed in tumor biopsies obtained before and after 21 days of therapy. Clinical response was determined at 8 weeks. RESULTS: Sequential tumor biopsies from 33 patients were examined. Partial responses occurred in four patients with breast cancer, and disease stabilization occurred in 11 others with various malignancies. Responders exhibited variable levels of inhibition of p-ErbB1, p-ErbB2, p-Erk1/2, p-Akt, cyclin D1, and transforming growth factor alpha. Even some nonresponders demonstrated varying degrees of biomarker inhibition. Increased tumor cell apoptosis (TUNEL) occurred in patients with evidence of tumor regression but not in nonresponders (progressive disease). Clinical response was associated with a pretreatment TUNEL score > 0 and increased pretreatment expression of ErbB2, p-ErbB2, Erk1/2, p-Erk1/2, insulin-like growth factor receptor-1, p70 S6 kinase, and transforming growth factor alpha compared with nonresponders. CONCLUSION: Lapatinib exhibited preliminary evidence of biologic and clinical activity in ErbB1 and/or ErbB2-overexpressing tumors. However, the limited sample size of this study and the variability of the biologic endpoints suggest that further work is needed to prioritize biomarkers for disease-directed studies, and underscores the need for improved trial design strategies in early clinical studies of targeted agents.

Authors
Spector, NL; Xia, W; Burris, H; Hurwitz, H; Dees, EC; Dowlati, A; O'Neil, B; Overmoyer, B; Marcom, PK; Blackwell, KL; Smith, DA; Koch, KM; Stead, A; Mangum, S; Ellis, MJ; Liu, L; Man, AK; Bremer, TM; Harris, J; Bacus, S
MLA Citation
Spector, NL, Xia, W, Burris, H, Hurwitz, H, Dees, EC, Dowlati, A, O'Neil, B, Overmoyer, B, Marcom, PK, Blackwell, KL, Smith, DA, Koch, KM, Stead, A, Mangum, S, Ellis, MJ, Liu, L, Man, AK, Bremer, TM, Harris, J, and Bacus, S. "Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies." J Clin Oncol 23.11 (April 10, 2005): 2502-2512.
PMID
15684311
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
11
Publish Date
2005
Start Page
2502
End Page
2512
DOI
10.1200/JCO.2005.12.157

Significance of histological response to preoperative chemoradiotherapy for pancreatic cancer.

BACKGROUND: Neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer offers theoretical advantages over the standard approach of surgery followed by adjuvant CRT. We hypothesized that histological responses to CRT would be significant prognostic factors in patients undergoing neoadjuvant CRT followed by resection. METHODS: Since 1994, 193 patients with biopsy-proven pancreatic adenocarcinoma have completed neoadjuvant CRT, and 70 patients have undergone resection. Specimens were retrospectively examined by an individual pathologist for histological responses (tumor necrosis, tumor fibrosis, and residual tumor load) and immunohistochemical staining for p53 and epidermal growth factor receptor. Factors influencing overall survival were analyzed with the Kaplan-Meier (univariate) and Cox proportional hazards (multivariate) methods. RESULTS: The estimated overall survival (median +/- SE) in the entire group of patients undergoing resection was 23 +/- 4.2 months, with an estimated 3-year survival of 37% +/- 6.6% and a median follow-up of 28 months. Complete histological responses occurred in 6% of patients. Overexpression of p53 was more common in patients with large residual tumor loads. Tumor necrosis was an independent negative prognostic factor, as were positive lymph nodes, a large residual tumor load, and poor tumor differentiation. CONCLUSIONS: Histological response to neoadjuvant CRT--as measured by residual tumor load--may be useful as a surrogate marker for treatment efficacy. Characterization of the tumor cells that survive neoadjuvant CRT may help us to identify new or more appropriate targets for systemic therapy.

Authors
White, RR; Xie, HB; Gottfried, MR; Czito, BG; Hurwitz, HI; Morse, MA; Blobe, GC; Paulson, EK; Baillie, J; Branch, MS; Jowell, PS; Clary, BM; Pappas, TN; Tyler, DS
MLA Citation
White, RR, Xie, HB, Gottfried, MR, Czito, BG, Hurwitz, HI, Morse, MA, Blobe, GC, Paulson, EK, Baillie, J, Branch, MS, Jowell, PS, Clary, BM, Pappas, TN, and Tyler, DS. "Significance of histological response to preoperative chemoradiotherapy for pancreatic cancer." Ann Surg Oncol 12.3 (March 2005): 214-221.
PMID
15827813
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
12
Issue
3
Publish Date
2005
Start Page
214
End Page
221
DOI
10.1245/ASO.2005.03.105

Targeting vascular endothelial growth factor and angiogenesis for the treatment of colorectal cancer.

Angiogenesis, the development and proliferation of new blood vessels, is critical for the growth of tumors. The process of new blood vessel formation is under complex control from a variety of pro- and anti-angiogenesis factors. By identifying and understanding these factors, new therapies have been developed to inhibit tumor growth and survival by blocking tumor-related angiogenesis. Recent success with the monoclonal antibody against vascular endothelial growth factor (VEGF; bevacizumab) in a large, randomized, phase III study has provided a critical proof of principle for this therapeutic area. This review will outline the biology of angiogenesis in colorectal cancer and discuss the current status of angiogenesis inhibition in its treatment.

Authors
Collins, TS; Hurwitz, HI
MLA Citation
Collins, TS, and Hurwitz, HI. "Targeting vascular endothelial growth factor and angiogenesis for the treatment of colorectal cancer." Semin Oncol 32.1 (February 2005): 61-68. (Review)
PMID
15726507
Source
pubmed
Published In
Seminars in Oncology
Volume
32
Issue
1
Publish Date
2005
Start Page
61
End Page
68
DOI
10.1053/j.seminoncol.2004.09.026

Angiogenesis inhibition in the treatment of colorectal cancer. Part 3 of a 3-part series: Targeting VEGF - Current and future research directions

Treatment options for advanced colorectal have improved substantially in recent years as a number of agents have been developed that have different targets and mechanisms of action. Significant improvements in outcomes have been observed by combining multiple chemotherapeutic agents instead of the single-agent approach. Some debate still remains regarding which combination is most effective and in what order regimens should be given. In addition to cytotoxic chemotherapy drugs, targeted biologic agents have been developed to inhibit tumor agiogenesis, which may hamper the viability of the tumor. There may also be a synergistic effect between antiangiogenic agents and chemotherapy. Regulation of tumor angiogenesis may actually improve blood flow throughout the tumor, which could enhance delivery of chemotherapy through the circulation. One antiangiogenic agent currently approved for the treatment of advanced colorectal cancer is bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, a ligand known to be important for angiogenesis. The other currently approved biologic agent, cetuximab, targets the epidermal growth factor receptor. The combination of bevacizumab plus cetuximab has a biologic rationale. Randomized trials incorporating combination chemotherapy regimes plus both bevacizumab and cetuximab are currently underway, as are preliminary studies with novel angiogenesis inhibitors.

Authors
Goldberg, RM; Hurwitz, HI; Fuchs, CS
MLA Citation
Goldberg, RM, Hurwitz, HI, and Fuchs, CS. "Angiogenesis inhibition in the treatment of colorectal cancer. Part 3 of a 3-part series: Targeting VEGF - Current and future research directions." Clinical Advances in Hematology and Oncology 3.12 SUPPL. 12 (2005): 1+3-.
PMID
16555433
Source
scival
Published In
Clinical advances in hematology & oncology : H&O
Volume
3
Issue
12 SUPPL. 12
Publish Date
2005
Start Page
1+3

Bevacizumab combined with standard fluoropyrimidine-based chemotherapy regimens to treat colorectal cancer

For several decades, 5-fluorouracil (5-FU) with or without leucovorin defined the standard of care for the treatment of metastatic colorectal cancer (CRC). The addition of other chemotherapy regimensto 5-FU has improved survival, but often at the expense of increased toxicity. Recent advances in our understanding of the molecular basis of CRC have led to the production of novel targeted agents, such as bevacizumab (Avastin®). Bevacizumab is currently approved for the first-line treatment of metastatic CRC and is currently being tested in combination with standard therapies for a range of indications. Phase II/III trials have demonstrated that the addition of bevacizumab to 5-FU-based first-line chemotherapy improves survival, progression-free survival and response rate compared with chemotherapy alone. Combination therapy does not appear to exacerbate side effects known to be associated with the chemotherapy regimen. The most common side effects attributable to bevacizumab therapy include hypertension, proteinuria and bleeding. Although uncommon, gastrointestinal perforation and arterial thromobembolic events are the most serious side effects reported to date. Bevacizumab is currently being evaluated in combination with oxaliplatin (Eloxatin®)-based therapies and preliminary data are encouraging. Ongoing trials of bevacizumab in combination with standard first-line chemotherapy regimens will evaluate bevacizumab's potential in a range of cancer types. Copyright © 2005 S. Karger AG.

Authors
Hurwitz, H; Kabbinavar, F
MLA Citation
Hurwitz, H, and Kabbinavar, F. "Bevacizumab combined with standard fluoropyrimidine-based chemotherapy regimens to treat colorectal cancer." Oncology 69.SUPPL. 3 (2005): 17-24.
PMID
16301832
Source
scival
Published In
Oncology
Volume
69
Issue
SUPPL. 3
Publish Date
2005
Start Page
17
End Page
24
DOI
10.1159/000086627

Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab

Background: Bevacizumab (Avastin™; rhuMab VEGF), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), significantly prolongs survival when added to intravenous 5-fluorouracil-based chemotherapy in first-line metastatic colorectal cancer (CRC) treatment. Because antiangiogenic agents might inhibit wound healing, we assessed postoperative wound healing complications in two randomized trials of 5 mg/kg bevacizumab in CRC treatment. Methods: We assessed the wound healing complications in patients who: (1) underwent cancer surgery 28-60 days before study treatment and (2) underwent major surgery during study treatment. Cases were reviewed for wound healing complications occurring <60 days after surgery. Results: With cancer surgery 28-60 days before study treatment, wound healing complications occurred in 3/230 (1.3%) bevacizumab-treated patients and 1/194 (0.5%) control patients. With major surgery during study treatment, 10/75 bevacizumab-treated patients (13%) and 1/29 control patients (3.4%) had wound healing complications. Bevacizumab-treated patients experienced complications with surgery ≤30 and 31-60 days after the last dose. Conclusions: Bevacizumab administered in combination with 5-fluorouracil/leucovorin-based chemotherapy 28-60 days after primary cancer surgery caused no increased risk of wound healing complications compared with chemotherapy alone. While wound healing complications were increased in patients who had major surgery during bevacizumab therapy, the majority of bevacizumab-treated patients experienced no complications. © 2005 Wiley-Liss, Inc.

Authors
Scappaticci, FA; Fehrenbacher, L; Cartwright, T; Hainsworth, JD; Heim, W; Berlin, J; Kabbinavar, F; Novotny, W; Sarkar, S; Hurwitz, H
MLA Citation
Scappaticci, FA, Fehrenbacher, L, Cartwright, T, Hainsworth, JD, Heim, W, Berlin, J, Kabbinavar, F, Novotny, W, Sarkar, S, and Hurwitz, H. "Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab." Journal of Surgical Oncology 91.3 (2005): 173-180.
PMID
16118771
Source
scival
Published In
Journal of Surgical Oncology
Volume
91
Issue
3
Publish Date
2005
Start Page
173
End Page
180
DOI
10.1002/jso.20301

Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab

Background: A recent phase III trial showed that the addition of bevacizumab, a monoclonal antibody to vascular endothelial growth factor-A, to first-line irinotecan, 5-fluorouracil, and leucovorin (IFL) prolonged median survival in patients with metastatic colorectal cancer. We carried out a retrospective analysis of patients in the trial to evaluate whether mutation status of k-ras, b-raf, or p53 or P53 expression could predict which patients were more likely to respond to bevacizumab. Methods: Microdissected tumors from 295 patients (274 primary tumors, 21 metastases) were subject to DNA sequence analysis to identify mutations in k-ras, b-raf, and p53. Nuclear P53 expression was determined by immunohistochemistry. Hazard ratios and 95% confidence intervals (CI) for overall survival were estimated using Cox regression analysis. Results: In all biomarker subgroups, estimated hazard ratios for risk of death were less than 1 for bevacizumab-treated patients as compared with those for placebo-treated patients. Mutations in k-ras and/or b-raf were observed in 88 of 213 patients (41%). Hazard ratios for death among patients with tumors with wild-type k-ras/b-raf status, as compared with those of patients with mutations in one or both genes, were 0.51 (95% CI = 0.28 to 0.95) among those treated with IFL plus bevacizumab and 0.66 (95% CI = 0.37 to 1.18) among those treated with IFL plus placebo. Mutations in p53 were found in 139 of 205 patients (68%), and P53 was overexpressed in 191 of 266 patients (72%); neither p53 mutation nor P53 overexpression was statistically significantly associated with survival. Conclusions: We did not find a statistically significant relationship between mutations of k-ras, b-raf, or p53 and the increase in median survival associated with the addition of bevacizumab to IFL in metastatic colorectal cancer. © The Author 2005. Published by Oxford University Press. All rights reserved.

Authors
Ince, WL; Jubb, AM; Holden, SN; Holmgren, EB; Tobin, P; Sridhar, M; Hurwitz, HI; Kabbinavar, F; Novotny, WF; Hillan, KJ; Koeppen, H
MLA Citation
Ince, WL, Jubb, AM, Holden, SN, Holmgren, EB, Tobin, P, Sridhar, M, Hurwitz, HI, Kabbinavar, F, Novotny, WF, Hillan, KJ, and Koeppen, H. "Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab." Journal of the National Cancer Institute 97.13 (2005): 981-989.
PMID
15998951
Source
scival
Published In
Journal of the National Cancer Institute
Volume
97
Issue
13
Publish Date
2005
Start Page
981
End Page
989
DOI
10.1093/jnci/dji174

New combinations in metastatic colorectal cancer: What are our expectations?

Authors
Hurwitz, H
MLA Citation
Hurwitz, H. "New combinations in metastatic colorectal cancer: What are our expectations?." Oncologist 10.5 (2005): 320-322.
PMID
15851788
Source
scival
Published In
Oncologist
Volume
10
Issue
5
Publish Date
2005
Start Page
320
End Page
322
DOI
10.1634/theoncologist.10-5-320

Angiogenesis pathway inhibitors.

Authors
Herbst, RS; LoRusso, P; Isobe, T; Hurwitz, HI
MLA Citation
Herbst, RS, LoRusso, P, Isobe, T, and Hurwitz, HI. "Angiogenesis pathway inhibitors." Cancer chemotherapy and biological response modifiers 22 (2005): 225-245.
PMID
16110614
Source
scival
Published In
Cancer chemotherapy and biological response modifiers
Volume
22
Publish Date
2005
Start Page
225
End Page
245

Combined analysis of efficacy: The addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer

Purpose: Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA), a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody that inhibits tumor angiogenesis, has demonstrated survival benefit in patients with previously untreated metastatic colorectal cancer when combined with irinotecan/fluourouracil (FU)/leucovorin (LV; IFL). Three randomized clinical studies have evaluated bevacizumab in combination with FU/LV alone. A combined analysis of raw data from these studies was performed to better assess the efficacy of bevacizumab with FU/LV. Patients and Methods: The analysis used primary efficacy data from three independent studies, including 241 patients in a combined control group receiving either FU/LV or IFL and 249 patients receiving FU/LV/bevacizumab (5 mg/kg once every 2 weeks). The efficacy data included response rate, progression-free survival, and overall survival. Results: The median duration of survival was 17.9 months in the FU/LV/bevacizumab group, compared with 14.6 months in the combined control group, corresponding to a hazard ratio for death of 0.74 (P = .008). The median duration of progression-free survival was 8.8 months in the FU/LV/bevacizumab group, compared with 5.6 months in the combined control group, corresponding to a hazard ratio for disease progression of 0.63 (P ≤ .0001). The addition of bevacizumab also improved the response rate (34.1% v 24.5%; P = .019). Conclusion: The addition of bevacizumab to FU/LV provides a statistically significant and clinically relevant benefit to patients with previously untreated metastatic colorectal cancer. © 2005 by American Society of Clinical Oncology.

Authors
Kabbinavar, FF; Hambleton, J; Mass, RD; Hurwitz, HI; Bergsland, E; Sarkar, S
MLA Citation
Kabbinavar, FF, Hambleton, J, Mass, RD, Hurwitz, HI, Bergsland, E, and Sarkar, S. "Combined analysis of efficacy: The addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer." Journal of Clinical Oncology 23.16 (2005): 3706-3712.
PMID
15867200
Source
scival
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
3706
End Page
3712
DOI
10.1200/JCO.2005.00.232

Complications of pancreaticoduodenectomy after neoadjuvant chemoradiation in patients with and without preoperative biliary drainage.

BACKGROUND: It has been suggested that preoperative biliary drainage increases the risk of infectious complications of pancreaticoduodenectomy. AIMS: The aim of this study was to assess complications related to biliary stents/drains and postoperative morbidity in patients undergoing neoadjuvant chemoradiotherapy for periampullary cancer. PATIENTS: One hundred and eighty-four patients with periampullary neoplasms were prospectively selected for neoadjuvant external beam radiation therapy and 5-fluorouracil-based chemotherapy between 1995 and 2002. METHODS: The data were retrospectively completed and analysed with respect to biliary drainage, efficacy and complications of endoscopic biliary stents and postoperative morbidity. Patients who had undergone a surgical biliary bypass were excluded. RESULTS: Data were completed in 168 patients. One hundred and nineteen patients were treated with endoscopic biliary stents, 18 patients had a percutaneous biliary drain and 31 patients did not require biliary drainage. Hospitalisation for stent-related complications was necessary in 15% of the patients with endoscopic biliary stents. Seventy-two patients underwent pancreaticoduodenectomy. There was no significant difference in the rate of wound infections, intra-abdominal abscesses and overall complications between the groups with and without preoperative biliary drainage. CONCLUSIONS: Postoperative infectious complications are common in patients both with and without preoperative biliary drainage. A statistically significant difference in complication rates was not observed between these groups.

Authors
Gerke, H; White, R; Byrne, MF; Stiffier, H; Mitchell, RM; Hurwitz, HI; Morse, MA; Branch, MS; Jowell, PS; Czito, B; Clary, B; Pappas, TN; Tyler, DS; Baillie, J
MLA Citation
Gerke, H, White, R, Byrne, MF, Stiffier, H, Mitchell, RM, Hurwitz, HI, Morse, MA, Branch, MS, Jowell, PS, Czito, B, Clary, B, Pappas, TN, Tyler, DS, and Baillie, J. "Complications of pancreaticoduodenectomy after neoadjuvant chemoradiation in patients with and without preoperative biliary drainage." Dig Liver Dis 36.6 (June 2004): 412-418.
PMID
15248382
Source
pubmed
Published In
Digestive and Liver Disease
Volume
36
Issue
6
Publish Date
2004
Start Page
412
End Page
418

A Phase I trial of preoperative eniluracil plus 5-fluorouracil and radiation for locally advanced or unresectable adenocarcinoma of the rectum and colon.

PURPOSE: Eniluracil, an effective inactivator of dihydropyrimidine dehydrogenase, allows for oral dosing of 5-fluorouracil (5-FU), which avoids the morbidity of continuous infusion 5-FU. We addressed the safety of oral eniluracil and 5-FU combined with preoperative radiotherapy and determined the recommended Phase II dose and dose-limiting toxicity in patients with locally advanced rectal and colon cancer. METHODS AND MATERIALS: Patients with TNM Stage II or III rectal cancer and residual or recurrent colon cancer received eniluracil (starting at 6.0 mg/m(2) every 12 h) and 5-FU (starting at 0.6 mg/m(2) every 12 h). Eniluracil and 5-FU were given with a 5-week course of preoperative radiotherapy of 4500 cGy, with a possible 540-cGy boost. Surgery was performed approximately 4 weeks after completion of chemoradiotherapy. RESULTS: Twenty-two patients were enrolled; 1 patient was withdrawn owing to noncompliance. Chemotherapy was completed in all patients; radiotherapy was completed in 20 patients. The recommended Phase II dose of eniluracil and 5-FU was 8 mg/m(2) every 12 h and 0.8 mg/m(2) every 12 h, respectively. Diarrhea was the dose-limiting toxicity. Eleven of the 17 patients with primary rectal cancer underwent a sphincter-sparing procedure. One patient had a pathologic complete response. CONCLUSION: Preoperative chemoradiotherapy with oral eniluracil and 5-FU is feasible and well tolerated. Additional investigation is warranted.

Authors
Czito, BG; Hong, TJ; Cohen, DP; Tyler, DS; Lee, CG; Anscher, MS; Ludwig, KA; Seigler, HF; Mantyh, C; Morse, MA; Lockhart, AC; Petros, WP; Honeycutt, W; Spector, NL; Ertel, PJ; Mangum, SG; Hurwitz, HI
MLA Citation
Czito, BG, Hong, TJ, Cohen, DP, Tyler, DS, Lee, CG, Anscher, MS, Ludwig, KA, Seigler, HF, Mantyh, C, Morse, MA, Lockhart, AC, Petros, WP, Honeycutt, W, Spector, NL, Ertel, PJ, Mangum, SG, and Hurwitz, HI. "A Phase I trial of preoperative eniluracil plus 5-fluorouracil and radiation for locally advanced or unresectable adenocarcinoma of the rectum and colon." Int J Radiat Oncol Biol Phys 58.3 (March 1, 2004): 779-785.
PMID
14967434
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
58
Issue
3
Publish Date
2004
Start Page
779
End Page
785
DOI
10.1016/S0360-3016(03)01567-0

Circulating D-dimer levels are better predictors of overall survival and disease progression than carcinoembryonic antigen levels in patients with metastatic colorectal carcinoma

BACKGROUND. Fibrin formation is required for tumor angiogenesis, metastasis, and invasion. D-dimer, a fibrin degradation product, is produced when crosslinked fibrin is degraded by plasmin. The current study prospectively examined D-dimer levels in patients with metastatic colorectal carcinoma treated in a Phase II randomized trial comparing bevacizumab (Avastin, Genentech, South San Francisco, CA) plus 5-fluorouracil/leucovorin (5-FU/LV) with 5-FU/LV alone. METHODS. At least one circulating D-dimer level was evaluable in 98 of the 104 previously untreated patients with metastatic colorectal carcinoma in the current trial. Plasma D-dimer levels were determined using a quantitative immunoassay kit at enrollment, before each treatment, and at the time of trial completion or disease progression. RESULTS. At trial enrollment, 86 of 104 patients (88%) had elevated D-dimer levels (> 20 ng/mL), and 86 of 102 patients (84%) had elevated carcinoembryonic antigen (CEA) levels (> 3 ng/mL). Baseline D-dimer levels were correlated with the following baseline characteristics: CEA (Pearson coefficient, 0.31; P = 0.002), albumin levels (Pearson coefficient, -0.32; P = 0.002), tumor burden (Pearson coefficient, 0.30; P = 0.003), and number of metastatic sites (Pearson coefficient, 0.21; P = 0.04). At the time of progression, plasma D-dimer levels reached a maximum postbaseline value in 51 of 61 patients (84%), whereas the CEA level was at its maximum postbaseline value in 39 of 55 patients (71%). Baseline D-dimer levels were a strong predictor of overall survival on univariate analysis (P = 0.008) and multivariate analysis (P = 0.03). Overall, treatment with bevacizumab (5 mg/kg) and baseline D-dimer levels were the only predictors of overall survival (P < 0.05). CONCLUSIONS. The current study indicates that fibrin remodeling is an important prognostic feature in metastatic colorectal carcinoma. D-dimer levels should be incorporated into prognostic models, and D-dimer may represent a useful biomarker for patients treated with antiangiogenic agents. © 2004 American Cancer Society.

Authors
Blackwell, K; Hurwitz, H; Liebérman, G; Novotny, W; Snyder, S; Dewhirst, M; Greenberg, C
MLA Citation
Blackwell, K, Hurwitz, H, Liebérman, G, Novotny, W, Snyder, S, Dewhirst, M, and Greenberg, C. "Circulating D-dimer levels are better predictors of overall survival and disease progression than carcinoembryonic antigen levels in patients with metastatic colorectal carcinoma." Cancer 101.1 (2004): 77-82.
PMID
15221991
Source
scival
Published In
Cancer
Volume
101
Issue
1
Publish Date
2004
Start Page
77
End Page
82
DOI
10.1002/cncr.20336

Bevacizumab in colorectal cancer [2] (multiple letters)

Authors
Sonpavde, G; Sharieff, W; Hurwitz, HI; Novotny, W; Kabbinavar, F
MLA Citation
Sonpavde, G, Sharieff, W, Hurwitz, HI, Novotny, W, and Kabbinavar, F. "Bevacizumab in colorectal cancer [2] (multiple letters)." New England Journal of Medicine 351.16 (2004): 1690-1691.
PMID
15483292
Source
scival
Published In
New England Journal of Medicine
Volume
351
Issue
16
Publish Date
2004
Start Page
1690
End Page
1691
DOI
10.1056/NEJM200410143511622

Integrating the anti-VEGF - A humanized monoclonal antibody bevacizumab with chemotherapy in advanced colorectal cancer

Recent advances in the treatment of colorectal cancer (CRC) include the incorporation of new drugs to treat a disease where only one drug was known to be active. Oxaliplatin and irinotecan have been incorporated into 5-fluorouracil (5-FU)-based regimens where they have increased response rates and survival. Targeted therapies against the epidermal growth factor pathway and the vascular endothelial growth factor (VEGF) pathway are also on the forefront of oncology research, and are beginning to play a role in the treatment of CRC. Current research efforts are trying to optimize the integration of targeted therapies into chemotherapy regimens such as IFL (irinotecan/bolus 5-FU/leucovorin [LV]), FOLFIRI (irinotecan/infusional 5-FU/LV), and FOLFOX (oxaliplatin/infusional 5-FU/LV). In this article, the incorporation of the monoclonal antibody bevacizumab into the IFL regimen will be reviewed in detail. Bevacizumab targets VEGF-A, an important angiogenesis signaling factor commonly expressed in metastatic CRC. The addition of bevacizumab to the IFL regimen significantly increased response rates, median time to progression, and overall survival in patients receiving first-line treatment for CRC, thus leading the Food and Drug Administration to approve bevacizumab for the treatment of CRC in combination with 5-FU-based regimens. Bevacizumab treatment is associated with an increased rate of hypertension. In addition, there may be slight (1%-2%) but relevant increased risks related to gastrointestinal perforations and cardiovascular events. A modest increased risk of wound healing complications was observed in patients who underwent surgery while still receiving, or shortly after receiving, bevacizumab. Bevacizumab plus 5-FU is also 4 highly active first-line regimen. The role of bevacizumab with other first-line combination regimens, as well as its activity in the second-line setting, is now being determined by ongoing clinical trials.

Authors
Hurwitz, H
MLA Citation
Hurwitz, H. "Integrating the anti-VEGF - A humanized monoclonal antibody bevacizumab with chemotherapy in advanced colorectal cancer." Clinical Colorectal Cancer 4.SUPPL. 2 (2004): S62-S68.
Source
scival
Published In
Clinical colorectal cancer
Volume
4
Issue
SUPPL. 2
Publish Date
2004
Start Page
S62
End Page
S68

Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. METHODS: Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. RESULTS: The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progression-free survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. CONCLUSIONS: The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer. Copyright © 2004 Massachusetts Medical Society.

Authors
Hurwitz, H; Fehrenbacher, L; Novotny, W; Cartwright, T; Hainsworth, J; Heim, W; Berlin, J; Baron, A; Griffing, S; Holmgren, E; Ferrara, N; Fyfe, G; Rogers, B; Ross, R; Kabbinavar, F
MLA Citation
Hurwitz, H, Fehrenbacher, L, Novotny, W, Cartwright, T, Hainsworth, J, Heim, W, Berlin, J, Baron, A, Griffing, S, Holmgren, E, Ferrara, N, Fyfe, G, Rogers, B, Ross, R, and Kabbinavar, F. "Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer." New England Journal of Medicine 350.23 (2004): 2335-2342.
PMID
15175435
Source
scival
Published In
The New England journal of medicine
Volume
350
Issue
23
Publish Date
2004
Start Page
2335
End Page
2342
DOI
10.1056/NEJMoa032691

The Damjanov/Meropol article reviewed

Authors
Collins, TS; Hurwitz, HI
MLA Citation
Collins, TS, and Hurwitz, HI. "The Damjanov/Meropol article reviewed." ONCOLOGY 18.4 (2004): 488-493.
Source
scival
Published In
Oncology
Volume
18
Issue
4
Publish Date
2004
Start Page
488
End Page
493

A Phase I Study of Oral BMS-275291, a Novel Nonhydroxamate Sheddase-Sparing Matrix Metalloproteinase Inhibitor, in Patients with Advanced or Metastatic Cancer

Purpose: BMS-275291 is a novel broad-spectrum inhibitor of matrix metalloproteinase (MMPs) rationally designed to spare a class of closely related metalloproteinases known as sheddases. Inadvertent sheddase inhibition is hypothesized to play a role in the dose-limiting joint toxicities occurring with hydroxamate-based MMP inhibitors. This trial was conducted to establish the recommended phase II dose; determine safety, toxicity, and pharmacokinetics of BMS-275291; and to assess potential markers of sheddase activity [tumor necrosis factor-α (TNFα) release and TNFα-RII shedding]. Experimental Design: This was an open label, single arm, phase I study conducted at two centers. Patients with advanced or metastatic cancer were treated with once-daily oral BMS-275291 at doses escalating from 600 to 2400 mg/ day. Six to eight patients/dose level were to be studied with the recommended phase II dose level expanded to a total of 15 patients. Pharmacokinetic sampling was performed on days 1, 15, and 29 at 0, 0.5, 1, 2, 4, 6, 8, and 24 h after dosing. Radiological tumor assessment was performed every 8 weeks. Results: Forty-four evaluable patients were enrolled in this study with the most frequent tumor types being colorectal cancer and non-small cell lung cancer. Dose limiting toxicities were observed at 600 mg/day (one of eight patients with grade 3 transaminitis) and at 1200 mg/day (1 of 15 patients with grade 3 rash and grade 4 shortness of breath), both in the context of predisposing conditions. No dose-limiting toxicities occurred at 900, 1800, or 2400 mg/day. The most frequent adverse events considered possibly, probably, or definitely drug-related were joint toxicity (myalgia/ arthralgia), rash, fatigue, headache, nausea, and taste change, all of which were mild, grade 1, grade 2, and not dose-limiting. No objective tumor responses were observed. Twelve of forty-four patients received treatment for 4+ months, six for 8+ months, three for >1 year. Desired trough levels of parent BMS-275291 were maintained with once daily dosing. The mean plasma concentration of parent BMS-275291 at trough exceeded the calculated in vitro IC80 value for MMP-2 and IC90 value for MMP-9 at the recommended phase II dose of 1200 mg/day. No major changes in serum concentrations of sheddase enzymatic products, TNFα of TNFα-RII, were observed. Conclusions: BMS-275291 is a nonhydroxamate MMP inhibitor with a novel mercaptoacyl zinc-binding group. In this study, plasma concentrations of BMS-275291 continuously exceeded in vitro MMP IC50 values without dose-limiting joint toxicity. In this refractory patient population, a suggestion of disease stabilization was observed in 12 patients. On the basis of preclinical, clinical, and pharmacokinetic data, the recommended phase II dose for future study is 1200 mg/day.

Authors
Rizvi, NA; Humphrey, JS; Ness, EA; Johnson, MD; Gupta, E; Williams, K; Daly, DJ; Sonnichsen, D; Conway, D; Marshall, J; Hurwitz, H
MLA Citation
Rizvi, NA, Humphrey, JS, Ness, EA, Johnson, MD, Gupta, E, Williams, K, Daly, DJ, Sonnichsen, D, Conway, D, Marshall, J, and Hurwitz, H. "A Phase I Study of Oral BMS-275291, a Novel Nonhydroxamate Sheddase-Sparing Matrix Metalloproteinase Inhibitor, in Patients with Advanced or Metastatic Cancer." Clinical Cancer Research 10.6 (2004): 1963-1970.
PMID
15041713
Source
scival
Published In
Clinical Cancer Research
Volume
10
Issue
6
Publish Date
2004
Start Page
1963
End Page
1970
DOI
10.1158/1078-0432.CCR-1183-02

Targeted therapy of colorectal cancer: clinical experience with bevacizumab.

Advanced colorectal cancer remains an urgent health concern, despite improvements in systemic chemotherapy. Targeted therapeutics promise effective tumor therapy with minimal side effects. Angiogenesis (the formation of new blood vessels) is essential for tumor growth and metastasis and may be an ideal target in the search for new antineoplastic agents. Vascular endothelial growth factor is one of the best characterized of the proangiogenic growth factors that regulate angiogenesis and is a logical target in colorectal cancer therapy. Bevacizumab (Avastin; Genentech Inc.; South San Francisco, CA), a humanized murine monoclonal antibody directed at vascular endothelial growth factor, is being evaluated in the treatment of various types of cancer. It has shown promising efficacy in phase II clinical trials in patients with metastatic colorectal cancer. Addition of bevacizumab at a dose of 5 mg/kg to chemotherapy (5-fluorouracil plus leucovorin) resulted in a higher objective response rate (40% versus 17%), longer time to disease progression (9.0 versus 5.2 months), and longer median survival time (21.5 versus 13.8 months). Hypertension and thrombosis were the principal safety concerns, but were manageable. Further phase II/III studies of bevacizumab, administered with 5-fluorouracil plus leucovorin, with or without irinotecan and/or oxaliplatin, in colorectal cancer, are under way.

Authors
Fernando, NH; Hurwitz, HI
MLA Citation
Fernando, NH, and Hurwitz, HI. "Targeted therapy of colorectal cancer: clinical experience with bevacizumab." Oncologist 9 Suppl 1 (2004): 11-18. (Review)
PMID
15178811
Source
pubmed
Published In
The oncologist
Volume
9 Suppl 1
Publish Date
2004
Start Page
11
End Page
18

Introduction: Targeting angiogenesis in cancer therapy

Authors
Hurwitz, HI
MLA Citation
Hurwitz, HI. "Introduction: Targeting angiogenesis in cancer therapy." Oncologist 9.SUPPL. 1 (2004): 1--.
Source
scival
Published In
Oncologist
Volume
9
Issue
SUPPL. 1
Publish Date
2004
Start Page
1-

Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs. percutaneous FNA.

BACKGROUND: Studies have suggested an increased risk of peritoneal seeding in patients with pancreatic cancer diagnosed by percutaneous FNA. EUS-FNA is an alternate method of diagnosis. The aim of this study was to compare the frequency of peritoneal carcinomatosis as a treatment failure pattern in patients with pancreatic cancer diagnosed by EUS-FNA vs. percutaneous FNA. METHODS: Retrospective review of patients with non-metastatic pancreatic cancer identified 46 patients in whom the diagnosis was made by EUS-FNA and 43 with the diagnosis established by percutaneous FNA. All had neoadjuvant chemoradiation. Patients underwent restaging CT after completion of therapy, followed by attempted surgical resection if there was no evidence of disease progression. RESULTS: There were no significant differences in tumor characteristics between the two study groups. In the EUS-FNA group, one patient had developed peritoneal carcinomatosis compared with 7 in the percutaneous FNA group (2.2% vs. 16.3%; p<0.025). No patient with a potentially resectable tumor in the EUS-FNA group had developed peritoneal carcinomatosis. CONCLUSIONS: Peritoneal carcinomatosis may occur more frequently in patients who undergo percutaneous FNA compared with those who have EUS-FNA for the diagnosis of pancreatic cancer. A concern for peritoneal seeding of pancreatic cancer via percutaneous FNA is warranted. EUS-guided FNA is recommended as the method of choice for diagnosis in patients with potentially resectable pancreatic cancer.

Authors
Micames, C; Jowell, PS; White, R; Paulson, E; Nelson, R; Morse, M; Hurwitz, H; Pappas, T; Tyler, D; McGrath, K
MLA Citation
Micames, C, Jowell, PS, White, R, Paulson, E, Nelson, R, Morse, M, Hurwitz, H, Pappas, T, Tyler, D, and McGrath, K. "Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs. percutaneous FNA." Gastrointest Endosc 58.5 (November 2003): 690-695.
PMID
14595302
Source
pubmed
Published In
Gastrointestinal Endoscopy
Volume
58
Issue
5
Publish Date
2003
Start Page
690
End Page
695

A clinical model of dermal wound angiogenesis.

Full-thickness dermal biopsies were performed in healthy volunteers to establish the range of angiogenic responses in wound healing in a normal population. Four-millimeter punch biopsies were made in the forearms of 15 healthy volunteers. Each wound was evaluated microscopically 4-5 times per week for 2 weeks. A semiquantitative wound scoring system to evaluate the neovasculature at the wound periphery was investigated. A vascular score was calculated for each wound at each observation. Two independent observers analyzed the microscopic wound images using the scoring system. At the end of the 14-day period, repeat biopsies were performed on some of the volunteers, and the granulation tissue was stained with anti-CD31. The Kaplan-Meier method was used to estimate the distribution of the time to reach predetermined target average vascular scores. A mixed-effects regression model indicated that time, age, and observer were predictors for the average vascular score outcome. The pattern and time course for wound neovascularization was highly reproducible in this group of healthy volunteers, and the assay was feasible and well tolerated. This wound angiogenesis model may be useful for monitoring the effects of antiangiogenic agents on normal wound neovascularization.

Authors
Lockhart, AC; Braun, RD; Yu, D; Ross, JR; Dewhirst, MW; Klitzman, B; Yuan, F; Grichnik, JM; Proia, AD; Conway, DA; Mann, G; Hurwitz, HI
MLA Citation
Lockhart, AC, Braun, RD, Yu, D, Ross, JR, Dewhirst, MW, Klitzman, B, Yuan, F, Grichnik, JM, Proia, AD, Conway, DA, Mann, G, and Hurwitz, HI. "A clinical model of dermal wound angiogenesis." Wound Repair Regen 11.4 (July 2003): 306-313.
PMID
12846919
Source
pubmed
Published In
Wound Repair and Regeneration
Volume
11
Issue
4
Publish Date
2003
Start Page
306
End Page
313

Adjuvant hepatic arterial chemotherapy following metastasectomy in patients with isolated liver metastases.

OBJECTIVE: To examine survival and toxicity by querying a single-institutional experience with adjuvant hepatic arterial infusional (HAI) chemotherapy. SUMMARY BACKGROUND DATA: Three randomized series in the literature have examined adjuvant HAI after complete resection of liver metastases. Only one of these trials showed an overall survival benefit at 2 years but not over the entire time period of the study. Previous studies in patients with unresectable disease were plagued by high rates of biliary toxicity. METHODS: A retrospective review of a prospectively maintained database was performed. Hepatic arterial pumps were placed in the standard fashion. Patients received floxuridine at doses previously demonstrated as safe in the literature. Standard statistical methods were used. RESULTS: Twenty-one of 92 patients underwent placement of hepatic arterial pumps at the time of liver resection. The HAI group was similar in all demographic measures to the non-HAI group, with the exception that the HAI patients were significantly younger. No differences were seen between the groups in either disease-free or overall survival, although a trend toward improved hepatic progression-free survival was noted. Significant biliary sclerosis developed in six patients in the HAI group, requiring chronic indwelling stents in four patients. One patient died of progressive liver failure associated with this toxicity. CONCLUSIONS: Biliary toxicity is an important potential side effect of hepatic arterial chemotherapy. Although larger randomized studies and this one suggest significant improvements in hepatic recurrences, these have not reliably translated into overall survival benefit. This fact, in light of the potential toxicity, would argue for a larger confirmatory trial of HAI in the adjuvant setting, incorporating recent advances in systemic therapy and careful attention to hepatotoxicity.

Authors
Onaitis, M; Morse, M; Hurwitz, H; Cotton, P; Tyler, D; Clavien, P; Clary, B
MLA Citation
Onaitis, M, Morse, M, Hurwitz, H, Cotton, P, Tyler, D, Clavien, P, and Clary, B. "Adjuvant hepatic arterial chemotherapy following metastasectomy in patients with isolated liver metastases." Ann Surg 237.6 (June 2003): 782-788.
PMID
12796574
Source
pubmed
Published In
Annals of Surgery
Volume
237
Issue
6
Publish Date
2003
Start Page
782
End Page
788
DOI
10.1097/01.SLA.0000071561.76384.19

Immunotherapy with autologous, human dendritic cells transfected with carcinoembryonic antigen mRNA.

Immunizations with dendritic cells (DC) transfected with RNA encoding tumor antigens induce potent tumor antigen-specific immune responses in vitro and in murine models. We performed a phase I study of patients with advanced carcinoembryonic antigen (CEA)-expressing malignancies followed by a phase II study of patients with resected hepatic metastases of colon cancer to assess safety and feasibility of administering autologous DC loaded with CEA mRNA. The immunizations were well tolerated. Of the 24 evaluable patients in the dose-escalation phase, there was 1 complete response (by tumor marker), 2 minor responses, 3 with stable disease, and 18 with progressive disease. In the phase II study, 9 of 13 patients have relapsed at a median of 122 days. Evidence of an immunologic response was demonstrated in biopsies of DC injection sites and peripheral blood of selected patients. We conclude that it is feasible and safe to administer mRNA-loaded DC to patients with advanced malignancies.

Authors
Morse, MA; Nair, SK; Mosca, PJ; Hobeika, AC; Clay, TM; Deng, Y; Boczkowski, D; Proia, A; Neidzwiecki, D; Clavien, P-A; Hurwitz, HI; Schlom, J; Gilboa, E; Lyerly, HK
MLA Citation
Morse, MA, Nair, SK, Mosca, PJ, Hobeika, AC, Clay, TM, Deng, Y, Boczkowski, D, Proia, A, Neidzwiecki, D, Clavien, P-A, Hurwitz, HI, Schlom, J, Gilboa, E, and Lyerly, HK. "Immunotherapy with autologous, human dendritic cells transfected with carcinoembryonic antigen mRNA." Cancer Invest 21.3 (June 2003): 341-349.
PMID
12901279
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
21
Issue
3
Publish Date
2003
Start Page
341
End Page
349

The social context of gastrointestinal cancer pain: a preliminary study examining the relation of patient pain catastrophizing to patient perceptions of social support and caregiver stress and negative responses.

A number of studies have shown that catastrophizing is an important predictor of pain and disability in persons having persistent pain conditions. The newly developed communal model of catastrophizing maintains that catastrophizing is a part of broader, interpersonal style of coping in which coping efforts are directed at interpersonal goals, rather than solely at pain reduction. This study examined the potential interpersonal correlates of pain catastrophizing in a sample of 70 patients having gastrointestinal cancers and their caregivers. Measures of pain catastrophizing, perceptions of social support, pain level, and pain behavior were obtained from patients. Caregivers completed measures that included their judgments about the patient's pain level, caregiver stress, and their tendency to engage in negative responses (critical or avoidant behaviors). Overall, patients who engaged in catastrophizing reported receiving higher levels of instrumental support. Caregivers of patients who catastrophized, rated the patient as having more pain and engaging in more pain behavior. Caregivers of patients who catastrophized, also reported higher levels of caregiver stress and critical behaviors. Taken together, these preliminary findings suggest that pain catastrophizing has interpersonal correlates and support the need for additional research examining the social context of pain catastrophizing.

Authors
Keefe, FJ; Lipkus, I; Lefebvre, JC; Hurwitz, H; Clipp, E; Smith, J; Porter, L
MLA Citation
Keefe, FJ, Lipkus, I, Lefebvre, JC, Hurwitz, H, Clipp, E, Smith, J, and Porter, L. "The social context of gastrointestinal cancer pain: a preliminary study examining the relation of patient pain catastrophizing to patient perceptions of social support and caregiver stress and negative responses." Pain 103.1-2 (May 2003): 151-156.
PMID
12749969
Source
pubmed
Published In
PAIN
Volume
103
Issue
1-2
Publish Date
2003
Start Page
151
End Page
156

Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor.

PURPOSE: The purpose of this study was to evaluate the feasibility of incorporating a novel wound angiogenesis assay into a Phase I study of BMS-275291, a broad-spectrum matrix metalloproteinase inhibitor, and to determine whether the wound angiogenesis assay was able to detect the inhibition of angiogenesis in patients treated with BMS-275291. EXPERIMENTAL DESIGN: Before treatment began, a 4-mm skin biopsy was performed. The wound was imaged for 14 days. Treatment was started on day 0, and a separate 4-mm biopsy was performed 14 days later. The second wound was also imaged for 14 days. Wound angiogenesis was scored by two independent observers who were blinded to treatment status. RESULTS: The median times in days (95% confidence interval) to reach the target average vascular score (AVS) of 1.5 and 2.0 based on the data of Observer 1 were 3.7 (2.2-6.9) and 8.0 (5.0-10.0) pretreatment whereas on-treatment the values were 4.9 (3.7-8.0) and 9.3 (7.0-11.5), respectively. The delay in the median time to reach an AVS of 1.5 was 1.2 days or a 32% reduction when comparing pretreatment with on-treatment (P = 0.06). For the target AVS of 2.0 the delay in the median time pretreatment versus on-treatment was 1.3 days or a 16% reduction (P = 0.04). CONCLUSIONS: The wound angiogenesis assay used in this study was practical, well tolerated, and reproducible. Delays in wound angiogenesis because of BMS-275291 were detectable with this assay. This technique warrants additional investigation in clinical trials of other antiangiogenic agents.

Authors
Lockhart, AC; Braun, RD; Yu, D; Ross, JR; Dewhirst, MW; Humphrey, JS; Thompson, S; Williams, KM; Klitzman, B; Yuan, F; Grichnik, JM; Proia, AD; Conway, DA; Hurwitz, HI
MLA Citation
Lockhart, AC, Braun, RD, Yu, D, Ross, JR, Dewhirst, MW, Humphrey, JS, Thompson, S, Williams, KM, Klitzman, B, Yuan, F, Grichnik, JM, Proia, AD, Conway, DA, and Hurwitz, HI. "Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor." Clin Cancer Res 9.2 (February 2003): 586-593.
PMID
12576422
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
2
Publish Date
2003
Start Page
586
End Page
593

Inhibition of vascular endothelial growth factor in the treatment of colorectal cancer

Angiogenesis is essential for tumor growth and metastasis and is a promising target in the search for new anti-neoplastic agents. Angiogenesis is a tightly regulated process dependent on the complex interplay between inhibitory and stimulatory angiogenic factors. Vascular endothelial growth factor is one of the best characterized of the pro-angiogenic growth factors, and multiple strategies have been developed to inhibit this pathway. Bevacizumab, a monoclonal antibody developed against vascular endothelial growth factor, has shown initial preclinical and clinical activity. This review will outline the conceptual basis of anti-angiogenic therapy, discuss the critical role of vascular endothelial growth factor, and summarize the available data on the use of bevacizumab in colorectal cancer. © 2003 Elsevier Inc. All rights reserved.

Authors
Fernando, NH; Hurwitz, HI
MLA Citation
Fernando, NH, and Hurwitz, HI. "Inhibition of vascular endothelial growth factor in the treatment of colorectal cancer." Seminars in Oncology 30.3 SUPPL. 6 (2003): 39-50.
Source
scival
Published In
Seminars in Oncology
Volume
30
Issue
3 SUPPL. 6
Publish Date
2003
Start Page
39
End Page
50
DOI
10.1016/S0093-7754(03)00124-6

Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer.

PURPOSE: This phase II trial investigated the safety and efficacy of two doses of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, plus fluorouracil (FU)/leucovorin (LV) versus FU/LV alone in patients with metastatic colorectal cancer. PATIENTS AND METHODS: One hundred four previously untreated patients with measurable metastatic colorectal cancer were randomly assigned to one of the following three treatment groups: 36 to FU (500 mg/m(2))/LV (500 mg/m(2)) alone, 35 to FU/LV + low-dose bevacizumab (5 mg/kg every 2 weeks), and 33 to FU/LV + high-dose bevacizumab (10 mg/kg every 2 weeks). FU/LV was given weekly for the first 6 weeks of each 8-week cycle. RESULTS: Compared with the FU/LV control arm, treatment with bevacizumab (at both dose levels) plus FU/LV resulted in higher response rates (control arm, 17%, 95% confidence interval [CI], 7% to 34%; low-dose arm, 40%, 95% CI, 24% to 58%; high-dose arm, 24%, 95% CI, 12% to 43%), longer median time to disease progression (control arm, 5.2 months, 95% CI, 3.5 to 5.6 months; low-dose arm, 9.0 months, 95% CI, 5.8 to 10.9 months; high-dose arm, 7.2 months, 95% CI, 3.8 to 9.2 months), and longer median survival (control arm, 13.8 months; 95% CI, 9.1 to 23.0 months; low-dose arm, 21.5 months, 95% CI, 17.3 to undetermined; high-dose arm, 16.1 months; 95% CI, 11.0 to 20.7 months). After cross-over, two of 22 patients had a partial response to bevacizumab alone. Thrombosis was the most significant adverse event and was fatal in one patient. Hypertension, proteinuria, and epistaxis were other potential safety concerns. CONCLUSION: The encouraging results of this randomized trial support further study of bevacizumab 5 mg/kg plus chemotherapy as first-line therapy for metastatic colorectal cancer.

Authors
Kabbinavar, F; Hurwitz, HI; Fehrenbacher, L; Meropol, NJ; Novotny, WF; Lieberman, G; Griffing, S; Bergsland, E
MLA Citation
Kabbinavar, F, Hurwitz, HI, Fehrenbacher, L, Meropol, NJ, Novotny, WF, Lieberman, G, Griffing, S, and Bergsland, E. "Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 21.1 (2003): 60-65.
PMID
12506171
Source
scival
Published In
Journal of Clinical Oncology
Volume
21
Issue
1
Publish Date
2003
Start Page
60
End Page
65

Analysis of age, estimated creatinine clearance and pretreatment hematologic parameters as predictors of fludarabine toxicity in patients treated for chronic lymphocytic leukemia: a CALGB (9011) coordinated intergroup study.

PURPOSE: Fludarabine is a renally excreted agent that is an effective treatment for chronic lymphocytic leukemia (CLL), a disease predominantly of the elderly. We sought to determine whether age, renal function or pretreatment hematologic status predicted toxicity of fludarabine treatment for CLL. METHODS: We evaluated 192 patients with previously untreated B-cell CLL who were entered onto the fludarabine treatment arm (25 mg/m(2) daily for 5 days every 28 days) of CALGB study 9011, an intergroup study with participation from SWOG, CTG/NCI-C and ECOG. Patients were required to have serum creatinine within 1.5 times normal. Hematologic indices and infections were recorded during the first 28-day cycle of treatment. A time-to-toxicity endpoint was evaluated over the entire course of fludarabine treatment. Creatinine clearance (CrCl(est)) was estimated using serum creatinine, age and body mass index. RESULTS: The median age was 64 years (range 37-87 years) and median CrCl(est) was 62 ml/min (range 27-162 ml/min, interquartile range 52-79 ml/min). We found no association between age and incidence of hematologic toxicity or infection during the first cycle of treatment. There was a strong association between CrCl(est) and the time-to-toxicity endpoint. Patients with CrCl(est) below 80 ml/min had increased incidence of toxicity during their treatment course ( P<0.0001). Pretreatment anemia, thrombocytopenia and Rai stage were highly associated with the incidence of neutrophil toxicity and grade III/IV hematologic toxicities during the first cycle of treatment ( P<0.0001). CONCLUSIONS: Patient age was not an independent risk factor for fludarabine-related toxicity, but CrCl(est) was associated with time to toxicity.

Authors
Martell, RE; Peterson, BL; Cohen, HJ; Petros, WP; Rai, KR; Morrison, VA; Elias, L; Shepherd, L; Hines, J; Larson, RA; Schiffer, CA; Hurwitz, HI
MLA Citation
Martell, RE, Peterson, BL, Cohen, HJ, Petros, WP, Rai, KR, Morrison, VA, Elias, L, Shepherd, L, Hines, J, Larson, RA, Schiffer, CA, and Hurwitz, HI. "Analysis of age, estimated creatinine clearance and pretreatment hematologic parameters as predictors of fludarabine toxicity in patients treated for chronic lymphocytic leukemia: a CALGB (9011) coordinated intergroup study." Cancer Chemother Pharmacol 50.1 (July 2002): 37-45.
PMID
12111110
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
50
Issue
1
Publish Date
2002
Start Page
37
End Page
45
DOI
10.1007/s00280-002-0443-5

Phase I evaluation of prolonged-infusion gemcitabine with mitoxantrone for relapsed or refractory acute leukemia.

PURPOSE: To ascertain the maximum tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with mitoxantrone at 12 mg/m(2) daily for 3 days in the treatment of acute leukemia. PATIENTS AND METHODS: Thirty-four patients were enrolled. Stratum I consisted of 26 patients, median age 50 years (range, 25 to 71 years), with relapsed or refractory leukemia. Stratum II contained eight patients, median age 62.5 years (range, 38 to 83 years), who had received fewer than three cycles of myelotoxic therapy for chronic myeloid leukemia or myelodysplasia that had evolved into leukemia. Patients received mitoxantrone at 12 mg/m(2) daily for 3 days. After the first mitoxantrone dose, gemcitabine was provided intravenously at 10 mg/m(2)/min with the duration adjusted by following a continuous reassessment model. RESULTS: Severe myelosuppression, and stomatitis or esophagitis were the most common hematologic and nonhematologic dose-limiting toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours (7,200 mg/m(2)). The mean steady-state concentration of gemcitabine was 24.72 micromol/L and varied over a fivefold range among patients. Overall response rates in this phase I trial for strata I and II were 42% and 63%, respectively. CONCLUSION: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m(2)/min for 12 hours with 12 mg/m(2)/d mitoxantrone for 3 days is a tolerable induction regimen and achieves plasma concentrations sufficient for maximal intracellular activation. Stomatitis or esophagitis should be anticipated; however, this regimen may induce significant responses in patients with difficult-to-treat leukemias.

Authors
Rizzieri, DA; Bass, AJ; Rosner, GL; Gockerman, JP; DeCastro, CM; Petros, WP; Adams, DJ; Laughlin, MJ; Davis, P; Foster, T; Jacobson, R; Hurwitz, H; Moore, JO
MLA Citation
Rizzieri, DA, Bass, AJ, Rosner, GL, Gockerman, JP, DeCastro, CM, Petros, WP, Adams, DJ, Laughlin, MJ, Davis, P, Foster, T, Jacobson, R, Hurwitz, H, and Moore, JO. "Phase I evaluation of prolonged-infusion gemcitabine with mitoxantrone for relapsed or refractory acute leukemia." J Clin Oncol 20.3 (February 1, 2002): 674-679.
PMID
11821447
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
20
Issue
3
Publish Date
2002
Start Page
674
End Page
679
DOI
10.1200/JCO.2002.20.3.674

The feasibility and safety of immunotherapy with dendritic cells loaded with CEA mRNA following neoadjuvant chemoradiotherapy and resection of pancreatic cancer.

BACKGROUND: Resected pancreatic cancer has a high risk of recurrence and mortality despite the the use of chemoradiotherapy. Because pancreatic cancers express tumor antigens such as carcinoembryonic antigen (CEA), it may be possible to immunize patients to induce tumor antigen-specific immune responses. We hypothesize that high-frequency tumor antigen-specific immune responses will reduce recurrence and increase survival. Autologous dendritic cells (DCs) loaded with tumor antigens are particularly potent at inducing tumor antigen-specific immune responses. METHODS: Three patients with resected pancreatic adenocarcinoma following neoadjuvant chemoradiotherapy received autologous, monocyte-derived DCs loaded with the mRNA encoding CEA monthly for 6 mo. RESULTS: It was feasible to generate an adequate number of DC from these patients and to cryopreserve them for repeated use. The DC demonstrated the typical immature phenotype. The immunizations were well-tolerated without evidence of adverse events. All three developed injection site reactivity. All three are alive without evidence of disease at more than 2 1/2 yr from the original diagnosis. CONCLUSION: The postoperative period following neoadjuvant chemoradiotherapy and pancreaticoduodenectomy for pancreatic cancer is an ideal environment to test novel immune-based therapies. DC-based immunotherapy in this setting is safe and feasible and may lead to prolonged survival.

Authors
Morse, MA; Nair, SK; Boczkowski, D; Tyler, D; Hurwitz, HI; Proia, A; Clay, TM; Schlom, J; Gilboa, E; Lyerly, HK
MLA Citation
Morse, MA, Nair, SK, Boczkowski, D, Tyler, D, Hurwitz, HI, Proia, A, Clay, TM, Schlom, J, Gilboa, E, and Lyerly, HK. "The feasibility and safety of immunotherapy with dendritic cells loaded with CEA mRNA following neoadjuvant chemoradiotherapy and resection of pancreatic cancer." Int J Gastrointest Cancer 32.1 (2002): 1-6.
PMID
12630764
Source
pubmed
Published In
International Journal of Gastrointestinal Cancer
Volume
32
Issue
1
Publish Date
2002
Start Page
1
End Page
6
DOI
10.1385/IJGC:32:1:1

Prenylation of CaaX-type proteins: Basic principles through clinical applications

Post-translational modification by attachment of lipid moieties is critical for the biological activity of many membrane-associated proteins. This process, termed lipidation, serves to direct and anchor specific proteins to the cell membrane and can also play a role in important protein-protein interactions. A wide variety of lipids can be attached to proteins, including saturated acyl groups such as myristoyl and palmitoyl chains, glycosylphosphatidylinositol (GPI) moieties, and the 15- and 20-carbon isoprenoid groups famesyl and geranylgeranyl, respectively. Some lipidated proteins have only a single modification, whereas many others may have multiple, in some cases variable, modifications, in which each permuation confers a unique chemical property and distinct functional characteristic to the parent protein. This chapter deals primarily with the biochemistry and biology of protein prenylation, focusing on those proteins that contain a so-called CaaX motif at their C-terminus. The C-terminal processing of CaaX proteins is initiated by addition of either a farnesyl or geranylgeranyl isoprenoid to the conserved cysteine of the CaaX motif. Farnesylation of Ras proteins in particular has attracted a great deal of attention and is the primary reason why the enzyme responsible, termed protein farnesyltransferase (FTase), has been targeted for development of inhibitors that are currently being evaluated in clinical trials as anticancer agents. © 2002.

Authors
Hurwitz, HI; Casey, PJ
MLA Citation
Hurwitz, HI, and Casey, PJ. "Prenylation of CaaX-type proteins: Basic principles through clinical applications." Current Topics in Membranes 52 (2002): 531-550.
Source
scival
Published In
Current Topis in Membranes
Volume
52
Publish Date
2002
Start Page
531
End Page
550

Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas.

BACKGROUND: The use of neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors. This article reports our experience with neoadjuvant CRT for localized pancreatic cancer. METHODS: Since 1995, 111 patients with radiographically localized, pathologically confirmed pancreatic adenocarcinoma have received neoadjuvant external beam radiation therapy (EBRT; median, 4500 cGy) with 5-flourouracil-based chemotherapy. Tumors were defined as potentially resectable (PR, n = 53) in the absence of arterial involvement and venous occlusion and locally advanced (LA, n = 58) with arterial involvement or venous occlusion by CT. RESULTS: Five patients (4.5%) were not restaged due to death (n = 3) or intolerance of therapy (n = 2). Twenty-one patients (19%) manifested distant metastatic disease on restaging CT. Twenty-eight patients with initially PR tumors (53%) and 11 patients with initially LA tumors (19%) were resected after CRT. Histologic examination revealed significant fibrosis in all resected specimens and two complete responses. Surgical margins were negative in 72%, and lymph nodes were negative in 70% of resected patients. Median survival in resected patients has not been reached at a median follow-up of 16 months. CONCLUSIONS: Neoadjuvant CRT provided an opportunity for patients with occult metastatic disease to avoid the morbidity of resection and resulted in tumor downstaging in a minority of patients with LA tumors. Survival after neoadjuvant CRT and resection appears to be at least comparable to survival after resection and adjuvant (postoperative) CRT.

Authors
White, RR; Hurwitz, HI; Morse, MA; Lee, C; Anscher, MS; Paulson, EK; Gottfried, MR; Baillie, J; Branch, MS; Jowell, PS; McGrath, KM; Clary, BM; Pappas, TN; Tyler, DS
MLA Citation
White, RR, Hurwitz, HI, Morse, MA, Lee, C, Anscher, MS, Paulson, EK, Gottfried, MR, Baillie, J, Branch, MS, Jowell, PS, McGrath, KM, Clary, BM, Pappas, TN, and Tyler, DS. "Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas." Ann Surg Oncol 8.10 (December 2001): 758-765.
PMID
11776488
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
8
Issue
10
Publish Date
2001
Start Page
758
End Page
765

Complete response to neoadjuvant chemoradiation for rectal cancer does not influence survival.

BACKGROUND: Up to 30% of patients with locally advanced rectal cancer have a complete clinical or pathologic response to neoadjuvant chemoradiation. This study analyzes complete clinical and pathologic responders among a large group of rectal cancer patients treated with neoadjuvant chemoradiation. METHODS: From 1987 to 2000, 141 consecutive patients with biopsy-proven, locally advanced rectal cancer were treated with preoperative 5-fluorouracil-based chemotherapy and radiation. Clinical restaging after treatment consisted of proctoscopic examination and often computed tomography scan. One hundred forty patients then underwent operative resection, with results tracked in a database. Standard statistical methods were used to examine the outcomes of those patients with complete clinical or pathologic responses. RESULTS: No demographic differences were detected between either clinical complete and clinical partial responders or pathologic complete and pathologic partial responders. The positive predictive value of clinical restaging was 60%, and accuracy was 82%. By use of the Kaplan-Meier life table analysis, clinical complete responders had no advantage in local recurrence, disease-free survival, or overall survival rates when compared with clinical partial responders. Pathologic complete responders also had no recurrence or survival advantage when compared with pathologic partial responders. Of the 34 pathologic T0 tumors, 4 (13%) had lymph node metastases. CONCLUSIONS: Clinical assessment of complete response to neoadjuvant chemoradiation is unreliable. Micrometastatic disease persists in a proportion of patients despite pathologic complete response. Observation or local excision for patients thought to be complete responders should be undertaken with caution.

Authors
Onaitis, MW; Noone, RB; Fields, R; Hurwitz, H; Morse, M; Jowell, P; McGrath, K; Lee, C; Anscher, MS; Clary, B; Mantyh, C; Pappas, TN; Ludwig, K; Seigler, HF; Tyler, DS
MLA Citation
Onaitis, MW, Noone, RB, Fields, R, Hurwitz, H, Morse, M, Jowell, P, McGrath, K, Lee, C, Anscher, MS, Clary, B, Mantyh, C, Pappas, TN, Ludwig, K, Seigler, HF, and Tyler, DS. "Complete response to neoadjuvant chemoradiation for rectal cancer does not influence survival." Ann Surg Oncol 8.10 (December 2001): 801-806.
PMID
11776494
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
8
Issue
10
Publish Date
2001
Start Page
801
End Page
806

Staging of pancreatic cancer before and after neoadjuvant chemoradiation.

Neoadjuvant chemoradiation therapy is used at many institutions for treatment of localized adenocarcinoma of the pancreas. Accurate staging before neoadjuvant therapy identifies patients with distant metastatic disease, and restaging after neoadjuvant therapy selects patients for laparotomy and attempted resection. The aims of this study were to (1) determine the utility of staging laparoscopy in candidates for neoadjuvant therapy and (2) evaluate the accuracy of restaging CT following chemoradiation. Staging laparoscopy was performed in 98 patients with radiographically potentially resectable (no evidence of arterial abutment or venous occlusion) or locally advanced (arterial abutment or venous occlusion) adenocarcinoma of the pancreas. Unsuspected distant metastasis was identified in 8 (18%) of 45 patients with potentially resectable tumors and 13 (24%) of 55 patients with locally advanced tumors by CT. Neoadjuvant chemoradiation therapy and restaging CT were completed in a total of 103 patients. Thirty-three patients with potentially resectable tumors by restaging CT underwent surgical exploration and resections were performed in 27 (82%). Eleven (22%) of 49 patients with locally advanced tumors by restaging CT were resected, with negative margins in 55%; the tumors in these 11 patients had been considered locally advanced because of arterial involvement on restaging CT. Staging laparoscopy is useful for the exclusion of patients with unsuspected metastatic disease from aggressive neoadjuvant chemoradiation protocols. Following neoadjuvant chemoradiation, restaging CT guides the selection of patients for laparotomy but may overestimate unresectability to a greater extent than does prechemoradiation CT.

Authors
White, RR; Paulson, EK; Freed, KS; Keogan, MT; Hurwitz, HI; Lee, C; Morse, MA; Gottfried, MR; Baillie, J; Branch, MS; Jowell, PS; McGrath, KM; Clary, BM; Pappas, TN; Tyler, DS
MLA Citation
White, RR, Paulson, EK, Freed, KS, Keogan, MT, Hurwitz, HI, Lee, C, Morse, MA, Gottfried, MR, Baillie, J, Branch, MS, Jowell, PS, McGrath, KM, Clary, BM, Pappas, TN, and Tyler, DS. "Staging of pancreatic cancer before and after neoadjuvant chemoradiation." J Gastrointest Surg 5.6 (November 2001): 626-633.
PMID
12086901
Source
pubmed
Published In
Journal of Gastrointestinal Surgery
Volume
5
Issue
6
Publish Date
2001
Start Page
626
End Page
633

Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience.

OBJECTIVE: To examine clinical outcomes in patients receiving neoadjuvant chemoradiation for locally advanced rectal adenocarcinoma. SUMMARY BACKGROUND DATA: Preoperative radiation therapy, either alone or in combination with 5-fluorouracil-based chemotherapy, has proven both safe and effective in the treatment of rectal cancer. However, data are lacking regarding which subgroups of patients benefit from the therapy in terms of decreased local recurrence and increased survival rates. METHODS: A retrospective chart review was performed on 141 consecutive patients who received neoadjuvant chemoradiation (5-fluorouracil +/- cisplatin and 4,500-5,040 cGy) for biopsy-proven locally advanced adenocarcinoma of the rectum. Surgery was performed 4 to 8 weeks after completion of chemoradiation. Standard statistical methods were used to analyze recurrence and survival. RESULTS: Median follow-up was 27 months, and mean age was 59 years (range 28-81). Mean tumor distance from the anal verge was 6 cm (range 1-15). Of those staged before surgery with endorectal ultrasound or magnetic resonance imaging, 57% of stage II patients and 82% of stage III patients were downstaged. The chemotherapeutic regimens were well tolerated, and resections were performed on 140 patients. The percentage of sphincter-sparing procedures increased from 20% before 1996 to 76% after 1996. On pathologic analysis, 24% of specimens were T0. However, postoperative pathologic T stage had no effect on either recurrence or survival. Positive lymph node status predicted increased local recurrence and decreased survival. CONCLUSIONS: Neoadjuvant chemoradiation is safe, effective, and well tolerated. Postoperative lymph node status is the only independent predictor of recurrence and survival.

Authors
Onaitis, MW; Noone, RB; Hartwig, M; Hurwitz, H; Morse, M; Jowell, P; McGrath, K; Lee, C; Anscher, MS; Clary, B; Mantyh, C; Pappas, TN; Ludwig, K; Seigler, HF; Tyler, DS
MLA Citation
Onaitis, MW, Noone, RB, Hartwig, M, Hurwitz, H, Morse, M, Jowell, P, McGrath, K, Lee, C, Anscher, MS, Clary, B, Mantyh, C, Pappas, TN, Ludwig, K, Seigler, HF, and Tyler, DS. "Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience." Ann Surg 233.6 (June 2001): 778-785.
PMID
11371736
Source
pubmed
Published In
Annals of Surgery
Volume
233
Issue
6
Publish Date
2001
Start Page
778
End Page
785

Pharmacokinetics and bioequivalence of a combined oral formulation of eniluracil, an inactivator of dihydropyrimidine dehydrogenase, and 5-fluorouracil in patients with advanced solid malignancies.

BACKGROUND: This study was performed to evaluate the pharmacokinetics, bioequivalence, and feasibility of a combined oral formulation of 5-flurouracil (5-FU) and eniluracil (Glaxo Wellcome Inc., Research Triangle Park, North Carolina), an inactivator of dihydropyrimidine dehydrogenase (DPD). The rationale for developing a combined eniluracil/5-FU formulation oral dosing form is to simplify treatment with these agents, which has been performed using separate dosing forms, and decrease the probability of severe toxicity and/or suboptimal therapeutic results caused by inadvertently high or conversely insufficient 5-FU dosing. PATIENTS AND METHODS: The trial was a randomized, three-way crossover bioequivalence study of three oral dosing forms of eniluracil/5-FU tablets in adults with solid malignancies. Each period consisted of two days of treatment and a five- to seven-day washout phase. Eniluracil at a dose of 20 mg, which results in maximal DPD inactivation, was administered twice daily on the first day and in the evening on the second day of each of the three treatments. On the morning of the second day, all patients received a total eniluracil dose of 20 mg orally and a total 5-FU dose of 2 mg orally as either separate tablets (treatment A) or combined eniluracil/5-FU tablets in two different strengths (2 tablets of eniluracil/5-FU at a strength (mg/mg) of 10/1 (treatment B) or 8 tablets at a strength of 2.5/0.25 (treatment C)). The pharmacokinetics of plasma 5-FU, eniluracil, and uracil, and the urinary excretion of eniluracil, 5-FU, uracil, and alpha-fluoro-beta-alanine (FBAL), were studied. To determine the bioequivalence of the combined eniluracil/5-FU dosing forms compared to the separate tablets, an analysis of variance on pharmacokinetic parameters reflecting eniluracil and 5-FU exposure was performed. RESULTS: Thirty-nine patients with advanced solid malignancies had complete pharmacokinetic studies performed during treatments A, B, and C. The pharmacokinetics of eniluracil and 5-FU were similar among the three types of treatment. Both strengths of the combined eniluracil/5-FU dosing form and the separate dosing forms were bioequivalent. Mean values for terminal half-life, systemic clearance, and apparent volume of distribution for oral 5-FU during treatments A/B/C were 5.5/5.6/5.6 hours, 6.6/6.6/6.5 liters/hour, and 50.7/51.5/50.0 liters, respectively. The intersubject coefficient of variation for pharmacokinetic variables reflecting 5-FU exposure and clearance in treatments ranged from 23% to 33%. The urinary excretion of unchanged 5-FU over 24 hours following treatments A, B, and C averaged 52.2%, 56.1%, and 50.8'%, of the administered dose of 5-FU, respectively. Parameters reflecting DPD inhibition, including plasma uracil and urinary FBAL excretion following treatments A, B, and C were similar. Toxicity was generally mild and similar following all three types of treatments. CONCLUSIONS: The pharmacokinetics of 5-FU and eniluracil were similar and met bioequivalence criteria following treatment with the separate oral formulations of 5-FU and eniluracil and two strengths of the combined formulation. The availability of a combined eniluracil/5-FU oral dosing form will likely simplify dosing and decrease the probability of severe toxicity or suboptimal therapeutic results caused by an inadvertent 5-FU overdose or insufficient 5-FU dosing in the case of separate oral formulations, thereby enhancing the overall feasibility and 0therapeutic index of oral 5-FU therapy.

Authors
Ochoa, L; Hurwitz, HI; Wilding, G; Cohen, D; Thomas, JP; Schwartz, G; Monroe, P; Petros, WP; Ertel, VP; Hsieh, A; Hoffman, C; Drengler, R; Magnum, S; Rowinsky, EK
MLA Citation
Ochoa, L, Hurwitz, HI, Wilding, G, Cohen, D, Thomas, JP, Schwartz, G, Monroe, P, Petros, WP, Ertel, VP, Hsieh, A, Hoffman, C, Drengler, R, Magnum, S, and Rowinsky, EK. "Pharmacokinetics and bioequivalence of a combined oral formulation of eniluracil, an inactivator of dihydropyrimidine dehydrogenase, and 5-fluorouracil in patients with advanced solid malignancies." Ann Oncol 11.10 (October 2000): 1313-1322.
PMID
11106122
Source
pubmed
Published In
Annals of Oncology
Volume
11
Issue
10
Publish Date
2000
Start Page
1313
End Page
1322

A pilot study of preoperative continuous infusion 5-fluorouracil, external microwave hyperthermia, and external beam radiotherapy for treatment of locally advanced, unresectable, or recurrent rectal cancer.

PURPOSE: To determine the feasibility of combining external beam radiotherapy, continuous infusion 5-fluorouracil (5-FU), and external microwave hyperthermia in patients with locally advanced, unresectable, or recurrent adenocarcinoma of the rectum. METHODS AND MATERIALS: From 7/95 through 2/99, 15 patients were enrolled in the study. The treatment regimen consisted of continuous infusion 5-FU 250 mg/m(2)/d 7 days/week beginning on day 1, external beam radiotherapy to the pelvis, 4500 cGy, 180 cGy/d 5 days/week using a 3 or 4-field technique, and external microwave hyperthermia on days 3, 8, 15, 22, and 29. Chemotherapy was stopped on the last day of radiotherapy. Surgical resection, if feasible, was scheduled 3-6 weeks after completing thermochemoradiotherapy. For this regimen to be considered feasible, no more than 2 of the 15 patients should fail to complete therapy due to life-threatening toxicity. Toxicity was scored using National Cancer Institute Criteria. RESULTS: All patients completed the chemoradiotherapy portion of the protocol. Eleven of the 15 patients completed all 5 hyperthermia treatments. Of the 4 patients who did not receive the full course of hyperthermia, only 1 patient had treatment stopped due to life-threatening toxicity. The other 3 patients did not complete hyperthermia due to scheduling errors (n = 2) or patient request (n = 1). Five of 15 patients required a treatment interruption due to toxicity > or = Grade 3. Seven patients experienced lesser degrees of toxicity which did not require treatment interruption. Three patients experienced no side effects. The most common toxicities were dermatitis and diarrhea. Of the 14 patients in whom surgery was planned, 11 (79%) were resectable. There was one pathologic complete response. CONCLUSIONS: It is feasible to deliver thermochemoradiotherapy, as prescribed in this study, to patients with locally advanced, unresectable, or recurrent rectal cancer. The therapy is moderately toxic, with one-third of patients requiring temporary treatment interruptions. The regimen appears active against rectal cancer, and appears to warrant further consideration as a treatment option for this patient population.

Authors
Anscher, MS; Lee, C; Hurwitz, H; Tyler, D; Prosnitz, LR; Jowell, P; Rosner, G; Samulski, T; Dewhirst, MW
MLA Citation
Anscher, MS, Lee, C, Hurwitz, H, Tyler, D, Prosnitz, LR, Jowell, P, Rosner, G, Samulski, T, and Dewhirst, MW. "A pilot study of preoperative continuous infusion 5-fluorouracil, external microwave hyperthermia, and external beam radiotherapy for treatment of locally advanced, unresectable, or recurrent rectal cancer." Int J Radiat Oncol Biol Phys 47.3 (June 1, 2000): 719-724.
PMID
10837956
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
47
Issue
3
Publish Date
2000
Start Page
719
End Page
724

Intensified adjuvant combined modality therapy for resected periampullary adenocarcinoma: Acceptable toxicity and suggestion of improved 1-year disease-free survival

Purpose: (1) To determine the toxicity of an intensified postoperative adjuvant regimen for periampullary adenocarcinoma (pancreatic and nonpancreatic) utilizing concurrent 5-fluorouracil (5-FU), leucovorin (LV), dipyridamole (DPM), and mitomycin-C (MMC) combined with split-course locoregional external beam radiotherapy (EBRT) to 50 Gy. This was followed by 4 cycles of the same chemotherapy as adjuvant therapy. (2) To determine preliminary estimates of the overall and disease-free survival associated with the use of this regimen. (3) To compare the toxicities and early survival results of patients treated with the current regimen to those of patients who completed our prior trial of concurrent chemoradiation infusion with 5-FU/LV chemotherapy and regional nodal and prophylactic hepatic irradiation. Methods: Postpancreaticoduodenectomy, patients received every 4 weeks bolus administration of 5-FU, (400 mg/m 2), and LV, (20 mg/m 2, Days l-3), DPM (75 mg p.o., 4 times per day, Days 0-3, and every 8 weeks), MMC, (10 mg/m 2; maximum of 20 mg, Day l during EBRT). This was followed by 4 months of the same chemotherapy, beginning 1 month following the completion of EBRT. EBRT consisted of split-course 5000 cGy/20 fractions with a 2-week planned rest after the first 10 fractions (2500 cGy). Results: From 4/96 to 6/99, 45 patients were enrolled and treated. Their experience constitutes the basis of this analysis. There were 29 patients with pancreatic cancer and 16 with nonpancreatic periampullary cancer. Seventeen patients had tumors of 3 cm or more, and 39 patients had at least 1 histologically involved lymph node. Thirteen patients had a histologically positive margin of resection. The mean time to start of treatment was 63 days following surgery. During chemoradiation therapy there were no Grade 3 or worse nonhematologic toxicities and 47% Grade 3 or Grade 4 hematologic toxicities of short duration. Following chemoradiation, during chemotherapy treatment only, there was one Grade 3 hepatic and one Grade 3 pulmonary toxicity which was nondebilitating (2% each case) and 42% Grade 3 or 4 hematologic toxicity. There were 2 episodes of neutropenic fever requiring admission and no treatment-related mortalities. One patient developed a mild case of HUS, which responded to standard management. One patient developed persistent shortness of breath (nondebilitating), and another patient had occasional dyspnea on exertion, both occurring after all therapy. The majority of patients complained of increased fatigue (Grade 1-2), greatest during the combined therapy and improving post all treatment. As of 6/23/99, 20 of 45 patients have relapsed, 13 in the liver. Twelve patients have died. Median follow-up for surviving patients is 14.3 months. Disease-free survival at 12 months following surgery is 66% (as compared to 25% in our prior study), and the median disease-free survival is 17 months (as compared to 8.3 months in our prior study). Median survival has not yet been reached, but will be greater than 17 months. Conclusion: With a 14.3-month median follow-up, acute toxicity has been acceptable and manageable. Observed relapses were seen 9-13 months following surgical resection. Early survival analysis suggests a trend toward increased median disease-free survival (8.3 vs. 17 months), especially for patients with nonpancreatic periampullary adenocarcinoma. Copyright (C) 2000 Elsevier Science Inc.

Authors
Chakravarthy, A; Abrams, RA; Yeo, CJ; Korman, LT; Donehower, RC; Hruban, RH; Zahurek, ML; Grochow, LB; O'Reilly, S; Hurwitz, H; Jaffee, EM; Lillemoe, KD; Cameron, JL
MLA Citation
Chakravarthy, A, Abrams, RA, Yeo, CJ, Korman, LT, Donehower, RC, Hruban, RH, Zahurek, ML, Grochow, LB, O'Reilly, S, Hurwitz, H, Jaffee, EM, Lillemoe, KD, and Cameron, JL. "Intensified adjuvant combined modality therapy for resected periampullary adenocarcinoma: Acceptable toxicity and suggestion of improved 1-year disease-free survival." International Journal of Radiation Oncology Biology Physics 48.4 (2000): 1089-1096.
PMID
11072167
Source
scival
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
48
Issue
4
Publish Date
2000
Start Page
1089
End Page
1096
DOI
10.1016/S0360-3016(00)00755-0

Preoperative chemoradiation for patients with locally advanced adenocarcinoma of the pancreas.

BACKGROUND: Improved resectability is a major theoretical benefit of preoperative chemoradiation for pancreatic cancer. Since 1994, patients at Duke University Medical Center with locally advanced pancreatic cancer have been treated with multimodality preoperative therapy. The purpose of this study was to review our experience with preoperative therapy for locally advanced pancreatic cancer and determine if an aggressive neoadjuvant regimen would not only downstage these tumors pathologically but also improve the odds of complete surgical resection. METHODS: The charts of 25 patients treated with neoadjuvant chemoradiation at Duke University Medical Center with biopsy-proven, locally advanced adenocarcinoma of the pancreas were reviewed. Tumors were defined as locally advanced based on radiographic or intraoperative evidence of disease that abuts the superior mesenteric artery or vein (n = 22) or involves lymph nodes that are within the proposed radiation field (n = 3). All 25 patients received external beam radiotherapy (median dose 4500 cGy) in daily fractions of 180 cGy over 5 weeks. All patients concurrently received 5-fluorouracil (FU), and many also received mitomycin C or cisplatin, or both. Patients were given a 3- to 4-week break before a restaging computed tomographic (CT) scan was performed. Three patients were not restaged: one died from metastatic disease; one was reclassified as having a neuroendocrine tumor; and one was lost to follow-up. RESULTS: On restaging after neoadjuvant therapy, 64% of patients had stable or decreased primary tumor size. Radiographically, two patients appeared potentially resectable, and seven others developed evidence of metastatic disease. Eight patients underwent exploration, but only five could be resected. Of the five patients resected, only one had negative margins and negative lymph nodes. This patient had significant pancreatitis on initial exploration. After neoadjuvant therapy, he had a complete response radiographically, and there was no residual cancer in his resection specimen. Pathologic examination of the other resection specimens suggested that despite significant tumor fibrosis, malignant cells persist even at the periphery of the lesions. CONCLUSION: Although neoadjuvant chemoradiation has many theoretical advantages in managing pancreatic malignancy, true pathologic downstaging of locally advanced lesions into tumors that can be removed with negative nodes and margins appears to be a rare event with currently used therapeutic regimens.

Authors
White, R; Lee, C; Anscher, M; Gottfried, M; Wolff, R; Keogan, M; Pappas, T; Hurwitz, H; Tyler, D
MLA Citation
White, R, Lee, C, Anscher, M, Gottfried, M, Wolff, R, Keogan, M, Pappas, T, Hurwitz, H, and Tyler, D. "Preoperative chemoradiation for patients with locally advanced adenocarcinoma of the pancreas." Ann Surg Oncol 6.1 (January 1999): 38-45.
PMID
10030414
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
6
Issue
1
Publish Date
1999
Start Page
38
End Page
45

Influence of prognostic groupings and treatment results in the management of unresectable hepatoma: Experience with Cis-platinum-based chemoradiotherapy in 76 patients

Purpose: Internationally, hepatoma is a common cause of cancer death. Although the only curative therapy is surgical, most tumors are unresectable and cause death. The value of nonsurgical, antineoplastic therapy for such tumors is controversial. This study was undertaken to extend and confirm promising, but preliminary, treatment observations in the unresectable context. Methods and Materials: From 1988 to 1993, 76 patients with unresectable, biopsy proven, hepatoma underwent uniform pretreatment assessment followed by induction therapy with external beam radiotherapy (21 Gy/7 fractions/10 days) and intravenous Cisplatinum 50 mg/m2. One month later patients began monthly intrahepatic artery Cisplatinum, 50 mg/m2. Clinical course and treatment outcomes were correlated with previously published prognostic factors and groupings (Nomura et al., Okuda et al., Stillwagon, et al.). Results: The toxicity of this therapy was modest and nonlimiting. Twenty-four patients (32%) progressed during induction and prior to receiving two cycles of intrahepatic artery Cisplatinum without evidence of benefit. Patients showing this early progression were more likely to be Stillwagon unfavorable than favorable (p = 0.013), Okuda Stage II than Stage I (p = 0.024), and slightly but not statistically more likely to be alpha- fetoprotein positive than alpha-fetoprotein negative (p = 0.098). The overall objective response rate was 43% (38% among AFP positive and 62% among AFP negative patients) (p = 0.15). Although 21 patients had evidence of extra hepatic metastases, survival for these patients did not differ from patients without metastases (p = 0.09) and patients with extra hepatic metastases were just as likely to show intrahepatic response (p = 0.84). Conclusion: The chemoradiotherapy program utilized produced objective response and minimal toxicity. One-third of patients progressed rapidly in spite of treatment. Among the remaining patients, response occurred frequently. This treatment appears to represent an important therapeutic option for many, but not all, patients with unresectable hepatoma.

Authors
Abrams, RA; Cardinale, RM; Enger, C; Haulk, TL; Hurwitz, H; Osterman, F; Sitzmann, JV
MLA Citation
Abrams, RA, Cardinale, RM, Enger, C, Haulk, TL, Hurwitz, H, Osterman, F, and Sitzmann, JV. "Influence of prognostic groupings and treatment results in the management of unresectable hepatoma: Experience with Cis-platinum-based chemoradiotherapy in 76 patients." International Journal of Radiation Oncology Biology Physics 39.5 (1997): 1077-1085.
PMID
9392547
Source
scival
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
39
Issue
5
Publish Date
1997
Start Page
1077
End Page
1085
DOI
10.1016/S0360-3016(97)00389-1

Use of murine models of cytokine-secreting tumor vaccines to study feasibility and toxicity issues critical to designing clinical trials

In preclinical models, tumor cells genetically altered to secrete cytokines or express costimulatory molecules can generate systemic antitumor immunity. In some studies, these tumor vaccines have been shown to eradicate micrometastases. These results have lead to the initiation of numerous Phase I clinical trials employing either genetically modified autologous or allogeneic tumor vaccines. We address a number of feasibility and toxicity issues critical to the design of these immunotherapy trials, using the B16 melanoma vaccine model. First, we demonstrated the efficacy of freeze/thawed vaccine cells, a process required for conducting clinical trials with large numbers of vaccine cells. Second, we performed pharmacokinetic studies and showed peak levels of granulocyte-macrophage colony-stimulating factor (GM- CSF) that are far below levels expected to result in significant side effects in patients. Third, we performed autoimmune toxicity studies using the RENCA renal and B16 melanoma tumor vaccines and failed to demonstrate evidence of significant histologic or functional abnormalities. Overall, these novel studies address important issues that should be considered in the design of clinical trials evaluating genetically modified tumor vaccines.

Authors
Jaffee, EM; Lazenby, A; Meurer, J; Marshall, F; Hauda, KM; Counts, C; Hurwitz, H; Simons, JW; Levitsky, HI; Pardoll, DM
MLA Citation
Jaffee, EM, Lazenby, A, Meurer, J, Marshall, F, Hauda, KM, Counts, C, Hurwitz, H, Simons, JW, Levitsky, HI, and Pardoll, DM. "Use of murine models of cytokine-secreting tumor vaccines to study feasibility and toxicity issues critical to designing clinical trials." Journal of Immunotherapy 18.1 (1995): 1-9.
PMID
8535565
Source
scival
Published In
Journal of Immunotherapy
Volume
18
Issue
1
Publish Date
1995
Start Page
1
End Page
9

Primary chemotherapy in epithelial ovarian cancer

Ovarian cancer is an important disease due to its occurrence in women in the prime of life (40-70) and its responsiveness to therapy but generally poor outcome due to the emergence of drug-resistant cells. In early-stage disease, adjuvant therapies may improve outcome, but previous studies have concentrated more on the reduction of toxicity of therapy than on improved survival, although modern approaches are evaluating more aggressive intervention in these patients with good survival rates (40%-90% cure with surgery). In advanced disease, the most common presentation, it appears that more aggressive staging and surgical debulking as well as new classes of drugs for treatment have altered, albeit modestly, the outcome in this disease. Future approaches will evaluate taxol, a new active agent, as well as more dose-intense therapy and a continued search will be made for new active drugs and methods to overcome intrinsic and acquired drug resistance.

Authors
Hurwitz, HI; III, WPM
MLA Citation
Hurwitz, HI, and III, WPM. "Primary chemotherapy in epithelial ovarian cancer." Obstetrics and Gynecology Clinics of North America 21.1 (1994): 141-154.
PMID
7912423
Source
scival
Published In
Obstetrics and Gynecology Clinics of North America
Volume
21
Issue
1
Publish Date
1994
Start Page
141
End Page
154
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