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George, Daniel James

Positions:

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Professor in Surgery

Surgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1992

M.D. — Duke University

News:

Can a Modified Poliovirus Fight Advanced Prostate Cancer Too?

August 26, 2015 — Duke Translational Medicine Institute

Grants:

Celldex CDX1127-06

Administered By
Duke Cancer Institute
AwardedBy
Celldex Therapeutics, Inc.
Role
Principal Investigator
Start Date
September 01, 2015
End Date
August 31, 2020

Prostate Cancer Outcomes: An International Registry

Administered By
Medicine, Medical Oncology
AwardedBy
Movember Foundation
Role
Principal Investigator
Start Date
September 01, 2016
End Date
November 30, 2018

ABI-RACE

Administered By
Duke Cancer Institute
AwardedBy
Janssen Pharmaceutica, Inc.
Role
Principal Investigator
Start Date
June 01, 2013
End Date
May 31, 2018

Conditional lethality of copper and disulfiram as a therapeutic modality for prostate cancer

Administered By
Medicine, Medical Oncology
AwardedBy
V Foundation for Cancer Research
Role
Co Investigator
Start Date
May 15, 2016
End Date
May 15, 2018

Validation and interrogation of differentially expressed and alternatively spliced genes in African American prostate ca

Administered By
Duke Cancer Institute
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 30, 2014
End Date
September 29, 2017

Novel Immune Modulating Cellular Vaccine for Prostate Cancer Immunotherapy

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 30, 2013
End Date
September 29, 2017

PCRP Clinical Consortium: Duke University Clinical Research Site

Administered By
Medicine, Medical Oncology
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
March 01, 2007
End Date
September 29, 2017

Development of Circulating Molecular Predictors of Chemotherapy and Novel Hormonal Therapy Benefit in Men with Metastatic Castration Resistant Prostate Cancer (mCRPC)

Administered By
Medicine, Medical Oncology
AwardedBy
Prostate Cancer Foundation
Role
Investigator
Start Date
August 01, 2014
End Date
August 01, 2017

An IND-enabling Trial to Determine the Number and Volume of Injections Necessary for Adequate Distribution Throughout Cancer Metastases and to Validate Poliovirus Receptor (CD155) Expression in PC

Administered By
Medicine, Medical Oncology
AwardedBy
V Foundation for Cancer Research
Role
Co Investigator
Start Date
July 15, 2016
End Date
July 15, 2017

Bayer-Exini Radium-223 Retrospective Study

Administered By
Duke Cancer Institute
AwardedBy
Bayer Healthcare Pharmaceuticals Inc
Role
Principal Investigator
Start Date
March 01, 2016
End Date
February 28, 2017

Aptamer Targeted Drug and Toxin Delivery to Prostate Cancer

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Collaborator
Start Date
September 30, 2014
End Date
November 29, 2016

A Phase 3, Randomized, Controlled Study of Cabozantinib (XL184) vs Everolimus in Subjects with Metastatic Renal Cell

Administered By
Duke Cancer Institute
AwardedBy
Exelixis, Inc
Role
Principal Investigator
Start Date
September 01, 2013
End Date
August 31, 2016

Using Aptamer Coated Nanoparticles Encapsulating Prostate Tumor Antigen Encoding mRNA to Target Dendritic Cells In Vivo

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 01, 2012
End Date
August 31, 2015

Alternative splicing and epithelial-mesenchymal plasticity in prostate tumors

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Collaborating Investigator
Start Date
December 01, 2008
End Date
November 30, 2014

PRACTICUM - SANOFI 3 DAY DISEASE STATE TRAINING PROGRAM (PROSTATE, STEM CELL TRANSPLANT,LEUKEMIA /LYMPHOMA)

Administered By
Medicine, Medical Oncology
AwardedBy
Sanofi US
Role
Principal Investigator
Start Date
June 01, 2014
End Date
November 25, 2014

Prostate Cancer, Stem Cell Transplantation and Leukemia/Lymphoma Practicum

Administered By
Medicine, Medical Oncology
AwardedBy
Sanofi US
Role
Principal Investigator
Start Date
May 01, 2014
End Date
September 18, 2014

CTSA UL

Administered By
Duke Clinical & Translational Science Institute
AwardedBy
National Institutes of Health
Role
Advisor
Start Date
September 30, 2006
End Date
September 01, 2012

mTOR Therapy in Prostate Cancer: Signatures of Response and Biology of Resistance

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 25, 2007
End Date
July 31, 2010
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Publications:

Design and Rationale of the Metastatic Renal Cell Carcinoma (MaRCC) Registry: A Prospective Academic and Community-Based Study of Patients With Metastatic Renal Cell Cancer.

The Metastatic Renal Cell Cancer Registry, a large, nationally representative, prospective registry of patients with metastatic renal cell carcinoma (mRCC), aims to understand real-world treatment patterns and outcomes of patients with mRCC in routine clinical practice across the United States. This observational study is designed to enroll 500 patients with previously untreated mRCC from approximately 60 academic and community treatment sites; as of December 7, 2016, 500 patients have enrolled at 54 sites. Key endpoints include real-world data on reasons for treatment initiation and discontinuation; treatment regimens; disease progression; patient-reported outcomes; and healthcare resource utilization in this patient population.

Authors
Bhavsar, NA; Harrison, MR; Hirsch, BR; Creel, P; Wolf, SP; Samsa, GP; Abernethy, AP; Simantov, R; Borham, A; George, DJ
MLA Citation
Bhavsar, NA, Harrison, MR, Hirsch, BR, Creel, P, Wolf, SP, Samsa, GP, Abernethy, AP, Simantov, R, Borham, A, and George, DJ. "Design and Rationale of the Metastatic Renal Cell Carcinoma (MaRCC) Registry: A Prospective Academic and Community-Based Study of Patients With Metastatic Renal Cell Cancer." Cancer investigation (April 3, 2017): 1-12.
PMID
28368708
Source
epmc
Published In
Cancer Investigation (Informa)
Publish Date
2017
Start Page
1
End Page
12
DOI
10.1080/07357907.2017.1289215

Cabozantinib in genitourinary malignancies.

Cabozantinib inhibits a variety of cellular receptors including VEGFR1-3, MET, AXL, RET, FLT3 and KIT. These signaling pathways have been shown to be important in genitourinary malignancies. Along its clinical development, it has shown most activity in advanced renal cell carcinoma; the METEOR study compared cabozantinib to everolimus and showed clinically and statistically significant improvements in both progression-free survival and overall survival. Herein, we review the development of cabozantinib in the genitourinary malignancies of renal cell carcinoma, prostate adenocarcinoma and urothelial carcinoma.

Authors
Zhang, T; Park, SE; Hong, C; George, DJ
MLA Citation
Zhang, T, Park, SE, Hong, C, and George, DJ. "Cabozantinib in genitourinary malignancies." Future oncology (London, England) 13.8 (April 2017): 755-765.
PMID
27842445
Source
epmc
Published In
Future oncology (London, England)
Volume
13
Issue
8
Publish Date
2017
Start Page
755
End Page
765
DOI
10.2217/fon-2016-0358

Phase Ib Trial of Cabazitaxel and Tasquinimod in Men With Heavily Pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): The CATCH Trial.

Tasquinimod is an immunomodulating and anti-antiangiogenic oral agent with anti-prostate cancer activity in preclinical studies and in clinical trials of men with metastatic castration resistant prostate cancer (mCRPC), including single agent activity and in combination with taxanes. We sought to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of tasquinimod in combination with cabazitaxel and prednisone in men with chemorefractory mCRPC.Men with mCRPC who had failed prior docetaxel chemotherapy received cabazitaxel 25 mg/m2 every 3 weeks with oral tasquinimod at 1 of 3 escalating dose levels (0.25, 0.5, and 1.0 mg once daily) with prednisone and PEG-filgastrim support, using a 3 + 3 dose escalation design. Treatment continued until progressive disease or unacceptable toxicity.We enrolled 25 men with chemorefractory mCRPC. The RP2D was 0.5 mg tasquinimod based on excess DLTs (two of three men) observed at dose level 3 (1.0 mg) including grade 3 sensory neuropathy and grade 3 atrial fibrillation. Dose level 2 was expanded to 14 men, where 3 DLTs were observed: grade 3 fatigue, grade 4 febrile neutropenia, and grade 3 liver function abnormalities. The proportion of men with a ≥30% PSA decline was 63% and the median composite progression-free survival (PFS) was 8.5 months (95% CI 4.2-16.4 months) based on 12 PFS events. The median number of cycles of cabazitaxel was 6 (range 1-13), with six men receiving >10 cycles. Best overall RECIST responses (CR + PR) were observed in three men (12%), with stable disease in 12 (48%). No pharmacokinetic interactions were observed.We determined the RP2D of tasquinimod combined with cabazitaxel to be 0.5 mg daily following a 3 week lead-in of tasquinimod 0.25 mg with growth factor support. No unexpected toxicities occurred. Prostate 77: 385-395, 2017. © 2016 Wiley Periodicals, Inc.

Authors
Armstrong, AJ; Humeniuk, MS; Healy, P; Szmulewitz, R; Winters, C; Kephart, J; Harrison, MR; Martinez, E; Mundy, K; Halabi, S; George, D
MLA Citation
Armstrong, AJ, Humeniuk, MS, Healy, P, Szmulewitz, R, Winters, C, Kephart, J, Harrison, MR, Martinez, E, Mundy, K, Halabi, S, and George, D. "Phase Ib Trial of Cabazitaxel and Tasquinimod in Men With Heavily Pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): The CATCH Trial." March 2017.
PMID
27862097
Source
epmc
Published In
The Prostate
Volume
77
Issue
4
Publish Date
2017
Start Page
385
End Page
395
DOI
10.1002/pros.23277

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

Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial.

Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P = .012). ORR was 46% (95% CI, 34 to 57) for cabozantinib versus 18% (95% CI, 10 to 28) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC.

Authors
Choueiri, TK; Halabi, S; Sanford, BL; Hahn, O; Michaelson, MD; Walsh, MK; Feldman, DR; Olencki, T; Picus, J; Small, EJ; Dakhil, S; George, DJ; Morris, MJ
MLA Citation
Choueiri, TK, Halabi, S, Sanford, BL, Hahn, O, Michaelson, MD, Walsh, MK, Feldman, DR, Olencki, T, Picus, J, Small, EJ, Dakhil, S, George, DJ, and Morris, MJ. "Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 35.6 (February 2017): 591-597.
PMID
28199818
Source
epmc
Published In
Journal of Clinical Oncology
Volume
35
Issue
6
Publish Date
2017
Start Page
591
End Page
597
DOI
10.1200/jco.2016.70.7398

Prostate-specific antigen response in black and white patients treated with abiraterone acetate for metastatic castrate-resistant prostate cancer.

Evidence suggests differences in androgen receptor AR signaling between black (B) and white (W) patients with prostate cancer, but pivotal trials of abiraterone acetate (AA) for patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled few black patients, a population with a higher mortality from prostate cancer. Our primary objective was to determine differences in response to AA between B and W patients.We performed a retrospective case-control study of B vs. W patients treated with AA between May 1, 2008 and June 16, 2015 at Duke University Medical Center. Patients were identified (W control patients were matched 2:1 to B patients stratified based on previous docetaxel exposure) through pharmacy records and were eligible if treated with AA for metastatic castration-resistant prostate cancer. Patients with previous enzalutamide use were excluded. The primary objective was to compare the rate of≥90% prostate-specific antigen (PSA) decline from baseline between B vs. W patients. Secondary outcomes included comparing time on therapy, time to PSA progression, and overall survival among groups.Baseline characteristics among patients (n = 45 B, n = 90 W) were identified; these included Karnofsky performance status, PSA, Gleason score, alkaline phosphatase, albumin, hemoglobin, lactate dehydrogenase, opiate use for pain, and metastatic sites. Baseline characteristics among groups were similar except for median hemoglobin (B = 11.4g/dl, W = 12.3g/dl). The proportion of B patients achieving a≥90% PSA level decline was 37.8% vs. 28.9% for W patients (P = 0.296). Statistically significant differences were found in the proportion of patients achieving a≥50% PSA level decline (B = 68.9%, W = 48.9% [P = 0.028]) and≥30% PSA level decline (B = 77.8%, W = 54.4% [P = 0.008]). Rates of primary abiraterone-refractory disease (PSA increase as best response) trended higher in W (31.1%) than in B (15.6%) patients (P = 0.052). Median treatment duration (B = 9.4 mo, W = 8.3 mo) did not differ (Wilcoxon P = 0.444). Median overall survival (B = 27.3 mo [95% CI: 13.9, not estimable], W = 24.8 mo [95% CI: 19, 31.6] [P = 0.669]) and median time to PSA progression (B = 11.0 mo [95% CI: 4.3, 18.0], W = 9.4 mo [95% CI: 6.2, 13.0] [P = 0.917]) did not differ.Black patients may have a higher PSA response to AA than white patients. An ongoing prospective clinical study (NCT01940276) is evaluating outcomes between black and white patients treated with AA.

Authors
Ramalingam, S; Humeniuk, MS; Hu, R; Rasmussen, J; Healy, P; Wu, Y; Harrison, MR; Armstrong, AJ; George, DJ; Zhang, T
MLA Citation
Ramalingam, S, Humeniuk, MS, Hu, R, Rasmussen, J, Healy, P, Wu, Y, Harrison, MR, Armstrong, AJ, George, DJ, and Zhang, T. "Prostate-specific antigen response in black and white patients treated with abiraterone acetate for metastatic castrate-resistant prostate cancer." Urologic oncology (January 23, 2017).
PMID
28126272
Source
epmc
Published In
Urologic Oncology: Seminars and Original Investigations
Publish Date
2017
DOI
10.1016/j.urolonc.2016.12.016

Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.

Background Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. Methods In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. Results The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. Conclusions Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).

Authors
Ravaud, A; Motzer, RJ; Pandha, HS; George, DJ; Pantuck, AJ; Patel, A; Chang, Y-H; Escudier, B; Donskov, F; Magheli, A; Carteni, G; Laguerre, B; Tomczak, P; Breza, J; Gerletti, P; Lechuga, M; Lin, X; Martini, J-F; Ramaswamy, K; Casey, M; Staehler, M; Patard, J-J
MLA Citation
Ravaud, A, Motzer, RJ, Pandha, HS, George, DJ, Pantuck, AJ, Patel, A, Chang, Y-H, Escudier, B, Donskov, F, Magheli, A, Carteni, G, Laguerre, B, Tomczak, P, Breza, J, Gerletti, P, Lechuga, M, Lin, X, Martini, J-F, Ramaswamy, K, Casey, M, Staehler, M, and Patard, J-J. "Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy." The New England journal of medicine 375.23 (December 2016): 2246-2254.
PMID
27718781
Source
epmc
Published In
The New England journal of medicine
Volume
375
Issue
23
Publish Date
2016
Start Page
2246
End Page
2254
DOI
10.1056/nejmoa1611406

Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen-targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer.

This phase 1/2 study evaluated the dose-limiting toxicity and maximum tolerated dose of MLN2704, a humanized monoclonal antibody MLN591 targeting prostate-specific membrane antigen, linked to the maytansinoid DM1 in patients with progressive metastatic castration-resistant prostate cancer.A total of 62 patients received MLN2704 at ascending doses on 4 schedules: weekly (60, 84, 118, and 165mg/m2; 12 patients); every 2 weeks (120, 168, 236, and 330mg/m2; 15 patients); every 3 weeks (330 and 426mg/m2; 18 patients); and on days 1 and 15 of a 6-week schedule (6-week cycle, 330mg/m2; 17 patients). The primary efficacy endpoint was a sustained ≥50% decline from baseline prostate-specific antigen (PSA) without evidence of disease progression. Toxicity, pharmacokinetics, immunogenicity, and antitumor activity were assessed.Neurotoxicity was dose-limiting. Overall, 44 patients (71%) exhibited peripheral neuropathy: 6 (10%) had grade 3/4. Neurotoxicity rates remained high despite increasing the dosing interval to 3 (13 of 14; one grade 3) and 6 weeks (16 of 17; three grade 3). MLN2704 pharmacokinetics were dose-linear. Rapid deconjugation of DM1 from the conjugated antibody was seen. In all, 5 patients (8%) experienced ≥50% decline in PSA; 5 (8%) had PSA stabilization lasting≥90 days. Only 2 of 35 patients on the 3- and 6-week schedules achieved a PSA decline of >50%.MLN2704 has limited activity in metastatic castration-resistant prostate cancer. Disulfide linker lability and rapid deconjugation lead to neurotoxicity and a narrow therapeutic window.

Authors
Milowsky, MI; Galsky, MD; Morris, MJ; Crona, DJ; George, DJ; Dreicer, R; Tse, K; Petruck, J; Webb, IJ; Bander, NH; Nanus, DM; Scher, HI
MLA Citation
Milowsky, MI, Galsky, MD, Morris, MJ, Crona, DJ, George, DJ, Dreicer, R, Tse, K, Petruck, J, Webb, IJ, Bander, NH, Nanus, DM, and Scher, HI. "Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen-targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer." Urologic oncology 34.12 (December 2016): 530.e15-530.e21.
PMID
27765518
Source
epmc
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
34
Issue
12
Publish Date
2016
Start Page
530.e15
End Page
530.e21
DOI
10.1016/j.urolonc.2016.07.005

Metastatic clear cell renal cell carcinoma: Circulating biomarkers to guide antiangiogenic and immune therapies.

The therapeutic armamentarium for metastatic renal cell carcinoma has rapidly expanded over the past decade to include a number of anti-angiogenic therapies and more recently, an immunotherapy. Biomarkers in the peripheral circulation are easily accessible, can provide important prognostic value, and have the potential to give important information about disease progression and treatment sensitivity or response.Herein, we review a variety of circulating markers including circulating protein markers (VEGF-A, inflammatory cytokines, and LDH), circulating nucleic acids (cell free DNA and micro RNAs), and circulating cellular factors (circulating tumor cells, circulating endothelial cells, and immune cell subsets). We discuss these biomarkers in the context of their ability to provide prognostic and predictive information to anti-angiogenic and immunotherapeutic agents.While promising, there is still much work to be done, and prospective evaluation of any potential predictive biomarker for these therapies is greatly needed.

Authors
Zhang, T; Zhu, J; George, DJ; Nixon, AB
MLA Citation
Zhang, T, Zhu, J, George, DJ, and Nixon, AB. "Metastatic clear cell renal cell carcinoma: Circulating biomarkers to guide antiangiogenic and immune therapies." Urologic oncology 34.11 (November 2016): 510-518.
PMID
27498927
Source
epmc
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
34
Issue
11
Publish Date
2016
Start Page
510
End Page
518
DOI
10.1016/j.urolonc.2016.06.020

Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models.

Intratumoral inoculation of viruses with tumor-selective cytotoxicity may induce cancer cell death and, thereby, shrink neoplastic lesions. It is unlikely, however, that viral tumor cell killing alone could produce meaningful, durable clinical responses, as clinically suitable 'oncolytic' viruses are severely attenuated and their spread and propagation are opposed by host immunity. Thus, a more propitious event in this context is the innate antiviral response to intratumoral virus administration, in particular for recruiting durable adaptive immune effector responses. It may represent a double-edged sword, as innate immune activation may eliminate infected tumor cells early, intercept viral spread and block any meaningful therapeutic response. The innate response to viral infection of tumors may be very different from that in non-malignant target tissues, owing to the unusual composition/tissue properties of tumor stroma. In this work, we report investigations of the innate immune response to the oncolytic poliovirus recombinant, PVSRIPO, in two mouse xenotransplantation models for breast and prostate cancer. Our observations indicate short-term virus persistence in infected tumors and virus recovery indicative of modest intratumoral propagation and persistence. Yet, a powerful innate inflammatory response coincided with chemokine induction and myeloid cell infiltration into tumors that was, interestingly, dominated by neutrophils. The combined effect of PVSRIPO tumor infection and the innate response it elicits was significant tumor regression in both models.

Authors
Holl, EK; Brown, MC; Boczkowski, D; McNamara, MA; George, DJ; Bigner, DD; Gromeier, M; Nair, SK
MLA Citation
Holl, EK, Brown, MC, Boczkowski, D, McNamara, MA, George, DJ, Bigner, DD, Gromeier, M, and Nair, SK. "Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models." Oncotarget 7.48 (November 2016): 79828-79841.
PMID
27806313
Source
epmc
Published In
Oncotarget
Volume
7
Issue
48
Publish Date
2016
Start Page
79828
End Page
79841
DOI
10.18632/oncotarget.12975

What is the role of sipuleucel-T in the treatment of patients with advanced prostate cancer? An update on the evidence.

Prostate cancer is the most common cancer in men and the second most deadly. About one-third of patients with prostate cancer will develop metastatic disease. We discuss the six United States Food and Drug Administration (FDA) approved treatments for metastatic castrate-resistant prostate cancer (mCRPC) with a strong focus on sipuleucel-T. Sipuleucel-T is the first immunotherapy shown to improve survival in asymptomatic or minimally-symptomatic mCRPC. Herein, we discuss the proposed mechanism of sipuleucel-T and its synthesis. We describe in detail the three randomized controlled trials (RTCs) that led to its approval. We also compiled the newest research regarding use of sipuleucel-T with other agents and in different patient populations. Finally, we discuss the current ongoing trials.

Authors
Hu, R; George, DJ; Zhang, T
MLA Citation
Hu, R, George, DJ, and Zhang, T. "What is the role of sipuleucel-T in the treatment of patients with advanced prostate cancer? An update on the evidence." Therapeutic advances in urology 8.4 (August 2016): 272-278. (Review)
PMID
27928429
Source
epmc
Published In
Therapeutic Advances in Urology
Volume
8
Issue
4
Publish Date
2016
Start Page
272
End Page
278

Can Radiologic Staging With Multiparametric MRI Enhance the Accuracy of the Partin Tables in Predicting Organ-Confined Prostate Cancer?

The purpose of this study is to investigate the accuracy of multiparametric MRI with endorectal coil and Partin tables in predicting organ-confined (OC) prostate cancer in a contemporary cohort undergoing radical prostatectomy (RP) and to assess the possible added value of radiologic staging based on multiparametric MRI to the predictive accuracy of Partin tables.One hundred fifty-eight consecutive subjects underwent 3-T multiparametric MRI with endorectal coil before RP between November 2010 and November 2013. Data were randomly split 60% and 40% into derivation (n = 95) and validation (n = 62) datasets. Multiparametric MRI was used to assess the radiologic stage, and logistic regression models were created using the derivation dataset and were fit on the independent validation dataset using multiparametric MRI staging alone and with prostate-specific antigen (PSA) level as the covariate. The probability of each patient to harbor OC disease was calculated using an updated version of Partin tables, using either clinical staging from digital rectal examination (DRE) or radiologic staging (multiparametric MRI). The AUC was calculated to evaluate accuracy of these predictive methods.The accuracy of multiparametric MRI to predict OC disease on pathologic analysis was greater (AUC, 0.88) than that of Partin tables (AUC, 0.70) and improved when multiparametric MRI was combined with PSA level (AUC, 0.91). The accuracy of Partin nomograms to predict OC disease decreased (AUC, 0.63) when staging was based on multiparametric MRI versus DRE.The superior predictive accuracy of multiparametric MRI compared with Partin tables to predict OC disease validates the results of smaller previously published studies. Although there is no added benefit of substituting multiparametric MRI stage for clinical stage when using Partin tables, multiparametric MRI staging information is valuable as a stand-alone test.

Authors
Gupta, RT; Brown, AF; Silverman, RK; Tay, KJ; Madden, JF; George, DJ; Polascik, TJ
MLA Citation
Gupta, RT, Brown, AF, Silverman, RK, Tay, KJ, Madden, JF, George, DJ, and Polascik, TJ. "Can Radiologic Staging With Multiparametric MRI Enhance the Accuracy of the Partin Tables in Predicting Organ-Confined Prostate Cancer?." AJR. American journal of roentgenology 207.1 (July 2016): 87-95.
PMID
27064383
Source
epmc
Published In
AJR. American journal of roentgenology
Volume
207
Issue
1
Publish Date
2016
Start Page
87
End Page
95
DOI
10.2214/ajr.15.15878

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

Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science.

Contemporary therapies for metastatic castration-resistant prostate cancer (mCRPC) have shown survival improvements, which do not account for patient experience and health-related quality of life (HRQoL).This literature review included a search of MEDLINE for randomized clinical trials enrolling ⩾50 patients with mCRPC and reporting on patient-reported outcomes (PROs) since 2010.Nineteen of 25 publications describing seven treatment regimens (10 clinical trials and nine associated secondary analyses) met the inclusion criteria and were critically appraised. The most commonly used measures were the Functional Assessment of Cancer Therapy-Prostate (n=5 trials) and Brief Pain Inventory Short Form (n=4 trials) questionnaires. The published data indicated that HRQoL and pain status augmented the clinical efficacy data by providing a better understanding of treatment impact in mCRPC. Abiraterone acetate and prednisone, enzalutamide, radium-223 dichloride and sipuleucel-T offered varying levels of HRQoL benefit and/or pain mitigation versus their respective comparators, whereas three treatments (mitoxantrone, estramustine phosphate and docetaxel, and cabazitaxel) had no meaningful impact on HRQoL or pain. The main limitation of the data were that the PROs utilized were not developed for use in mCRPC patients and hence may not have comprehensively captured symptoms important to this population.Recently published randomized clinical trials of new agents for mCRPC have captured elements of the patient experience while on treatment. Further research is required to standardize methods for measuring, quantifying and reporting on HRQoL and pain in patients with mCRPC in the clinical practice setting.

Authors
Nussbaum, N; George, DJ; Abernethy, AP; Dolan, CM; Oestreicher, N; Flanders, S; Dorff, TB
MLA Citation
Nussbaum, N, George, DJ, Abernethy, AP, Dolan, CM, Oestreicher, N, Flanders, S, and Dorff, TB. "Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science." Prostate cancer and prostatic diseases 19.2 (June 2016): 111-121. (Review)
PMID
26832363
Source
epmc
Published In
Prostate Cancer and Prostatic Diseases
Volume
19
Issue
2
Publish Date
2016
Start Page
111
End Page
121
DOI
10.1038/pcan.2015.42

Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3.

Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups.An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations.PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials.PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval.

Authors
Scher, HI; Morris, MJ; Stadler, WM; Higano, C; Basch, E; Fizazi, K; Antonarakis, ES; Beer, TM; Carducci, MA; Chi, KN; Corn, PG; de Bono, JS; Dreicer, R; George, DJ; Heath, EI; Hussain, M; Kelly, WK; Liu, G; Logothetis, C; Nanus, D; Stein, MN; Rathkopf, DE; Slovin, SF; Ryan, CJ; Sartor, O; Small, EJ; Smith, MR; Sternberg, CN; Taplin, M-E; Wilding, G; Nelson, PS; Schwartz, LH; Halabi, S; Kantoff, PW; Armstrong, AJ
MLA Citation
Scher, HI, Morris, MJ, Stadler, WM, Higano, C, Basch, E, Fizazi, K, Antonarakis, ES, Beer, TM, Carducci, MA, Chi, KN, Corn, PG, de Bono, JS, Dreicer, R, George, DJ, Heath, EI, Hussain, M, Kelly, WK, Liu, G, Logothetis, C, Nanus, D, Stein, MN, Rathkopf, DE, Slovin, SF, Ryan, CJ, Sartor, O, Small, EJ, Smith, MR, Sternberg, CN, Taplin, M-E, Wilding, G, Nelson, PS, Schwartz, LH, Halabi, S, Kantoff, PW, and Armstrong, AJ. "Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34.12 (April 2016): 1402-1418.
PMID
26903579
Source
epmc
Published In
Journal of Clinical Oncology
Volume
34
Issue
12
Publish Date
2016
Start Page
1402
End Page
1418
DOI
10.1200/jco.2015.64.2702

A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy in men with PSA recurrent prostate cancer after radical prostatectomy.

In men with high Gleason PC and rapid PSA progression after surgery, failure rates remain unacceptably high despite salvage radiation. We explored a novel multimodality approach of docetaxel with anti-angiogenic therapy before salvage radiotherapy (RT).This was a phase 2 single-arm prospective open-label trial with historic controls. Eligible men had a rising PSA of 0.1-3.0 ng ml(-1) within 4 years of radical prostatectomy, no metastases except resected nodal disease, no prior androgen-deprivation therapy (ADT) and Gleason 7-10. Men received four cycles of docetaxel 70 mg m(-2) every 3 weeks with low dose prednisone and sunitinib 37.5 mg daily for 14/21 days each cycle, with no ADT. Salvage prostate bed RT (66 Gy) started at day 100. The primary end point was progression-free survival (PFS) rate at 24 months. Safety data, quality of life (QOL) and dose-limiting toxicities (DLTs) were measured over time.Thirty-four men accrued in this multi-institutional clinical trial: 24% of men were node positive, 47% were Gleason 8-10, median PSA at entry was 0.54. The trial was terminated prematurely owing to excess DLTs (nine) including grade 3 hand-foot syndrome (n=4), neutropenic fever (n=2), AST increase (n=1), fatigue (n=1) and vomiting with diarrhea (n=1). PFS rate at 24 months was 51% (95% CI: 33, 67%) with a median PFS of 26.2 months (95% CI: 12.5, -). Six men (17.6%) had an undetectable PSA at 2 years.Sunitinib and docetaxel/prednisone followed by salvage RT resulted in excess pre-specified DLTs. Although nearly half of the men experienced durable disease control, efficacy was not greater than expected with radiation alone. The use of the intermediate end point of PFS in this salvage setting permitted an early decision on further development of this combination.

Authors
Armstrong, AJ; Halabi, S; Healy, P; Lee, WR; Koontz, BF; Moul, JW; Mundy, K; Creel, P; Wood, S; Davis, K; Carducci, MA; Stein, M; Hobbs, C; Reimer, B; Nguyen, M; Anand, M; Bratt, L; Kim, S; Tran, PT; George, DJ
MLA Citation
Armstrong, AJ, Halabi, S, Healy, P, Lee, WR, Koontz, BF, Moul, JW, Mundy, K, Creel, P, Wood, S, Davis, K, Carducci, MA, Stein, M, Hobbs, C, Reimer, B, Nguyen, M, Anand, M, Bratt, L, Kim, S, Tran, PT, and George, DJ. "A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy in men with PSA recurrent prostate cancer after radical prostatectomy." March 2016.
PMID
26754260
Source
epmc
Published In
Prostate Cancer and Prostatic Diseases
Volume
19
Issue
1
Publish Date
2016
Start Page
100
End Page
106
DOI
10.1038/pcan.2015.59

Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial.

Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma.We enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov, number NCT01108445.Between Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months [80% CI 5·8-11·4] vs 5·6 months [5·5-6·0]; hazard ratio 1·41 [80% CI 1·03-1·92]; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3-4 adverse events were hypertension (12 [24%] of 51 patients in the sunitinib group vs one [2%] of 57 patients in the everolimus group), infection (six [12%] vs four [7%]), diarrhoea (five [10%] vs one [2%]), pneumonitis (none vs five [9%]), stomatitis (none vs five [9%]), and hand-foot syndrome (four [8%] vs none).In patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors.Novartis and Pfizer.

Authors
Armstrong, AJ; Halabi, S; Eisen, T; Broderick, S; Stadler, WM; Jones, RJ; Garcia, JA; Vaishampayan, UN; Picus, J; Hawkins, RE; Hainsworth, JD; Kollmannsberger, CK; Logan, TF; Puzanov, I; Pickering, LM; Ryan, CW; Protheroe, A; Lusk, CM; Oberg, S; George, DJ
MLA Citation
Armstrong, AJ, Halabi, S, Eisen, T, Broderick, S, Stadler, WM, Jones, RJ, Garcia, JA, Vaishampayan, UN, Picus, J, Hawkins, RE, Hainsworth, JD, Kollmannsberger, CK, Logan, TF, Puzanov, I, Pickering, LM, Ryan, CW, Protheroe, A, Lusk, CM, Oberg, S, and George, DJ. "Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial." The Lancet. Oncology 17.3 (March 2016): 378-388.
PMID
26794930
Source
epmc
Published In
The Lancet Oncology
Volume
17
Issue
3
Publish Date
2016
Start Page
378
End Page
388
DOI
10.1016/s1470-2045(15)00515-x

Abstract B18: Development of novel therapeutic splice-switching oligonucleotides against aggressive prostate cancer in men of African descent

Authors
Freedman, JA; Robinson, TJ; LaCroix, B; Patierno, BM; George, DJ; Sullenger, BA; Patierno, SR
MLA Citation
Freedman, JA, Robinson, TJ, LaCroix, B, Patierno, BM, George, DJ, Sullenger, BA, and Patierno, SR. "Abstract B18: Development of novel therapeutic splice-switching oligonucleotides against aggressive prostate cancer in men of African descent." March 2016.
Source
crossref
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
25
Issue
3 Supplement
Publish Date
2016
Start Page
B18
End Page
B18
DOI
10.1158/1538-7755.DISP15-B18

Resource Use in the Last Year of Life Among Patients Who Died With Versus of Prostate Cancer.

We conducted a retrospective analysis of Surveillance, Epidemiology, and End Results-Medicare data of men with prostate cancer. Among 34,727 patients, those who died of their prostate cancer had more hospice and outpatient use, less inpatient and intensive care unit use, and lower overall costs. Efforts to shift care toward the outpatient setting might provide more efficient and judicious care for patients during the end of life.Prostate cancer poses a significant financial burden in the United States. However, most men with prostate cancer will die from noncancer causes. Concerns about increased resource utilization at the end of life have not been appropriately examined in this context.We conducted a retrospective analysis of Surveillance, Epidemiology, and End Results-Medicare data of men who were diagnosed with and died of, as opposed to with, prostate cancer between 2000 and 2007. Within these 2 populations, we compared changes in the use of medical interventions, hospice, and overall health care costs to Medicare in the last year of life.Among 34,727 patients, those who died of prostate cancer had lower costs ($43,572 vs. $45,830; P < .001), largely because of lower mean inpatient costs ($20,769 vs. $29,851) and fewer hospitalizations (1.8 vs. 2.1), inpatient days (12.2 vs. 15.7), intensive care unit (ICU) days (1.4 vs. 3.4), and skilled nursing facility days (11.7 vs. 14.7; P < .001 for all). Outpatient and hospice costs were significantly greater among patients who died of prostate cancer, as was use of chemotherapy and androgen deprivation therapy. Patients who died of prostate cancer had approximately 12% lower costs than patients who died from other causes in adjusted analyses (fold-change, 0.88; 95% confidence interval [CI], 0.85-0.92). The single strongest predictor of increased costs at the end of life was receipt of multiple invasive procedures (fold increase in costs, 2.39; 95% CI, 2.22-2.58).Patients who died of prostate cancer rather than from other causes had more hospice and outpatient use, less inpatient and ICU use, and lower overall costs. Efforts to shift care toward outpatient settings might provide more efficient and judicious care for patients during the end of life.

Authors
Dinan, MA; Li, Y; Zhang, Y; Stewart, SB; Curtis, LH; George, DJ; Reed, SD
MLA Citation
Dinan, MA, Li, Y, Zhang, Y, Stewart, SB, Curtis, LH, George, DJ, and Reed, SD. "Resource Use in the Last Year of Life Among Patients Who Died With Versus of Prostate Cancer." Clinical genitourinary cancer 14.1 (February 2016): 28-37.e2.
PMID
26382223
Source
epmc
Published In
Clinical genitourinary cancer
Volume
14
Issue
1
Publish Date
2016
Start Page
28
End Page
37.e2
DOI
10.1016/j.clgc.2015.07.006

Phase Ib trial of docetaxel, prednisone, and pazopanib, in men with metastatic castration resistant prostate cancer (mCRPC).

Authors
George, DJ; Halabi, S; Healy, P; Gemberling, S; Winters, C; Mundy, K; Harrison, MR; Szmulewitz, RZ; Armstrong, AJ
MLA Citation
George, DJ, Halabi, S, Healy, P, Gemberling, S, Winters, C, Mundy, K, Harrison, MR, Szmulewitz, RZ, and Armstrong, AJ. "Phase Ib trial of docetaxel, prednisone, and pazopanib, in men with metastatic castration resistant prostate cancer (mCRPC)." January 10, 2016.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
34
Issue
2
Publish Date
2016

Objective response of the dual CYP17-Lyase (L) inhibitor/androgen receptor (AR) antagonist, VT-464, in patients with CRPC.

Authors
Nordquist, LT; Shore, ND; De Bono, JS; Gupta, S; Berry, WR; Gillessen, S; Liu, G; Vogelzang, NJ; Efstathiou, E; Fleming, MT; George, DJ; Araujo, JC; Zhang, J; Kurman, MR; Eisner, JR; Moore, WR
MLA Citation
Nordquist, LT, Shore, ND, De Bono, JS, Gupta, S, Berry, WR, Gillessen, S, Liu, G, Vogelzang, NJ, Efstathiou, E, Fleming, MT, George, DJ, Araujo, JC, Zhang, J, Kurman, MR, Eisner, JR, and Moore, WR. "Objective response of the dual CYP17-Lyase (L) inhibitor/androgen receptor (AR) antagonist, VT-464, in patients with CRPC." January 10, 2016.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
34
Issue
2
Publish Date
2016

Physician treatment selection in the prospective Metastatic Renal Cell Cancer (MaRCC) Registry.

Authors
Kyriakopoulos, C; Harrison, MR; Bhavsar, NA; Wolf, SP; Costello, BA; Stadler, WM; Hammers, HJ; Vaishampayan, UN; Appleman, LJ; Creel, PA; Samsa, GP; Richardson, EM; Johnson, KA; Borham, A; George, DJ
MLA Citation
Kyriakopoulos, C, Harrison, MR, Bhavsar, NA, Wolf, SP, Costello, BA, Stadler, WM, Hammers, HJ, Vaishampayan, UN, Appleman, LJ, Creel, PA, Samsa, GP, Richardson, EM, Johnson, KA, Borham, A, and George, DJ. "Physician treatment selection in the prospective Metastatic Renal Cell Cancer (MaRCC) Registry." January 10, 2016.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
34
Issue
2
Publish Date
2016

Front-line management patterns in the prospective metastatic renal cell cancer (MaRCC) registry.

Authors
Harrison, MR; Bhavsar, NA; Wolf, SP; Costello, BA; Stadler, WM; Hammers, HJ; Vaishampayan, UN; Appleman, LJ; Tsao, C-K; Creel, PA; Samsa, GP; Richardson, EM; Johnson, KA; Borham, A; George, DJ
MLA Citation
Harrison, MR, Bhavsar, NA, Wolf, SP, Costello, BA, Stadler, WM, Hammers, HJ, Vaishampayan, UN, Appleman, LJ, Tsao, C-K, Creel, PA, Samsa, GP, Richardson, EM, Johnson, KA, Borham, A, and George, DJ. "Front-line management patterns in the prospective metastatic renal cell cancer (MaRCC) registry." January 10, 2016.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
34
Issue
2
Publish Date
2016

Physician treatment selection in the prospective metastatic renal cell cancer (MaRCC) registry

Authors
Costello, BA; Harrison, MR; Bhavsar, NA; Wolf, SP; Kyriakopoulos, CE; Stadler, WM; Hammers, HJ; Vaishampayan, U; Appleman, LJ; Creel, P; Samsa, GP; Richardson, EM; Johnson, KA; Borham, A; George, DJ
MLA Citation
Costello, BA, Harrison, MR, Bhavsar, NA, Wolf, SP, Kyriakopoulos, CE, Stadler, WM, Hammers, HJ, Vaishampayan, U, Appleman, LJ, Creel, P, Samsa, GP, Richardson, EM, Johnson, KA, Borham, A, and George, DJ. "Physician treatment selection in the prospective metastatic renal cell cancer (MaRCC) registry." December 2015.
Source
wos-lite
Published In
Bju International
Volume
116
Publish Date
2015
Start Page
7
End Page
7

Front-line management patterns in the prospective metastatic renal cell cancer (MaRCC) registry

Authors
Harrison, MR; Bhavsar, NA; Wolf, SP; Costello, BA; Stadler, WM; Hammers, HJ; Vaishampayan, U; Appleman, LJ; Tsao, C-K; Creel, P; Samsa, GP; Richardson, EM; Johnson, KA; Barham, A; George, DJ
MLA Citation
Harrison, MR, Bhavsar, NA, Wolf, SP, Costello, BA, Stadler, WM, Hammers, HJ, Vaishampayan, U, Appleman, LJ, Tsao, C-K, Creel, P, Samsa, GP, Richardson, EM, Johnson, KA, Barham, A, and George, DJ. "Front-line management patterns in the prospective metastatic renal cell cancer (MaRCC) registry." December 2015.
Source
wos-lite
Published In
Bju International
Volume
116
Publish Date
2015
Start Page
12
End Page
12

The metastatic renal cell carcinoma (MaRCC) Registry: a prospective academic and community-based study of metastatic renal cell cancer patients

Authors
Bhavsar, NA; Harrison, MR; Hirsch, BR; Creel, P; Wolf, SP; Samsa, GP; Richardson, EM; Johnson, KA; Borham, A; George, DJ
MLA Citation
Bhavsar, NA, Harrison, MR, Hirsch, BR, Creel, P, Wolf, SP, Samsa, GP, Richardson, EM, Johnson, KA, Borham, A, and George, DJ. "The metastatic renal cell carcinoma (MaRCC) Registry: a prospective academic and community-based study of metastatic renal cell cancer patients." December 2015.
Source
wos-lite
Published In
Bju International
Volume
116
Publish Date
2015
Start Page
3
End Page
4

Development of a Standardized Set of Patient-centered Outcomes for Advanced Prostate Cancer: An International Effort for a Unified Approach.

There are no universally monitored outcomes relevant to men with advanced prostate cancer, making it challenging to compare health outcomes between populations.We sought to develop a standard set of outcomes relevant to men with advanced prostate cancer to follow during routine clinical care.The International Consortium for Health Outcomes Measurement assembled a multidisciplinary working group to develop the set.We used a modified Delphi method to achieve consensus regarding the outcomes, measures, and case mix factors included.The 25 members of the multidisciplinary international working group represented academic and nonacademic centers, registries, and patients. Recognizing the heterogeneity of men with advanced prostate cancer, the group defined the scope as men with all stages of incurable prostate cancer (metastatic and biochemical recurrence ineligible for further curative therapy). We defined outcomes important to all men, such as overall survival, and measures specific to subgroups, such as time to metastasis. Measures gathered from clinical data include measures of disease control. We also identified patient-reported outcome measures (PROMs), such as degree of urinary, bowel, and erectile dysfunction, mood symptoms, and pain control.The international multidisciplinary group identified clinical data and PROMs that serve as a basis for international health outcome comparisons and quality-of-care assessments. The set will be revised annually.Our international group has recommended a standardized set of patient-centered outcomes to be followed during routine care for all men with advanced prostate cancer.

Authors
Morgans, AK; van Bommel, ACM; Stowell, C; Abrahm, JL; Basch, E; Bekelman, JE; Berry, DL; Bossi, A; Davis, ID; de Reijke, TM; Denis, LJ; Evans, SM; Fleshner, NE; George, DJ; Kiefert, J; Lin, DW; Matthew, AG; McDermott, R; Payne, H; Roos, IAG; Schrag, D; Steuber, T; Tombal, B; van Basten, J-P; van der Hoeven, JJM; Penson, DF
MLA Citation
Morgans, AK, van Bommel, ACM, Stowell, C, Abrahm, JL, Basch, E, Bekelman, JE, Berry, DL, Bossi, A, Davis, ID, de Reijke, TM, Denis, LJ, Evans, SM, Fleshner, NE, George, DJ, Kiefert, J, Lin, DW, Matthew, AG, McDermott, R, Payne, H, Roos, IAG, Schrag, D, Steuber, T, Tombal, B, van Basten, J-P, van der Hoeven, JJM, and Penson, DF. "Development of a Standardized Set of Patient-centered Outcomes for Advanced Prostate Cancer: An International Effort for a Unified Approach." European urology 68.5 (November 2015): 891-898.
PMID
26129856
Source
epmc
Published In
European Urology
Volume
68
Issue
5
Publish Date
2015
Start Page
891
End Page
898
DOI
10.1016/j.eururo.2015.06.007

Clinical Trial Participants With Metastatic Renal Cell Carcinoma Differ From Patients Treated in Real-World Practice.

Although narrow eligibility criteria improve the internal validity of clinical trials, they may result in differences between study populations and real-world patients, threatening generalizability. Therefore, we evaluated whether patients treated for metastatic renal cell cancer (mRCC) in routine clinical practice are similar to those enrolled onto clinical trials.In this cohort study, we compared baseline characteristics of patients with mRCC in phase III clinical trials of new targeted therapies and those in a retrospective registry composed of academic (Duke) and community (ACORN Network) practices.A total of 438 registry patients received sunitinib, sorafenib, temsirolimus, or pazopanib (most commonly used agents) in first-line treatment. Registry patients receiving tyrosine kinase inhibitors (sunitinib, sorafenib, or pazopanib) were more likely to have poor-risk disease by Memorial Sloan Kettering Cancer Center criteria (poor, 7.4% v 2.9%; P < .001; favorable, 30.1% v 43.8%; P < .001) and to have impaired performance status (Eastern Cooperative Oncology Group > 1, 11.1% v 0.6%; P < .001). However, registry patients receiving temsirolimus were less likely to have poor-risk disease (poor, 10.2% v 69.4%; P < .001; favorable, 16.9% v 0%; P < .001). Thus, 39.0% of registry patients would have been excluded from the phase III clinical trial testing the drug they received.Patients with mRCC treated with tyrosine kinase inhibitors in real-world clinical practice are sicker than those enrolled onto pivotal clinical trials, and more than one third are trial ineligible. Application of clinical trial findings to dissimilar populations may result in patient harm. Clinical research with more inclusive eligibility criteria is needed to appropriately guide real-world practice.

Authors
Mitchell, AP; Harrison, MR; Walker, MS; George, DJ; Abernethy, AP; Hirsch, BR
MLA Citation
Mitchell, AP, Harrison, MR, Walker, MS, George, DJ, Abernethy, AP, and Hirsch, BR. "Clinical Trial Participants With Metastatic Renal Cell Carcinoma Differ From Patients Treated in Real-World Practice." Journal of oncology practice 11.6 (November 2015): 491-497.
PMID
26330533
Source
epmc
Published In
Journal of Oncology Practice
Volume
11
Issue
6
Publish Date
2015
Start Page
491
End Page
497
DOI
10.1200/jop.2015.004929

A Molecular Model for Predicting Overall Survival in Patients with Metastatic Clear Cell Renal Carcinoma: Results from CALGB 90206 (Alliance).

Prognosis associated with metastatic renal cell carcinoma (mRCC) can vary widely.This study used pretreatment nephrectomy specimens from a randomized phase III trial. Expression levels of candidate genes were determined from archival tumors using the OpenArray® platform for TaqMan® RT-qPCR. The dataset was randomly divided at 2:1 ratio into training (n = 221) and testing (n = 103) sets to develop a multigene prognostic signature.Gene expressions were measured in 324 patients. In the training set, multiple models testing 424 candidate genes identified a prognostic signature containing 8 genes plus MSKCC clinical risk factors. In the testing set, the time dependent (td) AUC for a prognostic model containing the 8 genes with and without MSKCC risk factors were 0.72 and 0.69, respectively. The tdAUC for the clinical risk factors alone was 0.61. Additional primary mRCCs from patients with mRCC (n = 12) were sampled in multiple sites and standard deviations of gene expressions within a tumor were used as a measure of heterogeneity. All 8 genes in the final prognostic model met our criteria for minimal heterogeneity.A molecular prognostic signature based on 8 genes was developed and is ready for external validation in this patient population and other related settings such as nonmetastatic RCC.

Authors
Kim, HL; Halabi, S; Li, P; Mayhew, G; Simko, J; Nixon, AB; Small, EJ; Rini, B; Morris, MJ; Taplin, M-E; George, D
MLA Citation
Kim, HL, Halabi, S, Li, P, Mayhew, G, Simko, J, Nixon, AB, Small, EJ, Rini, B, Morris, MJ, Taplin, M-E, and George, D. "A Molecular Model for Predicting Overall Survival in Patients with Metastatic Clear Cell Renal Carcinoma: Results from CALGB 90206 (Alliance)." EBioMedicine 2.11 (November 2015): 1814-1820.
PMID
26870806
Source
epmc
Published In
EBioMedicine
Volume
2
Issue
11
Publish Date
2015
Start Page
1814
End Page
1820
DOI
10.1016/j.ebiom.2015.09.012

Survival Outcomes of Sipuleucel-T Phase III Studies: Impact of Control-Arm Cross-Over to Salvage Immunotherapy.

Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic/minimally symptomatic metastatic castrate-resistant prostate cancer (CRPC). After disease progression, control-arm patients on three double-blind, randomized phase III sipuleucel-T trials were offered, in nonrandomized open-label protocols, APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control manufacture. These exploratory analyses evaluated potential effects on survival outcomes associated with such treatment. Of 249 control-treated patients, 165 (66.3%) received APC8015F. We explored the effects of APC8015F on the overall survival (OS; Cox regression) of control-arm patients and treatment effects of sipuleucel-T versus control adjusted for APC8015F treatment [iterative parameter estimation model (IPE)]. The median time to first APC8015F infusion was 5.2 months (range, 1.8-33.1) after randomization and 2.2 months (0.5-14.6) after progression. After disease progression, median survival was longer for APC8015F-treated versus control-only treated patients [20.0 vs. 9.8 months; HR, 0.53; 95% confidence interval (CI), 0.38-0.74; P < 0.001]; however, baseline characteristics were more favorable for APC8015F-treated patients. Multivariate regression analyses identified lactate dehydrogenase, alkaline phosphatase, hemoglobin, ECOG status, age, and number of bone metastases as potential (P < 0.1) independent predictors of postprogression survival. After adjusting for these predictors, APC8015F (HR, 0.78; 95% CI, 0.54-1.11; P = 0.17) treatment trended toward improved survival. Estimated median OS benefit for sipuleucel-T versus control adjusted for APC8015F treatment was 3.9 months if APC8015F had no effect and was 8.1 months if APC8015F was equally as effective as sipuleucel-T. Exploratory analyses indicate that APC8015F treatment may have extended patient survival, suggesting the sipuleucel-T OS advantage in CRPC may be more robust than previously estimated.

Authors
George, DJ; Nabhan, C; DeVries, T; Whitmore, JB; Gomella, LG
MLA Citation
George, DJ, Nabhan, C, DeVries, T, Whitmore, JB, and Gomella, LG. "Survival Outcomes of Sipuleucel-T Phase III Studies: Impact of Control-Arm Cross-Over to Salvage Immunotherapy." Cancer immunology research 3.9 (September 2015): 1063-1069.
PMID
25943532
Source
epmc
Published In
Cancer Immunology Research
Volume
3
Issue
9
Publish Date
2015
Start Page
1063
End Page
1069
DOI
10.1158/2326-6066.cir-15-0006

Exploring the Clinical Benefit of Docetaxel or Enzalutamide After Disease Progression During Abiraterone Acetate and Prednisone Treatment in Men With Metastatic Castration-Resistant Prostate Cancer.

Abiraterone acetate (AA) has demonstrated improved outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). However, data are lacking on the effect of AA on subsequent efficacy of enzalutamide or docetaxel.We included men with mCRPC who received AA and subsequent enzalutamide or docetaxel by August 12, 2013. Patients were separated into 3 groups: group A, treated with AA then enzalutamide before chemotherapy; group B, treated with AA then docetaxel; and group C, treated with AA and enzalutamide after chemotherapy. The primary objective was to describe the response and overall survival with subsequent therapy.There were 28 evaluable patients who received enzalutamide after AA (9 in group A and 19 in group C) and 13 patients who received docetaxel after AA (group B). Group A patients had more visceral disease and higher baseline prostate-specific antigen (PSA) levels, and group C men had a higher level of pain and multiple poor prognostic features. Median progression-free survival was 3.6, 5.1, and 2.8 months, respectively, and median overall survival was 8.5, not reached, and 9.6 months, respectively. A ≥ 50% PSA decline was achieved in 11%, 63%, and 5% of group A, B, and C patients, respectively. Radiographic or clinical progression as best response was noted in 55.5%, 30.8%, and 68.4% in each respective group.In this chart review of consecutive men with progressive mCRPC after AA, we found modest activity for enzalutamide and docetaxel, with clear cross-resistance for AA and enzalutamide. These data might inform the complex treatment decisions after AA treatment.

Authors
Zhang, T; Dhawan, MS; Healy, P; George, DJ; Harrison, MR; Oldan, J; Chin, B; Armstrong, AJ
MLA Citation
Zhang, T, Dhawan, MS, Healy, P, George, DJ, Harrison, MR, Oldan, J, Chin, B, and Armstrong, AJ. "Exploring the Clinical Benefit of Docetaxel or Enzalutamide After Disease Progression During Abiraterone Acetate and Prednisone Treatment in Men With Metastatic Castration-Resistant Prostate Cancer." Clinical genitourinary cancer 13.4 (August 2015): 392-399.
PMID
25708161
Source
epmc
Published In
Clinical genitourinary cancer
Volume
13
Issue
4
Publish Date
2015
Start Page
392
End Page
399
DOI
10.1016/j.clgc.2015.01.004

A Single-Arm Phase 1b Study of Everolimus and Sunitinib in Patients With Advanced Renal Cell Carcinoma.

Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), and sunitinib, an oral inhibitor of vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor tyrosine kinase signaling, have both been shown to provide clinical benefit in patients with advanced renal cell carcinoma (RCC). We sought to determine the safety and efficacy of combination therapy with these agents in patients with advanced RCC.We conducted a phase 1b dose escalation trial of sunitinib and everolimus in patients with advanced metastatic RCC. Prior nephrectomy was required, and prior radiation or chemotherapy other than VEGF/mTOR-based therapies was permitted. The primary end point was to determine the maximum tolerated dose/recommended phase 2 dose.A total of 4 out of a planned 30 subjects were enrolled onto this study (M:F = 2:2; mean age 52 years, 50% with Karnofsky performance status < 80). The first 3 patients were enrolled onto a 4 + 2 dosing schedule of daily sunitinib 50 mg and weekly everolimus 30 mg. Mean time receiving drug was 99 days. One partial response was seen. Toxicities included mucositis, thrombocytopenia, anemia, fatigue, dehydration, and hypoglycemia. Because of multiple grade 3 to 4 toxicities, the protocol was amended to 2 + 1 dosing of sunitinib 37.5 mg and daily everolimus 5 mg. The first patient on this schedule died from multiorgan failure with septic shock after 1 cycle of treatment. Subsequently, the study was closed. Pharmacokinetic results inconclusively suggest that toxicities could be attributed to the drug exposure.Combined use of everolimus and sunitinib in the treatment of metastatic RCC was not well tolerated in this small cohort.

Authors
Kanesvaran, R; Watt, K; Turnbull, JD; Armstrong, AJ; Wolkowiez, MC; George, DJ
MLA Citation
Kanesvaran, R, Watt, K, Turnbull, JD, Armstrong, AJ, Wolkowiez, MC, and George, DJ. "A Single-Arm Phase 1b Study of Everolimus and Sunitinib in Patients With Advanced Renal Cell Carcinoma." Clinical genitourinary cancer 13.4 (August 2015): 319-327.
PMID
26174223
Source
epmc
Published In
Clinical genitourinary cancer
Volume
13
Issue
4
Publish Date
2015
Start Page
319
End Page
327
DOI
10.1016/j.clgc.2014.12.011

BEST: A Randomized Phase II Study of Vascular Endothelial Growth Factor, RAF Kinase, and Mammalian Target of Rapamycin Combination Targeted Therapy With Bevacizumab, Sorafenib, and Temsirolimus in Advanced Renal Cell Carcinoma--A Trial of the ECOG-ACRIN Cancer Research Group (E2804).

On the basis of evidence that resistance to vascular endothelial growth factor (VEGF) receptor inhibition is caused by hypoxia-driven residual VEGF and other proangiogenic factors, combinations of agents from these classes were hypothesized to improve treatment outcomes relative to single-agent VEGF pathway blockade.A total of 361 patients with metastatic clear cell renal cell carcinoma were randomly assigned equally to arm A (bevacizumab monotherapy 10 mg/kg intravenously [IV] every 2 weeks), B (bevacizumab 10 mg/kg IV every 2 weeks and temsirolimus 25 mg IV every week), C (bevacizumab 5 mg/kg IV every 2 weeks and sorafenib 200 mg orally twice daily on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26), or D (sorafenib 200 mg twice daily and temsirolimus 25 mg IV weekly). Progression-free survival was the primary end point.Among 331 eligible treated patients, median PFS was 7.5 months for bevacizumab alone (90% CI, 5.8 to 10.8 months), 7.6 months for bevacizumab plus temsirolimus (90% CI, 6.7 to 9.2 months), 9.2 months for bevacizumab plus sorafenib (90% CI, 7.5 to 11.4 months), and 7.4 months for sorafenib plus temsirolimus (90% CI, 5.6 to 7.9 months). Hazard ratios from stratified Cox proportional hazards models were 1.01, 0.89, and 1.07 (with respective P values of .95, .49, and .68) for the three combinations, respectively, compared with bevacizumab alone. Adverse events did not differ significantly among treatment arms.The activity of sorafenib, temsirolimus, and bevacizumab administered in doublet combinations did not significantly improve median progression-free survival in comparison with bevacizumab monotherapy.

Authors
Flaherty, KT; Manola, JB; Pins, M; McDermott, DF; Atkins, MB; Dutcher, JJ; George, DJ; Margolin, KA; DiPaola, RS
MLA Citation
Flaherty, KT, Manola, JB, Pins, M, McDermott, DF, Atkins, MB, Dutcher, JJ, George, DJ, Margolin, KA, and DiPaola, RS. "BEST: A Randomized Phase II Study of Vascular Endothelial Growth Factor, RAF Kinase, and Mammalian Target of Rapamycin Combination Targeted Therapy With Bevacizumab, Sorafenib, and Temsirolimus in Advanced Renal Cell Carcinoma--A Trial of the ECOG-ACRIN Cancer Research Group (E2804)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.21 (July 2015): 2384-2391.
PMID
26077237
Source
epmc
Published In
Journal of Clinical Oncology
Volume
33
Issue
21
Publish Date
2015
Start Page
2384
End Page
2391
DOI
10.1200/jco.2015.60.9727

DEVELOPMENT OF A STANDARDIZED SET OF PATIENT-CENTERED OUTCOMES FOR ADVANCED PROSTATE CANCER: AN INTERNATIONAL EFFORT FOR A UNIFIED APPROACH

Authors
Morgans, AK; van Bommel, ACM; Stowell, C; Abrahm, JL; Basch, E; Bekelman, JE; Berry, DL; Bossi, A; Davis, ID; de Reijke, TM; Denis, LJ; Evans, SM; Fleshner, NE; George, DJ; Kiefert, J; Lin, DW; Matthew, AG; McDermott, R; Payne, H; Roos, IAG; Schrag, D; Steuber, T; Tombal, B; van Basten, J; van der Hoeven, JJM; Penson, D
MLA Citation
Morgans, AK, van Bommel, ACM, Stowell, C, Abrahm, JL, Basch, E, Bekelman, JE, Berry, DL, Bossi, A, Davis, ID, de Reijke, TM, Denis, LJ, Evans, SM, Fleshner, NE, George, DJ, Kiefert, J, Lin, DW, Matthew, AG, McDermott, R, Payne, H, Roos, IAG, Schrag, D, Steuber, T, Tombal, B, van Basten, J, van der Hoeven, JJM, and Penson, D. "DEVELOPMENT OF A STANDARDIZED SET OF PATIENT-CENTERED OUTCOMES FOR ADVANCED PROSTATE CANCER: AN INTERNATIONAL EFFORT FOR A UNIFIED APPROACH." ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY 11 (July 2015): 29-29.
Source
wos-lite
Published In
Asia-Pacific Journal of Clinical Oncology
Volume
11
Publish Date
2015
Start Page
29
End Page
29

Deferred systemic therapy in patients with metastatic renal cell carcinoma.

With the advent of small-molecule "targeted" therapies, the prevailing treatment paradigm for metastatic renal cell carcinoma (mRCC) is that all patients who are able to tolerate systemic therapy should receive it. However, oncologists often defer the initiation of systemic therapy for patients with mRCC. The outcomes of and clinical reasoning behind the initial management of patients with mRCC without systemic therapy have not been well described.We conducted a retrospective cohort study of all patients with mRCC treated within the Duke University Health System and diagnosed from January 1, 2007, to January 1, 2011. We defined our cohort as patients who did not receive systemic therapy during the first year after mRCC diagnosis. The clinical rationale for the lack of immediate treatment was ascertained by manual chart review.A total of 60 of 268 patients (22%) with mRCC managed without initial systemic therapy were included in our study. The median age was 61.2 years, the median duration from diagnosis of localized RCC to development of mRCC was 41.9 months, and 91% of patients had Eastern Cooperative Oncology Group functional status of ≤ 1. Of the patients, 60% were managed with surgical metastasectomy alone, 12% received multiple local treatment modalities, 13% received active surveillance, 7% were managed supportively, and 8% were categorized as "other."The majority of patients in our cohort had favorable disease characteristics and experienced favorable outcomes with surgery alone. Our results suggest that this population could represent 20% of patients with mRCC in tertiary care settings. Prospective data are needed to evaluate deferred systemic therapy as a management strategy.

Authors
Mitchell, AP; Hirsch, BR; Harrison, MR; Abernethy, AP; George, DJ
MLA Citation
Mitchell, AP, Hirsch, BR, Harrison, MR, Abernethy, AP, and George, DJ. "Deferred systemic therapy in patients with metastatic renal cell carcinoma." Clinical genitourinary cancer 13.3 (June 2015): e159-e166.
PMID
25770767
Source
epmc
Published In
Clinical genitourinary cancer
Volume
13
Issue
3
Publish Date
2015
Start Page
e159
End Page
e166
DOI
10.1016/j.clgc.2014.12.017

Optimizing the efficiency and quality of sipuleucel-T delivery in an academic institution.

Sipuleucel-T, an autologous cellular immunotherapy, is approved for the treatment of certain patients with metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T is the first personalized treatment for prostate cancer to be manufactured using the immune system of each individual patient. Patient preparation and compliance are critical because patients undergo serial leukapheresis and reinfusion procedures within a relatively short time period, which may result in transient reactions.The study aims to identify patients best suited for sipuleucel-T treatment, provide an overview of treatment, and encourage infusion sites to consider a primary contact model for the efficient coordination of care.Treatment experiences were evaluated from 124 patients with mCRPC who received sipuleucel-T from January 2010 to August 2013 according to current best practices. Feedback was collected from reflective interdisciplinary discussion within the sipuleucel-T delivery team (nurses, advanced practice providers, urologists, and medical oncologists).Early patient identification and education on treatment rationale, delivery, and expectations help ensure a successful sipuleucel-T treatment experience. A multidisciplinary coordinated-care process can facilitate proficient sipuleucel-T delivery, and the selection of a primary contact for care coordination offers benefits, such as clear and efficient education.

Authors
Davis, K; Wood, S; Dill, E; Fesko, Y; Bitting, RL; Harrison, MR; Armstrong, AJ; Moul, JW; George, DJ
MLA Citation
Davis, K, Wood, S, Dill, E, Fesko, Y, Bitting, RL, Harrison, MR, Armstrong, AJ, Moul, JW, and George, DJ. "Optimizing the efficiency and quality of sipuleucel-T delivery in an academic institution." Clinical journal of oncology nursing 19.3 (June 2015): 297-303.
PMID
26000580
Source
epmc
Published In
Clinical Journal of Oncology Nursing
Volume
19
Issue
3
Publish Date
2015
Start Page
297
End Page
303
DOI
10.1188/15.cjon.297-303

The future of kidney cancer treatment.

Authors
George, DJ
MLA Citation
George, DJ. "The future of kidney cancer treatment." Clinical advances in hematology & oncology : H&O 13.6 (June 2015): 368-371.
PMID
26352892
Source
epmc
Published In
Clinical advances in hematology & oncology : H&O
Volume
13
Issue
6
Publish Date
2015
Start Page
368
End Page
371

Final clinical results of a randomized phase II international trial of everolimus vs. sunitinib in patients with metastatic non-clear cell renal cell carcinoma (ASPEN)

Authors
Armstrong, AJ; Broderick, S; Eisen, T; Stadler, WM; Jones, RJ; Garcia, JA; Vaishampayan, UN; Picus, J; Hawkins, RE; Hainsworth, JD; Kollmannsberger, CK; Logan, TF; Puzanov, I; Pickering, LM; Ryan, CW; Protheroe, A; Lusk, CM; Oberg, S; Halabi, S; George, DJ
MLA Citation
Armstrong, AJ, Broderick, S, Eisen, T, Stadler, WM, Jones, RJ, Garcia, JA, Vaishampayan, UN, Picus, J, Hawkins, RE, Hainsworth, JD, Kollmannsberger, CK, Logan, TF, Puzanov, I, Pickering, LM, Ryan, CW, Protheroe, A, Lusk, CM, Oberg, S, Halabi, S, and George, DJ. "Final clinical results of a randomized phase II international trial of everolimus vs. sunitinib in patients with metastatic non-clear cell renal cell carcinoma (ASPEN)." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal (GI) and genitourinary (GU) malignancies.

Authors
Zhang, T; Boominathan, R; Foulk, B; Connelly, MC; Rao, C; Kemeny, G; Strickler, JH; Abbruzzese, JL; Harrison, MR; George, DJ; Hurwitz, H; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Zhang, T, Boominathan, R, Foulk, B, Connelly, MC, Rao, C, Kemeny, G, Strickler, JH, Abbruzzese, JL, Harrison, MR, George, DJ, Hurwitz, H, Garcia-Blanco, MA, and Armstrong, AJ. "Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal (GI) and genitourinary (GU) malignancies." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Phase II trial of the PI3 kinase inhibitor BKM120 with or without enzalutamide in men with metastatic castration resistant prostate cancer (mCRPC).

Authors
Armstrong, AJ; Halabi, S; Healy, P; Alumkal, JJ; Yu, EY; Winters, C; Hobbs, C; Soleau, C; Slottke, R; Mundy, K; George, DJ
MLA Citation
Armstrong, AJ, Halabi, S, Healy, P, Alumkal, JJ, Yu, EY, Winters, C, Hobbs, C, Soleau, C, Slottke, R, Mundy, K, and George, DJ. "Phase II trial of the PI3 kinase inhibitor BKM120 with or without enzalutamide in men with metastatic castration resistant prostate cancer (mCRPC)." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Prognostic factors for survival following initiation of second-line treatment with everolimus for metastatic renal cell carcinoma: evidence from a nationwide sample of clinical practice in the United States.

OBJECTIVE: Comparing prognostic factors for overall survival (OS) in community-practice metastatic renal cell carcinoma (mRCC) patients receiving second-line everolimus with those previously reported in clinical trials. RESEARCH DESIGN AND METHODS: Two separate chart sets (2009 - 2012) were used to develop and validate a prognostic model for patients initiating second-line everolimus after first-line tyrosine kinase inhibitor (TKI). MAIN OUTCOME MEASURES: Prognostic factors for OS have been identified and validated in separate samples. RESULTS: One-year OS probabilities in the study (n = 220) and validation (n = 97) samples were 68 and 67%; median OS was 19 and 23 months - higher than the 1-year OS of 60% and median OS of 14.8 months of RECORD-1. Karnofsky performance score < 80%, duration of mRCC < 1 year, progression on first-line TKI, liver metastasis and clear cell histology were significant prognostic factors for shorter survival. One-year OS estimates were 84% for validation sample patients with 0 - 2 risk factors, 63% for 3 risk factors and 22% for 4 - 5 risk factors (log-rank p < 0.001). CONCLUSION: Real-world prognostic factors for OS following second-line everolimus for mRCC were largely consistent with those previously identified in trial data; however, OS was longer in the practice setting than in clinical trials and was not associated with type of first-line TKI.

Authors
Wong, MK; Jonasch, E; Pal, SK; Signorovitch, JE; Lin, PL; Wang, X; Liu, Z; Culver, K; Scott, JA; George, DJ; Vogelzang, NJ
MLA Citation
Wong, MK, Jonasch, E, Pal, SK, Signorovitch, JE, Lin, PL, Wang, X, Liu, Z, Culver, K, Scott, JA, George, DJ, and Vogelzang, NJ. "Prognostic factors for survival following initiation of second-line treatment with everolimus for metastatic renal cell carcinoma: evidence from a nationwide sample of clinical practice in the United States." Expert opinion on pharmacotherapy 16.6 (April 2015): 805-819.
PMID
25766864
Source
epmc
Published In
Expert Opinion on Pharmacotherapy
Volume
16
Issue
6
Publish Date
2015
Start Page
805
End Page
819
DOI
10.1517/14656566.2015.1020298

A randomized, crossover phase 1 study to assess the effects of formulation (capsule vs tablet) and meal consumption on the bioavailability of dovitinib (TKI258).

PURPOSE: This 2-arm crossover study compared the relative bioavailability of two dovitinib (TKI258) formulations [anhydrate clinical service form (CSF) capsule and monohydrate final market image (FMI) tablet; Arm 1] and determined the effect of food on dovitinib exposure (Arm 2). METHODS: Patients with advanced solid tumors, excluding breast cancer, were enrolled in 1 of the 2 arms of the study. Patients in Arm 1 were randomized to a single 500-mg dose of CSF capsule or FMI tablet followed by 7 days of rest and 500 mg of the other formulation. Patients in Arm 2 received 300 mg of FMI tablet daily and were randomized to follow 1 of 6 meal sequences, each with 3 prandial conditions: low fat (LF), high fat (HF), or no meal (NM). RESULTS: In Arm 1 (n = 21), 17 patients were evaluable. FMI tablet compared with CSF capsule showed only slight reductions in the adjusted geometric means for area under the plasma concentration-time curve (AUClast; 3%) and maximum plasma concentration (C max; 1%). In Arm 2 (n = 42), 19 patients were evaluable. HF meal versus NM showed a 9% decrease in the adjusted geometric mean for AUClast and an 18% decrease for C max. Comparison of LF meal versus NM showed a 1% decrease for AUClast and a 10% decrease for C max. Common adverse events suspected to be study drug related included vomiting, diarrhea, nausea, and fatigue. CONCLUSIONS: Dovitinib FMI tablet had similar systemic exposure to the CSF capsule and was not affected by food.

Authors
Infante, JR; Ramanathan, RK; George, D; Tan, E; Quinlan, M; Liu, A; Scott, JW; Sharma, S
MLA Citation
Infante, JR, Ramanathan, RK, George, D, Tan, E, Quinlan, M, Liu, A, Scott, JW, and Sharma, S. "A randomized, crossover phase 1 study to assess the effects of formulation (capsule vs tablet) and meal consumption on the bioavailability of dovitinib (TKI258)." Cancer chemotherapy and pharmacology 75.4 (April 2015): 729-737.
PMID
25648347
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
75
Issue
4
Publish Date
2015
Start Page
729
End Page
737
DOI
10.1007/s00280-015-2681-3

Clinical phenotypes associated with circulating tumor cell enumeration in metastatic castration-resistant prostate cancer

© 2015 Elsevier Inc.Background: The presence of ≥5 circulating tumor cells (CTCs) is prognostic for shorter survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, some men have low CTCs despite widespread disease, suggesting heterogeneity in CTC phenotype or detection. The aim of this study was to evaluate the association of CTC enumeration with clinical disease characteristics and overall survival in men with mCRPC at our institution. Design: CTCs were enumerated using the CellSearch method in a prospective correlative study in men with mCRPC starting a new systemic therapy. The primary objective was to determine the clinical phenotype of the subset of men with mCRPC who have a poor prognosis and low CTCs. Secondary end points included associations of CTCs with survival and known prognostic biomarkers, before therapy and at progression. Results: At baseline, median CTC count was 16 cells and prostate-specific antigen (PSA) level was 178. ng/ml. At progression, median CTC count was 42, PSA level was 245. ng/ml, levels of lactate dehydrogenase and alkaline phosphatase rose, and level of hemoglobin dropped. The median overall survival for this heavily pretreated population was 11.2 months, and the multivariable hazard ratio for death of men with CTCs<5 vs.≥5 was 0.43 (95% CI: 0.24-0.77). Median progression-free survival was 4.4 months. CTC enumeration modestly correlated with lactate dehydrogenase and alkaline phosphatase levels but only weakly correlated with PSA and hemoglobin levels. We were unable to identify a consistent subgroup of poor prognosis men with a low number of CTCs. Conclusion: CTC enumeration appears to be prognostic in men with mCRPC and describes a phenotype of hematogenous dissemination that cannot be predicted based on standard clinical and laboratory assessments.

Authors
Bitting, RL; Healy, P; Halabi, S; George, DJ; Goodin, M; Armstrong, AJ
MLA Citation
Bitting, RL, Healy, P, Halabi, S, George, DJ, Goodin, M, and Armstrong, AJ. "Clinical phenotypes associated with circulating tumor cell enumeration in metastatic castration-resistant prostate cancer." Urologic Oncology: Seminars and Original Investigations 33.3 (March 1, 2015): 110.e1-110.e9.
Source
scopus
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
33
Issue
3
Publish Date
2015
Start Page
110.e1
End Page
110.e9
DOI
10.1016/j.urolonc.2014.09.002

Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer.

Over the past decade, treatment options for men with metastatic castration-resistant prostate cancer (CRPC) have expanded with the addition of abiraterone acetate (AA), enzalutamide, sipuleucel-T, radium-223, docetaxel and cabazitaxel. The optimal sequencing of therapies in the context of efficacy and known cross-resistance remains uncertain.We review the development of enzalutamide (MDV3100, Xtandi), a novel second-generation androgen receptor (AR), and AA (Zytiga), a selective, irreversible inhibitor of cytochrome P17. In addition to discussing the clinical evidence, we also address evolving evidence of mechanisms of resistance and clinical cross-resistance during sequential therapy with these agents.AA and enzalutamide have both demonstrated tolerability and clinical benefit for multiple outcomes in patients with CRPC, in both post-chemotherapy and pre-chemotherapy settings. Both agents target the androgen-signaling pathway and have similar efficacy; however, they differ in prednisone use and their toxicity profiles, impacting the decision of upfront therapy. Mechanisms of resistance emerging after treatment include both alterations in AR signaling as well as mechanisms that bypass the AR. Retrospective analyses have demonstrated evidence that sequential treatment with these agents results in limited clinical benefit, supporting mechanisms of cross-resistance. Trials are ongoing to determine optimal timing, sequence and combination of these agents.

Authors
Zhang, T; Zhu, J; George, DJ; Armstrong, AJ
MLA Citation
Zhang, T, Zhu, J, George, DJ, and Armstrong, AJ. "Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer." Expert opinion on pharmacotherapy 16.4 (March 2015): 473-485.
PMID
25534660
Source
epmc
Published In
Expert Opinion on Pharmacotherapy
Volume
16
Issue
4
Publish Date
2015
Start Page
473
End Page
485
DOI
10.1517/14656566.2015.995090

Clinical phenotypes associated with circulating tumor cell enumeration in metastatic castration-resistant prostate cancer.

The presence of ≥5 circulating tumor cells (CTCs) is prognostic for shorter survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, some men have low CTCs despite widespread disease, suggesting heterogeneity in CTC phenotype or detection. The aim of this study was to evaluate the association of CTC enumeration with clinical disease characteristics and overall survival in men with mCRPC at our institution.CTCs were enumerated using the CellSearch method in a prospective correlative study in men with mCRPC starting a new systemic therapy. The primary objective was to determine the clinical phenotype of the subset of men with mCRPC who have a poor prognosis and low CTCs. Secondary end points included associations of CTCs with survival and known prognostic biomarkers, before therapy and at progression.At baseline, median CTC count was 16 cells and prostate-specific antigen (PSA) level was 178 ng/ml. At progression, median CTC count was 42, PSA level was 245 ng/ml, levels of lactate dehydrogenase and alkaline phosphatase rose, and level of hemoglobin dropped. The median overall survival for this heavily pretreated population was 11.2 months, and the multivariable hazard ratio for death of men with CTCs<5 vs.≥5 was 0.43 (95% CI: 0.24-0.77). Median progression-free survival was 4.4 months. CTC enumeration modestly correlated with lactate dehydrogenase and alkaline phosphatase levels but only weakly correlated with PSA and hemoglobin levels. We were unable to identify a consistent subgroup of poor prognosis men with a low number of CTCs.CTC enumeration appears to be prognostic in men with mCRPC and describes a phenotype of hematogenous dissemination that cannot be predicted based on standard clinical and laboratory assessments.

Authors
Bitting, RL; Healy, P; Halabi, S; George, DJ; Goodin, M; Armstrong, AJ
MLA Citation
Bitting, RL, Healy, P, Halabi, S, George, DJ, Goodin, M, and Armstrong, AJ. "Clinical phenotypes associated with circulating tumor cell enumeration in metastatic castration-resistant prostate cancer." Urologic oncology 33.3 (March 2015): 110.e1-110.e9.
PMID
25595577
Source
epmc
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
33
Issue
3
Publish Date
2015
Start Page
110.e1
End Page
110.e9
DOI
10.1016/j.urolonc.2014.09.002

Effects of cabozantinib on pain and narcotic use in patients with castration-resistant prostate cancer: Results from a phase 2 nonrandomized expansion cohort

© 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.Background Pain negatively affects quality of life for cancer patients. Preliminary data in metastatic castration-resistant prostate cancer (mCRPC) suggested a benefit of the oral tyrosine kinase inhibitor cabozantinib to pain palliation. Objective Prospective evaluation of cabozantinib's benefits on pain and narcotic use in mCRPC. Design, setting, and participants This was a nonrandomized expansion (NRE) cohort (n = 144) of a phase 2 randomized discontinuation trial in docetaxel-refractory mCRPC patients. Pain and interference of symptoms with sleep and general activity were electronically self-reported daily for 7-d intervals at baseline and regularly scheduled throughout the study. Mean per-patient scores were calculated for each interval. Narcotic use was recorded daily during the same intervals. Intervention Open-label cabozantinib (100 mg or 40 mg). Outcome measurements and statistical analysis The following stringent response definition was used: clinically meaningful pain reduction (≥30% improvement in mean scores from baseline) confirmed at a later interval without concomitant increases in narcotics. Only patients with moderate or severe baseline pain were analyzed. Results and limitations Sixty-five patients with moderate or severe baseline pain were evaluable. Of these, 27 (42%) experienced pain palliation according to the stringent response definition. Thirty-seven patients (57%) had clinically meaningful pain relief at two consecutive intervals, reported ≥6 wk apart in the majority. Forty-four patients (68%) had palliation at one or more intervals; 36 (55%) decreased narcotics use during one or more intervals. Clinically meaningful pain reduction was associated with significant (p ≤ 0.001) improvements in sleep quality and general activity. A limitation of this study was its open-label design. Conclusions Cabozantinib demonstrated clinically meaningful pain palliation, reduced or eliminated patients' narcotic use, and improved patient functioning, thus meriting prospective validation in phase 3 studies. Patient summary We evaluated the potential of cabozantinib to improve symptoms in patients with metastatic prostate cancer that no longer responds to standard therapies. We saw a promising reduction in pain and reduced need for narcotic painkillers. Larger, well-controlled trials are necessary to confirm these findings.

Authors
Basch, E; Autio, KA; Smith, MR; Bennett, AV; Weitzman, AL; Scheffold, C; Sweeney, C; Rathkopf, DE; Smith, DC; George, DJ; Higano, CS; Harzstark, AL; Sartor, AO; Gordon, MS; Vogelzang, NJ; De Bono, JS; Haas, NB; Corn, PG; Schimmoller, F; Scher, HI
MLA Citation
Basch, E, Autio, KA, Smith, MR, Bennett, AV, Weitzman, AL, Scheffold, C, Sweeney, C, Rathkopf, DE, Smith, DC, George, DJ, Higano, CS, Harzstark, AL, Sartor, AO, Gordon, MS, Vogelzang, NJ, De Bono, JS, Haas, NB, Corn, PG, Schimmoller, F, and Scher, HI. "Effects of cabozantinib on pain and narcotic use in patients with castration-resistant prostate cancer: Results from a phase 2 nonrandomized expansion cohort." European Urology 67.2 (February 1, 2015): 310-318.
Source
scopus
Published In
European Urology
Volume
67
Issue
2
Publish Date
2015
Start Page
310
End Page
318
DOI
10.1016/j.eururo.2014.02.013

Effects of cabozantinib on pain and narcotic use in patients with castration-resistant prostate cancer: results from a phase 2 nonrandomized expansion cohort.

Pain negatively affects quality of life for cancer patients. Preliminary data in metastatic castration-resistant prostate cancer (mCRPC) suggested a benefit of the oral tyrosine kinase inhibitor cabozantinib to pain palliation.Prospective evaluation of cabozantinib's benefits on pain and narcotic use in mCRPC.This was a nonrandomized expansion (NRE) cohort (n=144) of a phase 2 randomized discontinuation trial in docetaxel-refractory mCRPC patients. Pain and interference of symptoms with sleep and general activity were electronically self-reported daily for 7-d intervals at baseline and regularly scheduled throughout the study. Mean per-patient scores were calculated for each interval. Narcotic use was recorded daily during the same intervals.Open-label cabozantinib (100mg or 40mg).The following stringent response definition was used: clinically meaningful pain reduction (≥30% improvement in mean scores from baseline) confirmed at a later interval without concomitant increases in narcotics. Only patients with moderate or severe baseline pain were analyzed.Sixty-five patients with moderate or severe baseline pain were evaluable. Of these, 27 (42%) experienced pain palliation according to the stringent response definition. Thirty-seven patients (57%) had clinically meaningful pain relief at two consecutive intervals, reported ≥6 wk apart in the majority. Forty-four patients (68%) had palliation at one or more intervals; 36 (55%) decreased narcotics use during one or more intervals. Clinically meaningful pain reduction was associated with significant (p ≤ 0.001) improvements in sleep quality and general activity. A limitation of this study was its open-label design.Cabozantinib demonstrated clinically meaningful pain palliation, reduced or eliminated patients' narcotic use, and improved patient functioning, thus meriting prospective validation in phase 3 studies.We evaluated the potential of cabozantinib to improve symptoms in patients with metastatic prostate cancer that no longer responds to standard therapies. We saw a promising reduction in pain and reduced need for narcotic painkillers. Larger, well-controlled trials are necessary to confirm these findings.

Authors
Basch, E; Autio, KA; Smith, MR; Bennett, AV; Weitzman, AL; Scheffold, C; Sweeney, C; Rathkopf, DE; Smith, DC; George, DJ; Higano, CS; Harzstark, AL; Sartor, AO; Gordon, MS; Vogelzang, NJ; de Bono, JS; Haas, NB; Corn, PG; Schimmoller, F; Scher, HI
MLA Citation
Basch, E, Autio, KA, Smith, MR, Bennett, AV, Weitzman, AL, Scheffold, C, Sweeney, C, Rathkopf, DE, Smith, DC, George, DJ, Higano, CS, Harzstark, AL, Sartor, AO, Gordon, MS, Vogelzang, NJ, de Bono, JS, Haas, NB, Corn, PG, Schimmoller, F, and Scher, HI. "Effects of cabozantinib on pain and narcotic use in patients with castration-resistant prostate cancer: results from a phase 2 nonrandomized expansion cohort." European urology 67.2 (February 2015): 310-318.
PMID
24631409
Source
epmc
Published In
European Urology
Volume
67
Issue
2
Publish Date
2015
Start Page
310
End Page
318
DOI
10.1016/j.eururo.2014.02.013

Deferred systemic therapy in patients with metastatic renal cell carcinoma

© 2015 Elsevier Inc.Abstract Background With the advent of small-molecule "targeted" therapies, the prevailing treatment paradigm for metastatic renal cell carcinoma (mRCC) is that all patients who are able to tolerate systemic therapy should receive it. However, oncologists often defer the initiation of systemic therapy for patients with mRCC. The outcomes of and clinical reasoning behind the initial management of patients with mRCC without systemic therapy have not been well described. Methods We conducted a retrospective cohort study of all patients with mRCC treated within the Duke University Health System and diagnosed from January 1, 2007, to January 1, 2011. We defined our cohort as patients who did not receive systemic therapy during the first year after mRCC diagnosis. The clinical rationale for the lack of immediate treatment was ascertained by manual chart review. Results A total of 60 of 268 patients (22%) with mRCC managed without initial systemic therapy were included in our study. The median age was 61.2 years, the median duration from diagnosis of localized RCC to development of mRCC was 41.9 months, and 91% of patients had Eastern Cooperative Oncology Group functional status of ≤ 1. Of the patients, 60% were managed with surgical metastasectomy alone, 12% received multiple local treatment modalities, 13% received active surveillance, 7% were managed supportively, and 8% were categorized as "other." Conclusions The majority of patients in our cohort had favorable disease characteristics and experienced favorable outcomes with surgery alone. Our results suggest that this population could represent 20% of patients with mRCC in tertiary care settings. Prospective data are needed to evaluate deferred systemic therapy as a management strategy.

Authors
Mitchell, AP; Hirsch, BR; Harrison, MR; Abernethy, AP; George, DJ
MLA Citation
Mitchell, AP, Hirsch, BR, Harrison, MR, Abernethy, AP, and George, DJ. "Deferred systemic therapy in patients with metastatic renal cell carcinoma." Clinical Genitourinary Cancer 13.3 (January 1, 2015): e159-e166.
Source
scopus
Published In
Clinical genitourinary cancer
Volume
13
Issue
3
Publish Date
2015
Start Page
e159
End Page
e166
DOI
10.1016/j.clgc.2014.12.017

A systematic review of sequencing and combinations of systemic therapy in metastatic renal cancer.

The introduction of novel molecular-targeted agents has revolutionised the management of patients with metastatic renal cell carcinoma (mRCC). However, uncertainties remain over sequential or simultaneous combination therapies.To systematically review relevant literature comparing the clinical effectiveness and harms of different sequencing and combinations of systemic targeted therapies for mRCC.Relevant databases (including Medline, Cochrane Library, trial registries, and conference proceedings) were searched (January 2000 to September 2013) including only randomised controlled trials (RCTs). Risk of bias assessment was performed. A qualitative and quantitative synthesis of the evidence was presented.The literature search identified 5149 articles. A total of 24 studies reporting on 9589 patients were eligible for inclusion; data from four studies were included for meta-analysis. There were generally low risks of bias across studies; however, clinical and methodological heterogeneity prevented pooling of data for most studies. Overall, the data showed several targeted therapies were associated with an improvement in progression-free survival in patients with mRCC. There were limited data from RCTs regarding the issue of sequencing; studies on combination therapies have been hampered by difficulties with tolerability and safety.Although the role of vascular endothelial growth factor/vascular endothelial growth factor receptor targeting therapies and mammalian target of rapamycin inhibition in the management of mRCC is now established, limited reliable data are available regarding sequencing and combination therapies. Although data from retrospective cohort studies suggest a potential benefit for sequencing systemic therapies, significant uncertainties remain. Presently, mRCC systemic treatment should follow international guidelines (such as the European Society for Medical Oncology, National Comprehensive Cancer Network, and European Association of Urology) for patients fit to receive several lines of systemic therapies.We thoroughly examined the literature on the benefits and harms of combining drugs for the treatment of kidney cancer that has spread and on the sequence in which the drugs should be given.

Authors
Albiges, L; Choueiri, T; Escudier, B; Galsky, M; George, D; Hofmann, F; Lam, T; Motzer, R; Mulders, P; Porta, C; Powles, T; Sternberg, C; Bex, A
MLA Citation
Albiges, L, Choueiri, T, Escudier, B, Galsky, M, George, D, Hofmann, F, Lam, T, Motzer, R, Mulders, P, Porta, C, Powles, T, Sternberg, C, and Bex, A. "A systematic review of sequencing and combinations of systemic therapy in metastatic renal cancer." European urology 67.1 (January 2015): 100-110.
PMID
24841777
Source
epmc
Published In
European Urology
Volume
67
Issue
1
Publish Date
2015
Start Page
100
End Page
110
DOI
10.1016/j.eururo.2014.04.006

Pain, PSA flare, and bone scan response in a patient with metastatic castration-resistant prostate cancer treated with radium-223, a case report.

Radium-223 has been shown to improve overall survival in men with metastatic castration-resistant prostate cancer with symptomatic bone metastases. The bone scan response to radium-223 has only been described in one single center trial of 14 patients, none of whom achieved the outstanding bone scan response presented in the current case.In this case report, we describe a 75 year-old white man with extensively pre-treated metastatic castration-resistant prostate cancer and symptomatic bone metastases who experienced a flare in pain and prostate-specific antigen, followed by dramatic clinical (pain), biochemical (prostate-specific antigen), and imaging (bone scan) response.The flare phenomena and bone scan response we observed have not previously been described with radium-223. This case suggests that the degree and duration of bone scan response may be predictive of overall survival benefit.

Authors
McNamara, MA; George, DJ
MLA Citation
McNamara, MA, and George, DJ. "Pain, PSA flare, and bone scan response in a patient with metastatic castration-resistant prostate cancer treated with radium-223, a case report." BMC cancer 15 (January 2015): 371-.
PMID
25948240
Source
epmc
Published In
BMC Cancer
Volume
15
Publish Date
2015
Start Page
371
DOI
10.1186/s12885-015-1390-y

A systematic review of sequencing and combinations of systemic therapy in metastatic renal cancer

© 2014 European Association of Urology.Context The introduction of novel molecular-targeted agents has revolutionised the management of patients with metastatic renal cell carcinoma (mRCC). However, uncertainties remain over sequential or simultaneous combination therapies. Objective To systematically review relevant literature comparing the clinical effectiveness and harms of different sequencing and combinations of systemic targeted therapies for mRCC. Evidence acquisition Relevant databases (including Medline, Cochrane Library, trial registries, and conference proceedings) were searched (January 2000 to September 2013) including only randomised controlled trials (RCTs). Risk of bias assessment was performed. A qualitative and quantitative synthesis of the evidence was presented. Evidence synthesis The literature search identified 5149 articles. A total of 24 studies reporting on 9589 patients were eligible for inclusion; data from four studies were included for meta-analysis. There were generally low risks of bias across studies; however, clinical and methodological heterogeneity prevented pooling of data for most studies. Overall, the data showed several targeted therapies were associated with an improvement in progression-free survival in patients with mRCC. There were limited data from RCTs regarding the issue of sequencing; studies on combination therapies have been hampered by difficulties with tolerability and safety. Conclusions Although the role of vascular endothelial growth factor/vascular endothelial growth factor receptor targeting therapies and mammalian target of rapamycin inhibition in the management of mRCC is now established, limited reliable data are available regarding sequencing and combination therapies. Although data from retrospective cohort studies suggest a potential benefit for sequencing systemic therapies, significant uncertainties remain. Presently, mRCC systemic treatment should follow international guidelines (such as the European Society for Medical Oncology, National Comprehensive Cancer Network, and European Association of Urology) for patients fit to receive several lines of systemic therapies. Patient summary We thoroughly examined the literature on the benefits and harms of combining drugs for the treatment of kidney cancer that has spread and on the sequence in which the drugs should be given.

Authors
Albiges, L; Choueiri, T; Escudier, B; Galsky, M; George, D; Hofmann, F; Lam, T; Motzer, R; Mulders, P; Porta, C; Powles, T; Sternberg, C; Bex, A
MLA Citation
Albiges, L, Choueiri, T, Escudier, B, Galsky, M, George, D, Hofmann, F, Lam, T, Motzer, R, Mulders, P, Porta, C, Powles, T, Sternberg, C, and Bex, A. "A systematic review of sequencing and combinations of systemic therapy in metastatic renal cancer." European Urology 67.1 (2015): 100-110.
Source
scival
Published In
European Urology
Volume
67
Issue
1
Publish Date
2015
Start Page
100
End Page
110
DOI
10.1016/j.eururo.2014.04.006

Does the multidisciplinary approach improve oncological outcomes in men undergoing surgical treatment for prostate cancer?

OBJECTIVES: To determine whether oncological outcomes are improved in prostate cancer patients by using a multidisciplinary strategy as compared with a standard clinic paradigm, and whether time to treatment is delayed when using a multidisciplinary approach. METHODS: We retrospectively analyzed patients who were evaluated and pursued radical prostatectomy as primary treatment, by the same surgeons, in the prostate cancer multidisciplinary clinic (n = 194) and standard urology clinic (n = 741) at Duke University Medical Center from 2005 to 2009. Comparisons of baseline characteristics were examined using rank sum and χ(2) -tests. Differences in time to radical prostatectomy and oncological outcomes were evaluated using multivariate linear and Cox regression, respectively. RESULTS: A greater proportion of high-risk patients (D'Amico criteria) were evaluated at the multidisciplinary clinic compared with the urology clinic (23.2% vs 15.6%, P = 0.014). Mean-adjusted time from biopsy to radical prostatectomy was shorter for multidisciplinary clinic patients (85.6 vs 96.8 days, P = 0.006). After a median follow up of 21 months, no significant difference was found between the multidisciplinary clinic and urology clinic in the risk of biochemical recurrence after radical prostatectomy, whether controlling for clinical (hazard ratio 0.71, P = 0.249) or pathological variables (hazard ratio 0.75, P = 0.349). CONCLUSIONS: Despite higher-risk disease, men evaluated using the multidisciplinary approach have similar oncological outcomes compared with men undergoing standard evaluation. Furthermore, time to radical prostatectomy is not delayed by the multidisciplinary management of these patients.

Authors
Stewart, SB; Moul, JW; Polascik, TJ; Koontz, BF; Robertson, CN; Freedland, SJ; George, DJ; Lee, WR; Armstrong, AJ; Bañez, LL
MLA Citation
Stewart, SB, Moul, JW, Polascik, TJ, Koontz, BF, Robertson, CN, Freedland, SJ, George, DJ, Lee, WR, Armstrong, AJ, and Bañez, LL. "Does the multidisciplinary approach improve oncological outcomes in men undergoing surgical treatment for prostate cancer?." International journal of urology : official journal of the Japanese Urological Association 21.12 (December 2014): 1215-1219.
PMID
25041422
Source
epmc
Published In
International Journal of Urology
Volume
21
Issue
12
Publish Date
2014
Start Page
1215
End Page
1219
DOI
10.1111/iju.12561

Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: synthesis of findings from two multi-practice chart reviews in the United States.

BACKGROUND: Second-line targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors (TKIs). This study compares the effectiveness of these therapies in a multi-practice chart review and synthesizes the findings with those of a similarly designed study. METHODS: Medical oncologists/hematologists (N = 36) were recruited to review charts for patients aged ≥18 years, received a first-line TKI and initiated second-line targeted therapy in 2010 or later. The primary outcome was time from second-line initiation to treatment failure (TTF; discontinuation, physician-assessed progression, or death, whichever occurred first). TTF was compared among patients receiving second-line everolimus (EVE), temsirolimus (TEM), or TKI as a class, using a Cox proportional hazards model adjusting for type of initial TKI and response, histological subtype, performance status, and sites of metastasis. Hazard ratios (HRs) for TTF were pooled, in a meta-analysis, with previously reported HRs for progression-free survival from a chart review with a similar design. RESULTS: A total of 138, 64 and 79 patients received second-line therapy with EVE, TEM or a TKI, respectively. Adjusting for baseline characteristics, EVE was associated with numerical, but not statistically significant, reductions of 28% (HR = 0.72; 95% CI [0.45-1.16]) and 26% (HR = 0.74; 95% CI [0.48-1.15]) in the hazard of TTF compared to TEM and TKI, respectively. After pooling the HRs from both studies, EVE was associated with significantly reduced hazards of TTF compared to TEM and TKI (HR = 0.73; 95% CI [0.57-0.93]; and HR = 0.75; 95% CI [0.57-0.98], respectively). LIMITATIONS: LIMITATIONS include retrospective analyses with possible missing or erroneous chart data, confounding of unobserved factors due to non-randomization, and limited data for axitinib during the study period. CONCLUSIONS: In pooled results from two independent multi-practice chart reviews of second-line mRCC treatment, EVE was associated with significantly reduced hazards of treatment failure compared to TEM and to TKIs as a class.

Authors
Signorovitch, JE; Vogelzang, NJ; Pal, SK; Lin, PL; George, DJ; Wong, MK; Liu, Z; Wang, X; Culver, K; Scott, JA; Jonasch, E
MLA Citation
Signorovitch, JE, Vogelzang, NJ, Pal, SK, Lin, PL, George, DJ, Wong, MK, Liu, Z, Wang, X, Culver, K, Scott, JA, and Jonasch, E. "Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: synthesis of findings from two multi-practice chart reviews in the United States." Current medical research and opinion 30.11 (November 2014): 2343-2353.
PMID
25105304
Source
epmc
Published In
Current Medical Research and Opinion
Volume
30
Issue
11
Publish Date
2014
Start Page
2343
End Page
2353
DOI
10.1185/03007995.2014.949645

Cabozantinib in Chemotherapy-Pretreated Metastatic Castration-Resistant Prostate Cancer: Results of a Phase II Nonrandomized Expansion Study

Authors
Smith, MR; Sweeney, CJ; Corn, PG; Rathkopf, DE; Smith, DC; Hussain, M; George, DJ; Higano, CS; Harzstark, AL; Sartor, AO; Vogelzang, NJ; Gordon, MS; de Bono, JS; Haas, NB; Logothetis, CJ; Elfiky, A; Scheffold, C; Laird, AD; Schimmoller, F; Basch, EM; Scher, HI
MLA Citation
Smith, MR, Sweeney, CJ, Corn, PG, Rathkopf, DE, Smith, DC, Hussain, M, George, DJ, Higano, CS, Harzstark, AL, Sartor, AO, Vogelzang, NJ, Gordon, MS, de Bono, JS, Haas, NB, Logothetis, CJ, Elfiky, A, Scheffold, C, Laird, AD, Schimmoller, F, Basch, EM, and Scher, HI. "Cabozantinib in Chemotherapy-Pretreated Metastatic Castration-Resistant Prostate Cancer: Results of a Phase II Nonrandomized Expansion Study." October 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
30
Publish Date
2014
Start Page
3391
End Page
U224
DOI
10.1200/JCO.2013.54.5954

Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy: final analysis of a multicentre, open-label, early-access protocol trial.

In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy.We did a multicentre, open-label, early-access protocol trial in 23 countries. We enrolled patients who had metastatic castration-resistant prostate cancer progressing after taxane chemotherapy. Participants received oral doses of abiraterone acetate (1000 mg daily) and prednisone (5 mg twice a day) in 28-day cycles until disease progression, development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time to clinical progression) were gathered to guide treatment decisions. We included in our analysis all patients who received at least one dose of abiraterone acetate. This study is registered with ClinicalTrials.gov, number NCT01217697.Between Nov 17, 2010, and Sept 30, 2013, 2314 patients were enrolled into the early-access protocol trial. Median follow-up was 5·7 months (IQR 3·5-10·6). 952 (41%) patients had a grade 3 or 4 treatment-related adverse event, and grade 3 or 4 serious adverse events were recorded in 585 (25%) people. The most common grade 3 and 4 adverse events were hepatotoxicity (188 [8%]), hypertension (99 [4%]), cardiac disorders (52 [2%]), osteoporosis (31 [1%]), hypokalaemia (28 [1%]), and fluid retention or oedema (23 [1%]). 172 (7%) patients discontinued the study because of adverse events (64 [3%] were drug-related), as assessed by the investigator, and 171 (7%) people died. The funder assessed causes of death, which were due to disease progression (85 [4%]), an unrelated adverse experience (72 [3%]), and unknown reasons (14 [1%]). Of the 86 deaths not attributable to disease progression, 18 (<1%) were caused by a drug-related adverse event, as assessed by the investigator. Median time to PSA progression was 8·5 months (95% CI 8·3-9·7) and median time to clinical progression was 12·7 months (11·8-13·8).No new safety signals or unexpected adverse events were found in this early-access protocol trial to assess abiraterone acetate for patients with metastatic castration-resistant prostate cancer who progressed after chemotherapy. Future work is needed to ascertain the most effective regimen of abiraterone acetate to optimise patients' outcomes.Janssen Research & Development.

Authors
Sternberg, CN; Castellano, D; Daugaard, G; Géczi, L; Hotte, SJ; Mainwaring, PN; Saad, F; Souza, C; Tay, MH; Garrido, JMT; Galli, L; Londhe, A; De Porre, P; Goon, B; Lee, E; McGowan, T; Naini, V; Todd, MB; Molina, A; George, DJ
MLA Citation
Sternberg, CN, Castellano, D, Daugaard, G, Géczi, L, Hotte, SJ, Mainwaring, PN, Saad, F, Souza, C, Tay, MH, Garrido, JMT, Galli, L, Londhe, A, De Porre, P, Goon, B, Lee, E, McGowan, T, Naini, V, Todd, MB, Molina, A, and George, DJ. "Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy: final analysis of a multicentre, open-label, early-access protocol trial." The Lancet. Oncology 15.11 (October 2014): 1263-1268.
PMID
25242048
Source
epmc
Published In
The Lancet Oncology
Volume
15
Issue
11
Publish Date
2014
Start Page
1263
End Page
1268
DOI
10.1016/s1470-2045(14)70417-6

Copper signaling axis as a target for prostate cancer therapeutics.

Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies.

Authors
Safi, R; Nelson, ER; Chitneni, SK; Franz, KJ; George, DJ; Zalutsky, MR; McDonnell, DP
MLA Citation
Safi, R, Nelson, ER, Chitneni, SK, Franz, KJ, George, DJ, Zalutsky, MR, and McDonnell, DP. "Copper signaling axis as a target for prostate cancer therapeutics." Cancer research 74.20 (October 2014): 5819-5831.
Website
http://hdl.handle.net/10161/9192
PMID
25320179
Source
epmc
Published In
Cancer Research
Volume
74
Issue
20
Publish Date
2014
Start Page
5819
End Page
5831
DOI
10.1158/0008-5472.can-13-3527

The effect of formulation and food consumption on the bioavailability of dovitinib (TKI258) in patients with advanced solid tumors.

PURPOSE: This 2-arm, phase 1, crossover study compared the relative bioavailability of two dovitinib (TKI258) capsule formulations [anhydrate clinical service form (CSF) and monohydrate final market image (FMI); Arm 1] and determined the effect of food on dovitinib exposure (Arm 2). METHODS: Patients with advanced solid tumors were enrolled in one of the 2 arms. Arm 1 randomized patients to a single 500-mg dose of either CSF or FMI followed by 7 days of rest and 500 mg of the other formulation. Arm 2 patients received 300 mg of FMI once daily and were randomized to follow one of six meal sequences, each with three prandial conditions: low fat (LF), high fat (HF), or no meal (NM). RESULTS: Twenty-three and 37 patients were enrolled and 19 and 21 were evaluable in Arms 1 and 2, respectively. In Arm 1, the adjusted geometric means for FMI had small reductions relative to CSF [area under the plasma concentration-time curve (AUClast) decreased by 12%, maximum concentration (C max) decreased by 3%]. In Arm 2, the HF meal versus NM showed a 2% increase in the adjusted geometric mean for AUClast and a 5% decrease for C max. The LF meal versus NM comparison showed 9 and 6% increases for AUClast and C max, respectively. Overall, common adverse events included nausea, vomiting, diarrhea, and fatigue. CONCLUSIONS: Systemic exposure to dovitinib was similar for the FMI and CSF capsule formulations. Additionally, since prandial conditions did not affect the systemic exposure, dovitinib can be taken with or without food.

Authors
Sharma, S; Britten, CD; Mortimer, J; Kulkarni, S; Quinlan, M; Liu, A; Scott, JW; George, D
MLA Citation
Sharma, S, Britten, CD, Mortimer, J, Kulkarni, S, Quinlan, M, Liu, A, Scott, JW, and George, D. "The effect of formulation and food consumption on the bioavailability of dovitinib (TKI258) in patients with advanced solid tumors." Cancer chemotherapy and pharmacology 74.4 (October 2014): 867-874.
PMID
25193431
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
74
Issue
4
Publish Date
2014
Start Page
867
End Page
874
DOI
10.1007/s00280-014-2454-4

Use of "Real-World" data to describe adverse events during the treatment of metastatic renal cell carcinoma in routine clinical practice

Insights into the experience of metastatic renal cell carcinoma (mRCC) patients are needed to optimize patient care. A retrospective, multicenter registry of mRCC patients treated at academic (Duke) and community (ACORN) practices was developed to fill this need. Treatment data were collected on 466 patients who received first-line therapy from 2007 to 2011. Clinically significant adverse events (AEs) were abstracted from medical records and compared to clinical trials. Two hundred and seventy patients received first-line therapy with sunitinib, 60 temsirolimus, 53 sorafenib, 25 pazopanib, and 58 "other." A total of 85.8 % of all patients experienced at least one AE: fatigue (56.7 %), vomiting (40.1 %), diarrhea (33.7 %), asthenia (32.8 %), and mucosal inflammation (20.8 %). When comparisons were made between patients >65 versus <65 years old, rates of AEs were higher in the younger group. Dosing approaches and timing of AEs during therapy were varied. These data shine light on the patient experience in routine practice versus structured clinical trials. Real-world AE frequency and severity differ from pivotal trials demonstrating the need to monitor patients closely and manage their AEs to optimize outcomes. As the number of treatment options with similar effectiveness grows, it is imperative to understand the real-world patient experience.

Authors
Hirsch, BR; Harrison, MR; George, DJ; Walker, MS; Chen, C; Korytowsky, B; Stepanski, E; Abernethy, AP
MLA Citation
Hirsch, BR, Harrison, MR, George, DJ, Walker, MS, Chen, C, Korytowsky, B, Stepanski, E, and Abernethy, AP. "Use of "Real-World" data to describe adverse events during the treatment of metastatic renal cell carcinoma in routine clinical practice." Medical oncology (Northwood, London, England) 31.9 (September 1, 2014): 156-.
Source
scopus
Published In
Medical Oncology
Volume
31
Issue
9
Publish Date
2014
Start Page
156
DOI
10.1007/s12032-014-0156-8

Use of "Real-World" data to describe adverse events during the treatment of metastatic renal cell carcinoma in routine clinical practice.

Insights into the experience of metastatic renal cell carcinoma (mRCC) patients are needed to optimize patient care. A retrospective, multicenter registry of mRCC patients treated at academic (Duke) and community (ACORN) practices was developed to fill this need. Treatment data were collected on 466 patients who received first-line therapy from 2007 to 2011. Clinically significant adverse events (AEs) were abstracted from medical records and compared to clinical trials. Two hundred and seventy patients received first-line therapy with sunitinib, 60 temsirolimus, 53 sorafenib, 25 pazopanib, and 58 "other." A total of 85.8 % of all patients experienced at least one AE: fatigue (56.7 %), vomiting (40.1 %), diarrhea (33.7 %), asthenia (32.8 %), and mucosal inflammation (20.8 %). When comparisons were made between patients >65 versus <65 years old, rates of AEs were higher in the younger group. Dosing approaches and timing of AEs during therapy were varied. These data shine light on the patient experience in routine practice versus structured clinical trials. Real-world AE frequency and severity differ from pivotal trials demonstrating the need to monitor patients closely and manage their AEs to optimize outcomes. As the number of treatment options with similar effectiveness grows, it is imperative to understand the real-world patient experience.

Authors
Hirsch, BR; Harrison, MR; George, DJ; Walker, MS; Chen, C; Korytowsky, B; Stepanski, E; Abernethy, AP
MLA Citation
Hirsch, BR, Harrison, MR, George, DJ, Walker, MS, Chen, C, Korytowsky, B, Stepanski, E, and Abernethy, AP. "Use of "Real-World" data to describe adverse events during the treatment of metastatic renal cell carcinoma in routine clinical practice." Medical oncology (Northwood, London, England) 31.9 (September 2014): 156-.
PMID
25115744
Source
epmc
Published In
Medical Oncology
Volume
31
Issue
9
Publish Date
2014
Start Page
156
DOI
10.1007/s12032-014-0156-8

Highlights in advanced prostate cancer from the 2014 AUA and ASCO meetings.

MLA Citation
"Highlights in advanced prostate cancer from the 2014 AUA and ASCO meetings." Clinical advances in hematology & oncology : H&O 12.9 Suppl 17 (September 2014): 1-21.
PMID
25767995
Source
epmc
Published In
Clinical advances in hematology & oncology : H&O
Volume
12
Issue
9 Suppl 17
Publish Date
2014
Start Page
1
End Page
21

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 II study of single-agent orteronel (TAK-700) in patients with nonmetastatic castration-resistant prostate cancer and rising prostate-specific antigen.

Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17α-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M0).Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was percentage of patients achieving PSA ≤0.2 ng/mL (undetectable levels) at 3 months. Secondary endpoints included safety, PSA response, time to metastases, and correlated endpoints.Thirty-nine patients with a median baseline PSA doubling time of 2.4 months (range, 0.9-9.2) received a median of fourteen 28-day treatment cycles. PSA decreased >30% in 35 patients and 6 (16%) achieved PSA ≤ 0.2 ng/mL at 3 months. Median times to PSA progression and metastasis were 13.8 and 25.4 months, respectively. Kaplan-Meier estimates of freedom from PSA progression were 57% and 42% at 12 and 24 months, and of freedom from metastasis were 94% and 62% at 12 and 24 months, respectively. At 3 months, median testosterone declined by 89% from baseline. Adverse events led to therapy discontinuation in 12 patients and grade ≥3/4 adverse events occurred in 22 patients. Most frequent all-cause adverse events included fatigue (64%), hypertension (44%), diarrhea (38%), and nausea (33%), which were primarily grade 1/2.Single-agent orteronel produced marked and durable declines in PSA in patients with nmCRPC. Orteronel has moderate but manageable toxicities and its chronic administration without steroids appears feasible.

Authors
Hussain, M; Corn, PG; Michaelson, MD; Hammers, HJ; Alumkal, JJ; Ryan, CJ; Bruce, JY; Moran, S; Lee, S-Y; Lin, HM; George, DJ
MLA Citation
Hussain, M, Corn, PG, Michaelson, MD, Hammers, HJ, Alumkal, JJ, Ryan, CJ, Bruce, JY, Moran, S, Lee, S-Y, Lin, HM, and George, DJ. "Phase II study of single-agent orteronel (TAK-700) in patients with nonmetastatic castration-resistant prostate cancer and rising prostate-specific antigen." Clinical cancer research : an official journal of the American Association for Cancer Research 20.16 (August 2014): 4218-4227.
PMID
24965748
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
20
Issue
16
Publish Date
2014
Start Page
4218
End Page
4227
DOI
10.1158/1078-0432.ccr-14-0356

Preoperative enoxaparin versus postoperative semuloparin thromboprophylaxis in major abdominal surgery: a randomized controlled trial.

OBJECTIVE: To compare efficacy and safety of thromboprophylaxis with semuloparin started postoperatively versus enoxaparin started preoperatively in major abdominal surgery. BACKGROUND: Venous thromboembolism is an important complication following major abdominal surgery. Semuloparin is a novel ultra-low-molecular-weight heparin with high antifactor Xa and minimal antifactor IIa activity. METHODS: In this double-blind noninferiority trial, adult patients undergoing major abdominal or pelvic operation under general anesthesia lasting more than 45 minutes were assigned to either daily enoxaparin 40 mg commenced preoperatively or daily semuloparin 20 mg commenced postoperatively, for 7 to 10 days. Patients underwent bilateral leg venography between 7 and 11 days postsurgery. The primary efficacy end point was the composite of any deep vein thrombosis, nonfatal pulmonary embolism, or all-cause death. The primary safety outcome was bleeding. Both were independently adjudicated. RESULTS: In total, 4413 patients were randomized; 3030 (1499 in the enoxaparin and 1531 in the semuloparin groups) were evaluable for the primary efficacy end point, which occurred in 97 patients (6.3%) in the semuloparin group and 82 patients (5.5%) in the enoxaparin group [odds ratio (OR) = 1.16, 95% confidence interval (CI): 0.84-1.59]. On the basis of a noninferiority margin of 1.25, postoperative semuloparin did not demonstrate noninferiority to preoperative enoxaparin. Major bleeding occurred in 63 of 2175 patients (2.9%) in the semuloparin group and 98 of 2177 patients (4.5%) in the enoxaparin group (OR = 0.63, 95% CI: 0.46-0.87). CONCLUSIONS: Semuloparin commenced postoperatively did not demonstrate noninferiority to enoxaparin initiated preoperatively for thromboprophylaxis after major abdominal surgery. Study registered with clinicaltrials.gov: NCT00679588.

Authors
Kakkar, AK; Agnelli, G; Fisher, W; George, D; Lassen, MR; Mismetti, P; Mouret, P; Murphy, J; Lawson, F; Turpie, AGG
MLA Citation
Kakkar, AK, Agnelli, G, Fisher, W, George, D, Lassen, MR, Mismetti, P, Mouret, P, Murphy, J, Lawson, F, and Turpie, AGG. "Preoperative enoxaparin versus postoperative semuloparin thromboprophylaxis in major abdominal surgery: a randomized controlled trial." Annals of surgery 259.6 (June 2014): 1073-1079.
PMID
24374549
Source
epmc
Published In
Annals of Surgery
Volume
259
Issue
6
Publish Date
2014
Start Page
1073
End Page
1079
DOI
10.1097/sla.0000000000000430

Prognostic and predictive tumor-based biomarkers in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (IFN) with or without bevacizumab (Bev): Results from CALGB (Alliance) 90206. 2

Authors
Kluger, HM; Halabi, S; Solomon, NC; Jilaveanu, L; Zito, C; Sznol, J; Nixon, AB; Rini, BI; Small, EJ; George, DJ
MLA Citation
Kluger, HM, Halabi, S, Solomon, NC, Jilaveanu, L, Zito, C, Sznol, J, Nixon, AB, Rini, BI, Small, EJ, and George, DJ. "Prognostic and predictive tumor-based biomarkers in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (IFN) with or without bevacizumab (Bev): Results from CALGB (Alliance) 90206. 2." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Final analysis of a large, open-label global early access protocol (EAP) with abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy.

Authors
Sternberg, CN; Daugaard, G; Geczi, L; Hotte, SJ; Mainwaring, PN; Saad, F; Souza, C; Tay, MH; Garrido, JMT; Galli, L; Londhe, A; De Porre, P; Atian, D; Goon, B; Lee, E; McGowan, T; Naini, V; Todd, MB; Molina, A; George, DJ
MLA Citation
Sternberg, CN, Daugaard, G, Geczi, L, Hotte, SJ, Mainwaring, PN, Saad, F, Souza, C, Tay, MH, Garrido, JMT, Galli, L, Londhe, A, De Porre, P, Atian, D, Goon, B, Lee, E, McGowan, T, Naini, V, Todd, MB, Molina, A, and George, DJ. "Final analysis of a large, open-label global early access protocol (EAP) with abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Clinical benefit of docetaxel or enzalutamide after progression on first-line abiraterone acetate and prednisone in men with metastatic castration resistant prostate cancer (mCRPC)

Authors
Zhang, T; Dhawan, MS; Healy, P; George, DJ; Olden, J; Chin, B; Armstrong, AJ
MLA Citation
Zhang, T, Dhawan, MS, Healy, P, George, DJ, Olden, J, Chin, B, and Armstrong, AJ. "Clinical benefit of docetaxel or enzalutamide after progression on first-line abiraterone acetate and prednisone in men with metastatic castration resistant prostate cancer (mCRPC)." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Clinical trial subjects compared to "real world" patients: Generalizability of renal cell carcinoma trials

Authors
Mitchell, AP; Harrison, MR; George, DJ; Abernethy, AP; Walker, MS; Hirsch, BR
MLA Citation
Mitchell, AP, Harrison, MR, George, DJ, Abernethy, AP, Walker, MS, and Hirsch, BR. "Clinical trial subjects compared to "real world" patients: Generalizability of renal cell carcinoma trials." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

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

Comparative outcomes of everolimus, temsirolimus and sorafenib as second targeted therapies for metastatic renal cell carcinoma: a US medical record review.

OBJECTIVE: To compare outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus, temsirolimus, and sorafenib following initial treatment with a tyrosine kinase inhibitor (TKI) in community and academic practices throughout the US. RESEARCH DESIGN AND METHODS: Medical records of mRCC patients who received everolimus, temsirolimus or sorafenib as their second therapy following a TKI were retrospectively reviewed from a nationally representative panel of oncologists. Overall survival (OS) and progression-free survival (PFS) of second targeted therapies were compared using multivariable Cox proportional hazard models, with adjustment for demographics, disease severity and prior treatments. RESULTS: A total of 233, 178, and 123 mRCC patients receiving everolimus, temsirolimus, and sorafenib, respectively, as second targeted therapies were included. Eighty-six percent used sunitinib and the remainder used sorafenib or pazopanib as their initial TKI. After adjusting for baseline characteristics, everolimus was associated with significantly prolonged OS (hazard ratio [HR] 0.60; CI 0.42-0.85; p = 0.004) and PFS (HR 0.73; CI 0.54-0.97; p = 0.032) compared to temsirolimus. Everolimus was associated with significantly longer OS (HR 0.66; CI 0.44-0.99; p = 0.045) and numerically longer PFS compared to sorafenib. No significant differences were observed between temsirolimus and sorafenib. LIMITATIONS: Despite adjustment for multiple patient characteristics, comparisons between treatment groups may be confounded by unobserved factors in this retrospective observational study. Tolerability outcomes were not collected. CONCLUSIONS: In this retrospective, non-randomized study of mRCC patients with prior TKI treatment, everolimus was associated with significantly prolonged OS and PFS compared to temsirolimus and significantly prolonged OS compared to sorafenib.

Authors
Wong, MK; Yang, H; Signorovitch, JE; Wang, X; Liu, Z; Liu, NS; Qi, CZ; George, DJ
MLA Citation
Wong, MK, Yang, H, Signorovitch, JE, Wang, X, Liu, Z, Liu, NS, Qi, CZ, and George, DJ. "Comparative outcomes of everolimus, temsirolimus and sorafenib as second targeted therapies for metastatic renal cell carcinoma: a US medical record review." Current medical research and opinion 30.4 (April 2014): 537-545.
PMID
24329572
Source
epmc
Published In
Current Medical Research and Opinion
Volume
30
Issue
4
Publish Date
2014
Start Page
537
End Page
545
DOI
10.1185/03007995.2013.871243

Highlights in advanced prostate cancer from the 2014 American Society of Clinical Oncology genitourinary cancers symposium: commentary.

Authors
George, DJ
MLA Citation
George, DJ. "Highlights in advanced prostate cancer from the 2014 American Society of Clinical Oncology genitourinary cancers symposium: commentary." Clinical advances in hematology & oncology : H&O 12.4 Suppl 11 (April 2014): 12-16.
PMID
24870260
Source
epmc
Published In
Clinical advances in hematology & oncology : H&O
Volume
12
Issue
4 Suppl 11
Publish Date
2014
Start Page
12
End Page
16

Real-world outcomes in metastatic renal cell carcinoma: insights from a Joint Community-Academic Registry.

INTRODUCTION: As new therapeutics for metastatic renal cell carcinoma (mRCC) are quickly introduced to market, comparative randomized trial evidence guiding treatment decisions is lacking, especially in the second treatment exposure and beyond. As a demonstration case, we studied mRCC in real-world clinical settings by creating a joint community-academic retrospective mRCC registry to assess outcomes. MATERIALS AND METHODS: For this overall survival (OS) analysis, the analytic cohort included all patients in the registry diagnosed between January 1, 2007, to May 31, 2011 (N = 384). Patients were grouped by up to three treatment exposures according to each drug's mechanism of action: vascular endothelial growth factor tyrosine kinase inhibitor (VEGFR TKI), mammalian target of rapamycin inhibitor (mTOR), or no systemic treatment (NSTx, which could include radiation or surgery). OS by exposure sequence was evaluated using Kaplan-Meier, pairwise comparison, and Cox regression analyses. RESULTS: Median OS was 17.2 months. OS (months) for one exposure was: mTOR 5.4, TKI 18.2, NSTx 18.4; for two exposures: mTOR/TKI 9.3, TKI/mTOR 13.9, TKI/TKI 35.2; and for three exposures: TKI/mTOR/TKI 20.9, TKI/TKI/mTOR 33.1. By pairwise comparison, OS for TKI, mTOR/TKI, TKI/mTOR, TKI/TKI, TKI/mTOR/TKI and TKI/TKI/mTOR sequences was greater than mTOR (all P < .04); demographics confirmed that individuals treated with early mTOR inhibition more commonly had adverse prognostic features. In Cox regression analysis, compared with the referent (TKI), TKI/TKI (hazard ratio = 0.53; P = .03) had a lower risk of death, and mTOR (hazard ratio = 2.16; P = .002) had a higher risk of death. CONCLUSIONS: mRCC survival outcomes are different by pattern, with general findings consistent with trial-based expectations in similar patient populations. Real-world data can provide context around patterns of care and impact when experimental trial data are lacking.

Authors
Harrison, MR; Hirsch, BR; George, DJ; Walker, MS; Chen, C; Korytowsky, B; Stepanski, E; Abernethy, AP
MLA Citation
Harrison, MR, Hirsch, BR, George, DJ, Walker, MS, Chen, C, Korytowsky, B, Stepanski, E, and Abernethy, AP. "Real-world outcomes in metastatic renal cell carcinoma: insights from a Joint Community-Academic Registry." J Oncol Pract 10.2 (March 2014): e63-e72.
PMID
24281152
Source
pubmed
Published In
Journal of Oncology Practice
Volume
10
Issue
2
Publish Date
2014
Start Page
e63
End Page
e72
DOI
10.1200/JOP.2013.001180

Treatment selection in metastatic renal cell carcinoma: more confusion or a path forward?

Meaningful progress has been realized in the treatment of metastatic renal cell carcinoma with the recent approval of a number of new agents; more new agents are on the horizon. Despite the recent completion of many clinical trials that have changed or will change practice, many questions remain. In this manuscript, we highlight the most noteworthy developments in the first- and second-line treatment of metastatic renal cell carcinoma, as these are the areas of greatest change. We also emphasize ongoing trials and those areas that are most in need of study in order to move the field forward. Although more data are needed, exciting progress is being made.

Authors
Hirsch, BR; George, DJ; Harrison, MR
MLA Citation
Hirsch, BR, George, DJ, and Harrison, MR. "Treatment selection in metastatic renal cell carcinoma: more confusion or a path forward?." Clinical advances in hematology & oncology : H&O 12.3 (March 2014): 163-171.
PMID
24927264
Source
epmc
Published In
Clinical advances in hematology & oncology : H&O
Volume
12
Issue
3
Publish Date
2014
Start Page
163
End Page
171

Evidence for circulating tumor cell (CTC) alkaline phosphatase (AP) expression in men with bone-metastatic castration-resistant prostate cancer (CRPC) during abiraterone acetate treatment

Authors
Armstrong, AJ; Bitting, RL; Kemeny, G; George, DJ
MLA Citation
Armstrong, AJ, Bitting, RL, Kemeny, G, and George, DJ. "Evidence for circulating tumor cell (CTC) alkaline phosphatase (AP) expression in men with bone-metastatic castration-resistant prostate cancer (CRPC) during abiraterone acetate treatment." February 1, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
4
Publish Date
2014

The effect of gender and age on kidney cancer survival: Younger age is an independent prognostic factor in women with renal cell carcinoma

Objective: Gender-specific differences in incidence of renal cell carcinoma (RCC) and its outcome have previously been reported. We used age as a surrogate to test whether this might be hormone-related in a large international RCC cohort. Methods and Materials: This study included patients treated by nephrectomy at 10 international academic centers. Clinicopathologic features were assessed using chi-square and the Student t-tests. Kaplan-Meier survival estimates and Cox proportional hazards models addressed the effect of gender and age on disease-specific survival. Results: Of the 5,654 patients, 3,777 (67%) were men and 1,877 (33%) were women. Generally, women presented at lower T stages (P<0.001), had fewer metastases (P<0.001), and had lower-grade tumors (P<0.001). Women more frequently had clear. -cell (87% vs. 82%) and less frequently had papillary RCC (7% vs. 12%) than men (P<0.001). Women had a 19% reduced risk of death from RCC than men (hazard ratio 0.81, 95% confidence interval 0.73-0.90, P<0.001). The survival advantage for women was present to the greatest degree in the age group<42 years (P = 0.0136) and in women aged 42 to 58 years (P<0.001), but was not apparent in patients aged 59 years and older (P = 0.248). Age was an independent predictor of disease-specific survival in women (hazard ratio 1.011, 95% confidence interval 1.004-1.019, P = 0.004), but not in men. Conclusions: As a group, women present with less advanced tumors, leading to a 19% reduced risk of RCC-specific death compared with men. This survival difference is present only in patients aged<59 years. Because this gender-based survival difference is not related to pathologic features, the role of hormonal effects on the development and progression of RCC needs to be investigated. © 2014 Elsevier Inc.

Authors
Rampersaud, EN; Klatte, T; Bass, G; Patard, JJ; Bensaleh, K; Böhm, M; Allhoff, EP; Cindolo, L; De La Taille, A; Mejean, A; Soulie, M; Bellec, L; Christophe Bernhard, J; Pfister, C; Colombel, M; Belldegrun, AS; Pantuck, AJ; George, D
MLA Citation
Rampersaud, EN, Klatte, T, Bass, G, Patard, JJ, Bensaleh, K, Böhm, M, Allhoff, EP, Cindolo, L, De La Taille, A, Mejean, A, Soulie, M, Bellec, L, Christophe Bernhard, J, Pfister, C, Colombel, M, Belldegrun, AS, Pantuck, AJ, and George, D. "The effect of gender and age on kidney cancer survival: Younger age is an independent prognostic factor in women with renal cell carcinoma." Urologic Oncology: Seminars and Original Investigations 32.1 (January 1, 2014).
Source
scopus
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
32
Issue
1
Publish Date
2014
DOI
10.1016/j.urolonc.2012.10.012

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/m2) 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

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

Does the multidisciplinary approach improve oncological outcomes in men undergoing surgical treatment for prostate cancer?

© 2014 The Japanese Urological Association.Objectives: To determine whether oncological outcomes are improved in prostate cancer patients by using a multidisciplinary strategy as compared with a standard clinic paradigm, and whether time to treatment is delayed when using a multidisciplinary approach. Methods: We retrospectively analyzed patients who were evaluated and pursued radical prostatectomy as primary treatment, by the same surgeons, in the prostate cancer multidisciplinary clinic (n=194) and standard urology clinic (n=741) at Duke University Medical Center from 2005 to 2009. Comparisons of baseline characteristics were examined using rank sum and χ2-tests. Differences in time to radical prostatectomy and oncological outcomes were evaluated using multivariate linear and Cox regression, respectively. Results: A greater proportion of high-risk patients (D'Amico criteria) were evaluated at the multidisciplinary clinic compared with the urology clinic (23.2% vs 15.6%, P=0.014). Mean-adjusted time from biopsy to radical prostatectomy was shorter for multidisciplinary clinic patients (85.6 vs 96.8 days, P=0.006). After a median follow up of 21 months, no significant difference was found between the multidisciplinary clinic and urology clinic in the risk of biochemical recurrence after radical prostatectomy, whether controlling for clinical (hazard ratio 0.71, P=0.249) or pathological variables (hazard ratio 0.75, P=0.349). Conclusions: Despite higher-risk disease, men evaluated using the multidisciplinary approach have similar oncological outcomes compared with men undergoing standard evaluation. Furthermore, time to radical prostatectomy is not delayed by the multidisciplinary management of these patients.

Authors
Stewart, SB; Moul, JW; Polascik, TJ; Koontz, BF; Robertson, CN; Freedland, SJ; George, DJ; Lee, WR; Armstrong, AJ; Bañez, LL
MLA Citation
Stewart, SB, Moul, JW, Polascik, TJ, Koontz, BF, Robertson, CN, Freedland, SJ, George, DJ, Lee, WR, Armstrong, AJ, and Bañez, LL. "Does the multidisciplinary approach improve oncological outcomes in men undergoing surgical treatment for prostate cancer?." International Journal of Urology 21.12 (January 1, 2014): 1215-1219.
Source
scopus
Published In
International Journal of Urology
Volume
21
Issue
12
Publish Date
2014
Start Page
1215
End Page
1219
DOI
10.1111/iju.12561

Highlights in advanced prostate cancer from the 2014 AUA and ASCO meetings

Authors
George, DJ
MLA Citation
George, DJ. "Highlights in advanced prostate cancer from the 2014 AUA and ASCO meetings." Clinical Advances in Hematology and Oncology 12.9 (January 1, 2014): 18-21. (Review)
Source
scopus
Published In
Clinical advances in hematology & oncology : H&O
Volume
12
Issue
9
Publish Date
2014
Start Page
18
End Page
21

The effect of gender and age on kidney cancer survival: younger age is an independent prognostic factor in women with renal cell carcinoma.

OBJECTIVE: Gender-specific differences in incidence of renal cell carcinoma (RCC) and its outcome have previously been reported. We used age as a surrogate to test whether this might be hormone-related in a large international RCC cohort. METHODS AND MATERIALS: This study included patients treated by nephrectomy at 10 international academic centers. Clinicopathologic features were assessed using chi-square and the Student t-tests. Kaplan-Meier survival estimates and Cox proportional hazards models addressed the effect of gender and age on disease-specific survival. RESULTS: Of the 5,654 patients, 3,777 (67%) were men and 1,877 (33%) were women. Generally, women presented at lower T stages (P<0.001), had fewer metastases (P<0.001), and had lower-grade tumors (P<0.001). Women more frequently had clear-cell (87% vs. 82%) and less frequently had papillary RCC (7% vs. 12%) than men (P<0.001). Women had a 19% reduced risk of death from RCC than men (hazard ratio 0.81, 95% confidence interval 0.73-0.90, P<0.001). The survival advantage for women was present to the greatest degree in the age group<42 years (P = 0.0136) and in women aged 42 to 58 years (P<0.001), but was not apparent in patients aged 59 years and older (P = 0.248). Age was an independent predictor of disease-specific survival in women (hazard ratio 1.011, 95% confidence interval 1.004-1.019, P = 0.004), but not in men. CONCLUSIONS: As a group, women present with less advanced tumors, leading to a 19% reduced risk of RCC-specific death compared with men. This survival difference is present only in patients aged<59 years. Because this gender-based survival difference is not related to pathologic features, the role of hormonal effects on the development and progression of RCC needs to be investigated.

Authors
Rampersaud, EN; Klatte, T; Bass, G; Patard, J-J; Bensaleh, K; Böhm, M; Allhoff, EP; Cindolo, L; De La Taille, A; Mejean, A; Soulie, M; Bellec, L; Christophe Bernhard, J; Pfister, C; Colombel, M; Belldegrun, AS; Pantuck, AJ; George, D
MLA Citation
Rampersaud, EN, Klatte, T, Bass, G, Patard, J-J, Bensaleh, K, Böhm, M, Allhoff, EP, Cindolo, L, De La Taille, A, Mejean, A, Soulie, M, Bellec, L, Christophe Bernhard, J, Pfister, C, Colombel, M, Belldegrun, AS, Pantuck, AJ, and George, D. "The effect of gender and age on kidney cancer survival: younger age is an independent prognostic factor in women with renal cell carcinoma." Urol Oncol 32.1 (January 2014): 30.e9-30.13.
PMID
23422777
Source
pubmed
Published In
Urologic Oncology: seminars and original investigations
Volume
32
Issue
1
Publish Date
2014
Start Page
30.e9
End Page
30.13
DOI
10.1016/j.urolonc.2012.10.012

"real world" Treatment of metastatic renal cell carcinoma in a joint community-academic cohort: Progression-free survival over three lines of therapy

Background New targeted therapeutics approved for metastatic renal cell carcinoma (mRCC) offer multiple options in each line of therapy; however, there are few prospective data beyond the first-line settings, and overall comparative effectiveness data are limited. In the targeted therapy era, progression-free survival (PFS) has been the most common regulatory end point for demonstrating the benefit of new therapies. Patients and Methods Drawing on a joint community-academic retrospective mRCC registry, we analyzed all patients who had undergone at least 1 line of systemic therapy (N = 325) for PFS. Patients were grouped according to treatment choice (sorafenib, sunitinib, temsirolimus, everolimus, and "other") for up to 3 lines of therapy. PFS by treatment choice and line of therapy was evaluated using Kaplan-Meier and Cox regression analyses. Results PFS was longest in patients treated with sunitinib in the first and second lines of therapy. First-line PFS for sorafenib, sunitinib, temsirolimus, everolimus, and "other" was 6.9, 8.9, 4.2, not analyzed (too few patients), and 10.8 months, respectively. Second-line PFS was 4.6, 7.0, 3.2, 3.8, and 4.1 months, respectively. Third-line PFS was 4.5, 4.6, 9.9, 4.2, and 2.9, months, respectively. The risk of progression in patients treated with temsirolimus was about twice that of patients treated with sunitinib in the first and second lines of therapy. Conclusion Patients treated with sunitinib had the longest PFS in the first and second lines of therapy. PFS from practice-based data appear consistent with trial-based expectations; however, practice variation was still evident. © 2013 Elsevier Inc. All rights reserved.

Authors
Harrison, MR; George, DJ; Walker, MS; Chen, C; Korytowsky, B; Kirkendall, DT; Stepanski, EJ; Abernethy, AP
MLA Citation
Harrison, MR, George, DJ, Walker, MS, Chen, C, Korytowsky, B, Kirkendall, DT, Stepanski, EJ, and Abernethy, AP. ""real world" Treatment of metastatic renal cell carcinoma in a joint community-academic cohort: Progression-free survival over three lines of therapy." Clinical Genitourinary Cancer 11.4 (December 1, 2013): 441-450.
Source
scopus
Published In
Clinical genitourinary cancer
Volume
11
Issue
4
Publish Date
2013
Start Page
441
End Page
450
DOI
10.1016/j.clgc.2013.05.002

A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer

Background Phosphatase and tensin homologue (PTEN) loss is common in advanced prostate cancer, leading to constitutive activation of the PI3 kinase pathway. Temsirolimus blocks mammalian target of rapamycin (mTOR)/target of rapamycin complex 1 (TORC1), a key signaling node in this pathway; its activity in men with advanced castration-resistant metastatic prostate cancer (mCRPC) is unknown. Methods We conducted a single-arm trial of weekly intravenous temsirolimus administration in men with chemorefractory mCRPC who had ≥ 5 circulating tumor cells (CTCs) at baseline. The primary end point was the change in CTCs at 8 weeks; secondary end points were composite progression-free survival (PFS) (excluding prostate-specific antigen [PSA]), PSA and radiographic response rates, safety, and survival. At PSA/CTC progression, an anti-androgen could be added while continuing temsirolimus. Results Eleven patients were accrued out of a planned 20; the trial was stopped prematurely because of lack of efficacy/feasibility. Median age was 61 years, with 55% African-Americans and 36% Caucasian patients. Median baseline PSA level was 390 ng/dL, median baseline number of CTCs was 14 cells; 50% of patients had pain, and 63% had undergone ≥ 2 previous chemotherapy regimens. Median CTC decline was 48% and 3 patients experienced decline in CTCs to < 5. However, 73% of men had a persistently unfavorable number of CTCs (≥ 5) and only 1 patient had a ≥ 30% PSA decline. Median PFS was 1.9 months (95% confidence interval [CI], 0.9-3.1) and median overall survival (OS) was 8.8 months (95% CI, 3.1-15.6). Toxicities included grade 4 hypophosphatemia and central nervous system (CNS) hemorrhage, and frequent grade 3 fatigue, anemia, stomatitis, hypokalemia, weakness, and hyperglycemia. Conclusion Temsirolimus lacked sufficient clinical activity in men with mCRPC, despite transient CTC improvements in some men. Future studies should focus on combination approaches or novel PI3K pathway inhibitors. © 2013 Elsevier Inc. All rights reserved.

Authors
Armstrong, AJ; Shen, T; Halabi, S; Kemeny, G; Bitting, RL; Kartcheske, P; Embree, E; Morris, K; Winters, C; Jaffe, T; Fleming, M; George, DJ
MLA Citation
Armstrong, AJ, Shen, T, Halabi, S, Kemeny, G, Bitting, RL, Kartcheske, P, Embree, E, Morris, K, Winters, C, Jaffe, T, Fleming, M, and George, DJ. "A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer." Clinical Genitourinary Cancer 11.4 (December 1, 2013): 397-406.
Source
scopus
Published In
Clinical genitourinary cancer
Volume
11
Issue
4
Publish Date
2013
Start Page
397
End Page
406
DOI
10.1016/j.clgc.2013.05.007

A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer.

BACKGROUND: Phosphatase and tensin homologue (PTEN) loss is common in advanced prostate cancer, leading to constitutive activation of the PI3 kinase pathway. Temsirolimus blocks mammalian target of rapamycin (mTOR)/target of rapamycin complex 1 (TORC1), a key signaling node in this pathway; its activity in men with advanced castration-resistant metastatic prostate cancer (mCRPC) is unknown. METHODS: We conducted a single-arm trial of weekly intravenous temsirolimus administration in men with chemorefractory mCRPC who had ≥ 5 circulating tumor cells (CTCs) at baseline. The primary end point was the change in CTCs at 8 weeks; secondary end points were composite progression-free survival (PFS) (excluding prostate-specific antigen [PSA]), PSA and radiographic response rates, safety, and survival. At PSA/CTC progression, an anti-androgen could be added while continuing temsirolimus. RESULTS: Eleven patients were accrued out of a planned 20; the trial was stopped prematurely because of lack of efficacy/feasibility. Median age was 61 years, with 55% African-Americans and 36% Caucasian patients. Median baseline PSA level was 390 ng/dL, median baseline number of CTCs was 14 cells; 50% of patients had pain, and 63% had undergone ≥ 2 previous chemotherapy regimens. Median CTC decline was 48% and 3 patients experienced decline in CTCs to < 5. However, 73% of men had a persistently unfavorable number of CTCs (≥ 5) and only 1 patient had a ≥ 30% PSA decline. Median PFS was 1.9 months (95% confidence interval [CI], 0.9-3.1) and median overall survival (OS) was 8.8 months (95% CI, 3.1-15.6). Toxicities included grade 4 hypophosphatemia and central nervous system (CNS) hemorrhage, and frequent grade 3 fatigue, anemia, stomatitis, hypokalemia, weakness, and hyperglycemia. CONCLUSION: Temsirolimus lacked sufficient clinical activity in men with mCRPC, despite transient CTC improvements in some men. Future studies should focus on combination approaches or novel PI3K pathway inhibitors.

Authors
Armstrong, AJ; Shen, T; Halabi, S; Kemeny, G; Bitting, RL; Kartcheske, P; Embree, E; Morris, K; Winters, C; Jaffe, T; Fleming, M; George, DJ
MLA Citation
Armstrong, AJ, Shen, T, Halabi, S, Kemeny, G, Bitting, RL, Kartcheske, P, Embree, E, Morris, K, Winters, C, Jaffe, T, Fleming, M, and George, DJ. "A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer." Clin Genitourin Cancer 11.4 (December 2013): 397-406.
PMID
23830964
Source
pubmed
Published In
Clinical genitourinary cancer
Volume
11
Issue
4
Publish Date
2013
Start Page
397
End Page
406
DOI
10.1016/j.clgc.2013.05.007

"Real world" treatment of metastatic renal cell carcinoma in a joint community-academic cohort: progression-free survival over three lines of therapy.

BACKGROUND: New targeted therapeutics approved for metastatic renal cell carcinoma (mRCC) offer multiple options in each line of therapy; however, there are few prospective data beyond the first-line settings, and overall comparative effectiveness data are limited. In the targeted therapy era, progression-free survival (PFS) has been the most common regulatory end point for demonstrating the benefit of new therapies. PATIENTS AND METHODS: Drawing on a joint community-academic retrospective mRCC registry, we analyzed all patients who had undergone at least 1 line of systemic therapy (N = 325) for PFS. Patients were grouped according to treatment choice (sorafenib, sunitinib, temsirolimus, everolimus, and "other") for up to 3 lines of therapy. PFS by treatment choice and line of therapy was evaluated using Kaplan-Meier and Cox regression analyses. RESULTS: PFS was longest in patients treated with sunitinib in the first and second lines of therapy. First-line PFS for sorafenib, sunitinib, temsirolimus, everolimus, and "other" was 6.9, 8.9, 4.2, not analyzed (too few patients), and 10.8 months, respectively. Second-line PFS was 4.6, 7.0, 3.2, 3.8, and 4.1 months, respectively. Third-line PFS was 4.5, 4.6, 9.9, 4.2, and 2.9, months, respectively. The risk of progression in patients treated with temsirolimus was about twice that of patients treated with sunitinib in the first and second lines of therapy. CONCLUSION: Patients treated with sunitinib had the longest PFS in the first and second lines of therapy. PFS from practice-based data appear consistent with trial-based expectations; however, practice variation was still evident.

Authors
Harrison, MR; George, DJ; Walker, MS; Chen, C; Korytowsky, B; Kirkendall, DT; Stepanski, EJ; Abernethy, AP
MLA Citation
Harrison, MR, George, DJ, Walker, MS, Chen, C, Korytowsky, B, Kirkendall, DT, Stepanski, EJ, and Abernethy, AP. ""Real world" treatment of metastatic renal cell carcinoma in a joint community-academic cohort: progression-free survival over three lines of therapy." Clin Genitourin Cancer 11.4 (December 2013): 441-450.
PMID
23856102
Source
pubmed
Published In
Clinical genitourinary cancer
Volume
11
Issue
4
Publish Date
2013
Start Page
441
End Page
450
DOI
10.1016/j.clgc.2013.05.002

Bone marrow biopsy: RNA isolation with expression profiling in men with metastatic castration-resistant prostate cancer--factors affecting diagnostic success.

PURPOSE: To determine the rate at which computed tomographically guided pelvic percutaneous bone biopsy in men with metastatic castration-resistant prostate cancer (mCRPC) yields adequate tissue for genomic profiling and to identify issues likely to affect diagnostic yields. MATERIALS AND METHODS: This study was institutional review board approved, and written informed consent was obtained. In a phase II trial assessing response to everolimus, 31 men with mCRPC underwent 54 biopsy procedures (eight men before and 23 men both before and during treatment). Variables assessed were lesion location (iliac wing adjacent to sacroiliac joint, iliac wing anterior and/or superior to sacroiliac joint, sacrum, and remainder of pelvis), mean lesion attenuation, subjective lesion attenuation (purely sclerotic vs mixed), central versus peripheral lesion sampling, lesion size, core number, and use of zoledronic acid for more than 1 year. RESULTS: Of 54 biopsy procedures, 21 (39%) yielded adequate tissue for RNA isolation and genomic profiling. Three of four sacral biopsies were adequate. Biopsies of the ilium adjacent to the sacroiliac joints were more likely adequate than those from elsewhere in the ilium (48% vs 28%, respectively). All five biopsies performed in other pelvic locations yielded inadequate tissue for RNA isolation. Mean attenuation of lesions with inadequate tissue was 172 HU greater than those with adequate tissue (621.1 HU ± 166 vs 449 HU ± 221, respectively; P = .002). Use of zoledronic acid, peripheral sampling, core number, and lesion size affected yields, but the differences were not statistically significant. Histologic examination with hematoxylin-eosin staining showed that results of 36 (67%) biopsies were positive for cancer; only mean attenuation differences were significant (707 HU ± 144 vs 473 HU ± 191, negative vs positive, respectively; P < .001). CONCLUSION: In men with mCRPC, percutaneous sampling of osseous metastases for genomic profiling is possible, but use of zoledronic acid for more than 1 year may reduce the yield of adequate tissue for RNA isolation. Sampling large low-attenuating lesions at their periphery maximizes yield.

Authors
Spritzer, CE; Afonso, PD; Vinson, EN; Turnbull, JD; Morris, KK; Foye, A; Madden, JF; Roy Choudhury, K; Febbo, PG; George, DJ
MLA Citation
Spritzer, CE, Afonso, PD, Vinson, EN, Turnbull, JD, Morris, KK, Foye, A, Madden, JF, Roy Choudhury, K, Febbo, PG, and George, DJ. "Bone marrow biopsy: RNA isolation with expression profiling in men with metastatic castration-resistant prostate cancer--factors affecting diagnostic success." Radiology 269.3 (December 2013): 816-823.
PMID
23925271
Source
pubmed
Published In
Radiology
Volume
269
Issue
3
Publish Date
2013
Start Page
816
End Page
823
DOI
10.1148/radiol.13121782

Abstract C61: Phase I Study of pazopanib in combination with the investigational hypoxia-targeted drug TH-302.

Authors
Meadows, KL; Lee, PH; Riedel, RF; Morse, MA; Uronis, HE; Blobe, GC; George, DJ; Crawford, J; Hurwitz, HI
MLA Citation
Meadows, KL, Lee, PH, Riedel, RF, Morse, MA, Uronis, HE, Blobe, GC, George, DJ, Crawford, J, and Hurwitz, HI. "Abstract C61: Phase I Study of pazopanib in combination with the investigational hypoxia-targeted drug TH-302." Molecular Cancer Therapeutics 12.11_Supplement (November 1, 2013): C61-C61.
Source
crossref
Published In
Molecular cancer therapeutics
Volume
12
Issue
11_Supplement
Publish Date
2013
Start Page
C61
End Page
C61
DOI
10.1158/1535-7163.TARG-13-C61

The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance).

BACKGROUND: Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel. METHODS: In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm. RESULTS: Baseline characteristics between patients who did (N=277) and did not (N=728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P=.635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P=.342), the proportion achieving a decline ≥ 50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P=.129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P=.366). CONCLUSIONS: As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC.

Authors
Aggarwal, R; Halabi, S; Kelly, WK; George, D; Mahoney, JF; Millard, F; Stadler, WM; Morris, MJ; Kantoff, P; Monk, JP; Carducci, M; Small, EJ; Alliance for Clinical Trials in Oncology,
MLA Citation
Aggarwal, R, Halabi, S, Kelly, WK, George, D, Mahoney, JF, Millard, F, Stadler, WM, Morris, MJ, Kantoff, P, Monk, JP, Carducci, M, Small, EJ, and Alliance for Clinical Trials in Oncology, . "The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance)." Cancer 119.20 (October 15, 2013): 3636-3643.
PMID
23913744
Source
pubmed
Published In
Cancer
Volume
119
Issue
20
Publish Date
2013
Start Page
3636
End Page
3643
DOI
10.1002/cncr.28285

Rationing in urologic oncology: lessons from sipuleucel-T for advanced prostate cancer.

OBJECTIVES: As complex novel cancer drugs are developed, supply may transiently fail to meet demand as production capacity established for research purposes is scaled up to meet anticipated clinical volume. There are no clear guidelines for how clinicians and medical centers should allocate scarce cancer care resources among patients who may benefit from the intervention. MATERIALS AND METHODS: We describe a recent scenario in which demand exceeded supply for a novel immunotherapy, sipuleucel-T, that was newly approved by the FDA for castration-resistant prostate cancer. Production of this autologous cellular therapy was initially limited to one facility with supply projected to serve only 2,000 out of approximately 30,000 potentially eligible patients in the United States. RESULTS AND CONCLUSIONS: We propose basic guidelines that should be followed when allocating scarce cancer therapies and highlight ongoing challenges that must be resolved both with regard to rationing cancer care and with regard to access to high cost novel interventions in oncology in general.

Authors
Peppercorn, J; Armstrong, A; Zaas, DW; George, D
MLA Citation
Peppercorn, J, Armstrong, A, Zaas, DW, and George, D. "Rationing in urologic oncology: lessons from sipuleucel-T for advanced prostate cancer." Urol Oncol 31.7 (October 2013): 1079-1084.
PMID
22305627
Source
pubmed
Published In
Urologic Oncology: seminars and original investigations
Volume
31
Issue
7
Publish Date
2013
Start Page
1079
End Page
1084
DOI
10.1016/j.urolonc.2011.12.022

Highlights in advanced prostate cancer from the 2013 American Urological Association Annual Meeting and the 2013 American Society of Clinical Oncology Annual Meeting: commentary.

Authors
George, DJ; Armstrong, AJ; Harrison, MR
MLA Citation
George, DJ, Armstrong, AJ, and Harrison, MR. "Highlights in advanced prostate cancer from the 2013 American Urological Association Annual Meeting and the 2013 American Society of Clinical Oncology Annual Meeting: commentary." Clinical advances in hematology & oncology : H&O 11 Suppl 14.9 (September 2013): 16-22.
PMID
25856023
Source
epmc
Published In
Clinical advances in hematology & oncology : H&O
Volume
11 Suppl 14
Issue
9
Publish Date
2013
Start Page
16
End Page
22

Prevalence of pain and analgesic use in men with metastatic prostate cancer using a patient-reported outcome measure.

PURPOSE: Contemporary tumor-directed therapies for metastatic castration-resistant prostate cancer (mCRPC) are approved to prolong life, but their effects on symptoms such as pain are less well understood as a result of the lack of analytically valid assessments of pain prevalence and severity, clinically meaningful definitions of therapeutic benefit, and methodologic standards of trial conduct. This study establishes pain characteristics in the mCRPC population using a PRO measure. MATERIALS AND METHODS: Patients with prostate cancer participated in an anonymous survey at five US comprehensive cancer centers in the Prostate Cancer Clinical Trials Consortium that incorporated the Brief Pain Inventory (BPI), analgesic use, and interference with daily activities. Prevalence and severity of cancer-related pain and analgesic use were tabulated according to castration-resistant status and exposure to docetaxel chemotherapy. RESULTS: Four hundred sixty-one patients with prostate cancer participated, of whom 147 had mCRPC involving bone (61% [89 of 147] docetaxel exposed, 39% [58 of 147] docetaxel naive). Pain of any level was more common among docetaxel-exposed versus docetaxel-naive patients with mCRPC (70% [62 of 89] v 38% [22 of 58], respectively; P<.001). BPI score≥4 was reported by 38% (34 of 89) of docetaxel-pretreated and 24% (14 of 58) of docetaxel-naive patients with mCRPC; 40% of these patients with pain intensity≥4 reported no current narcotic analgesic. CONCLUSION: Pain prevalence and severity were higher in patients with prior docetaxel exposure. Analgesics were underutilized. These results provide a method for estimating accruals along the disease continuum, and for enabling design of trials appropriately powered to assess pain.

Authors
Autio, KA; Bennett, AV; Jia, X; Fruscione, M; Beer, TM; George, DJ; Carducci, MA; Logothetis, CJ; Kane, RC; Sit, L; Rogak, L; Morris, MJ; Scher, HI; Basch, EM
MLA Citation
Autio, KA, Bennett, AV, Jia, X, Fruscione, M, Beer, TM, George, DJ, Carducci, MA, Logothetis, CJ, Kane, RC, Sit, L, Rogak, L, Morris, MJ, Scher, HI, and Basch, EM. "Prevalence of pain and analgesic use in men with metastatic prostate cancer using a patient-reported outcome measure." J Oncol Pract 9.5 (September 2013): 223-229.
PMID
23943897
Source
pubmed
Published In
Journal of Oncology Practice
Volume
9
Issue
5
Publish Date
2013
Start Page
223
End Page
229
DOI
10.1200/JOP.2013.000876

Resource use and costs in the last year of life among Medicare beneficiaries who died from prostate cancer versus with the disease between 2000 and 2007.

Authors
Reed, SD; Dinan, MA; Li, Y; Zhang, Y; Curtis, LH; George, DJ; Stewart, SB
MLA Citation
Reed, SD, Dinan, MA, Li, Y, Zhang, Y, Curtis, LH, George, DJ, and Stewart, SB. "Resource use and costs in the last year of life among Medicare beneficiaries who died from prostate cancer versus with the disease between 2000 and 2007." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Interim safety results of a global early access protocol (EAP) of abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) progressing after taxane-based chemotherapy

Authors
George, DJ; McGowan, T; Daugaard, G; Flaig, TW; Geczi, L; Hotte, SJ; Mainwaring, PN; Saad, F; Smith, MR; Souza, C; Sternberg, CN; Tay, MH; Garrido, JMT; Londhe, A; Naini, V; Todd, MB; Molina, A
MLA Citation
George, DJ, McGowan, T, Daugaard, G, Flaig, TW, Geczi, L, Hotte, SJ, Mainwaring, PN, Saad, F, Smith, MR, Souza, C, Sternberg, CN, Tay, MH, Garrido, JMT, Londhe, A, Naini, V, Todd, MB, and Molina, A. "Interim safety results of a global early access protocol (EAP) of abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) progressing after taxane-based chemotherapy." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Identification of predictive biomarkers of overall survival (OS) in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (I) with or without bevacizumab (B): Results from CALGB 90206 (Alliance)

Authors
Nixon, AB; Halabi, S; Shterev, I; Starr, M; Brady, JC; Dutcher, JP; Hopkins, JO; Hurwitz, H; Small, EJ; Rini, BI; Febbo, PG; George, DJ; Oncology, ACT
MLA Citation
Nixon, AB, Halabi, S, Shterev, I, Starr, M, Brady, JC, Dutcher, JP, Hopkins, JO, Hurwitz, H, Small, EJ, Rini, BI, Febbo, PG, George, DJ, and Oncology, ACT. "Identification of predictive biomarkers of overall survival (OS) in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (I) with or without bevacizumab (B): Results from CALGB 90206 (Alliance)." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

An exploratory analysis of bone scan lesion area (BSLA), circulating tumor cell (CTC) change, pain reduction, and overall survival (OS) in patients (pts) with castration-resistant prostate cancer (CRPC) treated with cabozantinib (cabo): Updated results of a phase II nonrandomized expansion (NRE) cohort.

Authors
Scher, HI; Smith, MR; Sweeney, C; Corn, PG; Logothetis, C; Vogelzang, NJ; Smith, DC; Hussain, M; George, DJ; De Bono, JS; Higano, CS; Small, EJ; Goldin, J; Brown, MS; Aftab, DT; Noursalehi, M; Weitzman, A; Basch, EM
MLA Citation
Scher, HI, Smith, MR, Sweeney, C, Corn, PG, Logothetis, C, Vogelzang, NJ, Smith, DC, Hussain, M, George, DJ, De Bono, JS, Higano, CS, Small, EJ, Goldin, J, Brown, MS, Aftab, DT, Noursalehi, M, Weitzman, A, and Basch, EM. "An exploratory analysis of bone scan lesion area (BSLA), circulating tumor cell (CTC) change, pain reduction, and overall survival (OS) in patients (pts) with castration-resistant prostate cancer (CRPC) treated with cabozantinib (cabo): Updated results of a phase II nonrandomized expansion (NRE) cohort." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Safety, efficacy, and health-related quality of life (HRQoL) of the investigational single agent orteronel (ortl) in nonmetastatic castration-resistant prostate cancer (nmCRPC)

Authors
Hussain, M; Corn, PG; Michaelson, MD; Hammers, HJ; Alumkal, JJ; Ryan, CJ; Bruce, JY; Moran, S; MacLean, D; Lee, S-Y; Lin, HM; Zhu, Y; Shi, H; Mortimer, P; George, DJ
MLA Citation
Hussain, M, Corn, PG, Michaelson, MD, Hammers, HJ, Alumkal, JJ, Ryan, CJ, Bruce, JY, Moran, S, MacLean, D, Lee, S-Y, Lin, HM, Zhu, Y, Shi, H, Mortimer, P, and George, DJ. "Safety, efficacy, and health-related quality of life (HRQoL) of the investigational single agent orteronel (ortl) in nonmetastatic castration-resistant prostate cancer (nmCRPC)." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Survival following initiation of everolimus for second-line treatment of metastatic renal cell carcinoma: Prognostic factors in clinical practice and comparison to clinical trials.

Authors
Wong, MKK; Jonasch, E; Pal, SK; Signorovitch, JE; Lin, PL; Liu, Z; Wang, X; Culver, KW; Scott, JA; George, DJ; Vogelzang, NJ
MLA Citation
Wong, MKK, Jonasch, E, Pal, SK, Signorovitch, JE, Lin, PL, Liu, Z, Wang, X, Culver, KW, Scott, JA, George, DJ, and Vogelzang, NJ. "Survival following initiation of everolimus for second-line treatment of metastatic renal cell carcinoma: Prognostic factors in clinical practice and comparison to clinical trials." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Evaluation of clinical phenotype, survival, and circulating tumor cell (CTC) enumeration in men with metastatic castration-resistant prostate cancer (mCRPC).

Authors
Bitting, RL; Healy, P; Halabi, S; George, DJ; Ko, JH; Armstrong, AJ
MLA Citation
Bitting, RL, Healy, P, Halabi, S, George, DJ, Ko, JH, and Armstrong, AJ. "Evaluation of clinical phenotype, survival, and circulating tumor cell (CTC) enumeration in men with metastatic castration-resistant prostate cancer (mCRPC)." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

A randomized, crossover phase I study to assess the effects of formulation and meal consumption on the bioavailability of dovitinib (TKI258).

Authors
Sharma, S; Ramanathan, RK; George, DJ; Quinlan, M; Kulkarni, S; Homsi, A; Scott, JW; Infante, JR
MLA Citation
Sharma, S, Ramanathan, RK, George, DJ, Quinlan, M, Kulkarni, S, Homsi, A, Scott, JW, and Infante, JR. "A randomized, crossover phase I study to assess the effects of formulation and meal consumption on the bioavailability of dovitinib (TKI258)." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: Analysis of two practice-based chart reviews.

Authors
Signorovitch, JE; Vogelzang, NJ; Pal, SK; Lin, PL; George, DJ; Wong, MKK; Liu, Z; Wang, X; Culver, KW; Scott, JA; Jonasch, E
MLA Citation
Signorovitch, JE, Vogelzang, NJ, Pal, SK, Lin, PL, George, DJ, Wong, MKK, Liu, Z, Wang, X, Culver, KW, Scott, JA, and Jonasch, E. "Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: Analysis of two practice-based chart reviews." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

ASPEN: A randomized phase II trial of everolimus versus sunitinib in patients with metastatic non-clear cell renal cell carcinoma

Authors
Armstrong, AJ; Halabi, S; Eisen, T; Stadler, WM; Jones, RR; Vaishampayan, UN; Garcia, JA; Hawkins, RE; Kollmannsberger, CK; Lusk, C; Broderick, S; George, DJ
MLA Citation
Armstrong, AJ, Halabi, S, Eisen, T, Stadler, WM, Jones, RR, Vaishampayan, UN, Garcia, JA, Hawkins, RE, Kollmannsberger, CK, Lusk, C, Broderick, S, and George, DJ. "ASPEN: A randomized phase II trial of everolimus versus sunitinib in patients with metastatic non-clear cell renal cell carcinoma." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Novel immunotherapeutic strategies in development for renal cell carcinoma.

CONTEXT: The purpose of this report is to review immunotherapies under investigation for patients with renal cell carcinoma (RCC), the most common form of kidney cancer, for which the incidence and mortality rate continue to increase. OBJECTIVE: To summarize and evaluate current data on immunotherapies for RCC and discuss issues to be resolved before integration into the RCC treatment paradigm. EVIDENCE ACQUISITION: A search of Medline, clinicaltrials.gov, and congress abstracts/treatment guidelines was performed in May 2012 using the following terms (and variations): metastatic renal cell carcinoma, practice guidelines, response/resistance to current treatments, immunotherapy, novel immunotherapeutic strategies, T-cell modulation, immune priming, innate immunity, and combination therapy. EVIDENCE SYNTHESIS: Prior to the advent of novel agents targeting the vascular endothelial growth factor and mechanistic target of rapamycin pathways, interleukin-2 (IL-2) and interferon-α were the mainstays of RCC treatment. IL-2 remains one of the only treatments capable of curing advanced RCC, albeit in few patients. Despite recent advances, unmet need still exists for patients in the adjuvant setting, those with poor prognostic factors, and those who have progressed on prior targeted therapies. Improved understanding of host-tumor immune interactions has led to development of novel immunotherapeutic agents, including antibodies against immune checkpoint proteins (eg, programmed death-1 and cytotoxic T-lymphocyte antigen-4), and various vaccines. Because many of these compounds are in development, clinical experience with them is limited, although some have demonstrated activity in preliminary studies. CONCLUSIONS: It is not yet clear where these new immunotherapies will fit into RCC treatment paradigms, but they may provide new options for patients whose current choices are limited. Furthermore, predictive biomarkers are needed to identify patients who will derive the greatest benefit from immunotherapy.

Authors
Inman, BA; Harrison, MR; George, DJ
MLA Citation
Inman, BA, Harrison, MR, and George, DJ. "Novel immunotherapeutic strategies in development for renal cell carcinoma." Eur Urol 63.5 (May 2013): 881-889. (Review)
PMID
23084331
Source
pubmed
Published In
European Urology
Volume
63
Issue
5
Publish Date
2013
Start Page
881
End Page
889
DOI
10.1016/j.eururo.2012.10.006

Novel chemotherapies in development for management of castration-resistant prostate cancer.

PURPOSE OF REVIEW: Four new therapies have been recently approved for the treatment of men with castration-resistant prostate cancer; still, more treatment options are needed. This review summarizes the data supporting a role for novel chemotherapies including epothilones and immunomodulators (IMiDs), as well as other novel agents within the new landscape of approved therapies. RECENT FINDINGS: Epothilones are a class of chemotherapy that target microtubule disassembly, similar to taxanes. Results from phase II studies demonstrating a positive impact on serum prostate-specific antigen for patupilone and sagopilone, current epothilones in development, along with those of ixabepilone, are comparable with historical response rates to docetaxel, the current first-line chemotherapy for castration-resistant disease. IMiDs, including lenalidamide and thalidomide, are also in active development in castration-resistant prostate cancer. A recent phase III study evaluating the combination of lenalidomide and docetaxel revealed decreased overall survival relative to docetaxel alone; however, additional trials are currently recruiting to investigate lenalidomide in various other combination regimens. SUMMARY: Epothilones could be efficacious as an additional therapy in patients who respond to docetaxel chemotherapy. A role for IMiDs, perhaps in combination with chemotherapy or androgen pathway inhibitors, remains to be elucidated.

Authors
Tewari, AK; George, DJ
MLA Citation
Tewari, AK, and George, DJ. "Novel chemotherapies in development for management of castration-resistant prostate cancer." Curr Opin Urol 23.3 (May 2013): 220-229. (Review)
PMID
23511791
Source
pubmed
Published In
Current Opinion in Urology
Volume
23
Issue
3
Publish Date
2013
Start Page
220
End Page
229
DOI
10.1097/MOU.0b013e32835f7da2

Reply to M A Khattak et al.

Authors
Armstrong, AJ; George, DJ; Halabi, S
MLA Citation
Armstrong, AJ, George, DJ, and Halabi, S. "Reply to M A Khattak et al." J Clin Oncol 31.7 (March 1, 2013): 972-973. (Letter)
PMID
23565533
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
31
Issue
7
Publish Date
2013
Start Page
972
End Page
973
DOI
10.1200/JCO.2012.47.7224

Prognostic and Predictive Markers in Metastatic Renal Cell Carcinoma Reply

Authors
Armstrong, AJ; George, DJ; Halabi, S
MLA Citation
Armstrong, AJ, George, DJ, and Halabi, S. "Prognostic and Predictive Markers in Metastatic Renal Cell Carcinoma Reply." JOURNAL OF CLINICAL ONCOLOGY 31.7 (March 1, 2013): 972-973.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
7
Publish Date
2013
Start Page
972
End Page
973
DOI
10.1200/JCO.2012.47.7224

Activity of single-agent bevacizumab in patients with metastatic renal cell carcinoma previously treated with vascular endothelial growth factor tyrosine kinase inhibitors.

PURPOSE: The activity of systemic agents after progression when using vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in patients with metastatic renal cell carcinoma (mRCC) is poorly characterized. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab has a broad US Food and Drug Administration label and National Comprehensive Cancer Network guideline level 2b recommendation in this setting; we thus explored our institutional experience in this population. METHODS: We conducted a retrospective analysis of patients with mRCC who were treated with bevacizumab in the second- and/or third-line settings; the primary endpoint was progression-free survival (PFS). Overall response rates (ORR), overall survival (OS), and toxicity were analyzed. RESULTS: Twenty-one patients were treated with bevacizumab: the median age was 63 years old; 80% were white and 14% were black; 80% had clear cell histology. All the patients had prior VEGFR TKI therapy; 43% had prior mTOR inhibitor; the median number of prior therapies was 3. The median PFS was 4.4 months (95% CI, 2.8-9.6 months), and the median OS was 19.4 months (95% CI, 9.9-NR months). ORR was 9.5%; 52% of subjects had stable disease as best response, and 52% had disease progression. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4 and 13.2 months, respectively. Grade 3 to 4 toxicities included fatigue (29%), dehydration (24%), failure to thrive (10%), constipation (10%), and muscle weakness (10%). CONCLUSIONS: Single-agent bevacizumab has acceptable toxicity and moderate disease-stabilizing activity in selected patients with mRCC who have failed prior VEGFR TKI and mTOR inhibitors. These data support clinical benefit to continued ongoing VEGF inhibition. Further prospective studies of bevacizumab alone or with alternative targeted agents in previously treated populations with mRCC are warranted.

Authors
Turnbull, JD; Cobert, J; Jaffe, T; Harrison, MR; George, DJ; Armstrong, AJ
MLA Citation
Turnbull, JD, Cobert, J, Jaffe, T, Harrison, MR, George, DJ, and Armstrong, AJ. "Activity of single-agent bevacizumab in patients with metastatic renal cell carcinoma previously treated with vascular endothelial growth factor tyrosine kinase inhibitors." Clin Genitourin Cancer 11.1 (March 2013): 45-50.
PMID
23041453
Source
pubmed
Published In
Clinical genitourinary cancer
Volume
11
Issue
1
Publish Date
2013
Start Page
45
End Page
50
DOI
10.1016/j.clgc.2012.06.001

Recent advances in the management of castration-resistant prostate cancer.

Authors
George, DJ
MLA Citation
George, DJ. "Recent advances in the management of castration-resistant prostate cancer." Clin Adv Hematol Oncol 11.3 (March 2013): 181-183.
PMID
23598987
Source
pubmed
Published In
Clinical advances in hematology & oncology : H&O
Volume
11
Issue
3
Publish Date
2013
Start Page
181
End Page
183

The BEST trial (E2804): A randomized phase II study of VEGF, RAF kinase, and mTOR combination targeted therapy (CTT) with bevacizumab (bev), sorafenib (sor), and temsirolimus (tem) in advanced renal cell carcinoma (RCC)

Authors
McDermott, DF; Manola, J; Pins, M; Flaherty, KT; Atkins, MB; Dutcher, JP; George, DJ; Margolin, KA; DiPaola, RS
MLA Citation
McDermott, DF, Manola, J, Pins, M, Flaherty, KT, Atkins, MB, Dutcher, JP, George, DJ, Margolin, KA, and DiPaola, RS. "The BEST trial (E2804): A randomized phase II study of VEGF, RAF kinase, and mTOR combination targeted therapy (CTT) with bevacizumab (bev), sorafenib (sor), and temsirolimus (tem) in advanced renal cell carcinoma (RCC)." February 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
6
Publish Date
2013

A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer

Authors
Armstrong, AJ; Shen, T; Halabi, S; Kemeny, G; Bitting, RL; Kartcheske, P; Embree, E; Morris, K; Winters, C; Jaffe, T; Fleming, MT; George, DJ
MLA Citation
Armstrong, AJ, Shen, T, Halabi, S, Kemeny, G, Bitting, RL, Kartcheske, P, Embree, E, Morris, K, Winters, C, Jaffe, T, Fleming, MT, and George, DJ. "A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer." February 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
6
Publish Date
2013

Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy

Authors
Ryan, CJ; Smith, MR; de Bono, JS; Molina, A; Logothetis, CJ; de Souza, P; Fizazi, K; Mainwaring, P; Piulats, JM; Ng, S; Carles, J; Mulders, PFA; Basch, E; Small, EJ; Saad, F; Schrijvers, D; Van Poppel, H; Mukherjee, SD; Suttmann, H; Gerritsen, WR; Flaig, TW; George, DJ; Yu, EY; Efstathiou, E; Pantuck, A; Winquist, E; Higano, CS; Taplin, M-E; Park, Y; Kheoh, T; Griffin, T; Scher, HI; Rathkopf, DE; Investigators, C-A
MLA Citation
Ryan, CJ, Smith, MR, de Bono, JS, Molina, A, Logothetis, CJ, de Souza, P, Fizazi, K, Mainwaring, P, Piulats, JM, Ng, S, Carles, J, Mulders, PFA, Basch, E, Small, EJ, Saad, F, Schrijvers, D, Van Poppel, H, Mukherjee, SD, Suttmann, H, Gerritsen, WR, Flaig, TW, George, DJ, Yu, EY, Efstathiou, E, Pantuck, A, Winquist, E, Higano, CS, Taplin, M-E, Park, Y, Kheoh, T, Griffin, T, Scher, HI, Rathkopf, DE, and Investigators, C-A. "Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy." NEW ENGLAND JOURNAL OF MEDICINE 368.2 (January 10, 2013): 138-148.
PMID
23228172
Source
wos-lite
Published In
The New England journal of medicine
Volume
368
Issue
2
Publish Date
2013
Start Page
138
End Page
148
DOI
10.1056/NEJMoa1209096

A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer.

OBJECTIVES: Epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases may be involved in activation of androgen receptor and progression of prostate cancer. They represent potential therapeutic targets in prostate cancer. Lapatinib is an oral inhibitor of EGFR and HER-2. The objective of this study is to assess the preliminary clinical efficacy of lapatinib in the therapy of castration-resistant prostate cancer. METHODS: In this multicenter, open-label trial, patients with rising PSA on androgen deprivation therapy and not having received chemotherapy were eligible. They were treated with lapatinib at a dose of 1,500 mg once daily. The primary end point was a >50% confirmed PSA decline from baseline; safety, tolerability, and time to PSA progression were secondary outcomes. RESULTS: Twenty-nine patients enrolled in the study had a median age of 73 years and a baseline PSA of 21.6 ng/ml. Seven patients had no radiologic evidence of metastatic disease, while the remaining patients had bone or measurable disease or both. Treatment was well tolerated with only grade 3 treatment-related toxicities being diarrhea (14%) and rash (3%). One of 21 evaluable patients had >50% reduction in PSA, while another patient had 47% reduction in PSA with an ongoing duration of response of 45+ months. The median time to PSA progression was 29 days. CONCLUSIONS: Lapatinib showed single agent activity in a small subset of unselected patients with castration-resistant prostate cancer, as measured by PSA. Future trials should explore a trial design with time-to-event end points and predictive biomarkers and a combination with other agents.

Authors
Whang, YE; Armstrong, AJ; Rathmell, WK; Godley, PA; Kim, WY; Pruthi, RS; Wallen, EM; Crane, JM; Moore, DT; Grigson, G; Morris, K; Watkins, CP; George, DJ
MLA Citation
Whang, YE, Armstrong, AJ, Rathmell, WK, Godley, PA, Kim, WY, Pruthi, RS, Wallen, EM, Crane, JM, Moore, DT, Grigson, G, Morris, K, Watkins, CP, and George, DJ. "A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer." Urol Oncol 31.1 (January 2013): 82-86.
PMID
21396844
Source
pubmed
Published In
Urologic Oncology: seminars and original investigations
Volume
31
Issue
1
Publish Date
2013
Start Page
82
End Page
86
DOI
10.1016/j.urolonc.2010.09.018

The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: Results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance)

BACKGROUND Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel. METHODS In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm. RESULTS Baseline characteristics between patients who did (N = 277) and did not (N = 728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P =.635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P =.342), the proportion achieving a decline ≥50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P =.129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P =.366). CONCLUSIONS As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC. Cancer 2013;119:3636-3643. © 2013 American Cancer Society.

Authors
Aggarwal, R; Halabi, S; Kelly, WK; George, D; Mahoney, JF; Millard, F; Stadler, WM; Morris, MJ; Kantoff, P; Monk, JP; Carducci, M; Small, EJ
MLA Citation
Aggarwal, R, Halabi, S, Kelly, WK, George, D, Mahoney, JF, Millard, F, Stadler, WM, Morris, MJ, Kantoff, P, Monk, JP, Carducci, M, and Small, EJ. "The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: Results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance)." Cancer 119.20 (2013): 3636-3643.
Source
scival
Published In
Cancer
Volume
119
Issue
20
Publish Date
2013
Start Page
3636
End Page
3643
DOI
10.1002/cncr.28285

ICUD-EAU international consultation on bladder cancer 2012: Chemotherapy for urothelial carcinoma - Neoadjuvant and adjuvant settings

Context: We present a summary of the Second International Consultation on Bladder Cancer recommendations on chemotherapy for the treatment of bladder cancer using an evidence-based strategy. Objective: To review the data regarding chemotherapy in patients with clinically localized and metastatic bladder cancer with a focus on its use for patients in the neoadjuvant and adjuvant settings. Evidence acquisition: Medline databases were searched for original articles published prior to April 1, 2012, using the following search terms: bladder cancer, urothelial cancer, metastatic, advanced, neoadjuvant, and adjuvant therapy. Proceedings of major conferences from the last 5 yr also were searched. Novel and promising drugs currently in clinical trials were included. Evidence synthesis: The major findings are addressed in an evidence-based manner. Prospective trials and important cohort data were analyzed. Conclusions: Cisplatin-based combination chemotherapy for advanced and metastatic bladder cancer is an established standard, improving overall survival. In the advanced setting, cisplatin-ineligible patients may benefit from gemcitabine and carboplatin. Meta-analyses undertaken for neoadjuvant cisplatin-based combination chemotherapy show a 5% benefit in overall survival. Pathologic complete remission may be an intermediate surrogate for survival, but requires further validation. Use of neoadjuvant chemotherapy is low, and is attributable to patient and physician choice because of limited benefit, advanced age, and comorbidities including renal and/or cardiac dysfunction. Sufficient data to support adjuvant chemotherapy are lacking. © 2012 European Association of Urology.

Authors
Sternberg, CN; Bellmunt, J; Sonpavde, G; Siefker-Radtke, AO; Stadler, WM; Bajorin, DF; Dreicer, R; George, DJ; Milowsky, MI; Theodorescu, D; Vaughn, DJ; Galsky, MD; Soloway, MS; Quinn, DI
MLA Citation
Sternberg, CN, Bellmunt, J, Sonpavde, G, Siefker-Radtke, AO, Stadler, WM, Bajorin, DF, Dreicer, R, George, DJ, Milowsky, MI, Theodorescu, D, Vaughn, DJ, Galsky, MD, Soloway, MS, and Quinn, DI. "ICUD-EAU international consultation on bladder cancer 2012: Chemotherapy for urothelial carcinoma - Neoadjuvant and adjuvant settings." European Urology 63.1 (2013): 58-66.
PMID
22917984
Source
scival
Published In
European Urology
Volume
63
Issue
1
Publish Date
2013
Start Page
58
End Page
66
DOI
10.1016/j.eururo.2012.08.010

Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease.

BACKGROUND: Radium-223 chloride ((223)Ra; Alpharadin) is an alpha-emitting radioisotope that targets areas of osteoblastic metastasis and is excreted by the small intestine. When compared with beta-emitters (eg, strontium-89, samarium-153), (223)Ra delivers a high quantity of energy per track length with short tissue penetration. OBJECTIVE: This review describes the mechanism, radiobiology, and preclinical development of (223)Ra and discusses the clinical data currently available regarding its safety and efficacy profile. METHODS: Data from clinical trials including abstracts were collected and reviewed using the PubMed Database, as well as the American Society of Clinical Oncology abstract database. CONCLUSION: Current bone-targeted therapies fall into two main categories: antiresorptive agents (eg, zoledronic acid, denosumab), which have been shown to delay skeletal-related events, and radiopharmaceuticals (eg, samarium-153), which may have a role in pain palliation. Historically, neither antiresorptive agents nor radiopharmaceuticals have shown definitive evidence of improved overall survival or other antitumor effects in metastatic castrate-resistant prostate cancer (mCRPC). Radiopharmaceuticals are limited by myelosuppresion, thrombocytopenia, and renal excretion. In a recently reported randomized Phase III trial in men with symptomatic bone-metastatic CRPC who had received or were ineligible for docetaxel chemotherapy, (223)Ra treatment resulted in improved overall survival and delayed skeletal-related events. Toxicity consisted of minor gastrointestinal side effects and mild neutropenia and thrombocytopenia that were rarely severe. Pending regulatory approval, (223)Ra may represent a unique and distinct option for an important subgroup of patients with mCRPC; future trials should address its use in combination or in sequence with existing and novel agents.

Authors
Harrison, MR; Wong, TZ; Armstrong, AJ; George, DJ
MLA Citation
Harrison, MR, Wong, TZ, Armstrong, AJ, and George, DJ. "Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease." Cancer Manag Res 5 (2013): 1-14.
PMID
23326203
Source
pubmed
Published In
Cancer Manag Res
Volume
5
Publish Date
2013
Start Page
1
End Page
14
DOI
10.2147/CMAR.S25537

Clinical cancer advances 2012: Annual report on progress against cancer from the American Society of Clinical Oncology

Authors
Roth, BJ; Krilov, L; Adams, S; Aghajanian, CA; Bach, P; Braiteh, F; Brose, MS; Ellis, LM; Erba, H; George, DJ; Gilbert, MR; Jacobson, JO; Larsen, EC; Lichtman, SM; Partridge, AH; Patel, JD; Quinn, DI; Robison, LL; Roenn, JHV; Samlowski, W; Schwartz, GK; Vogelzang, NJ
MLA Citation
Roth, BJ, Krilov, L, Adams, S, Aghajanian, CA, Bach, P, Braiteh, F, Brose, MS, Ellis, LM, Erba, H, George, DJ, Gilbert, MR, Jacobson, JO, Larsen, EC, Lichtman, SM, Partridge, AH, Patel, JD, Quinn, DI, Robison, LL, Roenn, JHV, Samlowski, W, Schwartz, GK, and Vogelzang, NJ. "Clinical cancer advances 2012: Annual report on progress against cancer from the American Society of Clinical Oncology." Journal of Clinical Oncology 31.1 (2013): 131-161.
PMID
23213095
Source
scival
Published In
Journal of Clinical Oncology
Volume
31
Issue
1
Publish Date
2013
Start Page
131
End Page
161
DOI
10.1200/JCO.2012.47.1938

A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer

Objectives: Epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases may be involved in activation of androgen receptor and progression of prostate cancer. They represent potential therapeutic targets in prostate cancer. Lapatinib is an oral inhibitor of EGFR and HER-2. The objective of this study is to assess the preliminary clinical efficacy of lapatinib in the therapy of castration-resistant prostate cancer. Methods: In this multicenter, open-label trial, patients with rising PSA on androgen deprivation therapy and not having received chemotherapy were eligible. They were treated with lapatinib at a dose of 1,500 mg once daily. The primary end point was a >50% confirmed PSA decline from baseline; safety, tolerability, and time to PSA progression were secondary outcomes. Results: Twenty-nine patients enrolled in the study had a median age of 73 years and a baseline PSA of 21.6 ng/ml. Seven patients had no radiologic evidence of metastatic disease, while the remaining patients had bone or measurable disease or both. Treatment was well tolerated with only grade 3 treatment-related toxicities being diarrhea (14%) and rash (3%). One of 21 evaluable patients had >50% reduction in PSA, while another patient had 47% reduction in PSA with an ongoing duration of response of 45+ months. The median time to PSA progression was 29 days. Conclusions: Lapatinib showed single agent activity in a small subset of unselected patients with castration-resistant prostate cancer, as measured by PSA. Future trials should explore a trial design with time-to-event end points and predictive biomarkers and a combination with other agents. © 2013 Elsevier Inc.

Authors
Whang, YE; Armstrong, AJ; Rathmell, WK; Godley, PA; Kim, WY; Pruthi, RS; Wallen, EM; Crane, JM; Moore, DT; Grigson, G; Morris, K; Watkins, CP; George, DJ
MLA Citation
Whang, YE, Armstrong, AJ, Rathmell, WK, Godley, PA, Kim, WY, Pruthi, RS, Wallen, EM, Crane, JM, Moore, DT, Grigson, G, Morris, K, Watkins, CP, and George, DJ. "A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer." Urologic Oncology: Seminars and Original Investigations 31.1 (2013): 82-86.
Source
scival
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
31
Issue
1
Publish Date
2013
Start Page
82
End Page
86
DOI
10.1016/j.urolonc.2010.09.018

Novel immunotherapeutic strategies in development for renal cell carcinoma

Context: The purpose of this report is to review immunotherapies under investigation for patients with renal cell carcinoma (RCC), the most common form of kidney cancer, for which the incidence and mortality rate continue to increase. Objective: To summarize and evaluate current data on immunotherapies for RCC and discuss issues to be resolved before integration into the RCC treatment paradigm. Evidence acquisition: A search of Medline, clinicaltrials.gov, and congress abstracts/treatment guidelines was performed in May 2012 using the following terms (and variations): metastatic renal cell carcinoma, practice guidelines, response/resistance to current treatments, immunotherapy, novel immunotherapeutic strategies, T-cell modulation, immune priming, innate immunity, and combination therapy. Evidence synthesis: Prior to the advent of novel agents targeting the vascular endothelial growth factor and mechanistic target of rapamycin pathways, interleukin-2 (IL-2) and interferon-α were the mainstays of RCC treatment. IL-2 remains one of the only treatments capable of curing advanced RCC, albeit in few patients. Despite recent advances, unmet need still exists for patients in the adjuvant setting, those with poor prognostic factors, and those who have progressed on prior targeted therapies. Improved understanding of host-tumor immune interactions has led to development of novel immunotherapeutic agents, including antibodies against immune checkpoint proteins (eg, programmed death-1 and cytotoxic T-lymphocyte antigen-4), and various vaccines. Because many of these compounds are in development, clinical experience with them is limited, although some have demonstrated activity in preliminary studies. Conclusions: It is not yet clear where these new immunotherapies will fit into RCC treatment paradigms, but they may provide new options for patients whose current choices are limited. Furthermore, predictive biomarkers are needed to identify patients who will derive the greatest benefit from immunotherapy. © 2012 European Association of Urology.

Authors
Inman, BA; Harrison, MR; George, DJ
MLA Citation
Inman, BA, Harrison, MR, and George, DJ. "Novel immunotherapeutic strategies in development for renal cell carcinoma." European Urology 63.5 (2013): 881-889.
Source
scival
Published In
European Urology
Volume
63
Issue
5
Publish Date
2013
Start Page
881
End Page
889
DOI
10.1016/j.eururo.2012.10.006

Extended venous thromboembolism prophylaxis in patients undergoing hip fracture surgery - The SAVE-HIP3 study

There is currently limited information available on the benefits and risks of extended thromboprophylaxis after hip fracture surgery. SAVE-HIP3 was a randomised, double-blind study conducted to evaluate the efficacy and safety of extended thromboprophylaxis with the ultra-low molecular-weight heparin semuloparin compared with placebo in patients undergoing hip fracture surgery. After a seven- to ten-day open-label run-in phase with semuloparin (20 mg once daily subcutaneously, initiated post-operatively), patients were randomised to once-daily semuloparin (20 mg subcutaneously) or placebo for 19 to 23 additional days. The primary efficacy endpoint was a composite of any venous thromboembolism (VTE; any deep-vein thrombosis and non-fatal pulmonary embolism) or all-cause death until day 24 of the double-blind period. Safety parameters included major and clinically relevant non-major bleeding, laboratory data, and treatment-emergent adverse events (TEAEs). Extended thromboprophylaxis with semuloparin demonstrated a relative risk reduction of 79% in the rate of any VTE or all-cause death compared with placebo (3.9% vs 18.6%, respectively; odds ratio 0.18 (95% confidence interval 0.07 to 0.45), p < 0.001). Two patients in the semuloparin group and none in the placebo group experienced clinically relevant bleeding. TEAE rates were similar in both groups. In conclusion, the SAVE-HIP3 study results demonstrate that patients undergoing hip fracture surgery benefit from extended thromboprophylaxis. © 2013 The British Editorial Society of Bone and Joint Surgery.

Authors
Fisher, WD; Agnelli, G; George, DJ; Kakkar, AK; Lassen, MR; Mismetti, P; Mouret, P; Turpie, AGG
MLA Citation
Fisher, WD, Agnelli, G, George, DJ, Kakkar, AK, Lassen, MR, Mismetti, P, Mouret, P, and Turpie, AGG. "Extended venous thromboembolism prophylaxis in patients undergoing hip fracture surgery - The SAVE-HIP3 study." Bone and Joint Journal 95 B.4 (2013): 459-466.
PMID
23539696
Source
scival
Published In
Bone and Joint Journal
Volume
95 B
Issue
4
Publish Date
2013
Start Page
459
End Page
466
DOI
10.1302/0301-620X.95B4.30730

Rationing in urologic oncology: Lessons from sipuleucel-T for advanced prostate cancer

Objectives: As complex novel cancer drugs are developed, supply may transiently fail to meet demand as production capacity established for research purposes is scaled up to meet anticipated clinical volume. There are no clear guidelines for how clinicians and medical centers should allocate scarce cancer care resources among patients who may benefit from the intervention. Materials and methods: We describe a recent scenario in which demand exceeded supply for a novel immunotherapy, sipuleucel-T, that was newly approved by the FDA for castration-resistant prostate cancer. Production of this autologous cellular therapy was initially limited to one facility with supply projected to serve only 2,000 out of approximately 30,000 potentially eligible patients in the United States. Results and conclusions: We propose basic guidelines that should be followed when allocating scarce cancer therapies and highlight ongoing challenges that must be resolved both with regard to rationing cancer care and with regard to access to high cost novel interventions in oncology in general. © 2013 Elsevier Inc.

Authors
Peppercorn, J; Armstrong, A; Zaas, DW; George, D
MLA Citation
Peppercorn, J, Armstrong, A, Zaas, DW, and George, D. "Rationing in urologic oncology: Lessons from sipuleucel-T for advanced prostate cancer." Urologic Oncology: Seminars and Original Investigations 31.7 (2013): 1079-1084.
Source
scival
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
31
Issue
7
Publish Date
2013
Start Page
1079
End Page
1084
DOI
10.1016/j.urolonc.2011.12.022

Serum lactate dehydrogenase predicts for overall survival benefit in patients with metastatic renal cell carcinoma treated with inhibition of mammalian target of rapamycin.

PURPOSE: Lactate dehydrogenase (LDH) is an enzyme involved in anaerobic glycolysis and regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR)-containing complex 1 (PI3K/Akt/TORC1) pathway as well as tumor hypoxia/necrosis. High serum LDH levels are associated with poor prognosis in patients with cancer, including renal cell carcinoma (RCC). We tested whether serum LDH is prognostic and has predictive value in patients with metastatic RCC receiving an mTOR inhibitor. PATIENTS AND METHODS: We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk patients with RCC treated with the TORC1 inhibitor temsirolimus or interferon alfa in an international phase III randomized trial. The proportional hazards model was used to test for the prognostic and predictive association of LDH in predicting overall survival (OS). RESULTS: Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (ULN; range, 0.05 to 28.5 × ULN). The multivariable hazard ratio for death was 2.81 (95% CI, 2.01 to 3.94; P < .001) for patients with LDH more than 1 × ULN versus patients with LDH ≤ 1 × ULN. The LDH-treatment interaction term was statistically significant for OS (P = .016). Among 140 patients with LDH above the ULN, OS was significantly improved with temsirolimus (6.9 v 4.2 months; P < .002). Among 264 patients with normal LDH, OS was not significantly improved with temsirolimus as compared with interferon therapy (11.7 v 10.4 months; P = .514). CONCLUSION: Serum LDH is a prognostic and a predictive biomarker for the survival benefit conferred by TORC1 inhibition in poor-risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with PI3K/TORC1 pathway inhibition in other RCC risk groups and other tumor types is warranted.

Authors
Armstrong, AJ; George, DJ; Halabi, S
MLA Citation
Armstrong, AJ, George, DJ, and Halabi, S. "Serum lactate dehydrogenase predicts for overall survival benefit in patients with metastatic renal cell carcinoma treated with inhibition of mammalian target of rapamycin." J Clin Oncol 30.27 (September 20, 2012): 3402-3407.
PMID
22891270
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
27
Publish Date
2012
Start Page
3402
End Page
3407
DOI
10.1200/JCO.2011.40.9631

Beyond metastatic renal cell carcinoma (mRCC) clinical trials: Targeted therapy use and overall survival in community oncology clinics

Authors
Harrison, MR; George, DJ; Walker, MS; Hudson, LL; Chen, C; Korytowsky, B; Stepanski, EJ; Abernethy, AP
MLA Citation
Harrison, MR, George, DJ, Walker, MS, Hudson, LL, Chen, C, Korytowsky, B, Stepanski, EJ, and Abernethy, AP. "Beyond metastatic renal cell carcinoma (mRCC) clinical trials: Targeted therapy use and overall survival in community oncology clinics." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Isolation of circulating tumor cells using a novel EMT-based capture method.

Authors
Bitting, RL; Boominathan, R; Rao, C; Embree, E; George, DJ; Connelly, MC; Kemeny, G; Garcia-Blanco, M; Armstrong, AJ
MLA Citation
Bitting, RL, Boominathan, R, Rao, C, Embree, E, George, DJ, Connelly, MC, Kemeny, G, Garcia-Blanco, M, and Armstrong, AJ. "Isolation of circulating tumor cells using a novel EMT-based capture method." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Tasquinimod and survival in men with metastatic castration-resistant prostate cancer: Results of long-term follow-up of a randomized phase II placebo-controlled trial

Authors
Armstrong, AJ; Haggman, M; Stadler, WM; Gingrich, JR; Assikis, VJ; Polikoff, J; Denmeade, SR; George, DJ; Andreou, C; Clark, WR; Sieber, P; Agajanian, R; Belkoff, L; Damber, J-E; Nordle, O; Forsberg, G; Carducci, MA; Pili, R
MLA Citation
Armstrong, AJ, Haggman, M, Stadler, WM, Gingrich, JR, Assikis, VJ, Polikoff, J, Denmeade, SR, George, DJ, Andreou, C, Clark, WR, Sieber, P, Agajanian, R, Belkoff, L, Damber, J-E, Nordle, O, Forsberg, G, Carducci, MA, and Pili, R. "Tasquinimod and survival in men with metastatic castration-resistant prostate cancer: Results of long-term follow-up of a randomized phase II placebo-controlled trial." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Safety and activity of the investigational agent orteronel (ortl) without prednisone in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) and rising prostate-specific antigen (PSA): Updated results of a phase II study

Authors
George, DJ; Corn, PG; Michaelson, MD; Hammers, HJ; Alumkal, JJ; Ryan, CJ; Bruce, JY; Moran, S; Lee, S-Y; Mortimer, P; Hussain, M
MLA Citation
George, DJ, Corn, PG, Michaelson, MD, Hammers, HJ, Alumkal, JJ, Ryan, CJ, Bruce, JY, Moran, S, Lee, S-Y, Mortimer, P, and Hussain, M. "Safety and activity of the investigational agent orteronel (ortl) without prednisone in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) and rising prostate-specific antigen (PSA): Updated results of a phase II study." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Impact of salvage therapy with APC8015F on the overall survival (OS) benefit achieved with sipuleucel-T in three phase III studies of metastatic castrate-resistant prostate cancer (mCRPC)

Authors
Gomella, LG; Nabhan, C; DeVries, T; Whitmore, JB; Frohlich, MW; George, DJ
MLA Citation
Gomella, LG, Nabhan, C, DeVries, T, Whitmore, JB, Frohlich, MW, and George, DJ. "Impact of salvage therapy with APC8015F on the overall survival (OS) benefit achieved with sipuleucel-T in three phase III studies of metastatic castrate-resistant prostate cancer (mCRPC)." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE)

Authors
Smith, MR; Sweeney, C; Rathkopf, DE; Scher, HI; Logothetis, C; George, DJ; Higano, CS; Yu, EY; Harzstark, AL; Small, EJ; Sartor, AO; Gordon, MS; Vogelzang, NJ; Smith, DC; Hussain, M; De Bono, JS; Haas, NB; Scheffold, C; Lee, Y; Corn, PG
MLA Citation
Smith, MR, Sweeney, C, Rathkopf, DE, Scher, HI, Logothetis, C, George, DJ, Higano, CS, Yu, EY, Harzstark, AL, Small, EJ, Sartor, AO, Gordon, MS, Vogelzang, NJ, Smith, DC, Hussain, M, De Bono, JS, Haas, NB, Scheffold, C, Lee, Y, and Corn, PG. "Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE)." May 20, 2012.
PMID
25225437
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

The impact of prior therapy with ketoconazole (keto) on clinical outcomes after subsequent docetaxel treatment in metastatic castration-resistant prostate cancer (mCRPC) patients: Results from a randomized phase III trial (CALGB 90401)

Authors
Small, EJ; Halabi, S; Carducci, MA; Ryan, CJ; George, DJ; Mahoney, JF; Stadler, WM; Morris, MJ; Kantoff, P; Monk, JP; Kelly, WK
MLA Citation
Small, EJ, Halabi, S, Carducci, MA, Ryan, CJ, George, DJ, Mahoney, JF, Stadler, WM, Morris, MJ, Kantoff, P, Monk, JP, and Kelly, WK. "The impact of prior therapy with ketoconazole (keto) on clinical outcomes after subsequent docetaxel treatment in metastatic castration-resistant prostate cancer (mCRPC) patients: Results from a randomized phase III trial (CALGB 90401)." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Liver metastases (LM) to predict for short overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).

Authors
Kelly, WK; Halabi, S; Carducci, MA; George, DJ; Mahoney, JF; Stadler, WM; Morris, MJ; Kantoff, PW; Monk, JP; Small, EJ; Oncology, ACT
MLA Citation
Kelly, WK, Halabi, S, Carducci, MA, George, DJ, Mahoney, JF, Stadler, WM, Morris, MJ, Kantoff, PW, Monk, JP, Small, EJ, and Oncology, ACT. "Liver metastases (LM) to predict for short overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts)." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Overall and progression-free survival with everolimus, temsirolimus, or sorafenib as second targeted therapies for metastatic renal cell carcinoma: A retrospective US chart review.

Authors
Yang, H; Wong, MKK; Signorovitch, JE; Wang, X; Liu, Z; Liu, NS; Qi, Z; George, DJ
MLA Citation
Yang, H, Wong, MKK, Signorovitch, JE, Wang, X, Liu, Z, Liu, NS, Qi, Z, and George, DJ. "Overall and progression-free survival with everolimus, temsirolimus, or sorafenib as second targeted therapies for metastatic renal cell carcinoma: A retrospective US chart review." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401.

PURPOSE: A randomized, placebo-controlled study based on preclinical and clinical data that supports the potential role of vascular endothelial growth factor in prostate cancer was performed to evaluate the addition of bevacizumab to standard docetaxel and prednisone therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Patients with chemotherapy-naive progressive mCRPC with Eastern Cooperative Oncology Group performance status ≤ 2 and adequate bone marrow, hepatic, and renal function were randomly assigned to receive docetaxel 75 mg/m(2) intravenously (IV) over 1 hour for 21 days plus prednisone 5 mg orally twice per day (DP) with either bevacizumab 15 mg/kg IV every 3 weeks (DP + B) or placebo. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), 50% decline in prostate-specific antigen, objective response (OR), and toxicity. RESULTS: In total, 1,050 patients were randomly assigned. The median OS for patients given DP + B was 22.6 months compared with 21.5 months for patients treated with DP (hazard ratio, 0.91; 95% CI, 0.78 to 1.05; stratified log-rank P = .181). The median PFS time was superior in the DP + B arm (9.9 v 7.5 months, stratified log-rank P < .001) as was the proportion of patients with OR (49.4% v 35.5%; P = .0013). Grade 3 or greater treatment-related toxicity was more common with DP + B (75.4% v 56.2%; P ≤ .001), as was the number of treatment-related deaths (4.0% v 1.2%; P = .005). CONCLUSION: Despite an improvement in PFS and OR, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC and was associated with greater toxicity.

Authors
Kelly, WK; Halabi, S; Carducci, M; George, D; Mahoney, JF; Stadler, WM; Morris, M; Kantoff, P; Monk, JP; Kaplan, E; Vogelzang, NJ; Small, EJ
MLA Citation
Kelly, WK, Halabi, S, Carducci, M, George, D, Mahoney, JF, Stadler, WM, Morris, M, Kantoff, P, Monk, JP, Kaplan, E, Vogelzang, NJ, and Small, EJ. "Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401." J Clin Oncol 30.13 (May 1, 2012): 1534-1540.
PMID
22454414
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
13
Publish Date
2012
Start Page
1534
End Page
1540
DOI
10.1200/JCO.2011.39.4767

Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies.

Authors
Armstrong, AJ; Turnbull, JD; Cobert, J; Jaffe, T; Harrison, MR; George, DJ
MLA Citation
Armstrong, AJ, Turnbull, JD, Cobert, J, Jaffe, T, Harrison, MR, and George, DJ. "Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies." JOURNAL OF CLINICAL ONCOLOGY 30.5 (February 10, 2012).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
5
Publish Date
2012

Outcomes of "real world" treatment for metastatic renal cell carcinoma (mRCC).

Authors
Harrison, MR; George, DJ; Walker, MS; Hudson, LL; Chen, C; Korytowsky, B; Stepanski, EJ; Abernethy, AP
MLA Citation
Harrison, MR, George, DJ, Walker, MS, Hudson, LL, Chen, C, Korytowsky, B, Stepanski, EJ, and Abernethy, AP. "Outcomes of "real world" treatment for metastatic renal cell carcinoma (mRCC)." JOURNAL OF CLINICAL ONCOLOGY 30.5 (February 10, 2012).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
5
Publish Date
2012

An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study.

Authors
Nabhan, C; Gomella, LG; DeVries, T; Whitmore, JB; Frohlich, MW; George, DJ
MLA Citation
Nabhan, C, Gomella, LG, DeVries, T, Whitmore, JB, Frohlich, MW, and George, DJ. "An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study." JOURNAL OF CLINICAL ONCOLOGY 30.5 (February 10, 2012).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
5
Publish Date
2012

Emerging treatment options for patients with castration-resistant prostate cancer.

BACKGROUND: Most prostate cancer-related deaths occur in patients with castration-resistant prostate cancer (CRPC). Recent preclinical and clinical studies have identified intracellular signaling pathways and changes in the tumor and bone microenvironment as potential key drivers of CRPC. This increased understanding of mechanisms associated with CRPC has driven the development of numerous new agents, many of which are poised to alter the current CRPC treatment landscape. METHODS: A review of literature was conducted to identify ongoing and planned phase III studies of novel agents to treat CRPC. RESULTS: Multiple studies were identified, including novel androgen biosynthesis inhibitors (abiraterone, TAK-700), androgen-receptor inhibitors (MDV3100), angiogenesis inhibitors (aflibercept, tasquinimod), endothelin antagonists (zibotentan, atrasentan), a Src tyrosine kinase inhibitor (dasatinib), a novel radiotherapy (radium-223), and new immunotherapies (ipilimumab and ProstVac). In addition, both sipuleucel-T (an immunotherapy) and cabazitaxel (third-generation taxane) and the RANK-L inhibitor, denosumab, have recently been approved by the US Food and Drug Administration. CONCLUSIONS: Various combinations of these agents could theoretically be used to treat future patients with CRPC by targeting multiple signaling pathways as well as aspects of the tumor and bone microenvironments. Additional research will be needed to understand how to best use these agents and individualize care to optimize CRPC patient outcomes.

Authors
George, D; Moul, JW
MLA Citation
George, D, and Moul, JW. "Emerging treatment options for patients with castration-resistant prostate cancer." Prostate 72.3 (February 2012): 338-349. (Review)
PMID
21748753
Source
pubmed
Published In
The Prostate
Volume
72
Issue
3
Publish Date
2012
Start Page
338
End Page
349
DOI
10.1002/pros.21435

What to order from the prostate cancer treatment menu?

Authors
Armstrong, AJ; Moul, JW; George, DJ
MLA Citation
Armstrong, AJ, Moul, JW, and George, DJ. "What to order from the prostate cancer treatment menu?." Oncology (Williston Park) 26.1 (January 2012): 84-88.
PMID
22393801
Source
pubmed
Published In
Oncology
Volume
26
Issue
1
Publish Date
2012
Start Page
84
End Page
88

Utilization trends at a multidisciplinary prostate cancer clinic: initial 5-year experience from the Duke Prostate Center.

PURPOSE: The multidisciplinary approach is becoming increasingly encouraged but little is known about the multidisciplinary experience compared to routine care. For patients with prostate cancer the goal is to provide evaluations by urologists, medical and radiation oncologists at a single visit. Although additional resources are required, this strategy may enhance the overall health care experience. We compared utilization determinants between a multidisciplinary and a urology prostate cancer clinic at Duke University Medical Center and identified factors associated with pursuing treatment at the university medical center for multidisciplinary clinic patients. MATERIALS AND METHODS: We retrospectively analyzed data on patients referred for primary prostate cancer treatment evaluation at Duke University Medical Center from 2005 to 2009. Comparisons between 701 multidisciplinary clinic and 1,318 urology prostate cancer clinic patients were examined with the rank sum and chi-square tests. Predictive factors for pursuing treatment at the university medical center were assessed using multivariate adjusted logistic regression. RESULTS: Compared to patients at the urology prostate cancer clinic those at the multidisciplinary clinic were more likely to be younger and white, have a higher income and travel a longer distance for evaluation. Of multidisciplinary clinic patients 58% pursued primary treatment at the university medical center. They were more likely to be younger, black and physician referred, have a lower income and reside closer to the medical center. Factors predictive of pursuing treatment at the medical center included high risk disease and physician referral. Factors predictive of not receiving care at the university medical center were income greater than $40,000 and a distance traveled of greater than 100 miles. CONCLUSIONS: A different patient demographic is using the multidisciplinary approach. However, when treatment is pursued at the institution providing multidisciplinary services, the patient demographic resembles that of the treating institution.

Authors
Stewart, SB; Bañez, LL; Robertson, CN; Freedland, SJ; Polascik, TJ; Xie, D; Koontz, BF; Vujaskovic, Z; Lee, WR; Armstrong, AJ; Febbo, PG; George, DJ; Moul, JW
MLA Citation
Stewart, SB, Bañez, LL, Robertson, CN, Freedland, SJ, Polascik, TJ, Xie, D, Koontz, BF, Vujaskovic, Z, Lee, WR, Armstrong, AJ, Febbo, PG, George, DJ, and Moul, JW. "Utilization trends at a multidisciplinary prostate cancer clinic: initial 5-year experience from the Duke Prostate Center." J Urol 187.1 (January 2012): 103-108.
PMID
22088334
Source
pubmed
Published In
The Journal of Urology
Volume
187
Issue
1
Publish Date
2012
Start Page
103
End Page
108
DOI
10.1016/j.juro.2011.09.040

What to Order From the Prostate Cancer Treatment Menu? THE CRAWFORD/FLAIG ARTICLE REVIEWED

Authors
Armstrong, AJ; Moul, JW; George, DJ
MLA Citation
Armstrong, AJ, Moul, JW, and George, DJ. "What to Order From the Prostate Cancer Treatment Menu? THE CRAWFORD/FLAIG ARTICLE REVIEWED." ONCOLOGY-NEW YORK 26.1 (January 2012): 84-+.
Source
wos-lite
Published In
Oncology
Volume
26
Issue
1
Publish Date
2012
Start Page
84
End Page
+

What to order from the prostate cancer treatment menu?

Authors
Armstrong, AJ; Moul, JW; George, DJ
MLA Citation
Armstrong, AJ, Moul, JW, and George, DJ. "What to order from the prostate cancer treatment menu?." Oncology 26.1 (2012).
Source
scival
Published In
Oncology
Volume
26
Issue
1
Publish Date
2012

Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: A phase 1/2 clinical trial

Background: This phase 1/2 study assessed sunitinib combined with docetaxel (Taxotere) and prednisone in chemotherapy-naive metastatic, castration-resistant prostate cancer (mCRPC) patients. Patients and methods: To determine the recommended phase 2 dose (RP2D), 25 patients in four dose escalation cohorts received 3-week cycles of sunitinib (2 weeks on, 1 week off), docetaxel and prednisone, preceded by a 4-week sunitinib 50 mg/day lead in. RP2D was evaluated in 55 additional patients. The primary end point was prostate-specific antigen (PSA) response rate. Results: One phase 1 dose-limiting toxicity occurred (grade 3 hyponatremia). The RP2D was sunitinib 37.5 mg/day, docetaxel 75 mg/m 2 and prednisone 5 mg b.i.d. During phase 2, confirmed PSA responses occurred in 31 patients [56.4% (95% confidence interval 42.3-69.7)]. Median time to PSA progression was 9.8 months. Forty-one patients (75%) were treated >3 months, 12 (22%) completed the study (16 cycles) and 43 (78%) discontinued (36% for disease progression and 27% adverse events). The most frequent treatment-related grade 3/4 adverse events were neutropenia (53%; 15% febrile) and fatigue/asthenia (16%). Among 33 assessable patients, 14 (42.4%) had confirmed partial response. Median progression-free and overall survivals were 12.6 and 21.7 months, respectively. Conclusion: This combination was moderately well tolerated, with promising response rate and survival benefit, justifying further investigation in mCRPC. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Authors
Zurita, AJ; George, DJ; Shore, ND; Liu, G; Wilding, G; Hutson, TE; Kozloff, M; Mathew, P; Harmon, CS; Wang, SL; Chen, I; maneval, EC; Logothetis, CJ
MLA Citation
Zurita, AJ, George, DJ, Shore, ND, Liu, G, Wilding, G, Hutson, TE, Kozloff, M, Mathew, P, Harmon, CS, Wang, SL, Chen, I, maneval, EC, and Logothetis, CJ. "Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: A phase 1/2 clinical trial." Annals of Oncology 23.3 (2012): 688-694.
PMID
21821830
Source
scival
Published In
Annals of Oncology
Volume
23
Issue
3
Publish Date
2012
Start Page
688
End Page
694
DOI
10.1093/annonc/mdr349

Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer

BACKGROUND: Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism. Limited data support the clinical benefit of antithrombotic prophylaxis. METHODS: In this double-blind, multicenter trial, we evaluated the efficacy and safety of the ultralow- molecular-weight heparin semuloparin for prevention of venous thromboembolism in patients receiving chemotherapy for cancer. Patients with metastatic or locally advanced solid tumors who were beginning to receive a course of chemotherapy were randomly assigned to receive subcutaneous semuloparin, 20 mg once daily, or placebo until there was a change of chemotherapy regimen. The primary efficacy outcome was the composite of any symptomatic deep-vein thrombosis, any nonfatal pulmonary embolism, and death related to venous thromboembolism. Clinically relevant bleeding (major and nonmajor) was the main safety outcome. RESULTS: The median treatment duration was 3.5 months. Venous thromboembolism occurred in 20 of 1608 patients (1.2%) receiving semuloparin, as compared with 55 of 1604 (3.4%) receiving placebo (hazard ratio, 0.36; 95% confidence interval [CI], 0.21 to 0.60; P<0.001), with consistent efficacy among subgroups defined according to the origin and stage of cancer and the baseline risk of venous thromboembolism. The incidence of clinically relevant bleeding was 2.8% and 2.0% in the semuloparin and placebo groups, respectively (hazard ratio, 1.40; 95% CI, 0.89 to 2.21). Major bleeding occurred in 19 of 1589 patients (1.2%) receiving semuloparin and 18 of 1583 (1.1%) receiving placebo (hazard ratio, 1.05; 95% CI, 0.55 to 1.99). Incidences of all other adverse events were similar in the two study groups. CONCLUSIONS: Semuloparin reduces the incidence of thromboembolic events in patients receiving chemotherapy for cancer, with no apparent increase in major bleeding. (Funded by Sanofi; ClinicalTrials.gov number, NCT00694382.) Copyright © 2012 Massachusetts Medical Society.

Authors
Agnelli, G; George, DJ; Kakkar, AK; Fisher, W; Lassen, MR; Mismetti, P; Mouret, P; Chaudhari, U; Lawson, F; Turpie, AGG
MLA Citation
Agnelli, G, George, DJ, Kakkar, AK, Fisher, W, Lassen, MR, Mismetti, P, Mouret, P, Chaudhari, U, Lawson, F, and Turpie, AGG. "Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer." New England Journal of Medicine 366.7 (2012): 601-609.
PMID
22335737
Source
scival
Published In
The New England journal of medicine
Volume
366
Issue
7
Publish Date
2012
Start Page
601
End Page
609
DOI
10.1056/NEJMoa1108898

Is axitinib the preferred second-line agent for renal cell carcinoma?

Authors
Hirsch, BR; George, DJ
MLA Citation
Hirsch, BR, and George, DJ. "Is axitinib the preferred second-line agent for renal cell carcinoma?." Community Oncology 9.7 (2012): 212-213.
Source
scival
Published In
Community Oncology
Volume
9
Issue
7
Publish Date
2012
Start Page
212
End Page
213
DOI
10.1016/j.cmonc.2012.07.001

Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: Results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE

Background: Semuloparin is a novel ultra-low-molecular-weight heparin under development for venous thromboembolism (VTE) prevention in patients at increased risk, such as surgical and cancer patients. Objectives: Three Phase III studies compared semuloparin and enoxaparin after major orthopedic surgery: elective knee replacement (SAVE-KNEE), elective hip replacement (SAVE-HIP1) and hip fracture surgery (SAVE-HIP2). Patients/Methods: All studies were multinational, randomized and double-blind. Semuloparin and enoxaparin were administered for 7-10days after surgery. Mandatory bilateral venography was to be performed between days 7 and 11. The primary efficacy endpoint was a composite of any deep vein thrombosis, non-fatal pulmonary embolism or all-cause death. Safety outcomes included major bleeding, clinically relevant non-major (CRNM) bleeding, and any clinically relevant bleeding (major bleeding plus CRNM). Results: In total, 1150, 2326 and 1003 patients were randomized in SAVE-KNEE, SAVE-HIP1 and SAVE-HIP2, respectively. In all studies, the incidences of the primary efficacy endpoint were numerically lower in the semuloparin group vs. the enoxaparin group, but the difference was statistically significant only in SAVE-HIP1. In SAVE-HIP1, clinically relevant bleeding and major bleeding were significantly lower in the semuloparin vs. the enoxaparin group. In SAVE-KNEE and SAVE-HIP2, clinically relevant bleeding tended to be higher in the semuloparin group, but rates of major bleeding were similar in the two groups. Other safety parameters were generally similar between treatment groups. Conclusions: Semuloparin was superior to enoxaparin for VTE prevention after hip replacement surgery, but failed to demonstrate superiority after knee replacement surgery and hip fracture surgery. Semuloparin and enoxaparin exhibited generally similar safety profiles. © 2012 International Society on Thrombosis and Haemostasis.

Authors
Lassen, MR; Fisher, W; Mouret, P; Agnelli, G; George, D; Kakkar, A; Mismetti, P; Turpie, AGG; Leizorovicz, A; Borris, LC; Buyse, M; Sturbois, G; Fisher, MR; White, RH; Alvarisqueta, A; Horsley, M; Jackson, D; Salem, H; Chong, B; Richards, B; Baltrukevich, S; Pisesky, W; Kim, P; Martinez, S; Aguilera, B; Rocha, C; Reyes, A; Lopez, RB; Trc, T; Pink, T; Ludvik, J; Krbec, M; Repko, M; Mikkelsen, S; Gebuhr, P; Lassen, M; Borgwardt, A; Märtson, A; Kelk, M; Kööp, A; Tyllianakis, M; Kapetanos, G et al.
MLA Citation
Lassen, MR, Fisher, W, Mouret, P, Agnelli, G, George, D, Kakkar, A, Mismetti, P, Turpie, AGG, Leizorovicz, A, Borris, LC, Buyse, M, Sturbois, G, Fisher, MR, White, RH, Alvarisqueta, A, Horsley, M, Jackson, D, Salem, H, Chong, B, Richards, B, Baltrukevich, S, Pisesky, W, Kim, P, Martinez, S, Aguilera, B, Rocha, C, Reyes, A, Lopez, RB, Trc, T, Pink, T, Ludvik, J, Krbec, M, Repko, M, Mikkelsen, S, Gebuhr, P, Lassen, M, Borgwardt, A, Märtson, A, Kelk, M, Kööp, A, Tyllianakis, M, and Kapetanos, G et al. "Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: Results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE." Journal of Thrombosis and Haemostasis 10.5 (2012): 822-832.
PMID
22429800
Source
scival
Published In
Journal of Thrombosis and Haemostasis
Volume
10
Issue
5
Publish Date
2012
Start Page
822
End Page
832
DOI
10.1111/j.1538-7836.2012.04701.x

Better late than early: FDG-PET imaging in metastatic renal cell carcinoma.

Sunitinib treatment benefits patients with metastatic renal cell carcinoma (mRCC), but response duration can vary widely and resistance is not predicted by standard measures. [¹⁸F]fluoro-2-deoxy-2-D-glucose positron emission tomography (FDG-PET) uptake is variable in mRCC, but changes in FDG-PET uptake may be useful in monitoring disease progression. Further work is needed to personalize treatment for patients with mRCC.

Authors
Harrison, MR; George, DJ
MLA Citation
Harrison, MR, and George, DJ. "Better late than early: FDG-PET imaging in metastatic renal cell carcinoma." Clin Cancer Res 17.18 (September 15, 2011): 5841-5843.
PMID
21926167
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
18
Publish Date
2011
Start Page
5841
End Page
5843
DOI
10.1158/1078-0432.CCR-11-1768

Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers.

During cancer progression, malignant cells undergo epithelial-mesenchymal transitions (EMT) and mesenchymal-epithelial transitions (MET) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor cells (CTC) from patients with progressive metastatic solid tumors, with a focus on men with castration-resistant prostate cancer (CRPC) and women with metastatic breast cancer. We showed that the majority (> 80%) of these CTCs in patients with metastatic CRPC coexpress epithelial proteins such as epithelial cell adhesion molecule (EpCAM), cytokeratins (CK), and E-cadherin, with mesenchymal proteins including vimentin, N-cadherin and O-cadherin, and the stem cell marker CD133. Equally, we found that more than 75% of CTCs from women with metastatic breast cancer coexpress CK, vimentin, and N-cadherin. The existence and high frequency of these CTCs coexpressing epithelial, mesenchymal, and stem cell markers in patients with progressive metastases has important implications for the application and interpretation of approved methods to detect CTCs.

Authors
Armstrong, AJ; Marengo, MS; Oltean, S; Kemeny, G; Bitting, RL; Turnbull, JD; Herold, CI; Marcom, PK; George, DJ; Garcia-Blanco, MA
MLA Citation
Armstrong, AJ, Marengo, MS, Oltean, S, Kemeny, G, Bitting, RL, Turnbull, JD, Herold, CI, Marcom, PK, George, DJ, and Garcia-Blanco, MA. "Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers." Mol Cancer Res 9.8 (August 2011): 997-1007.
PMID
21665936
Source
pubmed
Published In
Molecular cancer research : MCR
Volume
9
Issue
8
Publish Date
2011
Start Page
997
End Page
1007
DOI
10.1158/1541-7786.MCR-10-0490

Clinical roundtable monograph: new and emerging treatments for advanced prostate cancer.

Historically, the treatment of metastatic castration-resistant prostate cancer (CRPC) has been limited to chemotherapeutic regimens that did not improve patient survival. In 2004, clinical studies began to demonstrate significant improvements in patient outcomes, including overall survival, with docetaxel versus mitoxantrone chemotherapy. Since these pivotal trials, the combination of docetaxel plus prednisone has become a standard of care for patients with metastatic CRPC. However, the limited survival benefit achieved with this regimen prompted several investigations into the development of alternative therapeutic options. Recent advances have now led to an unprecedented number of new drug approvals within the past year, providing many new treatment options for patients with metastatic CRPC. Sipuleucel-T, considered a new paradigm in cancer treatment, is the first such immunotherapeutic agent approved by the US Food and Drug Administration. Other successes include abiraterone acetate, the first androgen biosynthesis inhibitor, and cabazitaxel, a novel microtubule inhibitor, both of which have demonstrated improved survival following docetaxel failure. The bone-targeting agent denosumab, also recently approved in this setting, offers these patients significant improvement in the prevention of skeletal-related events. The data supporting the approval of each of these agents are described in this monograph, as are current approaches in the treatment of metastatic CRPC and ongoing clinical trials of novel treatments and strategies. The experts also discuss several of the issues regarding the introduction of these novel agents into clinical practice for metastatic CRPC patients.

Authors
George, DJ; Kantoff, PW; Lin, DW
MLA Citation
George, DJ, Kantoff, PW, and Lin, DW. "Clinical roundtable monograph: new and emerging treatments for advanced prostate cancer." Clin Adv Hematol Oncol 9.6 (June 2011): 1-11. (Review)
PMID
21941983
Source
pubmed
Published In
Clinical advances in hematology & oncology : H&O
Volume
9
Issue
6
Publish Date
2011
Start Page
1
End Page
11

Management Options in Advanced Prostate Cancer: What is the Role for Sipuleucel-T?

Most prostate cancer-related deaths occur in patients with castration-resistant prostate cancer (CRPC). Until recently, only therapy with docetaxel and prednisone has been shown to prolong survival in men with metastatic CRPC. With the United States Food and Drug Administration (US FDA) approvals of sipuleucel-T, cabazitaxel, and abiraterone acetate, all based on improvement in overall survival, the landscape for management of men with metastatic CRPC has dramatically changed. In this review we will discuss the pivotal clinical trial data leading to these approvals, with particular focus on the unique indication for sipuleucel-T and the implications for optimal management and sequencing of treatment in this patient population.

Authors
Bitting, RL; Armstrong, AJ; George, DJ
MLA Citation
Bitting, RL, Armstrong, AJ, and George, DJ. "Management Options in Advanced Prostate Cancer: What is the Role for Sipuleucel-T?." Clin Med Insights Oncol 5 (2011): 325-332.
PMID
22084621
Source
pubmed
Published In
Clinical Medicine Insights: Oncology
Volume
5
Publish Date
2011
Start Page
325
End Page
332
DOI
10.4137/CMO.S5977

Integrated safety data from 4 randomized, double-blind, controlled trials of autologous cellular immunotherapy with sipuleucel-T in patients with prostate cancer

Purpose: We describe the safety of sipuleucel-T using an integrated analysis of 4 randomized, controlled studies in patients with prostate cancer. Materials and Methods: Adverse events, survival data and laboratory evaluations were examined for common, rare and latent events. Results: In 5% or more of sipuleucel-T cases some adverse events were reported at a rate at least twice that in controls, including chills in 53.1%, pyrexia in 31.3%, headache in 18.1%, myalgia in 11.8%, influenza-like illness in 9.7% and hyperhidrosis in 5.0%. These events generally occurred within 1 day of infusion, were grade 1 or 2 in severity and resolved in 2 days or less. The incidence of serious adverse events reported was 24.0% in sipuleucel-T cases and 25.1% in controls. Grade 3 or greater adverse events were reported within 1 day of infusion in 40 of 601 sipuleucel-T cases (6.7%) and 7 of 303 controls (2.3%). The incidence rate of reported cerebrovascular events was 3.5% for sipuleucel-T cases and 2.6% in controls. Conclusions: Sipuleucel-T therapy in patients with prostate cancer has a side effect profile that is characterized by mild to moderate, short-term, reversible adverse events. There was no evidence of a treatment related increase in autoimmune complications or secondary malignancies after treatment with sipuleucel-T. Sipuleucel-T can be administered safely in the outpatient setting. © 2011 American Urological Association Education and Research, Inc.

Authors
Hall, SJ; Klotz, L; Pantuck, AJ; George, DJ; Whitmore, JB; Frohlich, MW; Sims, RB
MLA Citation
Hall, SJ, Klotz, L, Pantuck, AJ, George, DJ, Whitmore, JB, Frohlich, MW, and Sims, RB. "Integrated safety data from 4 randomized, double-blind, controlled trials of autologous cellular immunotherapy with sipuleucel-T in patients with prostate cancer." Journal of Urology 186.3 (2011): 877-881.
PMID
21788048
Source
scival
Published In
The Journal of Urology
Volume
186
Issue
3
Publish Date
2011
Start Page
877
End Page
881
DOI
10.1016/j.juro.2011.04.070

Axitinib bests second-line sorafenib for kidney cancer: Commentary

Authors
George, DJ
MLA Citation
George, DJ. "Axitinib bests second-line sorafenib for kidney cancer: Commentary." Oncology Report JULY-AUGUST (2011): 19--.
Source
scival
Published In
Oncology Report
Issue
JULY-AUGUST
Publish Date
2011
Start Page
19-

Increased mobilisation of circulating endothelial progenitors in von Hippel-Lindau disease and renal cell carcinoma

Background:Circulating endothelial cells (CECs) are a candidate biomarker for monitoring angiogenesis in cancer. Circulating endothelial cell subsets are mobilised by angiogenic mediators. Because of the highly angiogenic phenotype of renal cell carcinoma (RCC), we sought to assess the potential of CECs as a marker of RCC in patients with von Hippel-Lindau (VHL) disease and those with sporadic RCC.Methods:We performed multicolour flow cytometry to enumerate CECs in patients with RCC, patients with VHL disease with and without RCC, and normal subjects. Two subsets of CECs were evaluated: mature CECs (mCECs) and circulating endothelial progenitors (CEPs).Results:In patients with VHL disease and RCC and those with sporadic RCC (N10), CEPs and the CEP:mCEC ratio were higher than in normal subjects (N17) (median CEPs: 0.97 vs 0.19 cells l 1, respectively, P0.01; median CEP:mCEC: 0.92 vs 0.58, respectively, P0.04). However, in patients with VHL without RCC, CECs were not increased. In paired pre- and post-nephrectomy RCC patient samples (N20), CEPs decreased after surgery (median difference 0.02 cells l 1, 0.06 to 1.2; P0.05).Conclusion: Circulating endothelial progenitors were elevated in RCC, but not in patients with VHL without RCC. Circulating endothelial progenitor enumeration merits further investigation as a monitoring strategy for patients with VHL. © 2011 Cancer Research UK All rights reserved.

Authors
Bhatt, RS; Zurita, AJ; O'Neill, A; Norden-Zfoni, A; Zhang, L; Wu, HK; Wen, PY; George, D; Sukhatme, VP; Atkins, MB; Heymach, JV
MLA Citation
Bhatt, RS, Zurita, AJ, O'Neill, A, Norden-Zfoni, A, Zhang, L, Wu, HK, Wen, PY, George, D, Sukhatme, VP, Atkins, MB, and Heymach, JV. "Increased mobilisation of circulating endothelial progenitors in von Hippel-Lindau disease and renal cell carcinoma." British Journal of Cancer 105.1 (2011): 112-117.
PMID
21673679
Source
scival
Published In
British Journal of Cancer
Volume
105
Issue
1
Publish Date
2011
Start Page
112
End Page
117
DOI
10.1038/bjc.2011.186

Benefits and limitations of current treatment strategies in advanced prostate cancer

Authors
George, DJ
MLA Citation
George, DJ. "Benefits and limitations of current treatment strategies in advanced prostate cancer." Clinical Advances in Hematology and Oncology 9.6 (2011): 3-5.
Source
scival
Published In
Clinical advances in hematology & oncology : H&O
Volume
9
Issue
6
Publish Date
2011
Start Page
3
End Page
5

New and emerging treatments for advanced prostate cancer

Historically, the treatment of metastatic castration-resistant prostate cancer (CRPC) has been limited to chemotherapeutic regimens that did not improve patient survival. In 2004, clinical studies began to demonstrate signifcant improvements in patient outcomes, including overall survival, with docetaxel versus mitoxantrone chemotherapy. Since these pivotal trials, the combination of docetaxel plus prednisone has become a standard of care for patients with metastatic CRPC. However, the limited survival beneft achieved with this regimen prompted several investigations into the development of alternative therapeutic options. Recent advances have now led to an unprecedented number of new drug approvals within the past year, providing many new treatment options for patients with metastatic CRPC. Sipuleucel-T, considered a new paradigm in cancer treatment, is the frst such immunotherapeutic agent approved by the US Food and Drug Administration. Other successes include abiraterone acetate, the frst androgen biosynthesis inhibitor, and cabazitaxel, a novel microtubule inhibitor, both of which have demonstrated improved survival following docetaxel failure. The bone-targeting agent denosumab, also recently approved in this setting, offers these patients signifcant improvement in the prevention of skeletal-related events. The data supporting the approval of each of these agents are described in this monograph, as are current approaches in the treatment of metastatic CRPC and ongoing clinical trials of novel treatments and strategies. The experts also discuss several of the issues regarding the introduction of these novel agents into clinical practice for metastatic CRPC patients. © 2011 Millennium Medical Publishing, Inc.

Authors
George, DJ; Kantoff, PW; Lin, DW
MLA Citation
George, DJ, Kantoff, PW, and Lin, DW. "New and emerging treatments for advanced prostate cancer." Clinical Advances in Hematology and Oncology 9.6 (2011): 1-2.
PMID
22361744
Source
scival
Published In
Clinical advances in hematology & oncology : H&O
Volume
9
Issue
6
Publish Date
2011
Start Page
1
End Page
2

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) resistance in metastatic renal cell carcinoma (mRCC): Possible mechanisms and clinical approaches

Introduction: The approvals of sorafenib, sunitinib, and pazopanib have led to increased options for patients with mRCC. Unfortunately, some patients treated with these vascular endothelial growth factor receptor (VEGFR) TKI progress rapidly, while the majority of remaining patients will develop evidence of disease progression within 2 years. Objectives: We gathered preclinical and clinical evidence regarding potential mechanisms of VEGFR TKI resistance and clinical approaches to counter it. Methods: We searched the published medical literature, searching the National Library of Medicine (PubMed) as well as abstracts from annual meetings of the American Society of Clinical Oncology (ASCO) and American Association for Cancer Research (AACR). Results: No clear evidence-based mechanism of VEGFR TKI resistance has been defined to date; therefore, we summarize the existing hypothesisgenerating preclinical, biomarker, and clinical data. Potential mechanisms of resistance to VEGFR TKI include variations in the inherent genetic alterations associated with RCC, independent of VHL. In addition, response to hypoxia induced by VEGFR TKI may drive alternative growth factor mediated angiogenesis. Molecular imaging evidence of early angiogenesis and proliferation rebound following VEGFR TKI exposure suggests progression is still driven by a proangiogenic phenotype. Conclusion: By necessity, clinicians must currently make treatment decisions on the basis of limited data regarding the biology of VEGFR TKI resistance. RCC is a heterogeneous disease from the onset. Understanding the specific genetic profiles of sensitive and resistant subtypes of RCC may aid in both first-line and subsequent treatment selection. In addition, better understanding of tumor response and resistance may lead to novel combination strategies in the future.

Authors
Harrison, MR; George, DJ
MLA Citation
Harrison, MR, and George, DJ. "Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) resistance in metastatic renal cell carcinoma (mRCC): Possible mechanisms and clinical approaches." European journal of Clinical and Medical Oncology 3.4 (2011): 1-9.
Source
scival
Published In
European journal of Clinical and Medical Oncology
Volume
3
Issue
4
Publish Date
2011
Start Page
1
End Page
9

Is tumor response important for renal carcinoma?

Authors
Inman, BA; George, DJ
MLA Citation
Inman, BA, and George, DJ. "Is tumor response important for renal carcinoma?." European Urology 59.1 (2011): 16-17.
PMID
20970245
Source
scival
Published In
European Urology
Volume
59
Issue
1
Publish Date
2011
Start Page
16
End Page
17
DOI
10.1016/j.eururo.2010.10.010

Bevacizumab and everolimus in renal cancer: a rational way forward.

Authors
Stadler, WM; Phillips, G; George, DJ; Halabi, S; Small, E
MLA Citation
Stadler, WM, Phillips, G, George, DJ, Halabi, S, and Small, E. "Bevacizumab and everolimus in renal cancer: a rational way forward." J Clin Oncol 28.33 (November 20, 2010): e692-e693. (Letter)
PMID
20940194
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
33
Publish Date
2010
Start Page
e692
End Page
e693
DOI
10.1200/JCO.2010.30.7934

A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer.

PURPOSE: Given discrepancies between preclinical and clinical observations of mammalian target of rapamycin (mTOR) inhibition in prostate cancer, we sought to determine the pharmacodynamic effects of the mTOR/TORC1 inhibitor rapamycin in men with intermediate- to high-risk prostate cancer undergoing radical prostatectomy. EXPERIMENTAL DESIGN: Rapamycin was given at 3 or 6 mg orally for 14 days before radical prostatectomy in men with multifocal Gleason sum > or =7 prostate cancer; 10 untreated control subjects were included. The primary outcome was inhibition of phosphorylation of ribosomal S6 in posttreatment radical prostatectomy versus pretreatment biopsy tumor tissue, evaluated using a Simon two-stage design for pharmacodynamic efficacy. RESULTS: Thirty-two subjects were accrued: 20 at 3 mg, 2 at 6 mg, and 10 controls. No dose-limiting toxicities were observed at 3 mg; however, two of two men enrolled at 6 mg experienced dose-limiting toxicities including thrombocytopenia and fever with grade 3 stomatitis. Adverse events observed at 3 mg included stomatitis, rash, ileus, and neutropenia. Pharmacodynamic studies showed tumor S6 phosphorylation inhibition in 50% of 10 evaluable rapamycin-treated men with sufficient paired tissue [median 58% inhibition (P = 0.049) versus 2% inhibition in controls (P = 0.75)] with no significant effect on AKT activity. We observed no change in Ki-67 or caspase-3 cleavage but noted a reduction in cytoplasmic p27 staining with increased nuclear localization with rapamycin treatment. Prostate tissue rapamycin concentrations were 3- to 4-fold higher than blood. CONCLUSIONS: At 3 mg daily, rapamycin successfully and safely inhibited prostate cancer S6 phosphorylation and achieved relatively high prostate tissue concentrations. No effect on AKT phosphorylation, tumor proliferation, or apoptosis was observed.

Authors
Armstrong, AJ; Netto, GJ; Rudek, MA; Halabi, S; Wood, DP; Creel, PA; Mundy, K; Davis, SL; Wang, T; Albadine, R; Schultz, L; Partin, AW; Jimeno, A; Fedor, H; Febbo, PG; George, DJ; Gurganus, R; De Marzo, AM; Carducci, MA
MLA Citation
Armstrong, AJ, Netto, GJ, Rudek, MA, Halabi, S, Wood, DP, Creel, PA, Mundy, K, Davis, SL, Wang, T, Albadine, R, Schultz, L, Partin, AW, Jimeno, A, Fedor, H, Febbo, PG, George, DJ, Gurganus, R, De Marzo, AM, and Carducci, MA. "A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer." Clin Cancer Res 16.11 (June 1, 2010): 3057-3066.
PMID
20501622
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
16
Issue
11
Publish Date
2010
Start Page
3057
End Page
3066
DOI
10.1158/1078-0432.CCR-10-0124

Optimizing the use of docetaxel in men with castration-resistant metastatic prostate cancer.

In 2009, castration-resistant metastatic prostate cancer continues to account for more deaths in US men than any other cancer apart from lung cancer. Although novel targeted molecular, hormonal and immunologic agents are accelerating in their development in this disease, docetaxel and prednisone remain the standard palliative regimen for the majority of men who have progressed despite hormonal therapies. Thus, understanding the practical and often subtle issues of docetaxel initiation, duration of therapy, cessation of therapy and treatment holidays is critical for the informed use of this US Food and Drug Administration-approved regimen. In this review we address these topics in light of prognostic and predictive factors to help guide the rational use of docetaxel chemotherapy in men with this aggressive disease.

Authors
Armstrong, AJ; George, DJ
MLA Citation
Armstrong, AJ, and George, DJ. "Optimizing the use of docetaxel in men with castration-resistant metastatic prostate cancer." Prostate Cancer Prostatic Dis 13.2 (June 2010): 108-116. (Review)
PMID
20066005
Source
pubmed
Published In
Prostate Cancer and Prostatic Diseases
Volume
13
Issue
2
Publish Date
2010
Start Page
108
End Page
116
DOI
10.1038/pcan.2009.62

Public survey and survival data do not support recommendations to discontinue prostate-specific antigen screening in men at age 75.

OBJECTIVES: To evaluate the US Preventative Services Task Force (USPSTF) recommendation to discontinue prostate-specific antigen (PSA) screening at age 75. METHODS: Public survey: A cohort of 340 patients was surveyed at our PSA screening clinic and stratified by awareness of the recommendation and education level. Age (< 75, >or= 75), race, health insurance status, knowledge of prostate cancer, and opinion on screening discontinuation at age 75 was evaluated between groups. Disease risk and survival analysis: A cohort of 4196 men who underwent radical prostatectomy between 1988 and 2008 was stratified into age groups: < 65, 65-74, and >or= 75. Associations between clinicopathologic variables, disease risk, and survival were compared between age groups using univariate and multivariate analysis. RESULTS: Approximately 78% of men surveyed disagreed with the USPSTF recommendation. The number of men who disagreed was not significantly different between awareness groups (P = .962). Awareness of new screening guidelines showed a significant difference (P = .006) between education groups. Age >or= 75 years was predictive of high-risk disease based on D'Amico's criteria (odds ratio = 2.72, P = .003). Kaplan-Meier and Cox regression analyses showed an association of men aged >or= 75 years with higher rate of PSA recurrence, distant metastasis, and disease specific death compared with the age groups of < 65 and 65-74 (P <.05). CONCLUSIONS: Men presenting to our PSA screening clinic disagreed with discontinuation of screening at age 75. Men aged >or= 75 years had higher risk disease and poorer survival. The USPSTF recommendation was supported neither by public opinion nor disease risk and survival results.

Authors
Caire, AA; Sun, L; Robertson, CN; Polascik, TJ; Maloney, KE; George, DJ; Price, MM; Stackhouse, DA; Lack, BD; Albala, DM; Moul, JW
MLA Citation
Caire, AA, Sun, L, Robertson, CN, Polascik, TJ, Maloney, KE, George, DJ, Price, MM, Stackhouse, DA, Lack, BD, Albala, DM, and Moul, JW. "Public survey and survival data do not support recommendations to discontinue prostate-specific antigen screening in men at age 75." Urology 75.5 (May 2010): 1122-1127.
PMID
19815259
Source
pubmed
Published In
Urology
Volume
75
Issue
5
Publish Date
2010
Start Page
1122
End Page
1127
DOI
10.1016/j.urology.2009.06.091

The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival.

AIMS OF THE STUDY: There are no known predictive factors of response in men receiving chemotherapy for metastatic castration-resistant prostate cancer (mCRPC). We investigated pre-treatment factors that predicted a 30% PSA decline (30% PSAD) within 3 months of starting chemotherapy, and assessed performance of a risk group classification in predicting PSA declines and overall survival (OS) in men with mCRPC. METHODS: In TAX327, 1006 men with mCRPC were randomized to receive docetaxel (D) in two schedules, or mitoxantrone (M), each with prednisone: 989 provided data on PSA decline within 3 months. Predictive factors for a 30% PSAD were identified using multivariable regression in D-treated men (n=656) and validated in M-treated men (n=333). RESULTS: Four independent risk factors predicted 30% PSAD: pain, visceral metastases, anaemia and bone scan progression. Risk groups (good: 0-1 factors, intermediate: 2 factors and poor: 3-4 factors) were developed with median OS of 25.7, 18.7 and 12.8 months (p<0.0001); 30% PSAD in 78%, 66% and 58% of men (p<0.001); and measurable disease response in 19%, 9% and 5% of men (p=0.018), respectively. In the validation cohort, similar predictive ability was noted for 30% PSAD, tumour response and OS. PCWG2 subtypes were also predictive but resulted in unequal grouping. C-indices were 0.59 and 0.62 for 30% PSAD and OS in the validation dataset, respectively. CONCLUSIONS: Risk groups have been identified and validated that predict PSAD and OS in men with mCRPC and may facilitate evaluation of new systemic regimens warranting definitive testing in comparison with docetaxel and prednisone. Prospective validation of this classification system is needed.

Authors
Armstrong, AJ; Tannock, IF; de Wit, R; George, DJ; Eisenberger, M; Halabi, S
MLA Citation
Armstrong, AJ, Tannock, IF, de Wit, R, George, DJ, Eisenberger, M, and Halabi, S. "The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival." Eur J Cancer 46.3 (February 2010): 517-525.
PMID
20005697
Source
pubmed
Published In
European Journal of Cancer
Volume
46
Issue
3
Publish Date
2010
Start Page
517
End Page
525
DOI
10.1016/j.ejca.2009.11.007

How does sipuleucel-T alter our clinical practice?

Authors
George, D
MLA Citation
George, D. "How does sipuleucel-T alter our clinical practice?." BJU International 106.7 (2010): 945-946.
PMID
20931691
Source
scival
Published In
Bju International
Volume
106
Issue
7
Publish Date
2010
Start Page
945
End Page
946
DOI
10.1111/j.1464-410X.2010.09642.x

Toxicity spikes with first-line RCC drug combination: Comment

Authors
George, DJ
MLA Citation
George, DJ. "Toxicity spikes with first-line RCC drug combination: Comment." Oncology Report JULY-AUGUST (2010): 24--.
Source
scival
Published In
Oncology Report
Issue
JULY-AUGUST
Publish Date
2010
Start Page
24-

Bevacizumab as a treatment option in advanced renal cell carcinoma: An analysis and interpretation of clinical trial data

The availability of molecularly targeted agents has improved outcomes for patients with renal cell carcinoma (RCC), a disease long considered refractory to systemic therapy. The hypervascularity observed in RCC tumors, which is driven by the inactivation of the von Hippel-Lindau gene, provided a rationale for targeting angiogenesis, in particular vascular endothelial growth factor (VEGF). Bevacizumab, a potent and specific anti-VEGF monoclonal antibody, has demonstrated significant clinical benefits when used in combination with interferon-alfa (IFN-α) for the treatment of metastatic RCC in two randomized phase III trials. The use of bevacizumab with IFN-α received approval in Europe for the first-line treatment of patients with advanced or metastatic RCC, and more recently this combination was approved for use in patients with mRCC in the United States. Bevacizumab with IFN-α has also been recommended by the National Comprehensive Cancer Network for first-line therapy of relapsed or metastatic unresectable RCC with predominantly clear cell histology. Two phase II studies suggest that bevacizumab has single-agent activity, which is characterized by encouraging progression-free survival rates and evidence of tumor regressions in patients with advanced or metastatic RCC. Here we review these trials along with recent and ongoing studies that explore the combination of bevacizumab with other targeted agents, its optimal sequencing with tyrosine kinase inhibitors, and its combination with low-dose IFN-α. Collectively, these studies allow the role of bevacizumab-based therapy to be defined in the context of a new and evolving algorithm for the treatment of patients with advanced RCC. © 2009 Elsevier Ltd.

Authors
McDermott, DF; George, DJ
MLA Citation
McDermott, DF, and George, DJ. "Bevacizumab as a treatment option in advanced renal cell carcinoma: An analysis and interpretation of clinical trial data." Cancer Treatment Reviews 36.3 (2010): 216-223.
PMID
20116176
Source
scival
Published In
Cancer Treatment Reviews
Volume
36
Issue
3
Publish Date
2010
Start Page
216
End Page
223
DOI
10.1016/j.ctrv.2009.12.003

Prostate cancer: Clinical practice guidelines in oncology™

The intention of these guidelines is to provide a framework on which to base treatment decisions. Prostate cancer is a complex disease, with many controversial aspects of management and a dearth of sound data to support treatment recommendations. Several variables (including life expectancy, disease characteristics, predicted outcomes, and patient preferences) must be considered by patients and physicians when tailoring prostate cancer therapy to the individual patient. © Journal of the National Comprehensive Cancer Network.

Authors
Mohler, J; Bahnson, RR; Boston, B; Busby, JE; D'Amico, A; Eastham, JA; Enke, CA; George, D; Horwitz, EM; Huben, RP; Kantoff, P; Kawachi, M; Kuettel, M; Lange, PH; MacVicar, G; Plimack, ER; Pow-Sang, JM; III, MR; Rohren, E; Roth, BJ; Shrieve, DC; Smith, MR; Srinivas, S; Twardowski, P; Walsh, PC
MLA Citation
Mohler, J, Bahnson, RR, Boston, B, Busby, JE, D'Amico, A, Eastham, JA, Enke, CA, George, D, Horwitz, EM, Huben, RP, Kantoff, P, Kawachi, M, Kuettel, M, Lange, PH, MacVicar, G, Plimack, ER, Pow-Sang, JM, III, MR, Rohren, E, Roth, BJ, Shrieve, DC, Smith, MR, Srinivas, S, Twardowski, P, and Walsh, PC. "Prostate cancer: Clinical practice guidelines in oncology™." JNCCN Journal of the National Comprehensive Cancer Network 8.2 (2010): 162-200.
PMID
20141676
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
8
Issue
2
Publish Date
2010
Start Page
162
End Page
200

The molecular biology of kidney cancer and its clinical translation into treatment strategies

The most common histologic type of kidney cancer is clear cell renal carcinoma. Most clear cell renal carcinomas are linked to somatic inactivation of the von Hippel-Lindau tumor suppressor gene (VHL), either as a result of mutations or, less commonly, hypermethylation. The VHL gene product, pVHL, has multiple functions. The best understood function, and the one most tightly linked to renal carcinogenesis, is to serve as the substrate recognition component of an ubiquitin ligase complex that targets the HIFα transcription factor for destruction when tissue oxygenation is adequate. In hypoxic tumor cells, or in tumor cells lacking functional pVHL, HIFα becomes stabilized, binds to its partner protein HIFβ (also called ARNT), and transcriptionally activates ~100-200 genes that promote adaptation to hypoxia including the genes encoding vascular endothelial growth factor (VEGF) and platelet-derived growth factor B (PDGF B). This probably explains the neoangiogenesis that is typical of clear cell renal carcinomas and their sensitivity to drugs, such as sorafenib, sunitinib, and bevacizumab, that inhibit VEGF or its receptor KDR. In addition to pVHL, HIFα levels are also influenced by activity of the mTOR kinase. pVHL-defective tumor cells are sensitive to mTOR inhibitors in preclinical models and mTOR inhibitors have recently demonstrated activity in the clinic for the treatment of kidney cancer. © 2009 Humana Press.

Authors
Kaelin, WG; George, DJ
MLA Citation
Kaelin, WG, and George, DJ. "The molecular biology of kidney cancer and its clinical translation into treatment strategies." (December 1, 2009): 79-97. (Chapter)
Source
scopus
Publish Date
2009
Start Page
79
End Page
97
DOI
10.1007/978-1-59745-332-5_5

Men older than 70 years have higher risk prostate cancer and poorer survival in the early and late prostate specific antigen eras.

PURPOSE: We clarified whether men older than 70 years have a higher risk of prostate cancer and poorer survival in the early and late prostate specific antigen eras. MATERIALS AND METHODS: A cohort of 4,561 men who underwent radical prostatectomy were stratified into 3 age groups (younger than 60, 60 to 70 and older than 70 years), and early and late prostate specific antigen eras based on the year of surgery (before 2000 and 2000 or later). Race, body mass index, prostate specific antigen, prostate weight, tumor volume, pathological Gleason sum, pathological tumor stage, extracapsular extension, seminal vesicle invasion and surgical margin status were submitted for univariate and multivariable analyses against the previously mentioned groups. Survivals (prostate specific antigen recurrence, distant metastasis and disease specific death) were compared among the 3 age groups using univariate and multivariable methods. RESULTS: Compared with younger age groups (younger than 60, 60 to 70 years) men older than 70 years had a higher proportion of pathological tumor stage 3/4 (33.0 vs 44.3 vs 52.1%, p <0.001), pathological Gleason sum greater than 7 (9.5% vs 13.4% vs 17.2%, p <0.001) and larger tumor volume (3.7 vs 4.7 vs 5.2 cc, p <0.001). Pathological Gleason sum in men older than 70 years did not differ between the early and late prostate specific antigen eras (p = 0.071). Men older than 70 years had a higher risk of prostate specific antigen recurrence, distant metastasis and disease specific death on univariate (p <0.05) but not multivariable analysis. CONCLUSIONS: Men older than 70 years had higher risk disease and poorer survival in the early and late prostate specific antigen eras. Pathological Gleason sums did not change between the 2 eras. Patient age was an important variable in prostate specific antigen screening, biopsy, treatment and prognosis.

Authors
Sun, L; Caire, AA; Robertson, CN; George, DJ; Polascik, TJ; Maloney, KE; Walther, PJ; Stackhouse, DA; Lack, BD; Albala, DM; Moul, JW
MLA Citation
Sun, L, Caire, AA, Robertson, CN, George, DJ, Polascik, TJ, Maloney, KE, Walther, PJ, Stackhouse, DA, Lack, BD, Albala, DM, and Moul, JW. "Men older than 70 years have higher risk prostate cancer and poorer survival in the early and late prostate specific antigen eras." J Urol 182.5 (November 2009): 2242-2248.
PMID
19758616
Source
pubmed
Published In
The Journal of Urology
Volume
182
Issue
5
Publish Date
2009
Start Page
2242
End Page
2248
DOI
10.1016/j.juro.2009.07.034

Pazopanib okay gives clinicians 6 new drugs for advanced RCC: Commentary

Authors
George, DJ
MLA Citation
George, DJ. "Pazopanib okay gives clinicians 6 new drugs for advanced RCC: Commentary." Oncology Report WINT (2009): 6--.
Source
scival
Published In
Oncology Report
Issue
WINT
Publish Date
2009
Start Page
6-

Bevacizumab + interferon fails to improve overall RCC survival: Commentary

Authors
George, DJ
MLA Citation
George, DJ. "Bevacizumab + interferon fails to improve overall RCC survival: Commentary." Oncology Report FALL (2009): 27--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2009
Start Page
27-

Pazopanib halves risk of progression in RCC: Commentary

Authors
George, DJ
MLA Citation
George, DJ. "Pazopanib halves risk of progression in RCC: Commentary." Oncology Report FALL (2009): 27--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2009
Start Page
27-

Department of Defense prostate cancer clinical trials consortium: A new instrument for prostate cancer clinical research

Background: In 2005, the US Department of Defense, through the US Army Medical Research and Materiel Command, Office of the Congressionally Directed Medical Research Programs, created a funding mechanism to form a clinical trials consortium to conduct phase I and II studies in prostate cancer. This is the first report of the Prostate Cancer Clinical Trials Consortium (PCCTC). Patients and Methods: The Department of Defense award supports a consortium of 10 prostate cancer research centers. Memorial Sloan-Kettering Cancer Center was awarded the Coordinating Center grant for the consortium and charged with creating an infrastructure to conduct early-phase multicenter clinical trials. Each participating center was required to introduce ≥ 1 clinical trial per year and maintain accrual of a minimum of 35 patients per year. Results: The PCCTC was launched in 2006 and now encompasses 10 leading prostate cancer research centers. Fifty-one trials have been opened, and 1386 patients have been accrued at member sites. Members share an online clinical trial management system for protocol tracking, electronic data capture, and data storage. A legal framework has been instituted, and standard operating procedures, an administrative structure, editorial support, centralized budgeting, and mechanisms for scientific review are established. Conclusion: The PCCTC fulfills a congressional directive to create a clinical trials instrument dedicated to early-phase prostate cancer studies. The member institutions have built an administrative, informatics, legal, financial, statistical, and scientific infrastructure to support this endeavor. Clinical trials are open and accruing in excess of federally mandated goals.

Authors
Morris, MJ; Basch, EM; Wilding, G; Hussain, M; Carducci, MA; Higano, C; Kantoff, P; Oh, WK; Small, EJ; George, D; Mathew, P; Beer, TM; Slovin, SE; Ryan, C; Logothetis, C; Scher, HI
MLA Citation
Morris, MJ, Basch, EM, Wilding, G, Hussain, M, Carducci, MA, Higano, C, Kantoff, P, Oh, WK, Small, EJ, George, D, Mathew, P, Beer, TM, Slovin, SE, Ryan, C, Logothetis, C, and Scher, HI. "Department of Defense prostate cancer clinical trials consortium: A new instrument for prostate cancer clinical research." Clinical Genitourinary Cancer 7.1 (2009): 51-57.
PMID
19213669
Source
scival
Published In
Clinical genitourinary cancer
Volume
7
Issue
1
Publish Date
2009
Start Page
51
End Page
57
DOI
10.3816/CGC.2009.n.009

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

New drug development in metastatic prostate cancer.

In 2007, drug development in castration-resistant metastatic prostate cancer (CRPC) remains challenging, due to the number of potentially viable molecular targets and clinical trials available, the lack of established surrogates for overall survival, and competing causes of mortality. This review will highlight the highest impact phase II and phase III trials of novel agents in the current CRPC landscape, and focus on both molecular targets and clinical trial designs that are more likely to demonstrate clinical benefit. The need for tissue correlative studies for target evaluation and drug mechanism is stressed to continue to advance the field and to define biomarkers that may identify patient populations that may derive a greater benefit from these molecular agents.

Authors
Armstrong, AJ; George, DJ
MLA Citation
Armstrong, AJ, and George, DJ. "New drug development in metastatic prostate cancer." Urol Oncol 26.4 (July 2008): 430-437. (Review)
PMID
18593623
Source
pubmed
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
26
Issue
4
Publish Date
2008
Start Page
430
End Page
437
DOI
10.1016/j.urolonc.2007.11.006

Clinical endpoints for drug development in prostate cancer.

PURPOSE OF REVIEW: Overall survival remains the benchmark in phase III settings of novel agents in castration-resistant metastatic prostate cancer. This review highlights many of the current potential early measures of response and clinical benefit that are worthy of future study and validation in this disease. RECENT FINDINGS: The clinical evaluation of novel agents in advanced prostate cancer remains challenging for several reasons. Men with metastatic prostate cancer often have bone-only disease in which formal radiologic response and progression criteria may not apply. Declines in serum prostate-specific antigen levels may be modest surrogates of response to cytotoxic agents such as docetaxel, but have not been validated for agents with novel mechanisms of action, such as antiangiogenic, immunologic, or cytostatic drugs. Novel radiologic imaging techniques such as PET scans are not yet validated for use in monitoring or staging advanced prostate cancer. Measures of delay, control, and palliation of metastatic disease such as pain response, time to progression and progression-free survival, while appealing endpoints that may highlight the clinical benefit of novel agents, have been difficult to define rigorously and have not yet demonstrated adequate surrogacy for overall survival. SUMMARY: The measures of response highlighted in this review, if validated, may improve the current evaluation of novel agents in phase II settings and the potential accelerated approval of these agents.

Authors
Ramiah, V; George, DJ; Armstrong, AJ
MLA Citation
Ramiah, V, George, DJ, and Armstrong, AJ. "Clinical endpoints for drug development in prostate cancer." Curr Opin Urol 18.3 (May 2008): 303-308. (Review)
PMID
18382240
Source
pubmed
Published In
Current Opinion in Urology
Volume
18
Issue
3
Publish Date
2008
Start Page
303
End Page
308
DOI
10.1097/MOU.0b013e3282fb7807

Cell signaling modifiers in prostate cancer.

Despite advances in the treatment of hormone-refractory prostate cancer (HRPC) with docetaxel chemotherapy as evidenced by the TAX 327 and SWOG 99-16 trials, therapeutic options remain limited in patients with cancer that progresses while they are receiving hormone manipulation and chemotherapy. Targeted therapies against receptor tyrosine kinases of the ErbB family have shown some promise in the treatment of HRPC; however, patient characteristics defining susceptibility to ErbB-targeted therapies remain unknown in HRPC and limits their efficacy in the clinic. Targeted inhibition of downstream pathways, namely mammalian target of rapamycin (mTOR) may prove to be important in the treatment of HRPC because of the prevalence of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) loss, and it has been shown preclinically that mTOR inhibition reverses the phenotype of PTEN loss. Further investigation is necessary for the targeted inhibition of receptor tyrosine kinases and mTOR in HRPC. However, these classes of drugs may prove efficacious as tumoricidal agents or as chemo- and radiosensitizers.

Authors
Chen, FL; Armstrong, AJ; George, DJ
MLA Citation
Chen, FL, Armstrong, AJ, and George, DJ. "Cell signaling modifiers in prostate cancer." Cancer J 14.1 (January 2008): 40-45. (Review)
PMID
18303482
Source
pubmed
Published In
Cancer Journal
Volume
14
Issue
1
Publish Date
2008
Start Page
40
End Page
45
DOI
10.1097/PPO.0b013e318161d40f

Dual antiangiogenesis reduces PSA by 50% in most patients: Commentary

Authors
George, DJ
MLA Citation
George, DJ. "Dual antiangiogenesis reduces PSA by 50% in most patients: Commentary." Oncology Report FALL (2008): 41--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2008
Start Page
41-

First-line sunitinib extends survival in metastatic disease: Commentary

Authors
George, DJ
MLA Citation
George, DJ. "First-line sunitinib extends survival in metastatic disease: Commentary." Oncology Report FALL (2008): 44--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2008
Start Page
44-

HIF levels predict sunitinib response and time to progression: Commentary

Authors
George, DJ
MLA Citation
George, DJ. "HIF levels predict sunitinib response and time to progression: Commentary." Oncology Report FALL (2008): 44--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2008
Start Page
44-

Everolimus doubles PFS after sorafenib/sunitinib resistance: Commentary

Authors
George, DJ
MLA Citation
George, DJ. "Everolimus doubles PFS after sorafenib/sunitinib resistance: Commentary." Oncology Report FALL (2008): 43--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2008
Start Page
43-

Magnetic resonance Imaging - Measured blood flow change after antiangiogenic therapy with PTK787/ZK 222584 correlates with clinical outcome in metastatic renal cell carcinoma

Purpose: To measure changes in tumor blood flow following treatment with PTK787/ZK 222584, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, and their association with clinical response in patients with metastatic renal cell carcinoma. Experimental Design: In 10 patients with metastatic renal cell carcinoma treated with PTK787/ ZK 222584, tumor blood flow was evaluated by arterial spin labeling (ASL) magnetic resonance imaging before and 1 month on treatment. Changes in blood flow after 1 month of treatment were compared with bidimensional tumor response at 4 months of treatment using the Mann- Whitney test. Results: Changes in blood flow at 1 month and changes in tumor size measured at 4 months or at time of disease progression were significantly correlated (P = 0.01). Patients with progressive disease within 4 months on treatment (n = 4) had a nonsignificant increase in tumor blood flow at 1 month (+25 ± 33%; P = 0.43), whereas patients with stable disease or partial response at 4 months (n = 6) had a significant decrease in tumor blood flow at 1 month (-42 ± 22%; P = 0.02). Conclusion:These results suggest that decreasing tumor blood flow with PTK787/ZK 222584 therapy, as shown as soon as 1 month on therapy by ASL, may predict for a favorable clinical outcome. These data are consistent with a hypothetical functional role for tumor ischemia in the mechanism of response to anti-vascular endothelial growth factor therapy. ASL blood flow magnetic resonance imaging shows promise as an early predictor of clinical response to antiangiogenic therapies. © 2008 American Association for Cancer Research.

Authors
Bazelaire, CD; Alsop, DC; George, D; Pedrosa, I; Wang, Y; Michaelson, MD; Rofsky, NM
MLA Citation
Bazelaire, CD, Alsop, DC, George, D, Pedrosa, I, Wang, Y, Michaelson, MD, and Rofsky, NM. "Magnetic resonance Imaging - Measured blood flow change after antiangiogenic therapy with PTK787/ZK 222584 correlates with clinical outcome in metastatic renal cell carcinoma." Clinical Cancer Research 14.17 (2008): 5548-5554.
PMID
18765547
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
17
Publish Date
2008
Start Page
5548
End Page
5554
DOI
10.1158/1078-0432.CCR-08-0417

Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma.

PURPOSE: To assess the safety and efficacy of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma (mRCC) and explore biomarkers for sunitinib response. PATIENTS AND METHODS: Patients with mRCC and disease progression after bevacizumab-based therapy received oral sunitinib 50 mg once daily in 6-week cycles on a 4/2 schedule (4 weeks with treatment followed by 2 weeks without treatment) in a phase II multicenter study. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), duration of response (DR), overall survival (OS), and safety. Plasma soluble proteins (vascular endothelial growth factor [VEGF]-A, VEGF-C, soluble VEGF receptor [sVEGFR]-3, and placental growth factor [PlGF]) levels were measured. RESULTS: Sixty-one patients were enrolled. The ORR was 23.0% (95% CI, 13.2% to 35.5%), median PFS was 30.4 weeks (95% CI, 18.3 to 36.7 weeks), median DR was 44.1 weeks (95% CI, 25.0 to 102.7 weeks), and median OS was 47.1 weeks (95% CI, 36.9 to 79.4 weeks). Mean plasma VEGF-A and PlGF levels significantly increased whereas VEGF-C and sVEGFR-3 levels decreased with sunitinib treatment. Lower baseline levels of sVEGFR-3 and VEGF-C were associated with longer PFS and ORR. Most treatment-related adverse events were of mild-to-moderate intensity and included fatigue, hypertension, and hand-foot syndrome. CONCLUSION: Sunitinib has substantial antitumor activity in patients with bevacizumab-refractory mRCC and modulates circulating VEGF pathway biomarkers. These data support the hypothesis that sunitinib inhibits signaling pathways involved in bevacizumab resistance. Baseline levels of sVEGFR-3 and VEGF-C may have potential utility as biomarkers of clinical efficacy in this setting.

Authors
Rini, BI; Michaelson, MD; Rosenberg, JE; Bukowski, RM; Sosman, JA; Stadler, WM; Hutson, TE; Margolin, K; Harmon, CS; DePrimo, SE; Kim, ST; Chen, I; George, DJ
MLA Citation
Rini, BI, Michaelson, MD, Rosenberg, JE, Bukowski, RM, Sosman, JA, Stadler, WM, Hutson, TE, Margolin, K, Harmon, CS, DePrimo, SE, Kim, ST, Chen, I, and George, DJ. "Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.22 (2008): 3743-3748.
PMID
18669461
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
22
Publish Date
2008
Start Page
3743
End Page
3748
DOI
10.1200/JCO.2007.15.5416

Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma

Purpose: Histone deacetylase inhibitors can alter gene expression and mediate diverse antitumor activities. Herein, we report the safety and activity of the histone deacetylase inhibitor panobinostat (LBH589) in cutaneous T-cell lymphoma (CTCL) and identify genes commonly regulated by panobinostat. Experimental Design: Panobinostat was administered orally to patients with CTCL on Monday, Wednesday, and Friday of each week on a 28-day cycle. A dose of 30 mg was considered excessively toxic, and subsequent patients were treated at the expanded maximum tolerated dose of 20 mg. Biopsies from six patients taken 0,4, 8, and 24 h after administration were subjected to microarray gene expression profiling and real-time quantitative PCR of selected genes. Results: Patients attained a complete response (n = 2), attained a partial response (n - 4), achieved stable disease with ongoing improvement (n = 1), and progressed on treatment (n = 2). Microarray data showed distinct gene expression response profiles over time following panobinostat treatment, with the majority of genes being repressed. Twenty-three genes were commonly regulated by panobinostat in all patients tested. Conclusions: Panobinostat is well tolerated and induces clinical responses in CTCL patients. Microarray analyses of tumor samples indicate that panobinostat induces rapid changes in gene expression, and surprisingly more genes are repressed than are activated. A unique set of genes that can mediate biological responses such as apoptosis, immune regulation, and angiogenesis were commonly regulated in response to panobinostat. These genes are potential molecular biomarkers for panobinostat activity and are strong candidates for the future assessment of their functional role(s) in mediating the antitumor responses of panobinostat. © 2008 American Association for Cancer Research.

Authors
Ellis, L; Pan, Y; Smyth, GK; George, DJ; McCormack, C; Williams-Truax, R; Mita, M; Beck, J; Burris, H; Ryan, G; Atadja, P; Butterfoss, D; Dugan, M; Culver, K; Johnstone, RW; Prince, HM
MLA Citation
Ellis, L, Pan, Y, Smyth, GK, George, DJ, McCormack, C, Williams-Truax, R, Mita, M, Beck, J, Burris, H, Ryan, G, Atadja, P, Butterfoss, D, Dugan, M, Culver, K, Johnstone, RW, and Prince, HM. "Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma." Clinical Cancer Research 14.14 (2008): 4500-4510.
PMID
18628465
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
14
Publish Date
2008
Start Page
4500
End Page
4510
DOI
10.1158/1078-0432.CCR-07-4262

Satraplatin in the treatment of hormone-refractory metastatic prostate cancer.

Satraplatin is an orally bioavailable platinum chemotherapeutic agent under development for several cancer types, including hormone-refractory prostate cancer (HRPC). Satraplatin is being developed for the treatment of men with chemorefractory HRPC for several reasons: 1) relative ease of administration, 2) potential lack of cross-resistance with other platinum agents, 3) clinical benefits seen in early studies of HRPC, and 4) an unmet need in this patient population after docetaxel failure. As men who have progressed after docetaxel and prednisone have an expected median survival of approximately 12 months, there is great opportunity for improved palliation in this disease. Satraplatin may provide a palliative benefit for these men in terms of progression-free survival according to the most recent analyses of the phase III SPARC trial comparing satraplatin and prednisone to prednisone alone in the second-line setting for HRPC, and is currently under USFDA review for this indication. Whether satraplatin and prednisone offer an advantage over docetaxel retreatment or other cytotoxic agents in this setting is an unanswered question and worthy of study. Investigation of predictors of platinum sensitivity and the use of satraplatin in patients with neuroendocrine subsets of metastatic prostate cancer may be warranted given the advances in biomarker and genomic technology and the known sensitivity of small cell cancers to platinum agents. Further study of satraplatin alone or in combination with docetaxel or other molecular and chemotherapeutic agents seems warranted to improve on current outcomes.

Authors
Armstrong, AJ; George, DJ
MLA Citation
Armstrong, AJ, and George, DJ. "Satraplatin in the treatment of hormone-refractory metastatic prostate cancer." Ther Clin Risk Manag 3.5 (October 2007): 877-883.
PMID
18473011
Source
pubmed
Published In
Therapeutics and clinical risk management
Volume
3
Issue
5
Publish Date
2007
Start Page
877
End Page
883

Tumor laterality does not predict biochemical prostate cancer recurrence after radical prostatectomy

Authors
Mouraviev, V; Sun, L; Madden, JF; Mayes, JM; Moul, JW; George, DJ; Febbo, PG; Polascik, TJ
MLA Citation
Mouraviev, V, Sun, L, Madden, JF, Mayes, JM, Moul, JW, George, DJ, Febbo, PG, and Polascik, TJ. "Tumor laterality does not predict biochemical prostate cancer recurrence after radical prostatectomy." October 2007.
Source
wos-lite
Published In
Journal of Endourology
Volume
21
Publish Date
2007
Start Page
A216
End Page
A216

Prostate cancer laterality as a rationale for the clinical application of focal ablative therapy: An analysis of 1184 prostatectomy specimens

Authors
Polascik, TJ; Sun, L; Madden, JF; Mayes, JM; George, DJ; Febbo, PG; Mouraviev, V
MLA Citation
Polascik, TJ, Sun, L, Madden, JF, Mayes, JM, George, DJ, Febbo, PG, and Mouraviev, V. "Prostate cancer laterality as a rationale for the clinical application of focal ablative therapy: An analysis of 1184 prostatectomy specimens." October 2007.
Source
wos-lite
Published In
Journal of Endourology
Volume
21
Publish Date
2007
Start Page
A216
End Page
A216

Anti-angiogenic therapy in renal cell cancer.

Angiogenesis is an important hallmark of RCC, reflected in the natural history, Histology, genetics and now therapeutics of this disease. Clearly, the pro-angiogenic growth factor VEGF is a functional drug target in RCC and many strategies to inhibit this biology have shown clinical benefit. Multi-targeted TKI that inhibit VEGFRs have been approved by the FDA as standard treatment for advanced RCC. Pharmacodynamyc studies suggest that these agents and others also have anti-angiogenic effects. Currently, studies combining VEGFR-targeted strategies with other anti-angiogenic agents, including anti-VEGF antibodies, IFN or mTOR inhibitors, are underway. However, to what extent the clinical benefit of anti-angiogenic strategies in RCC can be built upon is unknown.

Authors
Srinivasan, R; Armstrong, AJ; Dahut, W; George, DJ
MLA Citation
Srinivasan, R, Armstrong, AJ, Dahut, W, and George, DJ. "Anti-angiogenic therapy in renal cell cancer." BJU Int 99.5 Pt B (May 2007): 1296-1300. (Review)
PMID
17441927
Source
pubmed
Published In
Bju International
Volume
99
Issue
5 Pt B
Publish Date
2007
Start Page
1296
End Page
1300
DOI
10.1111/j.1464-410X.2007.06834.x

Systemic strategies for prostate cancer.

Systemic therapy beyond hormonal therapy for advanced prostate cancer includes chemotherapy, antiangiogenic therapy, signal transduction inhibitors, immunomodulatory therapy, and other experimental therapeutics. This review will discuss the state of systemic therapy for advanced prostate cancer in 2007, with an emphasis on therapy in the neoadjuvant, adjuvant, and metastatic setting. As chemotherapy gains greater acceptance in the urologic oncology community for use in men with hormone-refractory disease, evaluating the role of systemic therapy in earlier disease states is essential given the success in other solid tumors for advancing cure rates. Current randomized phase III trials worldwide are addressing these questions in each disease state, and are anticipated to change the landscape of prostate cancer management for years to come. In this discussion, we will emphasize those agents that are currently being evaluated in phase II and III trials, with an emphasis on those trials that are likely to impact the standard of care in the near future. The collection of tumor or surrogate tissue is emphasized to define biomarkers that may predict for sensitivity to these systemic therapies.

Authors
Armstrong, AJ; Febbo, PG; George, DJ; Moul, J
MLA Citation
Armstrong, AJ, Febbo, PG, George, DJ, and Moul, J. "Systemic strategies for prostate cancer." Minerva Urol Nefrol 59.1 (March 2007): 11-25. (Review)
PMID
17431367
Source
pubmed
Published In
Minerva urologica e nefrologica = The Italian journal of urology and nephrology
Volume
59
Issue
1
Publish Date
2007
Start Page
11
End Page
25

Radiation therapy and sorafenib: clinical data and rationale for the combination in metastatic renal cell carcinoma.

Sorafenib, an inhibitor of multiple tyrosine kinases including vascular endothelial growth factor receptor and Raf/mitogen-activated protein kinase, increases progression-free survival in metastatic renal cell carcinoma (RCC) compared with placebo. The efficacy and toxicity of combined sorafenib and radiation therapy (RT) in the treatment of RCC are unknown. This is a retrospective report of 3 consecutive patients with metastatic or locally recurrent RCC treated with palliative RT while undergoing sorafenib therapy. All 3 patients experienced disease progression on sorafenib and remained on the drug without dose reduction during the RT plus sorafenib regimen. They were followed for toxicity and response by clinical history, physical examination, and contrast-enhanced computed tomography scans. Soon after completion of palliative RT, all 3 patients experienced complete pain relief without the need for narcotic pain medication. Posttreatment imaging revealed partial response with > 50% regression of tumor in all patients. None reported significant acute or late side effects at follow-up of 3, 6, and 8 months after RT and sorafenib. In the 3 patients with recurrent or metastatic RCC in this report, the combination of RT and sorafenib was well tolerated and resulted in excellent clinical and radiologic responses. This combination is promising and requires further study.

Authors
Kasibhatla, M; Steinberg, P; Meyer, J; Ernstoff, MS; George, DJ
MLA Citation
Kasibhatla, M, Steinberg, P, Meyer, J, Ernstoff, MS, and George, DJ. "Radiation therapy and sorafenib: clinical data and rationale for the combination in metastatic renal cell carcinoma." Clin Genitourin Cancer 5.4 (March 2007): 291-294.
PMID
17553211
Source
pubmed
Published In
Clinical genitourinary cancer
Volume
5
Issue
4
Publish Date
2007
Start Page
291
End Page
294
DOI
10.3816/CGC.2007.n.007

Phase 2 studies of sunitinib and AG013736 in patients with cytokine-refractory renal cell carcinoma.

Frequent loss of the von Hippel-Lindau (VHL) gene product in conventional-type renal cell carcinoma results in constitutive expression of proangiogenic growth factors, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). VEGF and PDGF function in a paracrine manner to stimulate tumor angiogenesis that results in a hypervascular phenotype. Dependency on this hypervascularity is underscored by the recent clinical efficacy shown by inhibition of the VEGF pathway. Most strategies that primarily target the VEGF pathway (neutralizing antibodies or receptor tyrosine kinase inhibitors) result in objective tumor responses in < or =10% of cases but show a significant delay in time to disease progression. In contrast, two multitargeted receptor tyrosine kinase inhibitors that target both VEGF and PDGF receptors (sunitinib and AG013736) have shown > or =40% objective responses with clinically important duration. Several hypotheses may explain the discrepancy of these response rates from other strategies in the class, including the synergistic effects of dual inhibition of VEGF and PDGF receptors, supported by preclinical studies. Ultimately, further clinical investigations with pharmacodynamic and correlative science end points are needed to clarify the mechanisms of action and resistance to build on the biological and clinical effects of these multitargeted agents.

Authors
George, DJ
MLA Citation
George, DJ. "Phase 2 studies of sunitinib and AG013736 in patients with cytokine-refractory renal cell carcinoma." Clin Cancer Res 13.2 Pt 2 (January 15, 2007): 753s-757s. (Review)
PMID
17255305
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
2 Pt 2
Publish Date
2007
Start Page
753s
End Page
757s
DOI
10.1158/1078-0432.CCR-06-2044

Current standard and investigational approaches to the management of hormone-refractory prostate cancer.

Prostate cancer is a common cause of death in men and remains incurable in the metastatic setting. In 2004, 2 landmark trials using docetaxel-based chemotherapy, TAX 327 and SWOG 99-16, showed a survival benefit for the first time in metastatic, hormone-refractory prostate cancer. Current research suggests that several distinct mechanisms of androgen-refractory disease may converge in patients with disease progression on androgen deprivation therapy. These findings have identified several potential targets for therapeutic intervention. Current standard and investigational treatment options for this disease are discussed, including chemotherapy and rapidly evolving therapies in phase II/III trials involving antiangiogenic therapies, signal transduction inhibitors, immunomodulatory agents, and nuclear receptor targets. In light of a growing array of treatment options and an increasingly chronic natural history, this review supports a multidisciplinary care approach to these patients, including medical oncologists, urologists, and radiation oncologists, to optimize survival and quality of life.

Authors
Mendiratta, P; Armstrong, AJ; George, DJ
MLA Citation
Mendiratta, P, Armstrong, AJ, and George, DJ. "Current standard and investigational approaches to the management of hormone-refractory prostate cancer." Rev Urol 9 Suppl 1 (2007): S9-S19.
PMID
17387372
Source
pubmed
Published In
Reviews in Urology
Volume
9 Suppl 1
Publish Date
2007
Start Page
S9
End Page
S19

Phase I/II study of vaccination with electrofused allogeneic dendritic cells/autologous tumor-derived cells in patients with stage IV renal cell carcinoma

In the present study, we assessed the feasibility, toxicity, immunologic response, and clinical efficacy of vaccination with allogeneic dendritic cell (DC)/tumor fusions in patients with metastatic renal cell carcinoma (RCC). Patients with stage IV RCC with accessible tumor lesions or independent therapeutic indications for nephrectomy were eligible for enrollment. Tumors were processed into single cell suspensions and cryopreserved. DCs were generated from adherent peripheral blood mononuclear cells isolated from normal volunteers and cultured with granulocyte macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-α. DCs were fused to patient derived RCC with serial electrical pulses. Patients received up to 3 vaccinations at a fixed dose of 4×10 to 1×10 cells administered at 6-week intervals. Twenty-four patients underwent vaccination. Twenty-one and 20 patients were evaluable for immunologic and clinical response, respectively. DCs demonstrated a characteristic phenotype with prominent expression of HLA class II and costimulatory molecules. A mean fusion efficiency of 20% was observed, determined by the percent of cells coexpressing DC and tumor antigens. No evidence of significant treatment related toxicity or auto-immunity was observed. Vaccination resulted in antitumor immune responses in 10/21 evaluable patients as manifested by an increase in CD4 and/or CD8 T-cell expression of interferon-γ after ex vivo exposure to tumor lysate. Two patients demonstrated a partial clinical response by Response Evaluation Criteria in Solid Tumors criteria and 8 patients had stabilization of their disease. Vaccination of patients with RCC with allogeneic DC/tumor fusions was feasible, well tolerated, and resulted in immunologic and clinical responses in a subset of patients. © 2007 Lippincott Williams & Wilkins, Inc.

Authors
Avigan, DE; Vasir, B; George, DJ; Oh, WK; Atkins, MB; McDermott, DF; Kantoff, PW; Figlin, RA; Vasconcelles, MJ; Xu, Y; Kufe, D; Bukowski, RM
MLA Citation
Avigan, DE, Vasir, B, George, DJ, Oh, WK, Atkins, MB, McDermott, DF, Kantoff, PW, Figlin, RA, Vasconcelles, MJ, Xu, Y, Kufe, D, and Bukowski, RM. "Phase I/II study of vaccination with electrofused allogeneic dendritic cells/autologous tumor-derived cells in patients with stage IV renal cell carcinoma." Journal of Immunotherapy 30.7 (2007): 749-761.
PMID
17893567
Source
scival
Published In
Journal of Immunotherapy
Volume
30
Issue
7
Publish Date
2007
Start Page
749
End Page
761
DOI
10.1097/CJI.0b013e3180de4ce8

Sunitinib Efficacy Against Advanced Renal Cell Carcinoma

Purpose: We assessed the efficacy of the oral multitargeted tyrosine kinase inhibitor sunitinib in patients with metastatic clear cell renal cell carcinoma. Materials and Methods: Patients with metastatic clear cell renal cell carcinoma were enrolled in this multicenter, phase II clinical trial. Major eligibility requirements were clear cell renal cell carcinoma histology, prior nephrectomy, measurable metastases and failed prior cytokine therapy as a result of disease progression. Sunitinib was given orally as second line therapy in 6-week cycles of 50 mg daily for 4 weeks, followed by 2 weeks off drug per treatment cycle. Response to sunitinib was rigorously assessed by an independent third party core imaging laboratory (central review). Results: Of 106 patients enrolled in the study 105 were evaluated for response. As determined by independent third party assessment, the objective response rate was 33% (95% CI 24%-43%) with a median response duration of 14.0 months. Median time to progression and median progression-free survival in the 105 evaluable patients was 10.7 and 8.8 months, respectively. Median survival was 23.9 months and 43 patients remained alive at a median followup of 29.7 months. Conclusions: The results of this trial demonstrate the efficacy of sunitinib for metastatic renal cell carcinoma. The optimal integration of surgery and sunitinib treatment requires further prospective investigation. © 2007 American Urological Association.

Authors
Motzer, RJ; Michaelson, MD; Rosenberg, J; Bukowski, RM; Curti, BD; George, DJ; Hudes, GR; Redman, BG; Margolin, KA; Wilding, G
MLA Citation
Motzer, RJ, Michaelson, MD, Rosenberg, J, Bukowski, RM, Curti, BD, George, DJ, Hudes, GR, Redman, BG, Margolin, KA, and Wilding, G. "Sunitinib Efficacy Against Advanced Renal Cell Carcinoma." Journal of Urology 178.5 (2007): 1883-1887.
PMID
17868732
Source
scival
Published In
The Journal of Urology
Volume
178
Issue
5
Publish Date
2007
Start Page
1883
End Page
1887
DOI
10.1016/j.juro.2007.07.030

Treatment options in renal cell carcinoma: Past, present and future

Cytokine therapies have been the standard of care in metastatic renal cell carcinoma (RCC). However, these agents only provide clinical benefit to a small subset of patients and are associated with significant toxicity. A better understanding of the molecular biology of RCC has identified the vascular endothelial growth factor (VEGF) and platelet-derived growth factor signalling pathways as rational targets for anticancer therapy. The multitargeted receptor tyrosine kinase inhibitors sunitinib and sorafenib have both demonstrated improved efficacy as second-line therapy in patients with RCC. Sunitinib has also been shown to be effective in the first-line setting, and has recently received European Union approval as first-line treatment for advanced and/or metastatic RCC. There is also recent evidence that temsirolimus (an inhibitor of the mammalian target of rapamycin) and bevacizumab (a mAb targeted against VEGF) may provide benefits in the first-line treatment setting. These results confirm that inhibiting these tumour targets is a feasible approach to treatment and provides a more positive outlook for the future management of metastatic RCC. © 2007 European Society for Medical Oncology.

Authors
Oudard, S; George, D; Medioni, J; Motzer, R
MLA Citation
Oudard, S, George, D, Medioni, J, and Motzer, R. "Treatment options in renal cell carcinoma: Past, present and future." Annals of Oncology 18.SUPPL. 10 (2007): x25-x31.
PMID
17761720
Source
scival
Published In
Annals of Oncology
Volume
18
Issue
SUPPL. 10
Publish Date
2007
Start Page
x25
End Page
x31
DOI
10.1093/annonc/mdm411

Introduction to 'A multitargeted approach: Clinical advances in the treatment of solid tumours'

Although single-target agents have been shown to improve patient outcomes in certain tumour types, drug resistance often occurs due to salvage pathways that compensate for the inhibited signalling pathway. Simultaneous inhibition of individual target receptors along multiple pathways has been shown to have additive inhibitory effects on tumour growth and vasculature, and data supporting the efficacy of strategies incorporating multitargeted agents in the treatment of several tumour types have already begun to emerge in the clinical setting. This supplement provides an overview of presentations from a satellite symposium that took place at the European Society of Medical Oncology congress on 29 September 2006, entitled 'A Multitargeted Approach: Clinical Advances in the Treatment of Solid Tumours', which discusses the most recent data on multitargeted agents with a focus on sunitinib malate (Sutent ®, Pfizer Inc.). © 2007 European Society for Medical Oncology.

Authors
George, D; Verweij, J
MLA Citation
George, D, and Verweij, J. "Introduction to 'A multitargeted approach: Clinical advances in the treatment of solid tumours'." Annals of Oncology 18.SUPPL. 10 (2007): x1-x2.
PMID
17761717
Source
scival
Published In
Annals of Oncology
Volume
18
Issue
SUPPL. 10
Publish Date
2007
Start Page
x1
End Page
x2
DOI
10.1093/annonc/mdm407

Bevacizumab plus interferon-α improves survival: Commentary

Authors
George, DJ; Moul, JW
MLA Citation
George, DJ, and Moul, JW. "Bevacizumab plus interferon-α improves survival: Commentary." Oncology Report FALL (2007): 57--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2007
Start Page
57-

Satraplatin boosts progression-free survival in SPARC: Commentary

Authors
George, DJ; Moul, JW
MLA Citation
George, DJ, and Moul, JW. "Satraplatin boosts progression-free survival in SPARC: Commentary." Oncology Report FALL (2007): 49--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2007
Start Page
49-

Innovations and challenges in renal cell carcinoma: Summary statement from the Second Cambridge Conference

Innovations and Challenges in Renal Cancer, chaired by Michael B. Atkins, was held April 28 to 29, 2006 in Cambridge, Massachusetts. The conference brought together leading experts in the fields of cancer research, medical oncology, urology, immunology, radiology, and immunotherapy, with the goal of advancing the field of renal cancer treatment by critiquing new data from ongoing clinical trials and stimulating communication among those involved in basic and clinical research. The conference proceedings published in this educational supplement to Clinical Cancer Research are intended to provide timely information and recommendations on important aspects of renal cancer genetics and biology and advances in prognostic classification and treatment. © 2007 American Association for Cancer Research.

Authors
Atkins, MB; Ernstoff, MS; Figlin, RA; Flaherty, KT; George, DJ; Jr, WGK; Kwon, ED; Libermann, TA; Linehan, WM; McDermott, DF; Ochoa, AC; Pantuck, AJ; Rini, BI; Rosen, MA; Sosman, JA; Sukhatme, VP; Vieweg, JW; Wood, CG; King, L
MLA Citation
Atkins, MB, Ernstoff, MS, Figlin, RA, Flaherty, KT, George, DJ, Jr, WGK, Kwon, ED, Libermann, TA, Linehan, WM, McDermott, DF, Ochoa, AC, Pantuck, AJ, Rini, BI, Rosen, MA, Sosman, JA, Sukhatme, VP, Vieweg, JW, Wood, CG, and King, L. "Innovations and challenges in renal cell carcinoma: Summary statement from the Second Cambridge Conference." Clinical Cancer Research 13.2 II (2007): 667s-670s.
PMID
17255291
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
2 II
Publish Date
2007
Start Page
667s
End Page
670s
DOI
10.1158/1078-0432.CCR-06-2231

Application of oligonucleotide microarrays to assess the biological effects of neoadjuvant imatinib mesylate treatment for localized prostate cancer.

PURPOSE: Neoadjuvant administration of antineoplastic therapies is used to rapidly assess the clinical and biological activity of novel systemic treatments. To assess the feasibility of using microarrays to assess molecular end points following targeted treatment in a heterogeneous tumor, we measured global gene expression in localized prostate cancer before and following neoadjuvant treatment with imatinib mesylate. PATIENTS AND METHODS: Patients with intermediate-risk to high-risk prostate cancer were treated for 6 weeks with 200 to 300 mg of oral imatinib mesylate. Frozen tissue was obtained from pretreatment ultrasound-guided biopsies and posttreatment radical prostatectomy specimens. Oligonucleotide microarray analysis following laser capture microdissection (LCM) and RNA amplification was used to assess gene expression changes associated with imatinib mesylate therapy. Immunohistochemistry was used to measure protein expression of MKP1 and CD31 and to assess cellular apoptosis. RESULTS: Of the 11 patients enrolled, high-quality microarray data was obtained from both biopsies (n = 7) and radical prostatectomy specimens (n = 9). Technically introduced intrasample gene expression variability was found to be significantly less than intertumor biological variability. Large gene expression differences were observed, and the gene with the most consistent differential expression (MKP1) was validated by immunohistochemistry. Gene set enrichment analysis suggests that imatinib mesylate therapy results in apoptosis of microvascular endothelial cells, an observation anecdotally supported by immunohistochemistry. CONCLUSIONS: This study shows that high-quality microarray data can be generated using LCM and RNA amplification to discover potential mechanisms of targeted therapy in cancer.

Authors
Febbo, PG; Thorner, A; Rubin, MA; Loda, M; Kantoff, PW; Oh, WK; Golub, T; George, D
MLA Citation
Febbo, PG, Thorner, A, Rubin, MA, Loda, M, Kantoff, PW, Oh, WK, Golub, T, and George, D. "Application of oligonucleotide microarrays to assess the biological effects of neoadjuvant imatinib mesylate treatment for localized prostate cancer." Clin Cancer Res 12.1 (January 1, 2006): 152-158.
PMID
16397037
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
1
Publish Date
2006
Start Page
152
End Page
158
DOI
10.1158/1078-0432.CCR-05-1652

Timing and patterns of recurrences and deaths from prostate cancer following adjuvant pelvic radiotherapy for pathologic stage T3/4 adenocarcinoma of the prostate.

To determine the timing and patterns of late recurrence after radical prostatectomy (RP) alone or RP plus adjuvant radiotherapy (RT). Between 1970 and 1983, 159 patients underwent RP for newly diagnosed adenocarcinoma of the prostate and were found to have positive surgical margins, extracapsular extension and/or seminal vesicle invasion. Of these, 46 received adjuvant RT and 113 did not. The RT group generally received 45-50 Gy to the whole pelvis, then a boost to the prostate bed (total dose of 55-65 Gy). In the RP group, 62% received neoadjuvant/adjuvant androgen deprivation vs 17% in the RT group. Patients were analyzed with respect to timing and patterns of failure. Only one patient was lost to follow-up. The median follow-up for surviving patients was nearly 20 years. The median time to failure in the surgery group was 7.5 vs 14.7 years in the RT group (P=0.1). Late recurrences were less common in the surgery group than the RT group (9 and 1% at 10 and 15 years, respectively vs 17 and 9%). In contrast to recurrences, nearly half of deaths from prostate cancer occurred more than 10 years after treatment. Deaths from prostate cancer represented 55% of all deaths in these patients. Recurrences beyond 10 years after RP in this group of patients were relatively uncommon. Despite its long natural history, death from prostate cancer was the most common cause of mortality in this population with locally advanced tumors, reflecting the need for more effective therapy.

Authors
Anscher, MS; Clough, R; Robertson, CN; Prosnitz, LR; Dahm, P; Walther, P; Donatucci, CF; Albala, DM; Febbo, P; George, DJ; Sun, L; Moul, JW
MLA Citation
Anscher, MS, Clough, R, Robertson, CN, Prosnitz, LR, Dahm, P, Walther, P, Donatucci, CF, Albala, DM, Febbo, P, George, DJ, Sun, L, and Moul, JW. "Timing and patterns of recurrences and deaths from prostate cancer following adjuvant pelvic radiotherapy for pathologic stage T3/4 adenocarcinoma of the prostate." Prostate Cancer Prostatic Dis 9.3 (2006): 254-260.
PMID
16880828
Source
pubmed
Published In
Prostate Cancer and Prostatic Diseases
Volume
9
Issue
3
Publish Date
2006
Start Page
254
End Page
260
DOI
10.1038/sj.pcan.4500903

Peripheral androgen blockage produces durable PSA responses in prostate cancer: Comment

Authors
Moul, JW; Freedland, SJ; George, DJ
MLA Citation
Moul, JW, Freedland, SJ, and George, DJ. "Peripheral androgen blockage produces durable PSA responses in prostate cancer: Comment." Oncology Report FALL (2006): 47--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2006
Start Page
47-

Zoledronic acid maintains BMD in GnRH agonist-treated men with prostate cancer: Comment

Authors
Freedland, SJ; George, DJ; Moul, JW
MLA Citation
Freedland, SJ, George, DJ, and Moul, JW. "Zoledronic acid maintains BMD in GnRH agonist-treated men with prostate cancer: Comment." Oncology Report FALL (2006): 51-52.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2006
Start Page
51
End Page
52

Improving outcomes with novel therapies for patients with newly diagnosed renal cell carcinoma.

With the approval of sunitinib and sorafenib, 2 new multitargeted tyrosine kinase inhibitors, for the treatment of advanced renal cell carcinoma (RCC), the natural history and prognosis of patients with this disease has significantly improved. These drugs were approved based upon clinical data demonstrating robust, unprecedented response rates in one case and dramatic prolongation of progression-free survival in the other. In both cases, these results were seen in study patients in whom standard therapy had failed and who, on average, carried substantial disease burden. Important challenges today include integrating these therapies with other standard therapeutic options and into other advanced-stage RCC patient populations. This article addresses current data and practice patterns regarding the clinical use of tyrosine kinase inhibitors in patients with advanced-stage RCC, including dose modifications and alternative dosing, the current role of debulking nephrectomy, and use in patients with indolent disease. Finally, a summary of the more common side effects and management strategies for these is also discussed. Ultimately, more clinical data is needed to address the chronic use of these agents alone, in combination with other agents, with radiation therapy, and in sequence.

Authors
Speca, J; Yenser, S; Creel, P; George, D
MLA Citation
Speca, J, Yenser, S, Creel, P, and George, D. "Improving outcomes with novel therapies for patients with newly diagnosed renal cell carcinoma." Clinical genitourinary cancer 5 Suppl 1 (2006): S24-S30.
PMID
17239281
Source
scival
Published In
Clinical genitourinary cancer
Volume
5 Suppl 1
Publish Date
2006
Start Page
S24
End Page
S30
DOI
10.3816/CGC.2006.s.004

Angiogenesis inhibitors in clinical oncology

Over the past 5 years the clinical applications of anti-angiogenic strategies have grown exponentially. This past year was no exception with the rapid development and introduction into practice of two multitargeted tyrosine kinase inhibitors (TKI) for the treatment of renal cell carcinoma. The development of TKIs for the vascular endothelial growth factor (VEGF) receptors in particular validates this target further in its role in angiogenesis and suggests further mechanisms that may complement previously established neutralizing antibodies to VEGF and similar strategies. Ongoing studies will combine these and other agents in what may be further advances in angiogenesis inhibition in the years to come. © 2006.

Authors
George, DJ; Moore, C
MLA Citation
George, DJ, and Moore, C. "Angiogenesis inhibitors in clinical oncology." Update on Cancer Therapeutics 1.4 (2006): 429-434.
Source
scival
Published In
Update on Cancer Therapeutics
Volume
1
Issue
4
Publish Date
2006
Start Page
429
End Page
434
DOI
10.1016/j.uct.2006.08.006

Sunitinib and temsirolimus: New standards of care for metastatic RCC? Comment

Authors
George, DJ; Moul, JW
MLA Citation
George, DJ, and Moul, JW. "Sunitinib and temsirolimus: New standards of care for metastatic RCC? Comment." Oncology Report FALL (2006): 53+57-.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2006
Start Page
53+57

Perioperative chemotherapy surprisingly underused for transitional cell carcinoma: Comment

Authors
George, DJ; Moul, JW
MLA Citation
George, DJ, and Moul, JW. "Perioperative chemotherapy surprisingly underused for transitional cell carcinoma: Comment." Oncology Report FALL (2006): 58-59.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2006
Start Page
58
End Page
59

Salvage chemotherapy yields high cure rate in recurrent germ cell tumors: Comment

Authors
George, DJ; Moul, JW
MLA Citation
George, DJ, and Moul, JW. "Salvage chemotherapy yields high cure rate in recurrent germ cell tumors: Comment." Oncology Report FALL (2006): 58--.
Source
scival
Published In
Oncology Report
Issue
FALL
Publish Date
2006
Start Page
58-

Development of an integrated prostate cancer research information system

Background: In this article, we describe the design and implementation of a comprehensive prostate cancer database developed to collect, store, and access clinical, treatment, and outcomes data for research and clinical care. Patients and Methods: The Prostate Cancer Clinical Research Information System is a relational database. Data are entered from multiple sources, including medical records, institutional laboratory, patient registration, pharmacy systems, and clinician forms. The history, design, and operational characteristics of the database are described. Issues regarding necessary staffing and funding of databases are reviewed. Results: Four thousand two hundred forty-six patients have information in the Prostate Cancer Clinical Research Information System. Mean age of patients is 62 years, and 89% are white. Seventy-one percent of patients presented at diagnosis with T1 or T2 disease, and 78% had biopsy Gleason scores of ≤ 7, 8-10 in 18%. Median prostate-specific antigen level at diagnosis was 7 ng/mL, and 77% of patients presented with increased prostate-specific antigen as a trigger symptom. Sixty-four percent of patients presented to our clinic having had no previous treatment for prostate cancer. The majority of approached patients provided consent for collection of clinical data, blood, and tissue. Quality control assessments demonstrate high levels of concordance among data entry personnel. Conclusion: Clinical databases are difficult to implement and maintain; however, they represent a valuable resource, particularly when linked to blood and tissue banks. Elements needed for a successful clinical database include engagement of clinicians, utility for research, and the ability to integrate with legacy systems. As cancer centers develop such databases, lessons learned from each experience should be shared in order to optimize the process.

Authors
Oh, WK; Hayes, J; Evan, C; Manola, J; George, DJ; Waldron, H; Donovan, M; Varner, J; Orechia, J; Katcher, B; Lu, D; Nevins, A; Wright, RL; Tormey, L; Talcott, J; Rubin, MA; Loda, M; Sellers, WR; Richie, JP; Kantoff, PW; Weeks, J
MLA Citation
Oh, WK, Hayes, J, Evan, C, Manola, J, George, DJ, Waldron, H, Donovan, M, Varner, J, Orechia, J, Katcher, B, Lu, D, Nevins, A, Wright, RL, Tormey, L, Talcott, J, Rubin, MA, Loda, M, Sellers, WR, Richie, JP, Kantoff, PW, and Weeks, J. "Development of an integrated prostate cancer research information system." Clinical Genitourinary Cancer 5.1 (2006): 61-66.
PMID
16859581
Source
scival
Published In
Clinical genitourinary cancer
Volume
5
Issue
1
Publish Date
2006
Start Page
61
End Page
66
DOI
10.3816/CGC.2006.n.019

Combined T2* and T1 measurements for improved perfusion and permeability studies in high field using dynamic contrast enhancement

This study analyzed the T2* effect of extracellularly distributed gadolinium contrast agents in arterial blood during tumor studies using T1-weighted sequences at high field strength. A saturation-prepared dual echo sequence with echo times of 1.5 and 3.5 ms was employed at 3 T to simultaneously characterize T1 and T2* of arterial blood during bolus administration of Gd-DTPA in 28 patients with body tumors. T2* effect and T1 effect of Gd-DTPA on image intensity of whole blood were calibrated in human blood samples with different concentrations of contrast agent. T2* was used to estimate concentration near the peak of the bolus. T1 was used to measure lower concentrations when T2* was not significant. T2* was measurable on calibration curves for Gd-DTPA concentrations higher than 4 mM. This concentration was exceeded in 18 patients. The mean signal intensity reduction because of T2* effect was estimated at 22±14% of the T2* compensated signal. Using T2* measurements reduced underestimations of peak arterial Gd-DTPA concentration (59±38%) and overestimation of permeability Ktrans (58%). The T2* effect of gadolinium contrast agents should therefore be accounted for when performing tumors study with T1-weighted sequences at high field strength. © Springer-Verlag 2006.

Authors
Bazelaire, CD; Rofsky, NM; Duhamel, G; Zhang, J; Michaelson, MD; George, D; Alsop, DC
MLA Citation
Bazelaire, CD, Rofsky, NM, Duhamel, G, Zhang, J, Michaelson, MD, George, D, and Alsop, DC. "Combined T2* and T1 measurements for improved perfusion and permeability studies in high field using dynamic contrast enhancement." European Radiology 16.9 (2006): 2083-2091.
PMID
16583215
Source
scival
Published In
European Radiology
Volume
16
Issue
9
Publish Date
2006
Start Page
2083
End Page
2091
DOI
10.1007/s00330-006-0198-1

Sunitinib in patients with metastatic renal cell carcinoma

Context: Current treatment options for metastatic renal cell carcinoma (RCC) are limited and there is a need to identify novel and effective therapies. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor, which has shown activity in an initial study of cytokine-refractory metastatic RCC patients. Objective: To confirm the antitumor efficacy of sunitinib as second-line treatment in patients with metastatic clear-cell RCC, the predominant cell type of this malignancy. Design, Setting, and Patients: Open-label, single-arm, multicenter clinical trial. Patients were enrolled between February and November 2004, with follow-up continuing until disease progression, unacceptable toxicity, or withdrawal of consent. The reported data apply through August 2005. Patients (N=106) had metastatic clear-cell RCC, which had progressed despite previous cytokine therapy. Intervention: Repeated 6-week cycles of sunitinib, 50 mg per day given orally for 4 consecutive weeks followed by 2 weeks off per treatment cycle. Main Outcome Measures: Assessment of clinical response, degree of tumor regression on imaging studies using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Primary end point was overall objective response rate (complete plus partial). Secondary end points were progression-free survival and safety. Response was evaluated by independent third-party core imaging laboratory and by treating physicians (investigator assessment). Results: All 106 patients received sunitinib and were included in the intent-to-treat population for safety analyses. Of these, 105 patients were evaluable for efficacy analyses. The objective response rate according to an independent third-party assessment resulted in 36 patients with partial response (34%; 95% confidence interval, 25%-44%), and a median progression-free survival of 8.3 months (95% confidence interval, 7.8-14.5 months). The most common adverse events experienced by patients were fatigue in 30 (28%) and diarrhea 21 (20%). Neutropenia, elevation of lipase, and anemia were the most common laboratory abnormalities observed in 45 (42%), 30 (28%), and 27 (26%) patients, respectively. Conclusion The results of this trial demonstrate the efficacy and manageable adverse-event profile of sunitinib as a single agent in second-line therapy for patients with cytokine-refractory metastatic clear-cell RCC. ©2006 American Medical Association. All rights reserved.

Authors
Motzer, RJ; Rini, BI; Bukowski, RM; Curti, BD; George, DJ; Hudes, GR; Redman, BG; Margolin, KA; Merchan, JR; Wilding, G; Ginsberg, MS; Bacik, J; Kim, ST; Baum, CM; Michaelson, MD
MLA Citation
Motzer, RJ, Rini, BI, Bukowski, RM, Curti, BD, George, DJ, Hudes, GR, Redman, BG, Margolin, KA, Merchan, JR, Wilding, G, Ginsberg, MS, Bacik, J, Kim, ST, Baum, CM, and Michaelson, MD. "Sunitinib in patients with metastatic renal cell carcinoma." Journal of the American Medical Association 295.21 (2006): 2516-2524.
PMID
16757724
Source
scival
Published In
JAMA : the journal of the American Medical Association
Volume
295
Issue
21
Publish Date
2006
Start Page
2516
End Page
2524
DOI
10.1001/jama.295.21.2516

Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma

Purpose: Renal cell carcinoma (RCC) is characterized by loss of von Hippel Lindau tumor suppressor gene activity, resulting in high expression of pro-angiogenic growth factors: vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). SU11248 (sunitinib malate), a small molecule inhibitor with high binding affinity for VEGF and PDGF receptors, was tested for clinical activity in patients with metastatic RCC. Patients and Methods: Patients with metastatic RCC and progression on first-line cytokine therapy were enrolled onto a multicenter phase II trial. SU11248 monotherapy was administered in repeated 6-week cycles of daily oral therapy for 4 weeks, followed by 2 weeks off. Overall response rate was the primary end point, and time to progression and safety were secondary end points. Results: Twenty-five (40%) of 63 patients treated with SU11248 achieved partial responses; 17 additional patients (27%) demonstrated stable disease lasting > 3 months. Median time to progression in the 63 patients was 8.7 months. Dosing was generally tolerated with manageable toxicities. Conclusion: SU11248, a multitargeted receptor tyrosine kinase inhibitor of VEGF and PDGF receptors, demonstrates antitumor activity in metastatic RCC as second-line therapy, a setting where no effective systemic therapy is presently recognized. The genetics of RCC and these promising clinical results support the hypothesis that VEGF and PDGF receptor-mediated signaling is an effective therapeutic target in RCC. © 2006 by American Society of Clinical Oncology.

Authors
Motzer, RJ; Michaelson, MD; Redman, BG; Hudes, GR; Wilding, G; Figlin, RA; Ginsberg, MS; Kim, ST; Baum, CM; DePrimo, SE; Li, JZ; Bello, CL; Theuer, CP; George, DJ; Rini, BI
MLA Citation
Motzer, RJ, Michaelson, MD, Redman, BG, Hudes, GR, Wilding, G, Figlin, RA, Ginsberg, MS, Kim, ST, Baum, CM, DePrimo, SE, Li, JZ, Bello, CL, Theuer, CP, George, DJ, and Rini, BI. "Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma." Journal of Clinical Oncology 24.1 (2006): 16-24.
PMID
16330672
Source
scival
Published In
Journal of Clinical Oncology
Volume
24
Issue
1
Publish Date
2006
Start Page
16
End Page
24
DOI
10.1200/JCO.2005.02.2574

Phase II study of sunitinib malate (SU11248) in bevacizumab-refractory metastatic renal cell carcinoma (MRCC)

Authors
Rini, BI; George, DJ; Michaelson, MD; Rosenberg, JE; Bukowski, RM; Sosman, JA; Stadler, WM; Margolin, K; Hutson, TE; Baum, CM
MLA Citation
Rini, BI, George, DJ, Michaelson, MD, Rosenberg, JE, Bukowski, RM, Sosman, JA, Stadler, WM, Margolin, K, Hutson, TE, and Baum, CM. "Phase II study of sunitinib malate (SU11248) in bevacizumab-refractory metastatic renal cell carcinoma (MRCC)." 2006.
Source
wos-lite
Published In
Annals of Oncology
Volume
17
Publish Date
2006
Start Page
144
End Page
144

Targeted therapy in renal cell carcinoma.

Hypoxia-regulated genes such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are both important for tumour progression in renal cell carcinoma (RCC). Drugs that block these and other pathways have been examined in Phase I and II clinical trials in patients with advanced or metastatic RCC. Results from a randomised study of an anti-VEGF antibody demonstrate a delay in the time to disease progression, suggesting a biological effect and change in the natural history of the disease. Results using small-molecule inhibitors of VEGF, FLT3, KIT and platelet-derived growth factor receptor tyrosine kinases, such as sunitinib, show a 40% objective response rate. Results from a Phase III clinical trial with sorafenib, an inhibitor of multiple tyrosine kinases, show only a 2% response rate; however, a statistically significant improvement in progression-free survival was observed. Objective responses have also been noted using an inhibitor of the mammalian target of rapamycin. Conversely, EGF receptor inhibitors, proteosome inhibitors, microtubule stabilising agents, cell-cycle inhibitors and imatinib were also examined with few objective responses. Ultimately, identifying the predictive factors for responsiveness to these targeted therapies may improve the clinical benefit; for example, RCC with biallelic mutations in the von Hippel-Lindau gene would have higher levels of hypoxia-inducible factor-1alpha, and may be more responsive to inhibitors of angiogenesis. Phase III studies comparing the combinations of targeted therapy could lead to a new standard of care for RCC.

Authors
Favaro, JP; George, DJ
MLA Citation
Favaro, JP, and George, DJ. "Targeted therapy in renal cell carcinoma." Expert Opin Investig Drugs 14.10 (October 2005): 1251-1258. (Review)
PMID
16185167
Source
pubmed
Published In
Expert Opinion on Investigational Drugs
Volume
14
Issue
10
Publish Date
2005
Start Page
1251
End Page
1258
DOI
10.1517/13543784.14.10.1251

Prognostic significance of plasma chromogranin a levels in patients with hormone-refractory prostate cancer treated in Cancer and Leukemia Group B 9480 study.

OBJECTIVES: To test the hypothesis that chromogranin A (CgA) levels are prognostic in patients with metastatic hormone-refractory prostate cancer (HRPC). The extent of neuroendocrine differentiation in prostate cancer correlates with aggressive disease and with progression to HRPC. Plasma CgA levels in patients with prostate cancer may reflect the extent of the tumor neuroendocrine phenotype. METHODS: Pretreatment plasma was collected from 390 patients with metastatic HRPC enrolled in the Cancer and Leukemia Group B (CALGB) 9480 trial, a study of three different doses of suramin. Plasma CgA levels were determined in 321 samples in duplicate using a quantitative sandwich immunoassay. The proportional hazards model was used to assess the prognostic significance of CgA in predicting overall survival. RESULTS: The median plasma CgA level was 12 U/L (interquartile range 7.7 to 19.3). In univariate analysis, plasma CgA correlated inversely with survival times, with a survival time of 17 months for low CgA (less than 12 U/L, 95% CI 14 to 19) compared with 11 months for high CgA (95% CI 8 to 14, P = 0.014) and at all exploratory cutpoints, including CgA of 9.5 U/L or less versus greater than 9.5 U/L, with survival of 19 months compared with 12 months (P = 0.0015). In multivariate models (adjusting for performance status, prostate-specific antigen, and lactate dehydrogenase), the plasma CgA levels remained predictive of overall survival. CONCLUSIONS: These results support the hypothesis that serum CgA levels correlate with outcome in patients with HRPC, although the clinical significance needs to be established in confirmatory studies before incorporation of CgA measurements in clinical practice.

Authors
Taplin, M-E; George, DJ; Halabi, S; Sanford, B; Febbo, PG; Hennessy, KT; Mihos, CG; Vogelzang, NJ; Small, EJ; Kantoff, PW
MLA Citation
Taplin, M-E, George, DJ, Halabi, S, Sanford, B, Febbo, PG, Hennessy, KT, Mihos, CG, Vogelzang, NJ, Small, EJ, and Kantoff, PW. "Prognostic significance of plasma chromogranin a levels in patients with hormone-refractory prostate cancer treated in Cancer and Leukemia Group B 9480 study." Urology 66.2 (August 2005): 386-391.
PMID
16098367
Source
pubmed
Published In
Urology
Volume
66
Issue
2
Publish Date
2005
Start Page
386
End Page
391
DOI
10.1016/j.urology.2005.03.040

Neoadjuvant docetaxel before radical prostatectomy in patients with high-risk localized prostate cancer.

PURPOSE: To determine the clinical, pathologic, and molecular effects of neoadjuvant docetaxel chemotherapy in high-risk localized prostate cancer. EXPERIMENTAL DESIGN: Patients with biopsy Gleason scores of 8 to 10, serum prostate-specific antigen levels >20 ng/mL, and/or clinical stage T3 disease received weekly docetaxel (36 mg/m2) for 6 months, followed by radical prostatectomy, and were monitored with weekly visits, serum prostate-specific antigen measurements, and endorectal magnetic resonance imaging (MRI). Frozen tumor specimens were collected for microarray analysis. RESULTS: The 19 patients enrolled received 82% of the planned chemotherapy. Toxicity was mild to moderate; fatigue and taste disturbance were common. Prostate-specific antigen declines of >50% were seen in 11 of 19 patients (58%; 95% confidence interval, 33-80%) and endorectal MRI showed maximum tumor volume reduction of at least 25% in 13 of 19 patients (68%; 95% confidence interval, 47-85%) and at least 50% in 4 patients (21%; 95% confidence interval, 6-46%). Sixteen patients completed chemotherapy and had radical prostatectomy; none achieved pathologic complete response. Microarray analysis identified coordinate up-regulation of genes involved in androgen metabolism associated with docetaxel therapy. Specifically, RNA expression for genes that decrease cellular levels of bioactive androgens was coordinately increased in response to chemotherapy. CONCLUSIONS: Neoadjuvant docetaxel administered for 6 months before radical prostatectomy is feasible, well tolerated, and often results in prostate-specific antigen declines of >50% and decreased tumor volume on endorectal MRI. No pathologic complete responses were observed. Altered androgen metabolism may partially account for the noted declines in prostate-specific antigen and be a mechanism for chemotherapy resistance.

Authors
Febbo, PG; Richie, JP; George, DJ; Loda, M; Manola, J; Shankar, S; Barnes, AS; Tempany, C; Catalona, W; Kantoff, PW; Oh, WK
MLA Citation
Febbo, PG, Richie, JP, George, DJ, Loda, M, Manola, J, Shankar, S, Barnes, AS, Tempany, C, Catalona, W, Kantoff, PW, and Oh, WK. "Neoadjuvant docetaxel before radical prostatectomy in patients with high-risk localized prostate cancer." Clin Cancer Res 11.14 (July 15, 2005): 5233-5240.
PMID
16033841
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
14
Publish Date
2005
Start Page
5233
End Page
5240
DOI
10.1158/1078-0432.CCR-05-0299

Update in the management of patients with hormone-refractory prostate cancer.

PURPOSE OF REVIEW: 2004 was a critical year for advances in prostate cancer treatment. The results from two pivotal multicenter phase III randomized studies are the first to demonstrate a survival benefit associated with chemotherapeutic treatment interventions in patients with hormone-refractory prostate cancer. This review will focus on an interpretation of the data from these two studies, the emerging role for chemotherapy in 2005 and beyond, and ongoing areas of clinical research. RECENT FINDINGS: Phase I and II studies have demonstrated biochemical and objective responses achieved with docetaxel-based chemotherapy in men with hormone-refractory prostate cancer. Two pivotal phase III clinical trials, TAX 327 and SWOG 9916 have demonstrated a survival advantage of docetaxel-based chemotherapy over mitoxantrone. Novel targeted therapies under investigation include calcitriol, growth factor-targeted agents, epothilones and others. SUMMARY: We now have a new standard of care for men with metastatic hormone-refractory prostate cancer. Further investigation of docetaxel-based regimens in earlier clinical states of disease is warranted and may demonstrate greater clinical benefit. Additional chemotherapy agents are being studied, and may also add to the future armamentarium available for prostate cancer. The enrolment of patients into these studies is critical to the ongoing evolution of prostate cancer management.

Authors
Moore, CN; George, DJ
MLA Citation
Moore, CN, and George, DJ. "Update in the management of patients with hormone-refractory prostate cancer." Curr Opin Urol 15.3 (May 2005): 157-162. (Review)
PMID
15815191
Source
pubmed
Published In
Current Opinion in Urology
Volume
15
Issue
3
Publish Date
2005
Start Page
157
End Page
162

The prognostic significance of plasma interleukin-6 levels in patients with metastatic hormone-refractory prostate cancer: results from cancer and leukemia group B 9480.

UNLABELLED: Interleukin-6 signaling can activate androgen receptor in a ligand-independent manner and may play an important functional role in hormone-refractory prostate cancer (HRCaP) progression and patient survival. Plasma and serum IL-6 levels have been associated with prostate cancer progression in several small studies. In order to evaluate its prognostic significance in metastatic HRCaP patients, we measured IL-6 in plasma collected at baseline from patients in a large cooperative group study [Cancer and Leukemia Group B 9480 (CALGB 9480)]. METHODS: 191 patients entered on CALGB 9480 had pretreatment plasma collected and centrally stored. Using a human IL-6 immunoassay, quantitative levels of IL-6 were measured in duplicate on 300 muL samples. The proportional hazard model was used to assess the prognostic significance of IL-6 in predicting overall survival. RESULTS: Median IL-6 level for the cohort of 191 patients was 4.80 pg/mL. Survival time among patients with IL-6 levels less than or equal to the median was 19 months (95% CI, 17-22) compared with 11 (95% CI, 8-14) months for patients above the median (P = 0.0004). In multivariate analysis, adjusting on performance status, lactate dehydrogenase, and prostate-specific antigen level, the hazard ratio was 1.38 (95% CI, 1.01-1.89; P = 0.043) using the median level as a cut point. Furthermore, a cut point of 13.31 pg/mL revealed robust prognostic significance with a hazard ratio of 2.02 (95% CI, 1.36-2.98; P = 0.0005). CONCLUSIONS: Plasma IL-6 level has prognostic significance in patients with metastatic HRCaP from CALGB 9480. These findings support using IL-6 levels in prognostic models and support the rationale for IL-6-targeted therapy in patients with HRCaP.

Authors
George, DJ; Halabi, S; Shepard, TF; Sanford, B; Vogelzang, NJ; Small, EJ; Kantoff, PW
MLA Citation
George, DJ, Halabi, S, Shepard, TF, Sanford, B, Vogelzang, NJ, Small, EJ, and Kantoff, PW. "The prognostic significance of plasma interleukin-6 levels in patients with metastatic hormone-refractory prostate cancer: results from cancer and leukemia group B 9480." Clin Cancer Res 11.5 (March 1, 2005): 1815-1820.
PMID
15756004
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
5
Publish Date
2005
Start Page
1815
End Page
1820
DOI
10.1158/1078-0432.CCR-04-1560

Prostate-specific antigen endpoints in hormone-refractory prostate cancer

Authors
Sartor, O; George, D
MLA Citation
Sartor, O, and George, D. "Prostate-specific antigen endpoints in hormone-refractory prostate cancer." Clinical Prostate Cancer 4.1 (2005): 5-6.
PMID
15992455
Source
scival
Published In
Clinical Prostate Cancer
Volume
4
Issue
1
Publish Date
2005
Start Page
5
End Page
6

Response to docetaxel/carboplatin in patients with hormone-refractory prostate cancer not responding to taxane-based chemotherapy

Few treatment options are available for patients with metastatic hormone-refractory prostate cancer (HRPC) that is not responsive to or continues to progress after taxane-based chemotherapy. Although single-agent carboplatin has modest activity in HRPC, carboplatin chemotherapy could induce a synergistic effect when combined with taxanes in patients with disease resistant to taxane-based chemotherapy. We report a case series of 4 consecutive patients treated with docetaxel (60-70 mg/m2) plus carboplatin (area under the curve of 4/5) following progression after taxane-based chemotherapy. Prostate-specific antigen levels decreased by > 50% in all 4 patients and were associated with improvement in symptoms in 3 of 4 patients. Treatment was well tolerated, with fatigue as the most common reported side effect. Patients received 4-11 cycles of treatment and, after initiation of docetaxel/carboplatin chemotherapy, survival ranged from 4.5 months to 12 months. In this small series, there is a suggestion of a greater than expected response with carboplatin and docetaxel for patients who exhibit disease progression despite taxane-based chemotherapy or do not respond to therapy. A clinical trial to evaluate this effect has been initiated.

Authors
Oh, WK; George, DJ; Tay, M-H
MLA Citation
Oh, WK, George, DJ, and Tay, M-H. "Response to docetaxel/carboplatin in patients with hormone-refractory prostate cancer not responding to taxane-based chemotherapy." Clinical Prostate Cancer 4.1 (2005): 61-64.
PMID
15992464
Source
scival
Published In
Clinical Prostate Cancer
Volume
4
Issue
1
Publish Date
2005
Start Page
61
End Page
64

Prediagnostic plasma vascular endothelial growth factor levels and risk of prostate cancer

Vascular endothelial growth factor (VEGF) plays important roles in endothelial cell proliferation, vascular permeability, and angiogenesis that may be critical to prostatic carcinogenesis and progression. Plasma VEGF levels were significantly greater in patients with metastatic prostate cancer compared with those with localized disease or healthy controls, and plasma VEGF level at prostate cancer diagnosis was an independent prognostic marker for survival in patients with hormone refractory prostate cancer. We therefore examined the association between prediagnostic plasma VEGF levels and risk of prostate cancer and disease phenotype. Using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, we conducted a nested case-control study among 504 men diagnosed with prostate cancer during 13 years of follow-up and 520 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multivariate logistic regression. Prediagnostic plasma VEGF levels were similar among cases and controls. Plasma VEGF concentration was not associated with subsequent risk of prostate cancer (third versus first tertile OR, 1.09; 95% CI, 0.80-1.49; Ptrend = 0.65). Furthermore, no association was observed among men with advanced (stage C or D) prostate cancer or among those who died of prostate cancer. Our results indicate that prediagnostic circulating VEGF levels are not associated with prostate cancer development and have limited value in predicting future risk of prostate cancer. Copyright © 2005 American Association for Cancer Research.

Authors
Li, H; Kantoff, PW; Ma, J; Stampfer, MJ; George, DJ
MLA Citation
Li, H, Kantoff, PW, Ma, J, Stampfer, MJ, and George, DJ. "Prediagnostic plasma vascular endothelial growth factor levels and risk of prostate cancer." Cancer Epidemiology Biomarkers and Prevention 14.6 (2005): 1557-1561.
PMID
15941972
Source
scival
Published In
Cancer Epidemiology Biomarkers and Prevention
Volume
14
Issue
6
Publish Date
2005
Start Page
1557
End Page
1561
DOI
10.1158/1055-9965.EPI-04-0456

Decreases in free cholesterol and fatty acid unsaturation in renal cell carcinoma demonstrated by breath-hold magnetic resonance spectroscopy

Increased utilization of cross-sectional imaging has resulted in increased detection of incidental renal tumors. The noninvasive characterization of renal tissue has important implications for the diagnosis of renal malignancies and treatment monitoring. Recently, multiple breath-hold averaged proton magnetic resonance spectroscopy (1H-MRS) performed at high field has enabled the use of this noninvasive metabolic profiling technique for the investigation of the abdomen. Multiple breath-hold averaged 1H-MRS at high field (3T) was obtained in the kidneys of 10 healthy volunteers and in renal cell carcinoma tumors of 14 patients. The spectra of normal kidneys showed four main groups of resonances: 1) at 5.4-5.6 ppm, attributed to C6 of cholesterol and the unsaturated parts of the olefinic region of fatty acids; 2) at 4.7 ppm, attributed to the residual water signal; 3) at 3.2 ppm, attributed to trimethylamine moiety of choline metabolites; and 4) at 1.3 and 0.9 ppm, attributed to the methylenes and terminal methyls of lipids. The ratio of the signal at 5.4 ppm to that of 1.3 ppm was 19-fold lower in renal cell carcinomas than in healthy kidneys, tied P = 0.0003 Mann-Whitney U-test, suggesting a decrease in both free cholesterol and the degree of unsaturation of fatty acids in the malignant tissue. This metabolic shift is in agreement with previous ex vivo studies of human renal cell carcinoma. The ability to detect renal metabolic shifts noninvasively may improve the specificity of preoperative renal tissue characterization and may provide a new modality for treatment monitoring. Copyright © 2005 the American Physiological Society.

Authors
Katz-Brull, R; Rofsky, NM; Morrin, MM; Pedrosa, I; George, DJ; Michaelson, MD; Marquis, RP; Maril, M; Noguera, C; Lenkinski, RE
MLA Citation
Katz-Brull, R, Rofsky, NM, Morrin, MM, Pedrosa, I, George, DJ, Michaelson, MD, Marquis, RP, Maril, M, Noguera, C, and Lenkinski, RE. "Decreases in free cholesterol and fatty acid unsaturation in renal cell carcinoma demonstrated by breath-hold magnetic resonance spectroscopy." American Journal of Physiology - Renal Physiology 288.4 57-4 (2005): F637-F641.
PMID
15572523
Source
scival
Published In
American Journal of Physiology - Renal Physiology
Volume
288
Issue
4 57-4
Publish Date
2005
Start Page
F637
End Page
F641
DOI
10.1152/ajprenal.00140.2004

Docetaxel/capecitabine well tolerated but less effective than docetaxel/estramustine

Authors
George, DJ; Moul, JW
MLA Citation
George, DJ, and Moul, JW. "Docetaxel/capecitabine well tolerated but less effective than docetaxel/estramustine." Oncology Report SPRING (2005): 54-55.
Source
scival
Published In
Oncology Report
Issue
SPRING
Publish Date
2005
Start Page
54
End Page
55

Combined GM-CSF/docetaxel beneficial against HR prostate cancer

Authors
George, DJ; Moul, JW
MLA Citation
George, DJ, and Moul, JW. "Combined GM-CSF/docetaxel beneficial against HR prostate cancer." Oncology Report SPRING (2005): 51-52.
Source
scival
Published In
Oncology Report
Issue
SPRING
Publish Date
2005
Start Page
51
End Page
52

CA9 shown to predict response to IL-2 therapy for renal cell carcinoma

Authors
George, DJ; Moul, JW
MLA Citation
George, DJ, and Moul, JW. "CA9 shown to predict response to IL-2 therapy for renal cell carcinoma." Oncology Report SPRING (2005): 59-60.
Source
scival
Published In
Oncology Report
Issue
SPRING
Publish Date
2005
Start Page
59
End Page
60

Arterial spin labeling blood flow magnetic resonance imaging for the characterization of metastatic renal cell carcinoma

Rationale and Objective. This study sought to assess the feasibility of arterial spin labeling (ASL) blood flow (BF) magnetic resonance imaging (MRI) for the study of metastatic renal cell carcinoma (RCC) in the body, where the respiratory, cardiac, and peristaltic motions present challenges when applying ASL. Materials and Methods. ASL was performed using a background-suppressed single-section flow-alternating inversion recovery (FAIR) preparation and a single-shot fast spin-echo imaging sequence on a 3.0-T whole body imager. Tumor BF was evaluated for 26 patients with RCC metastatic to the liver, bone, lung, or lymph nodes before VEGF receptor inhibitor therapy. Two cases with tumor size change after treatment were also scanned 1 month after therapy. For validation, kidney cortex BF in five normal volunteers was measured with the same technique and compared with literature values. Results. ASL was successfully performed in all normal volunteers and in 20 of 26 patients. The six failures resulted from a systematic error, which can be avoided in future studies. For normal volunteers, measured kidney cortex BF was 275 ± 14 mL/min/100 g, a value consistent with the literature. ASL determined tumor BF averaged across tumor volume and subjects was 194 mL/min/100 g (intersubject SD = 100), resulting in high perfusion signal and conspicuity of lesions. Bright signal was also seen in large vessels and occasionally in bowel. In the two cases studied 1 month after therapy, ASL perfusion changes were consistent with tumor size changes. Conclusion. With background suppression, ASL MRI is a feasible method for quantifying BF in patients with renal cell carcinoma. This technique may be useful for evaluating tumor response to antiangiogenic agents. © AUR, 2005.

Authors
Bazelaire, CD; Rofsky, NM; Duhamel, G; Michaelson, MD; George, D; Alsop, DC
MLA Citation
Bazelaire, CD, Rofsky, NM, Duhamel, G, Michaelson, MD, George, D, and Alsop, DC. "Arterial spin labeling blood flow magnetic resonance imaging for the characterization of metastatic renal cell carcinoma." Academic Radiology 12.3 (2005): 347-357.
PMID
15766695
Source
scival
Published In
Academic Radiology
Volume
12
Issue
3
Publish Date
2005
Start Page
347
End Page
357
DOI
10.1016/j.acra.2004.12.012

A phase I study of estramustine, weekly docetaxel, and carboplatin chemotherapy in patients with hormone-refractory prostate cancer

Purpose: To define the maximal tolerated dose, safety, and efficacy of docetaxel, carboplatin, and estramustine in patients with hormone-refractory prostate cancer (HRPC). Methods: Patients with HRPC received docetaxel for 3 weeks, followed by a rest week. Bocetaxel (20, 25, 30, 36, or 43 mg/m 2) was given on days 2, 9, and 16 of a 28-day cycle. Patients also received estramustine (140 mg p.o. three times daily on days 1-5, 8-12, and 15-19) and carboplatin [area under the curve, AUC (5) or (6) on day 2]. Results: Thirty patients were treated. Five patients received carboplatin [AUC (6)] but experienced delayed thrombocytopenia. After a protocol amendment, 25 subsequent patients received carboplatin [AUC (5)]. Median age was 64 years. Median prostate-specific antigen (PSA) was 117 ng/mL. Fifty-three percent received prior ketoconazole and 10% had mitoxantrone. No dose-limiting toxkities were noted. Although maximal tolerated dose was not reached, docetaxel dose escalation was stopped at 43 mg/m2. Significant myelosuppression was not seen until the highest dose level, when seven and four patients experienced grade 3 and 4 toxicities, respectively. Among all patients, PSA declines of ≥50% occurred in 63%. At the recommended phase II dose, PSA declines of ≥50% occurred in 75% (95% confidence interval, 43-95). Four of 14 (29%) patients with measurable disease had partial responses. Median survival was 14.6 months. Conclusions: Estramustine, docetaxel, and carboplatin are well tolerated and active in HRPC. Myelosuppression is the primary toxicity. The recommended phase II dose of decetaxel is 43 mg/m2 combined with estramustine and carboplatin. PSA declines were seen at every dose level.

Authors
Oh, WK; Hagmann, E; Manola, J; George, DJ; Gilligan, TD; Jacobson, JO; Smith, MR; Kaufman, DS; Kantoff, PW
MLA Citation
Oh, WK, Hagmann, E, Manola, J, George, DJ, Gilligan, TD, Jacobson, JO, Smith, MR, Kaufman, DS, and Kantoff, PW. "A phase I study of estramustine, weekly docetaxel, and carboplatin chemotherapy in patients with hormone-refractory prostate cancer." Clinical Cancer Research 11.1 (2005): 284-289.
PMID
15671557
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
1
Publish Date
2005
Start Page
284
End Page
289

Tyrosine kinase inhibitors in renal cell carcinoma.

Current standard treatments for patients with metastatic (stage IV) renal cell carcinoma involve both surgical removal of tumors and treatment with biological agents such as interleukin 2 and/or IFN-alpha. Unfortunately, such approaches are inadequate for most patients with stage IV disease; the result is a median time to progression of 2 to 4 months and an overall survival of 6 to 17 months. Standard chemotherapy has been uniformly disappointing in this disorder. It is clear that new therapies are needed to approach these patients. Recently, a greater understanding of cancer genetics has led to the successful development of novel therapeutics directed against targets linked to specific types of cancer. During the past decade, researchers have identified the von Hippel-Lindau (VHL) gene as an important tumor suppressor in clear cell carcinoma of the kidney. Elucidation of the VHL gene product (pVHL) and its regulation of hypoxia-inducible factor signaling have created a potential genetic basis for growth factor-targeted strategies in this disease. This review will focus on the potential growth factor targets in clear cell carcinoma, their relation to VHL and hypoxia-inducible factor, and the clinical challenges that face their development.

Authors
Potti, A; George, DJ
MLA Citation
Potti, A, and George, DJ. "Tyrosine kinase inhibitors in renal cell carcinoma." Clin Cancer Res 10.18 Pt 2 (September 15, 2004): 6371S-6376S. (Review)
PMID
15448033
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
18 Pt 2
Publish Date
2004
Start Page
6371S
End Page
6376S
DOI
10.1158/1078-0432.CCR-050014

Finasteride and bicalutamide as primary hormonal therapy in patients with advanced adenocarcinoma of the prostate.

BACKGROUND: Medical or surgical castration is effective in advanced prostate cancer but with profound side-effects, particularly on sexual function. Effective, less toxic therapies are needed. This study examined whether the addition of finasteride to high-dose bicalutamide enhanced disease control, as measured by additional decreases in serum prostate-specific antigen (PSA). PATIENTS AND METHODS: Forty-one patients with advanced prostate cancer received bicalutamide (150 mg/day). Finasteride (5 mg/day) was added at first PSA nadir. Serum PSA was measured every 2 weeks until disease progression. Questionnaires were administered to assess sexual function. RESULTS: Median follow-up is 3.9 years. At the first PSA nadir, median decrease in PSA from baseline was 96.5%. Thirty of 41 patients (73%) achieved a second PSA nadir and median decrease of 98.5% from baseline. Median time to each nadir was 3.7 and 5.8 weeks, respectively. Median time to treatment failure was 21.3 months. Toxicities were minor, including gynecomastia. Seventeen of 29 (59%) and 12 of 24 (50%) men had normal sex drive at baseline and at second PSA nadir, respectively. One-third of men had spontaneous erection at both time points. CONCLUSION: Finasteride provides additional intracellular androgen blockade when added to bicalutamide. Duration of control is comparable to castration, with preserved sexual function in some patients.

Authors
Tay, M-H; Kaufman, DS; Regan, MM; Leibowitz, SB; George, DJ; Febbo, PG; Manola, J; Smith, MR; Kaplan, ID; Kantoff, PW; Oh, WK
MLA Citation
Tay, M-H, Kaufman, DS, Regan, MM, Leibowitz, SB, George, DJ, Febbo, PG, Manola, J, Smith, MR, Kaplan, ID, Kantoff, PW, and Oh, WK. "Finasteride and bicalutamide as primary hormonal therapy in patients with advanced adenocarcinoma of the prostate." Ann Oncol 15.6 (June 2004): 974-978.
PMID
15151957
Source
pubmed
Published In
Annals of Oncology
Volume
15
Issue
6
Publish Date
2004
Start Page
974
End Page
978

Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy

BACKGROUND. The objective of this study was to assess the biologic activity of rosiglitazone, a peroxisome proliferator-activated receptor γ agonist that has been approved to treat type 2 diabetes, in men with recurrent prostate carcinoma using change in prostate specific antigen (PSA) doubling time (PSADT) as the primary outcome variable. METHODS. Men with histologically confirmed prostate carcinoma, no recent hormone therapy, a rising serum PSA level after radical prostatectomy and/or radiation therapy, and no radiographic evidence of metastases were assigned randomly to receive either oral rosiglitazone (4 mg twice daily) or placebo. The treatment was continued until the men developed disease progression or adverse effects. A positive outcome was defined as a posttreatment PSADT > 150% the baseline PSADT and no new metastases. RESULTS. One hundred six men were enrolled. The median treatment duration was 315 days for men in the placebo group and 338 days for men in the rosiglitazone group (P = 0.28). Forty percent of men in the in the placebo group and 38% of men in the rosiglitazone group had a posttreatment PSADT > 150% of the baseline PSADT and no new metastases (P = 1.00). In exploratory analyses, the rate of a positive outcome remained higher than expected in the placebo group, even when a positive outcome was redefined using more stringent criteria. The time to disease progression was similar between the groups. CONCLUSIONS. Rosiglitazone did not increase PSADT or prolong the time to disease progression more than placebo in men with a rising PSA level after radical prostatectomy and/or radiation therapy. The unexpected discordance between baseline and posttreatment PSADT in the placebo group reinforced the importance of randomized controlled trials in this setting. © 2004 American Cancer Society.

Authors
Smith, MR; Manola, J; Kaufman, DS; George, D; Oh, WK; Mueller, E; Slovin, S; Spiegelman, B; Small, E; Kantoff, PW
MLA Citation
Smith, MR, Manola, J, Kaufman, DS, George, D, Oh, WK, Mueller, E, Slovin, S, Spiegelman, B, Small, E, and Kantoff, PW. "Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy." Cancer 101.7 (2004): 1569-1574.
PMID
15468186
Source
scival
Published In
Cancer
Volume
101
Issue
7
Publish Date
2004
Start Page
1569
End Page
1574
DOI
10.1002/cncr.20493

Skeletal complications in patients with bone metastases from renal cell carcinoma and therapeutic benefits of zoledronic acid

Bone metastases in patients with renal cell carcinoma are associated with a high risk of skeletal complications. Therefore, a subset analysis of a larger clinical trial was performed to determine the efficacy of zoledronic acid in renal cell carcinoma patients. Patients with bone metastases from solid tumors other than breast or prostate cancer (n = 773) were randomized to receive zoledronic acid or placebo via 15-minute infusion every 3 weeks for 9 months. Patients were monitored for skeletal-related events, which were defined as pathological fracture, spinal cord compression, radiotherapy, or surgery to bone. Among the subset of 74 patients with renal cell carcinoma, 46 patients were treated with 4 mg of zoledronic acid or placebo. Significantly fewer patients treated with 4 mg zoledronic acid had a skeletal-related event (37% versus 74% for placebo, P = 0.015), and zoledronic acid significantly prolonged the time to first skeletal-related event (median not reached at 9 months versus 72 days for placebo; P = 0.006). Zoledronic acid significantly reduced the annual incidence of skeletal-related events by ∼21% (mean 2.68 versus 3.38 events per year for placebo, P = 0.014) and significantly reduced the risk of developing a skeletal-related event by 61% compared with placebo (risk ratio = 0.394, P = 0.008) by multiple event analysis. Median time to progression of bone lesions was also significantly extended with zoledronic acid treatment (P = 0.014). Zoledronic acid is the first bisphosphonate to significantly reduce skeletal morbidity and significantly prolong time to bone lesion progression in patients with bone metastases from renal cell carcinoma.

Authors
Lipton, A; Colombo-Berra, A; Bukowski, RM; Rosen, L; Zheng, M; Urbanowitz, G; Figlin, R; Yang, J; Gordon, M; Stadler, W; Eisen, T; George, D
MLA Citation
Lipton, A, Colombo-Berra, A, Bukowski, RM, Rosen, L, Zheng, M, Urbanowitz, G, Figlin, R, Yang, J, Gordon, M, Stadler, W, Eisen, T, and George, D. "Skeletal complications in patients with bone metastases from renal cell carcinoma and therapeutic benefits of zoledronic acid." Clinical Cancer Research 10.18 II (2004): 6397s-6403s.
PMID
15448038
Source
scival
Published In
Clinical Cancer Research
Volume
10
Issue
18 II
Publish Date
2004
Start Page
6397s
End Page
6403s
DOI
10.1158/1078-0432.CCR-040030

Debulking nephrectomy in metastatic renal cancer

Up to one third of patients with renal cell carcinoma will present with metastatic disease, and 20 to 40% of those with clinically localized disease will eventually be found to have metastatic involvement. Prognosis continues to be guarded for this population, with a 2-year survival of only 10 to 30%. Although advances are being made in the medical management of renal cell carcinoma, the role of surgery in the treatment algorithm is also being additionally refined. Palliative surgery either via nephrectomy or metastasectomy has a role in certain well-selected patients. There are also data to support total metastasectomy at the time of either nephrectomy or recurrence in a small subset of patients with minimal, resectable metastases. More controversial is the idea of cytoreductive nephrectomy as an adjunct to immunotherapy. Recent phase III trials indicate that nephrectomy may play an important role in management of metastatic renal cell carcinoma in conjunction with cytokine-based immunotherapy. Nephrectomy is also an essential component of tumor-based vaccine and adoptive immunotherapy protocols and may play a role in other novel therapies.

Authors
Flanigan, RC; Novick, A; Motzer, R; George, D; Linehan, WM; Atkins, M; Bukowski, R; Gordon, M
MLA Citation
Flanigan, RC, Novick, A, Motzer, R, George, D, Linehan, WM, Atkins, M, Bukowski, R, and Gordon, M. "Debulking nephrectomy in metastatic renal cancer." Clinical Cancer Research 10.18 II (2004): 6335s-6341s.
PMID
15448027
Source
scival
Published In
Clinical Cancer Research
Volume
10
Issue
18 II
Publish Date
2004
Start Page
6335s
End Page
6341s
DOI
10.1158/1078-0432.CCR-sup-040026

The von Hippel-Lindau tumor suppressor gene and kidney cancer

The von Hippel-Lindau tumor suppressor gene (VHL), which resides on chromosome 3p25, is mutated or silenced in >50% of sporadic clear cell renal cell carcinomas. Germline VHL mutations give rise to VHL disease, which is characterized by an increased risk of blood vessel tumors (hemangioblastomas) and renal cell carcinomas. In this setting, VHL inactivation gives rise to premalignant renal cysts. Additional genetic alterations are presumably required for conversion of these cysts to renal cell carcinomas. Restoration of VHL function in VHL-/- renal cell carcinomas is sufficient to inhibit tumorigenesis in vivo. On the basis of these and other data, VHL appears to be a critical gate-keeper with respect to the development of renal cell carcinoma. The VHL gene product, pVHL, is the substrate recognition module of an E3 ubiquitin ligase that targets the hypoxia-inducible factor (HIF) for destruction in the presence of oxygen. Hypoxic cells, or cells lacking pVHL, accumulate high levels of HIF, which activates the transcription of a variety of genes, including vascular endothelial growth factor, platelet-derived growth factor B, and transforming growth factor α. We have demonstrated that inhibition of HIF is necessary and sufficient for tumor suppression by pVHL in renal cell carcinoma nude mouse xenograft assays. This provides a rationale for treating VHL-/- renal cell carcinoma with inhibitors of HIF or its downstream targets. Genotype-phenotype correlations in VHL disease suggest, however, that pVHL has targets in addition to HIF. Elucidating these targets should provide a more complete picture of how pVHL suppresses tumor growth.

Authors
Jr, WGK; Yang, J; Linehan, WM; Iliopoulos, O; Atkins, M; George, D
MLA Citation
Jr, WGK, Yang, J, Linehan, WM, Iliopoulos, O, Atkins, M, and George, D. "The von Hippel-Lindau tumor suppressor gene and kidney cancer." Clinical Cancer Research 10.18 II (2004): 6290s-6295s.
PMID
15448019
Source
scival
Published In
Clinical Cancer Research
Volume
10
Issue
18 II
Publish Date
2004
Start Page
6290s
End Page
6295s
DOI
10.1158/1078-0432.CCR-sup-040025

Novel antiangiogenic therapies for renal cell cancer

Renal cell cancer remains a disease for which highly effective therapy for the majority of patients with metastatic disease is lacking. The biology of clear cell carcinomas and their association with mutations of the von Hippel-Lindau gene and its resultant increased expression of vascular endothelial growth factor (VEGF) make angiogenesis a potentially pathophysiologic mechanism for tumor development. As a result, the use of antiangiogenic therapy is an intriguing concept for the treatment of renal cell cancer. Various agents, aside from the inhibitors of VEGF, have been studied, including thalidomide, low-dose interferon, and novel antiangiogenic agents such as the thrombospondin-1 mimetics. Use of these agents has been associated with some degree of objective response or prolonged stabilization of disease, and their true value needs to be assessed in ongoing prospective studies. Combinations of antiangiogenic agents either with other similarly acting drugs or as a component of a "cocktail" with other noncytotoxic therapies should be explored in this patient population.

Authors
Gordon, MS; Atkins, M; Lipton, A; Stadler, W; Flanigan, R; George, D; Yang, J; Figlin, R; Kaelin, W
MLA Citation
Gordon, MS, Atkins, M, Lipton, A, Stadler, W, Flanigan, R, George, D, Yang, J, Figlin, R, and Kaelin, W. "Novel antiangiogenic therapies for renal cell cancer." Clinical Cancer Research 10.18 II (2004): 6377s-6381s.
PMID
15448034
Source
scival
Published In
Clinical Cancer Research
Volume
10
Issue
18 II
Publish Date
2004
Start Page
6377s
End Page
6381s
DOI
10.1158/1078-0432.CCR-050007

Innovations and challenges in renal cancer: Consensus statement from the first international conference

Renal cell carcinoma is a serious medical problem in the United States, with nearly 35,000 new cases and >12,000 cancer-related deaths reported in 2003 (21). A number exciting advances in understanding the genetics, biology, and prognostic and predictive factors for renal cell carcinoma, as well as better local therapies, are improving the outlook for patients with advanced renal cell carcinoma. Although combinations of various treatment approaches might produce synergistic antitumor activity, we lack the mechanisms to rapidly and efficiently identify potentially effective combinations. Good surrogates of biological effect are needed to efficiently study strategies for combining various approaches. Nonetheless, for the first time in many years, investigators are primed to make significant advances in the treatment of renal cell carcinoma.

Authors
Atkins, MB; Avigan, DE; Bukowski, RM; Childs, RW; Dutcher, JP; Eisen, TG; Figlin, RA; Finke, JH; Flanigan, RC; George, DJ; Goldberg, SN; Gordon, MS; Iliopoulos, O; Jr, WGK; Linehan, WM; Lipton, A; Motzer, RJ; Novick, AC; Stadler, WM; Teh, BT; Yang, JC; King, L
MLA Citation
Atkins, MB, Avigan, DE, Bukowski, RM, Childs, RW, Dutcher, JP, Eisen, TG, Figlin, RA, Finke, JH, Flanigan, RC, George, DJ, Goldberg, SN, Gordon, MS, Iliopoulos, O, Jr, WGK, Linehan, WM, Lipton, A, Motzer, RJ, Novick, AC, Stadler, WM, Teh, BT, Yang, JC, and King, L. "Innovations and challenges in renal cancer: Consensus statement from the first international conference." Clinical Cancer Research 10.18 II (2004): 6277s-6281s.
PMID
15448017
Source
scival
Published In
Clinical Cancer Research
Volume
10
Issue
18 II
Publish Date
2004
Start Page
6277s
End Page
6281s
DOI
10.1158/1078-0432.CCR-040720

Therapeutic options for variant renal cancer: A true orphan disease

Variant or nonclear cell renal cell cancer is a rare disease constituting only ∼5% to 8% of the metastatic renal cell cancer population. Pathological criteria for the three main variant subtypes, papillary, chromophobe, and collecting duct, have been specified. Nonetheless, there may be subtypes within these variants, many poorly differentiated tumors cannot be reliably classified, and expertise in recognizing specific subtypes is not widespread. Expression analysis and other molecular techniques are beginning to clarify and standardize the pathological classification scheme. Because these classifications are relatively new and the number of patients with any one subtype is limited, little is known about appropriate therapies for patients with metastatic disease. Retrospective series strongly suggest that immunotherapy is not effective in any nonclear cell subtype. Case reports suggest that cytotoxic chemotherapy used for transitional cell cancers may be helpful in patients with collecting duct cancers. A central registry of patients with variant renal cell cancer should be created in which response to various therapies is recorded. Such a registry could provide support for a more formal multi-institutional study investigating a specific drug or regimen.

Authors
Stadler, WM; Atkins, MB; George, DJ; Jr, WGK; Teh, BT; Figlin, RA
MLA Citation
Stadler, WM, Atkins, MB, George, DJ, Jr, WGK, Teh, BT, and Figlin, RA. "Therapeutic options for variant renal cancer: A true orphan disease." Clinical Cancer Research 10.18 II (2004): 6393s-6396s.
PMID
15448037
Source
scival
Published In
Clinical Cancer Research
Volume
10
Issue
18 II
Publish Date
2004
Start Page
6393s
End Page
6396s
DOI
10.1158/1078-0432.CCR-040032

Mammalian target of rapamycin inhibition

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that has been increasingly recognized as key to the regulation of cell growth and proliferation. mTOR either directly or indirectly regulates translation initiation, actin organization, tRNA synthesis, ribosome biogenesis, and many other key cell maintenance functions, including protein degradation and transcription functions. Inhibition of mTOR blocks traverse of the cell cycle from the G1 to S phase. Preclinical data show inhibition of tumor growth in a number of cell lines and xenograft models. Clinical trials are ongoing. In metastatic renal cell cancer, both tumor regression and prolonged stabilization have been noted. mTOR inhibition appears to be a key pathway that may be useful in antitumor therapy. Renal cell cancer may be particularly susceptible through both the translation inhibition pathway and pathways that enhance HIF-1α gene expression, a factor believed to stimulate growth in metastatic renal cell cancer. Additional clinical trials that use agents that inhibit mTOR are ongoing.

Authors
Dutcher, JP; Motzer, RJ; Atkins, MB; Figlin, RA; Jr, WGK; Stadler, WM; Gordon, MS; George, DJ
MLA Citation
Dutcher, JP, Motzer, RJ, Atkins, MB, Figlin, RA, Jr, WGK, Stadler, WM, Gordon, MS, and George, DJ. "Mammalian target of rapamycin inhibition." Clinical Cancer Research 10.18 II (2004): 6382s-6387s.
PMID
15448035
Source
scival
Published In
Clinical Cancer Research
Volume
10
Issue
18 II
Publish Date
2004
Start Page
6382s
End Page
6387s
DOI
10.1158/1078-0432.CCR-050008

Bevacizumab for patients with metastatic renal cancer: An update

Most clear cell renal cell cancer (RCC) is caused by biallelic loss of the von Hippel-Lindau gene. One consequence of this loss is up-regulation of vascular endothelial growth factor via a pathway involving accumulation of hypoxia inducible factor. Vascular endothelial growth factor, a potent angiogenic factor, is secreted by many human cancers, but clear cell RCC as a group produces particularly high levels and has a highly vascular histologic appearance. In a randomized, placebo-controlled, double-blind trial, we tested the use of a neutralizing antibody to vascular endothelial growth factor, bevacizumab, in patients with metastatic RCC. At 3 or 10 mg/kg every 2 weeks, toxic effects were minimal, with hypertension and proteinuria the most substantial events. There were four partial responses (10% response rate) and a highly substantial prolongation of time to tumor progression in patients who received the higher dose of bevacizumab. With a crossover design and very sensitive criteria for disease progression, no difference in survival was shown. Four patients have been undergoing long-term bevacizumab therapy without tumor progression for 3 to 5 years. Three have substantial proteinuria but retain normal renal function. A small pilot trial combining bevacizumab and thalidomide showed no unexpected toxic effects. Future trials should consider combination therapies and strategies in which patients are treated through initial disease progression with antiangiogenic agents such as bevacizumab.

Authors
Yang, JC; Gordon, M; Atkins, M; Motzer, R; Lipton, A; Flanigan, R; Figlin, R; Kaelin, W; George, D; Linehan, WM
MLA Citation
Yang, JC, Gordon, M, Atkins, M, Motzer, R, Lipton, A, Flanigan, R, Figlin, R, Kaelin, W, George, D, and Linehan, WM. "Bevacizumab for patients with metastatic renal cancer: An update." Clinical Cancer Research 10.18 II (2004): 6367s-6370s.
PMID
15448032
Source
scival
Published In
Clinical Cancer Research
Volume
10
Issue
18 II
Publish Date
2004
Start Page
6367s
End Page
6370s
DOI
10.1158/1078-0432.CCR-050006

Plasma levels of heat shock protein 70 in patients with prostate cancer: A potential biomarker for prostate cancer

Heat shock protein 70 (Hsp70) is a stress-inducible protein that is also known for its inhibitory effects on apoptosis. Increased Hsp70 expression is reported in a variety of tumor tissues. Heat shock protein 70 is detectable in plasma and could potentially be used as a biomarker for diagnosis or disease stratification. The relationship between plasma levels of Hsp70 and prostate cancer status has not been well studied. Our study was designed to test this relationship. One hundred twenty-five patients with localized/untreated or hormone-refractory prostate cancer were identified. Forty-five healthy male blood donors between 50 and 73 years of age served as controls. EDTA plasma was subjected to quantitative sandwich immunoassays for both Hsp70 and prostate-specific antigen (PSA). Wilcoxon rank-sum tests were used to examine differences by category. Maximally selected χ2 statistics were used to identify cutoff points to best distinguish between categories. Plasma Hsp70 levels in the patients with localized untreated disease (n = 68; median, 0.8 ng/mL; interquartile range, 0.5-2.0) were significantly higher than those in the control group (n = 45; median, 0.5 ng/mL; interquartile range, 0.3-0.8; P = 0.0037). Although the primary cutoff point (1.15 ng/mL) significantly distinguished the localized untreated patients from the control group, plasma Hsp70 levels did not prove more effective than PSA as a predictor for diagnosis or stratification of patients with prostate cancer in the context of group comparisons. Nonetheless, several patients in the localized untreated group showed higher plasma levels of Hsp70 than the primary cutoff point even though their PSA levels were within normal range (< 4 ng/mL). Heat shock protein 70 is a marker of prostate cancer, although its clinical utility is uncertain. It is possible that when used in conjunction with PSA it might prove useful in identifying patients with early-stage prostate cancer who might otherwise be missed by PSA screening alone.

Authors
Abe, M; Manola, JB; Oh, WK; Parslow, DL; George, DJ; Austin, CL; Kantoff, PW
MLA Citation
Abe, M, Manola, JB, Oh, WK, Parslow, DL, George, DJ, Austin, CL, and Kantoff, PW. "Plasma levels of heat shock protein 70 in patients with prostate cancer: A potential biomarker for prostate cancer." Clinical Prostate Cancer 3.1 (2004): 49-53.
PMID
15279691
Source
scival
Published In
Clinical Prostate Cancer
Volume
3
Issue
1
Publish Date
2004
Start Page
49
End Page
53

Radical prostatectomy lowers plasma vascular endothelial growth factor levels in patients with prostate cancer

Objectives. To measure the change in plasma vascular endothelial growth factor (VEGF) levels after radical prostatectomy (RP) and to examine the association of pre-RP VEGF levels with known prognostic factors. Methods. Plasma was collected from patients in two separate cohorts. The first cohort included 86 patients who consented to give blood before and after RP. The second cohort consisted of 280 plasma samples, obtained from untreated patients with clinically localized prostate cancer. Plasma VEGF levels were measured by enzyme-linked immunosorbent assay. The change in plasma VEGF before and 6 to 8 weeks after RP was analyzed using a Wilcoxon signed rank test. The associations between the pre-RP VEGF levels and prognostic factors were assessed with the Spearman correlation coefficient and the Kruskal-Wallis test. Results. In a cohort of 86 patients with clinically localized prostate cancer, the median preoperative VEGF level was 49.8 pg/mL. The median level 1 month after surgery was significantly lower at 39.1 pg/mL (P = 0.006, 20% decrease). A repeat analysis 6 months or more after surgery demonstrated that the percentage of decrease in the plasma VEGF levels persisted. Plasma VEGF levels were also measured in a separate cohort of 280 patients with localized prostate cancer and demonstrated no statistically significant association with risk groups or known tumor-associated prognostic factors. Conclusions. These results suggest that the prostate gland itself may be a significant source of systemic VEGF and raises the possibility that elevated plasma VEGF levels could be a reflection of prostatic VEGF production. © 2004 Elsevier Inc.

Authors
George, DJ; Regan, MM; Oh, WK; Tay, M-H; Manola, J; DeCalo, N; Duggan, S; DeWolf, WC; Kantoff, PW; Bubley, GJ
MLA Citation
George, DJ, Regan, MM, Oh, WK, Tay, M-H, Manola, J, DeCalo, N, Duggan, S, DeWolf, WC, Kantoff, PW, and Bubley, GJ. "Radical prostatectomy lowers plasma vascular endothelial growth factor levels in patients with prostate cancer." Urology 63.2 (2004): 327-332.
PMID
14972483
Source
scival
Published In
Urology
Volume
63
Issue
2
Publish Date
2004
Start Page
327
End Page
332
DOI
10.1016/j.urology.2003.09.059

Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes

Purpose: High-level expression of the telomerase reverse transcriptase (hTERT) in >85% of human cancers, in contrast with its restricted expression in normal adult tissues, points to hTERT as a broadly applicable molecular target for anticancer immunotherapy. CTLs recognize peptides derived from hTERT and kill hTERT+ tumor cells of multiple histologies in vitro. Moreover, because survival of hTERT+ tumor cells requires functionally active telomerase, hTERT mutation or loss as a means of escape may be incompatible with sustained tumor growth. Experimental Design: A Phase I clinical trial was performed to evaluate the clinical and immunological impact of vaccinating advanced cancer patients with the HLA-A2-restricted hTERT I540 peptide presented with keyhole limpet hemocyanin by ex vivo generated autologous dendritic cells. Results: As measured by peptide/MHC tetramer, enzyme-linked immunospot, and cytotoxicity assays, hTERT-specific T lymphocytes were induced in 4 of 7 patients with advanced breast or prostate carcinoma after vaccination with dendritic cells pulsed with hTERT peptide. Tetramer-guided high-speed sorting and polyclonal expansion achieved highly enriched populations of hTERT-specific cells that killed tumor cells in an MHC- restricted fashion. Despite concerns of telomerase activity in rare normal cells, no significant toxicity was observed. Partial tumor regression in 1 patient was associated with the induction of CD8+ tumor infiltrating lymphocytes. Conclusions: These results demonstrate the immunological feasibility of vaccinating patients against telomerase and provide rationale for targeting self-antigens with critical roles in oncogenesis.

Authors
Vonderheide, RH; Domchek, SM; Schultze, JL; George, DJ; Hoar, KM; Chen, D-Y; Stephans, KF; Masutomi, K; Loda, M; Xia, Z; Anderson, KS; Hahn, WC; Nadler, LM
MLA Citation
Vonderheide, RH, Domchek, SM, Schultze, JL, George, DJ, Hoar, KM, Chen, D-Y, Stephans, KF, Masutomi, K, Loda, M, Xia, Z, Anderson, KS, Hahn, WC, and Nadler, LM. "Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes." Clinical Cancer Research 10.3 (2004): 828-839.
PMID
14871958
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
3
Publish Date
2004
Start Page
828
End Page
839
DOI
10.1158/1078-0432.CCR-0620-3

Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: the MPAKT model.

To determine whether Akt activation was sufficient for the transformation of normal prostate epithelial cells, murine prostate restricted Akt kinase activity was generated in transgenic mice (MPAKT mice). Akt expression led to p70S6K activation, prostatic intraepithelial neoplasia (PIN), and bladder obstruction. mRNA expression profiles from MPAKT ventral prostate revealed similarities to human cancer and an angiogenic signature that included three angiogenin family members, one of which was found elevated in the plasma of men with prostate cancer. Thus, the MPAKT model may be useful in studying the role of Akt in prostate epithelial cell transformation and in the discovery of molecular markers relevant to human disease.

Authors
Majumder, PK; Yeh, JJ; George, DJ; Febbo, PG; Kum, J; Xue, Q; Bikoff, R; Ma, H; Kantoff, PW; Golub, TR; Loda, M; Sellers, WR
MLA Citation
Majumder, PK, Yeh, JJ, George, DJ, Febbo, PG, Kum, J, Xue, Q, Bikoff, R, Ma, H, Kantoff, PW, Golub, TR, Loda, M, and Sellers, WR. "Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: the MPAKT model." Proc Natl Acad Sci U S A 100.13 (June 24, 2003): 7841-7846.
PMID
12799464
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
100
Issue
13
Publish Date
2003
Start Page
7841
End Page
7846
DOI
10.1073/pnas.1232229100

Incidental discovery of an appendiceal carcinoid tumor and a renal cell carcinoma.

Authors
Levine, RL; George, DJ; Kulke, MH
MLA Citation
Levine, RL, George, DJ, and Kulke, MH. "Incidental discovery of an appendiceal carcinoid tumor and a renal cell carcinoma." Clinical advances in hematology & oncology : H&O 1.2 (2003): 99-100.
PMID
16224385
Source
scival
Published In
Clinical advances in hematology & oncology : H&O
Volume
1
Issue
2
Publish Date
2003
Start Page
99
End Page
100

Targeting PDGF receptors in cancer - Rationales and proof of concept clinical trials

The platelet-derived growth factors (PDGF) are a pleotrophic family of peptide growth factors that signal through cell surface, tyrosine kinase receptors (PDGFR) and stimulate various cellular functions including growth, proliferation, and differentiation. To date, PDGF expression has been demonstrated in a number of different solid tumors, from glioblastomas to prostate carcinomas. In these various tumor types, the biologic role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to subtler paracrine interactions involving adjacent stroma and vasculature. The tyrosine kinase inhibitor imatinib mesylate (formerly STI571, Gleevec™, Novartis Pharmaceuticals Corp, East Hanover, NJ) blocks activity of the Bcr-Abl oncoprotein and the cell surface tyrosine kinase receptor c-Kit, and as such was recently approved for several indications in the treatment on chronic myeloid leukemia and gastrointestinal stromal tumors. In both of these examples the target protein was identified by an oncogenic, activating mutation. Imatinib mesylate is also a potent inhibitor of PDGFR kinase and is currently being evaluated for the treatment of chronic myelomonocytic leukemia and glioblastoma multiforme, based upon evidence in these diseases of activating mutations in PDGFR. However, the PDGF pathway may represent a therapeutic target in other solid tumors in which it is not part of the oncogenic transformation. In order to investigate the potential biologic implications of inhibiting PDGFR in these tumor types, clinical trials that investigate both established clinical endpoints of response and benefit, as well as surrogate endpoints that describe the biologic significance of PDGF inhibition in vivo are needed.

Authors
George, D
MLA Citation
George, D. "Targeting PDGF receptors in cancer - Rationales and proof of concept clinical trials." Advances in Experimental Medicine and Biology 532 (2003): 141-151.
PMID
12908555
Source
scival
Published In
Advances in experimental medicine and biology
Volume
532
Publish Date
2003
Start Page
141
End Page
151

The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer

Authors
George, DJ; Jr, WGK
MLA Citation
George, DJ, and Jr, WGK. "The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer." New England Journal of Medicine 349.5 (2003): 419-421.
PMID
12890838
Source
scival
Published In
New England Journal of Medicine
Volume
349
Issue
5
Publish Date
2003
Start Page
419
End Page
421
DOI
10.1056/NEJMp030061

Mutations in Ribonuclease L Gene Do Not Occur at a Greater Frequency in Patients with Familial Prostate Cancer Compared with Patients with Sporadic Prostate Cancer

Several genetic loci are suspected to be involved in hereditary prostate cancer, including the hereditary prostate cancer 1 (HPC1) locus at chromosome 1q24-25. The ribonuclease L (RNase L) gene has been reported as the putative hereditary prostate cancer gene located at HPC1. If this is the case, mutations of RNase L should be found at a greater frequency in familial cancers than in sporadic prostate cancers. Examination of familial and sporadic cases of prostate cancer by polymerase chain reaction and DNA sequencing resulted in a mutational frequency rate that was not statistically different between the 2 forms of the disease. These results suggest that the mutations examined within this study are rare and may contribute to very few familial prostate cancers.

Authors
Downing, SR; Hennessy, KT; Abe, M; Manola, J; George, DJ; Kantoff, PW
MLA Citation
Downing, SR, Hennessy, KT, Abe, M, Manola, J, George, DJ, and Kantoff, PW. "Mutations in Ribonuclease L Gene Do Not Occur at a Greater Frequency in Patients with Familial Prostate Cancer Compared with Patients with Sporadic Prostate Cancer." Clinical Prostate Cancer 2.3 (2003): 177-180.
PMID
15040862
Source
scival
Published In
Clinical Prostate Cancer
Volume
2
Issue
3
Publish Date
2003
Start Page
177
End Page
180

Overview consensus statement. Newer approaches to androgen deprivation therapy in prostate cancer.

Authors
Carroll, PR; Kantoff, PW; Balk, SP; Brown, MA; D'amico, AV; George, DJ; Grossfeld, GD; Johnson, CS; Kelly, WK; Klotz, L; Lee, WR; Lubeck, DP; Mcleod, DG; Oh, WK; Pollack, A; Sartor, O; Smith, MR; Hart, C
MLA Citation
Carroll, PR, Kantoff, PW, Balk, SP, Brown, MA, D'amico, AV, George, DJ, Grossfeld, GD, Johnson, CS, Kelly, WK, Klotz, L, Lee, WR, Lubeck, DP, Mcleod, DG, Oh, WK, Pollack, A, Sartor, O, Smith, MR, and Hart, C. "Overview consensus statement. Newer approaches to androgen deprivation therapy in prostate cancer." Urology 60.3 Suppl 1 (September 2002): 1-6.
PMID
12231036
Source
epmc
Published In
Urology
Volume
60
Issue
3 Suppl 1
Publish Date
2002
Start Page
1
End Page
6
DOI
10.1016/s0090-4295(02)01559-5

Selective aromatase inhibition for patients with androgen-independent prostate carcinoma: A phase II study of letrozole

BACKGROUND. First and second-generation aromatase inhibitors have shown activity in patients with androgen-independent prostate carcinoma. These early-generation aromatase inhibitors are nonselective, however, and inhibition of other steroidogenic enzymes may contribute to their reported clinical activity. The authors conducted a Phase II clinical study of letrozole to determine the safety and efficacy of a potent and selective third- generation aromatase inhibitor in men with androgen-independent prostate carcinoma. METHODS. Forty-three men with androgen-independent prostate carcinoma were treated with oral letrozole (2.5 mg daily). Treatment was continued until progressive disease or Grade 3 toxicity developed. Response and progressive disease were defined according to recommendations of the Prostate Specific Antigen Working Group. RESULTS. In total, 380 weeks of treatment were administered to the 43 study patients. The median duration of treatment was 8 weeks. Forty men discontinued treatment due to progressive disease. Only one patient responded to treatment with a sustained decrease > 50% in serum prostate specific antigen (PSA) levels. Three other patients experienced transient minor decreases (< 50%) in serum PSA levels. There were no serious treatment-related adverse events. CONCLUSIONS. Selective aromatase inhibition with letrozole is not active in men with androgen-independent prostate carcinoma. © 2002 American Cancer Society.

Authors
Smith, MR; Kaufman, D; George, D; Oh, WK; Kazanis, M; Manola, J; Kantoff, PW
MLA Citation
Smith, MR, Kaufman, D, George, D, Oh, WK, Kazanis, M, Manola, J, and Kantoff, PW. "Selective aromatase inhibition for patients with androgen-independent prostate carcinoma: A phase II study of letrozole." Cancer 95.9 (2002): 1864-1868.
PMID
12404279
Source
scival
Published In
Cancer
Volume
95
Issue
9
Publish Date
2002
Start Page
1864
End Page
1868
DOI
10.1002/cncr.10844

Receptor tyrosine kinases as rational targets for prostate cancer treatment: Platelet-derived growth factor receptor and imatinib mesylate

Over the past 15 years, numerous signal transduction pathways have been elucidated whose dysregulation may play an important role in the growth and survival of cancer cells. The success of imatinib mesylate (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ), a small molecule that inhibits the activation of the BCR-Abl oncogene in the treatment of chronic myelogenous leukemia, has demonstrated how effective targeted strategies can be when properly applied. With the hope of selectively targeting other critical components of cancer growth and survival while minimizing toxicity to the host, numerous strategies have been developed to inhibit receptor tyrosine kinases for various growth factors commonly expressed by cancer cells. Success of targeted inhibitors is inherently dependent on the proper selection of patients whose tumors are dependent on these growth factor pathways. Unfortunately, in prostate cancer, such selection has been a difficult-to-impossible task to date. Because of the vast number of mutational events, it is difficult to demonstrate that any particular growth factor signaling pathway is critical. In addition, because of the type (mostly bone only) and nature (usually small foci) of metastases, limited access to tumor tissue in the advanced cancer population has hampered attempts to characterize patients by their molecular features or phenotype. This article will focus on defining alternative criteria for a rational drug target and novel study designs for testing these agents in prostate cancer. In particular, the neoadjuvant setting represents a unique opportunity for new drug development in prostate cancer. An example of a neoadjuvant study testing, imatinib mesylate, is presented to display the advantages and limitations of this study design. © 2002 Elsevier Science Inc.

Authors
George, DJ
MLA Citation
George, DJ. "Receptor tyrosine kinases as rational targets for prostate cancer treatment: Platelet-derived growth factor receptor and imatinib mesylate." Urology 60.3 SUPPL. 1 (2002): 115-122.
PMID
12231066
Source
scival
Published In
Urology
Volume
60
Issue
3 SUPPL. 1
Publish Date
2002
Start Page
115
End Page
122
DOI
10.1016/S0090-4295(02)01589-3

Initial decline in hemoglobin during neoadjuvant hormonal therapy predicts for early prostate specific antigen failure following radiation and hormonal therapy for patients with intermediate and high-risk prostate cancer

BACKGROUND. Declines in serum hemoglobin (Hgb) levels occur from the use of androgen suppression therapy (AST) in the treatment of prostate cancer patients. We studied whether time to prostate specific antigen (PSA) failure following external beam radiation therapy (RT) and AST could be predicted by the rate of decline in the Hgb level following the administration of neoadjuvant AST or by the Hgb level at presentation or at the start of RT. METHODS. The study cohort comprised 110 intermediate or high-risk prostate cancer patients who were managed using three-dimensional conformal RT (70 Gy) and 6 months of AST (2 months neoadjuvant, concurrent, and adjuvant). A Cox regression multivariable analysis was performed to evaluate the ability of the rate of decline of the Hgb from baseline to the start of RT, baseline PSA level, Gleason score, percent positive biopsies, and T-category to predict time to PSA failure. RESULTS. A decline in the Hgb level of 1 g/dL or more during the first month of AST was the only significant predictor of time to PSA failure (P = 0.02) on multivariable analysis. The relative risk of PSA failure (95% confidence interval) for patients with a decline in Hgb level during the first month (≥ I g/dL vs. < 1 g/dL) was 6.3 (2.4, 8.3) and the 3-year estimate of PSA outcome was 66% versus 82% (P = 0.04), respectively. There were no imbalances in the pretreatment prognostic factors or length of follow-up in each of these groups. CONCLUSION. A decline of 1 g/dL or more in Hgb level during the first month of neoadjuvant AST was a predictor of early PSA failure following RT and AST in intermediate and high-risk prostate cancer patients. © 2002 American Cancer Society.

Authors
D'Amico, AV; Saegaert, T; Chen, M-H; Renshaw, AA; George, D; Oh, W; Kantoff, PW
MLA Citation
D'Amico, AV, Saegaert, T, Chen, M-H, Renshaw, AA, George, D, Oh, W, and Kantoff, PW. "Initial decline in hemoglobin during neoadjuvant hormonal therapy predicts for early prostate specific antigen failure following radiation and hormonal therapy for patients with intermediate and high-risk prostate cancer." Cancer 95.2 (2002): 275-280.
PMID
12124826
Source
scival
Published In
Cancer
Volume
95
Issue
2
Publish Date
2002
Start Page
275
End Page
280
DOI
10.1002/cncr.10673

Rapid and durable recovery of visual function in a patient with von Hippel-Lindau syndrome after systemic therapy with vascular endothelial growth factor receptor inhibitor SU5416

Purpose: To present a case of rapid and durable recovery of visual function in a patient with von Hippel-Lindau syndrome and optic nerve head hemangioblastoma after systemic treatment with the vascular endothelial growth factor (VEGF) receptor inhibitor SU5416. Design: Interventional case report. Methods: Visual function parameters, including visual acuity, automated visual field, and contrast sensitivity, were evaluated using standardized methods repeatedly over a 15-month period. Fundus photographs and fluorescein angiograms were also obtained. Central nervous system lesions were monitored by computed tomography (CT) and magnetic resonance imaging (MRI) scans. Treatment involved the systemic administration of the VEGF receptor inhibitor SU5416. Main Outcome Measures: Clinical presentation, visual acuity using Early Treatment Diabetic Retinopathy Study protocol, Humphrey automated perimetry, (Zeiss Humphrey Systems, Dublin, CA) Vistech contrast sensitivity (Vistech Consultants Inc., Dayton, OH) Farnsworth (Farnsworth-Munsell Color Services, New Windsor, NY) dichotomous panel D-15, retinal photography, fluorescein angiography, and CT and MRI scans. Results: Within 4 weeks of therapy, visual acuity had improved from 20/32 -2 to 20/16 -1, the visual field had expanded from being circumferentially constricted to within 8° of fixation to normal, and contrast sensitivity improved in all but the lowest spatial frequency (1.5 cycles/degree). No change was observed in lesion size by fundus photography. Improvement has been maintained over 18 months with intermittent SU5416 therapy. Conclusions: We report rapid, extensive, and durable recovery of visual function after systemic administration of the VEGF receptor inhibitor SU5416 to a patient with VHL syndrome and optic nerve head hemangioblastoma. These findings suggest that continued evaluation of VEGF inhibitors for ocular neovascular disorders is warranted. © 2002 by the American Academy of Ophthalmology.

Authors
Aiello, LP; George, DJ; Cahill, MT; Wong, JS; Cavallerano, J; Hannah, AL; Jr, WGK
MLA Citation
Aiello, LP, George, DJ, Cahill, MT, Wong, JS, Cavallerano, J, Hannah, AL, and Jr, WGK. "Rapid and durable recovery of visual function in a patient with von Hippel-Lindau syndrome after systemic therapy with vascular endothelial growth factor receptor inhibitor SU5416." Ophthalmology 109.9 (2002): 1745-1751.
PMID
12208726
Source
scival
Published In
Ophthalmology: Journal of The American Academy of Ophthalmology
Volume
109
Issue
9
Publish Date
2002
Start Page
1745
End Page
1751
DOI
10.1016/S0161-6420(02)01159-4

A phase II trial of interferon-alpha and toremifene in advanced renal cell cancer patients

Treatment options for patients with metastatic renal cell carcinoma are limited. Interferon-alpha has an overall response rate of 10-15% in phase H and III clinical trials and is considered a standard option for patients. Though the anti-estrogen toremifene has shown only modest single agent activity in renal cell carcinoma, evidence for synergy of anti-estrogens with interferon-alpha exists in renal cell and other cancers. Therefore, a phase II trial was undertaken to test the combination of interferon-alpha and toremifene in advanced renal cell carcinoma. Thirteen patients with measurable metastatic or unresectable local disease were treated with interferon-alpha at a dose of 5 million units/m2 three times a week and daily oral toremifene at 300 mg daily in divided doses. Patients were treated for 12 weeks and then restaged. Clinical response was the primary endpoint of the trial. Four patients (31%) had evidence of stable disease at 12 weeks, while the remaining nine patients (69%) progressed on treatment. Toxicity was moderate, with grade 2 or 3 fatigue, nausea and anorexia each noted in 31% of patients. We conclude that the combination of interferon-alpha plus toremifene demonstrates no significant activity in advanced renal cell carcinoma.

Authors
Oh, WK; Manola, J; George, DJ; Fierman, A; Fontaine-Rothe, P; Morrissey, S; Prisby, J; Kaufman, DS; Shapiro, CL; Kantoff, PW; Smith, MR
MLA Citation
Oh, WK, Manola, J, George, DJ, Fierman, A, Fontaine-Rothe, P, Morrissey, S, Prisby, J, Kaufman, DS, Shapiro, CL, Kantoff, PW, and Smith, MR. "A phase II trial of interferon-alpha and toremifene in advanced renal cell cancer patients." Cancer Investigation 20.2 (2002): 186-191.
PMID
11901538
Source
scival
Published In
Cancer Investigation (Informa)
Volume
20
Issue
2
Publish Date
2002
Start Page
186
End Page
191
DOI
10.1081/CNV-120001145

Rapid rise of serum prostate specific antigen levels after discontinuation of the herbal therapy PC-SPES in patients with advanced prostate carcinoma: Report of four cases

BACKGROUND. PC-SPES is an herbal supplement whose mechanisms of action are poorly understood, but may be estrogenic. The objective of the current report is to describe the effects of discontinuing PC-SPES treatment in four patients with androgen-independent prostate carcinoma. METHODS. Patient charts were retrospectively reviewed. A MEDLINE search was performed to investigate whether these effects of PC-SPES had been previously reported. RESULTS. Four men whose metastatic prostate carcinoma progressed despite androgen ablation and subsequent PC-SPES treatment are described. All four patients developed a rapid increase in serum prostate specific antigen (PSA) within one month of stopping PC-SPES, ranging from 345% to 880%. Two patients increased their PSA levels to 1300% and 1400% after 7 weeks. Compared to the rate of rise of PSA levels prior to and during PC-SPES therapy, the rise after stopping this treatment was much higher than expected. Clinical symptoms remained relatively stable despite the serologic changes. CONCLUSIONS. Discontinuing PC-SPES therapy can be associated with a rapid rise in PSA. To the authors' knowledge, this effect has not been reported previously. This effect should be considered in the design of clinical trials as well as in the standard management of androgen-independent prostate carcinoma patients. © 2002 American Cancer Society.

Authors
Oh, WK; George, DJ; Kantoff, PW
MLA Citation
Oh, WK, George, DJ, and Kantoff, PW. "Rapid rise of serum prostate specific antigen levels after discontinuation of the herbal therapy PC-SPES in patients with advanced prostate carcinoma: Report of four cases." Cancer 94.3 (2002): 686-689.
PMID
11857300
Source
scival
Published In
Cancer
Volume
94
Issue
3
Publish Date
2002
Start Page
686
End Page
689
DOI
10.1002/cncr.10269

Overview consensus statement

Authors
Carroll, PR; Kantoff, PW; Balk, SP; Brown, MA; D'amico, AV; George, DJ; Grossfeld, GD; Johnson, CS; Kelly, WK; Klotz, L; Lee, WR; Lubeck, DP; Mcleod, DG; Oh, WK; Pollack, A; Sartor, O; Smith, MR; Hart, C
MLA Citation
Carroll, PR, Kantoff, PW, Balk, SP, Brown, MA, D'amico, AV, George, DJ, Grossfeld, GD, Johnson, CS, Kelly, WK, Klotz, L, Lee, WR, Lubeck, DP, Mcleod, DG, Oh, WK, Pollack, A, Sartor, O, Smith, MR, and Hart, C. "Overview consensus statement." Urology 60.3 SUPPL. 1 (2002): 1-6.
Source
scival
Published In
Urology
Volume
60
Issue
3 SUPPL. 1
Publish Date
2002
Start Page
1
End Page
6
DOI
10.1016/S0090-4295(02)01559-5

Platelet-derived growth factor receptors: a therapeutic target in solid tumors.

Platelet-derived growth factor (PDGF) was one of the first polypeptide growth factors identified that signals through a cell surface tyrosine kinase receptor (PDGF-R) to stimulate various cellular functions including growth, proliferation, and differentiation. Since then, several related genes have been identified constituting a family of ligands (primarily PDGF A and B) and their cognate receptors (PDGF-R alpha and beta). To date, PDGF expression has been shown in a number of different solid tumors, from glioblastomas to prostate carcinomas. In these various tumor types, the biologic role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to more subtle paracrine interactions involving adjacent stroma and even angiogenesis. The tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) blocks activity of the Bcr-Abl oncoprotein, and was recently approved for several indications in the treatment of chronic myeloid leukemia. Imatinib mesylate is also a potent inhibitor of the PDGF-R kinase and is currently being evaluated for the treatment of PDGF-responsive tumors such as prostate cancer. More clinical trials that investigate both established clinical endpoints of response and benefit, as well as surrogate endpoints that may describe the biologic significance of PDGF-R inhibition in vivo are needed to expand the applications that target the PDGF axis.

Authors
George, D
MLA Citation
George, D. "Platelet-derived growth factor receptors: a therapeutic target in solid tumors." Seminars in oncology 28.5 Suppl 17 (October 2001): 27-33.
PMID
11740804
Source
epmc
Published In
Seminars in Oncology
Volume
28
Issue
5 Suppl 17
Publish Date
2001
Start Page
27
End Page
33
DOI
10.1016/s0093-7754(01)90100-9

Neoadjuvant docetaxel followed by radical prostatectomy in patients with high-risk localized prostate cancer: a preliminary report.

Effective treatment options for high-risk localized prostate cancer are limited. Patients at high risk for recurrence include those with biopsy Gleason scores of 8 to 10, prostate specific antigen (PSA) levels > 20 ng/mL, and clinical stage T3 disease. Docetaxel chemotherapy is active in hormone-refractory prostate cancer, either combined with estramustine or used as a single agent. To determine if systemic therapy can improve the outcome of radical prostatectomy in men with high-risk localized prostate cancer, we are undertaking a pilot phase II clinical trial of weekly docetaxel at 36 mg/m(2) for up to 6 months, followed by surgery. Patients are monitored with weekly visits, monthly digital rectal examinations, PSA measurement, and testosterone tests, and endorectal magnetic resonance imaging done at baseline, after two cycles, and again after six cycles. To date, 15 patients have been enrolled, and 70 cycles of chemotherapy have been administered. Toxicity has been mostly grade 1 in intensity, and fatigue has been the most common grade 2 toxicity reported. The primary endpoint of the trial is measurement of pathologic complete response rate, for which data are not yet available. Recruitment to the trial is ongoing.

Authors
Oh, WK; George, DJ; Kaufman, DS; Moss, K; Smith, MR; Richie, JP; Kantoff, PW
MLA Citation
Oh, WK, George, DJ, Kaufman, DS, Moss, K, Smith, MR, Richie, JP, and Kantoff, PW. "Neoadjuvant docetaxel followed by radical prostatectomy in patients with high-risk localized prostate cancer: a preliminary report." Seminars in oncology 28.4 Suppl 15 (August 2001): 40-44.
PMID
11685727
Source
epmc
Published In
Seminars in Oncology
Volume
28
Issue
4 Suppl 15
Publish Date
2001
Start Page
40
End Page
44
DOI
10.1016/s0093-7754(01)90153-8

Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480.

PURPOSE: Plasma vascular endothelial growth factor (VEGF) levels are significantly elevated in patients with hormone-refractory prostate cancer (HRPC) compared with patients with localized disease and have been associated with disease progression in other cancer patient populations. Therefore, we measured VEGF levels in plasma prospectively collected from patients enrolled in Cancer and Leukemia Group B 9480, an intergroup study of suramin in patients with HRPC, to determine whether these levels had prognostic significance. EXPERIMENTAL DESIGN: Pretreatment plasma was collected from patients with HRPC enrolled in Cancer and Leukemia Group B 9480. In a subset of samples representative of the entire cohort, plasma VEGF levels were determined in duplicate using a Quantiglo chemiluminescent ELISA kit (R&D Systems, Minneapolis, MN). Statistical analyses were performed to determine the correlation between pretreatment plasma VEGF levels and time of overall survival. The proportional hazards model was used to assess the prognostic significance of various cut points in multivariate models. RESULTS: Plasma VEGF levels in this population ranged from 4-885 pg/ml, with a median level of 83 pg/ml. As a continuous variable, plasma VEGF levels inversely correlated with survival time (P = 0.002). Using various exploratory cut points, plasma VEGF levels appeared to correlate with survival. In multivariate models in which other prognostic factors (serum prostate-specific antigen, alkaline phosphatase, evidence of measurable disease, and hemoglobin) were included, plasma VEGF levels were significant at various cut points tested. CONCLUSION: Although these data are exploratory and need to be confirmed in an independent data set, they suggest that VEGF may have clinical significance in patients with HRPC.

Authors
George, DJ; Halabi, S; Shepard, TF; Vogelzang, NJ; Hayes, DF; Small, EJ; Kantoff, PW; Cancer and Leukemia Group B 9480,
MLA Citation
George, DJ, Halabi, S, Shepard, TF, Vogelzang, NJ, Hayes, DF, Small, EJ, Kantoff, PW, and Cancer and Leukemia Group B 9480, . "Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480." Clin Cancer Res 7.7 (July 2001): 1932-1936.
PMID
11448906
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
7
Issue
7
Publish Date
2001
Start Page
1932
End Page
1936

PTEN polymorphism (IVS4) is not associated with risk of prostate cancer

Authors
George, DJ; Shepard, TF; Ma, J; Giovannucci, E; Kantoff, PW; Stampfer, MJ
MLA Citation
George, DJ, Shepard, TF, Ma, J, Giovannucci, E, Kantoff, PW, and Stampfer, MJ. "PTEN polymorphism (IVS4) is not associated with risk of prostate cancer." Cancer Epidemiology Biomarkers and Prevention 10.4 (2001): 411-412.
PMID
11319185
Source
scival
Published In
Cancer Epidemiology Biomarkers and Prevention
Volume
10
Issue
4
Publish Date
2001
Start Page
411
End Page
412

An α-particle emitting antibody ([213Bi]J591) for radioimmmunotherapy of prostate cancer

Authors
George, DJ; McDevitt, MR; Barendswaard, E; Ma, D; Lai, L; Curcio, MJ; Sgouros, G; Ballangrud, AM; Yang, WH; Finn, RD; Pellegrini, V; Jr, GMW; Lee, M; Brechbiel, MW; Bander, NH; Cordon-Cardo, C; Scheinberg, DA
MLA Citation
George, DJ, McDevitt, MR, Barendswaard, E, Ma, D, Lai, L, Curcio, MJ, Sgouros, G, Ballangrud, AM, Yang, WH, Finn, RD, Pellegrini, V, Jr, GMW, Lee, M, Brechbiel, MW, Bander, NH, Cordon-Cardo, C, and Scheinberg, DA. "An α-particle emitting antibody ([213Bi]J591) for radioimmmunotherapy of prostate cancer." Prostate Journal 3.1 (2001): 1--.
Source
scival
Published In
Prostate Journal
Volume
3
Issue
1
Publish Date
2001
Start Page
1-
DOI
10.1046/j.1525-1411.2001.003001001.x

Neoadjuvant docetaxel followed by radical prostatectomy in patients with high-risk localized prostate cancer: A preliminary report

Effective treatment options for high-risk localized prostate cancer are limited. Patients at high risk for recurrence include those with biopsy Gleason scores of 8 to 10, prostate specific antigen (PSA) levels > 20 ng/mL, and clinical stage T3 disease. Docetaxel chemotherapy is active in hormone-refractory prostate cancer, either combined with estramustine or used as a single agent. To determine if systemic therapy can improve the outcome of radical prostatectomy in men with high-risk localized prostate cancer, we are undertaking a pilot phase II clinical trial of weekly docetaxel at 36 mg/m2 for up to 6 months, followed by surgery. Patients are monitored with weekly visits, monthly digital rectal examinations, PSA measurement, and testosterone tests, and endorectal magnetic resonance imaging done at baseline, after two cycles, and again after six cycles. To date, 15 patients have been enrolled, and 70 cycles of chemotherapy have been administered. Toxicity has been mostly grade 1 in intensity, and fatigue has been the most common grade 2 toxicity reported. The primary endpoint of the trial is measurement of pathologic complete response rate, for which data are not yet available. Recruitment to the trial is ongoing. Copyright © 2001 by W.B. Saunders Company.

Authors
Oh, WK; George, DJ; Kaufman, DS; Moss, K; Smith, MR; Richie, JP; Kantoff, PW
MLA Citation
Oh, WK, George, DJ, Kaufman, DS, Moss, K, Smith, MR, Richie, JP, and Kantoff, PW. "Neoadjuvant docetaxel followed by radical prostatectomy in patients with high-risk localized prostate cancer: A preliminary report." Seminars in Oncology 28.4 SUPPL. 15 (2001): 40-44.
Source
scival
Published In
Seminars in Oncology
Volume
28
Issue
4 SUPPL. 15
Publish Date
2001
Start Page
40
End Page
44

Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer

Purpose: To determine the safety and activity of weekly paclitaxel in combination with estramustine and carboplatin (TEC) in patients with advanced prostate cancer. Patients and Methods: In a dose-escalation study, patients with advanced prostate cancer were administered paclitaxel (weekly 1-hour infusions of 60 to 100 mg/m2), oral estramustine (10 mg/kg), and carboplatin (area under the curve, 6 mg/mL-min every 4 weeks). Paclitaxel levels were determined 0, 30, 60, 90, and 120 minutes and 18 hours after infusion, and a concentration-time curve was estimated. Once a safe dose was established, a multi-institutional phase II trial was conducted in patients with progressive androgen-independent disease. Results: Fifty-six patients with progressive androgen-independent disease were treated for a median of four cycles. The dose of paclitaxel was escalated from 60 to 100 mg/m2 without the occurrence of DLT. Posttherapy decreases in serum prostate-specific antigen levels of 50%, 80%, and 90% were seen in 67%, 48%, and 39% (95% confidence interval, 55% to 79%, 35% to 61%, 26% to 52%) of the patients, respectively. Of the 33 patients with measurable disease, two (6%) had a complete response and 13 (39%) had a partial response. The overall median time to progression was 21 weeks, and the median survival time for all patients was 19.9 months. Major grade 3 or 4 adverse effects were thromboembolic disease (in 25% of patients), hyperglycemia (in 38%), and hypophosphatemia (in 42%). Significant leukopenia, thrombocytopenia, and peripheral neuropathy were not observed. Conclusion: TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer. © 2001 by American Society of Clinical Oncology.

Authors
Kelly, WK; Curley, T; Slovin, S; Heller, G; McCaffrey, J; Bajorin, D; Ciolino, A; Regan, K; Schwartz, M; Kantoff, P; George, D; Oh, W; Smith, M; Kaufman, D; Small, EJ; Schwartz, L; Larson, S; Tong, W; Scher, H
MLA Citation
Kelly, WK, Curley, T, Slovin, S, Heller, G, McCaffrey, J, Bajorin, D, Ciolino, A, Regan, K, Schwartz, M, Kantoff, P, George, D, Oh, W, Smith, M, Kaufman, D, Small, EJ, Schwartz, L, Larson, S, Tong, W, and Scher, H. "Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer." Journal of Clinical Oncology 19.1 (2001): 44-53.
PMID
11134194
Source
scival
Published In
Journal of Clinical Oncology
Volume
19
Issue
1
Publish Date
2001
Start Page
44
End Page
53

Platelet-derived growth factor receptors: A therapeutic target in solid tumors

Platelet-derived growth factor (PDGF) was one of the first polypeptide growth factors identified that signals through a cell surface tyrosine kinase receptor (PDGF-R) to stimulate various cellular functions including growth, proliferation, and differentiation. Since then, several related genes have been identified constituting a family of ligands (primarily PDGF A and B) and their cognate receptors (PDGF-R α and β. To date, PDGF expression has been shown in a number of different solid tumors, from glioblastomas to prostate carcinomas. In these various tumor types, the biologic role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to more subtle paracrine interactions involving adjacent stroma and even angiogenesis. The tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) blocks activity of the Bcr-Abl oncoprotein, and was recently approved for several indications in the treatment of chronic myeloid leukemia. Imatinib mesylate is also a potent inhibitor of the PDGF-R kinase and is currently being evaluated for the treatment of PDGF-responsive tumors such as prostate cancer. More clinical trials that investigate both established clinical endpoints of response and benefit, as well as surrogate endpoints that may describe the biologic significance of PDGF-R inhibition in vivo are needed to expand the applications that target the PDGF axis. Copyright © 2001 by W.B. Saunders Company.

Authors
George, D
MLA Citation
George, D. "Platelet-derived growth factor receptors: A therapeutic target in solid tumors." Seminars in Oncology 28.5 SUPPL. 17 (2001): 27-33.
Source
scival
Published In
Seminars in Oncology
Volume
28
Issue
5 SUPPL. 17
Publish Date
2001
Start Page
27
End Page
33

Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer

Objectives. To retrospectively evaluate the response to treatment with PC-SPES, an herbal supplement, because patients with androgen-independent prostate cancer have limited treatment options. Methods. A retrospective analysis was performed of patients with prostate cancer progression despite androgen ablation therapy who were treated with PC-SPES (3 capsules twice daily). We explored potential predictors of response. Results. Twenty-three patients with androgen-independent prostate cancer were treated. The median age was 70 years. Eighteen patients had received prior secondary hormonal treatment and 10 prior chemotherapy. With a median follow-up of 8 months, 20 (87%; 95% confidence interval 66% to 97%) of 23 patients experienced a post-therapy decline in prostate-specific antigen (PSA). The median decline in PSA among these patients was 40% (range 1% to 88%). Of 23 patients, 12 (52%; 95% confidence interval 31% to 73%) had a greater than 50% decline in PSA. The median duration of the PSA response was 2.5 months (range 1 to 9+); the median time from the start of therapy to PSA progression was 6 months (range 2 to 12). Seven patients died of progressive prostate cancer. Toxicity was mild and included nipple tenderness, nausea, and diarrhea. One patient with a known history of coronary artery disease developed angina. In univariate analyses, older patients and those with a longer duration of initial androgen ablation therapy were more likely to respond to PC-SPES. Conclusions. PC-SPES is a well-tolerated and active treatment for androgen-independent prostate cancer. Additional testing is necessary to identify the active components of PC-SPES and its role in the treatment of patients with androgen-independent prostate cancer. Copyright © 2001 Elsevier Science Inc.

Authors
Oh, WK; George, DJ; Hackmann, K; Manola, J; Kantoff, PW
MLA Citation
Oh, WK, George, DJ, Hackmann, K, Manola, J, and Kantoff, PW. "Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer." Urology 57.1 (2001): 122-126.
PMID
11164156
Source
scival
Published In
Urology
Volume
57
Issue
1
Publish Date
2001
Start Page
122
End Page
126
DOI
10.1016/S0090-4295(00)00986-9

Removal of the entrapped basketed ureteral calculus: A novel technique

Authors
Low, RK; George, D
MLA Citation
Low, RK, and George, D. "Removal of the entrapped basketed ureteral calculus: A novel technique." Journal of Urology 163.6 (2000): 1863--.
PMID
10799203
Source
scival
Published In
Journal of Urology
Volume
163
Issue
6
Publish Date
2000
Start Page
1863-

Rational basis for Trk inhibition therapy for prostate cancer

BACKGROUND. Prostatic cancer cells are lethal because they acquire the ability to activate survival pathways that do not require androgenic stimulation As a rational approach to developing effective therapy for these devastating cells specific signal transduction pathways uniquely required for the survival of these nonandrogen-dependent prostate cancer cells must be identified. Previous studies suggested that the neurotrophin/trk signal transduction axis may regulate such unique survival pathways. In the present study, the changes in expression of the neurotrophins (NGF, BDNF, and NT-3) and their cognate receptors (i.e., trk and p75NTR) during the progression of normal prostatic epithelial cells to malignancy were documented. Additionally the consequences of inhibiting these trk signaling pathways on the in vitro survival of prostate cancer cells was tested. METHODS. Immmunocytochemistry, RT-PCR, and ELISA assays were used to characterize the changes in the neurotrophin ligands (i.e., NGF, BDNF, and NT-3) and their cognate high-affinity (i.e. trk A, B, and C) and low-affinity neurotrophin (i.e., p75 NTR) receptors in normal vs. malignant human prostatic tissues. CEP-751 is an indolocarbazole compound specifically designed to inhibit the initiation of these neurotrophin/trk signal transductions. The consequence of CEP-751 inhibition of trk signaling for in vitro clonogenic survival of a series of human prostatic cancer lines was also tested. RESULTS. These studies demonstrated that normal prostatic tissue from patients without prostate cancer contains substantial levels of nerve growth factor (NGF), which is produced in a paracrine manner by stromal cells. These stromal cells lack both trk and p75NTR receptors. In contrast, normal prostatic epithelial cells from patients without prostate cancer do not secrete detectable levels of neurotrophins, but do express trk A and p75 NTR. While the NGF/trkA/p75 NTR axis is present in the normal prostate, normal prostatic epithelial cells do not depend on this axis for their survival. In contrast, malignant prostate epithelial cells directly secrete a series of neurotrophins (i.e., NGF, BDNF, and/or NT-3) and express at least one if not more of the trk receptor proteins (i.e., trk A, B, and/or C), while no longer expressing the p75NTR receptors. In addition, inhibition of autocrine trk signaling via CEP-751 treatment induces the apoptotic death of these malignant cells. CONCLUSIONS. Prostate carcinogenesis involves molecular changes leading to the paracrine and/or autocrine production of a series of neurotrophins. This is coupled to the ectopic expression of trk B and trk C, as well as to the continued expression of trk A, and the loss of expression of p75NTR receptors. These changes result in the acquisition by malignant prostate cells of a unique requirement for trk signaling pathways for survival. Based on these findings, trk inhibition is a novel, rational approach for prostate cancer therapy. (C) Wiley-Liss, Inc.

Authors
Weeraratna, AT; Arnold, JT; George, DJ; DeMarzo, A; Isaacs, JT
MLA Citation
Weeraratna, AT, Arnold, JT, George, DJ, DeMarzo, A, and Isaacs, JT. "Rational basis for Trk inhibition therapy for prostate cancer." Prostate 45.2 (2000): 140-148.
PMID
11027413
Source
scival
Published In
The Prostate
Volume
45
Issue
2
Publish Date
2000
Start Page
140
End Page
148
DOI
10.1002/1097-0045(20001001)45:2<140::AID-PROS8>3.0.CO;2-#

Prognostic indicators in hormone refractory prostate cancer

Prognostic factors in hormone refractory prostate cancer currently are of limited use to clinicians. Although studies have identified several factors that predict for poor survival in patients, most are either retrospective, or nonrandomized. Therefore, large prospective, randomized trials are needed to validate the significance of these factors. In addition, these indicators are largely descriptive of the patients' condition or the extent of disease. As more treatment options are developed for these patients, functionally relevant and prognostic molecular markers are needed to direct their care.

Authors
George, DJ; Kantoff, PW
MLA Citation
George, DJ, and Kantoff, PW. "Prognostic indicators in hormone refractory prostate cancer." Urologic Clinics of North America 26.2 (1999): 303-310.
PMID
10361553
Source
scival
Published In
Urologic Clinics of North America
Volume
26
Issue
2
Publish Date
1999
Start Page
303
End Page
310
DOI
10.1016/S0094-0143(05)70070-7

Comparison of immune reconstitution after unrelated and related T-cell- depleted bone marrow transplantation: Effect of patient age and donor leukocyte infusions

Unrelated bone marrow transplantation (BMT) is often complicated by fatal opportunistic infections. To evaluate features unique to immune reconstitution after unrelated BMT, the lymphoid phenotype, in vitro function, and life-threatening opportunistic infections after unrelated and related T-cell-depleted (TCD) BMT were analyzed longitudinally and compared. The effects of posttransplant donor leukocyte infusions to treat or prevent cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infections on immune reconstitution were also analyzed. This study demonstrates that adult recipients of TCD unrelated BMTs experience prolonged and profound deficiencies of CD3+, CD4+, and CD8+ T-cell populations when compared with pediatric recipients of unrelated BMT and adults after related BMT (P < .01), that these adults have a significantly increased risk of life-threatening opportunistic infections, and that the rate of recovery of CD4 T cells correlates with the risk of developing these infections. Recovery of normal numbers of CD3+, CD8+, and CD4+ T-cell populations is similar in children after related or unrelated BMT. This study also demonstrates that adoptive immunotherapy with small numbers of unirradiated donor leukocytes can be associated with rapid restoration of CD3+, CD4+, and CD8+ T-cell numbers, antigen-specific T-cell responses, and resolution of CMV- and EBV-associated disease after unrelated TCD BMT.

Authors
Small, TN; Papadopoulos, EB; Boulad, F; Black, P; Castro-Malaspina, H; Childs, BH; Collins, N; Gillio, A; George, D; Jakubowski, A; Heller, G; Fazzari, M; Kernan, N; MacKinnon, S; Szabolcs, P; Young, JW; O'Reilly, RJ
MLA Citation
Small, TN, Papadopoulos, EB, Boulad, F, Black, P, Castro-Malaspina, H, Childs, BH, Collins, N, Gillio, A, George, D, Jakubowski, A, Heller, G, Fazzari, M, Kernan, N, MacKinnon, S, Szabolcs, P, Young, JW, and O'Reilly, RJ. "Comparison of immune reconstitution after unrelated and related T-cell- depleted bone marrow transplantation: Effect of patient age and donor leukocyte infusions." Blood 93.2 (1999): 467-480.
Source
scival
Published In
Blood
Volume
93
Issue
2
Publish Date
1999
Start Page
467
End Page
480

Sustained in vivo regression of Dunning H rat prostate cancers treated with combinations of androgen ablation and trk tyrosine kinase inhibitors, CEP-751 (KT-6587) or CEP-701 (KT-5555)

The indolocarbazole analogue CEP-751 is a potent and selective tyrosine kinase inhibitor of the neurotrophin-specific trk receptors that has demonstrated antitumor activity in nine different models of prostate cancer growth in vivo. In the slow-growing, androgen-sensitive Dunning H prostate cancers, which express trk receptors, CEP-751 induced transient regressions independent of effects on cell cycle. Because androgen ablation is the most commonly used treatment for prostate cancer, we examined whether the combination treatment of CEP-751 with castration would lead to better antitumor efficacy than either treatment alone. For a 60-day period, H tumor- bearing rats received treatment with either castration, CEP-751 (10 mg/kg once a day s.c. for 5 days every 2 weeks), a combination of both, or vehicle. Castration caused tumor regression, followed by tumor regrowth in 4-6 weeks, whereas intermittent CEP-751 treatments resulted in tumor regressions during each treatment, which were followed by a period of regrowth between intermittent drug treatment cycles. Overall, both monotherapies significantly inhibited tumor growth compared with the vehicle-treated control group. However, the combination of castration and concomitant CEP-751 produced the most dramatic results: significantly greater tumor regression than either therapy alone, with no signs of regrowth. A related experiment using an orally administered CEP-751 analogue (CEP-701), as the trk inhibitor, and a gonadotrophin-releasing hormone agonist, Leuprolide, to induce androgen ablation demonstrated similar results, indicating that these effects could be generalized to other forms of androgen ablation and other trk inhibitors within this class. In addition, when CEP-701 was given sequentially to rats bearing H tumors, which were progressing in the presence of continuous androgen ablation induced by Leuprolide, regression of the androgen- independent tumors occurred. In summary, these data demonstrate that CEP-751 or CEP-701, when combined with surgically or chemically induced androgen ablation, offer better antitumor efficacy than either monotherapy and suggest that each therapy produces prostate cancer cell death through complementary mechanisms.

Authors
George, DJ; Dionne, CA; Jani, J; Angeles, T; Murakata, C; Lamb, J; Isaacs, JT
MLA Citation
George, DJ, Dionne, CA, Jani, J, Angeles, T, Murakata, C, Lamb, J, and Isaacs, JT. "Sustained in vivo regression of Dunning H rat prostate cancers treated with combinations of androgen ablation and trk tyrosine kinase inhibitors, CEP-751 (KT-6587) or CEP-701 (KT-5555)." Cancer Research 59.10 (1999): 2395-2401.
PMID
10344749
Source
scival
Published In
Cancer Research
Volume
59
Issue
10
Publish Date
1999
Start Page
2395
End Page
2401

Mutational analysis of the TrkA gene in prostate cancer

BACKROUND. TrkA, the high affinity, tyrosine kinase receptor for nerve growth factor (NGF) has been implicated as an oncogene in several neoplasms. In prostate cancer, inhibitors of the NGF/TrkA signal pathway results in tumor growth inhibition. In contrast, inhibition of this trk pathway in the normal prostate produces no effect. One explanation for this difference between normal and malignant prostate is that TrkA is mutated in prostate cancer, changing its function. To test this possibility human primary prostate cancers were screened for evidence of mutations in the TrkA gene to identify how this gene might be activated in prostate cancer. METHODS. Single-strand conformation polymorphism was used to screen genomic DNA, isolated from 42 human primary prostate cancers. In samples in which an aberrant banding pattern was identified, the screen was repeated using both the tumor DNA and DNA isolated from normal tissue of the same patients. Genetic changes were confirmed by direct sequencing of the aberrantly migrating bands. RESULTS. Although somatic mutations were not identified in any of the exons screened, four polymorphisms were detected in three different exons. Some of these polymorphisms occurred in the majority of the patients screened, but their frequencies were similar when compared with DNA isolated from a control group. CONCLUSIONS. Genetic mutations of TrkA do not seem to play a significant role in activation of this pathway in prostate cancer. However, the absence of mutations in otherwise genetically unstable prostate tumor DNA suggests that intact NGF/TrkA pathways may be important in prostate cancer development.

Authors
George, DJ; Suzuki, H; Bova, GS; Isaacs, JT
MLA Citation
George, DJ, Suzuki, H, Bova, GS, and Isaacs, JT. "Mutational analysis of the TrkA gene in prostate cancer." Prostate 36.3 (1998): 172-180.
PMID
9687989
Source
scival
Published In
The Prostate
Volume
36
Issue
3
Publish Date
1998
Start Page
172
End Page
180
DOI
10.1002/(SICI)1097-0045(19980801)36:3<172::AID-PROS5>3.0.CO;2-J

Cell cycle-independent death of prostate adenocarcinoma is induced by the trk tyrosine kinase inhibitor CEP-751 (KT6587)

Advanced prostate cancer remains largely incurable, primarily because the very low growth fraction present in these tumors makes them generally resistant to treatment with standard chemotherapeutic agents that target cell division. Effective therapies should therefore induce death of prostate cancer cells, independent of their growth rate. trkA, the high-affinity tyrosine kinase-linked receptor for nerve growth factor, has been implicated in prostatic cancer growth and may represent a molecular target for therapeutic agents. At low mg/kg doses, the trk tyrosine kinase inhibitor CEP-751 (KT6587) inhibits prostatic cancer growth in nine different animal models independent of the tumor growth rate, androgen sensitivity, metastatic ability, or state of tumor differentiation. CEP-751 is selective for cancerous versus normal prostate cells and affects the growth of only a limited number of nonprostate tumors. Importantly, CEP-751 induces cell death of prostate cancer cells in a cell cycle-independent fashion and, therefore, represents a novel therapeutic approach to the management of both hormone- dependent and hormone-independent prostate cancer.

Authors
Dionne, CA; Camoratto, AM; Jani, JP; Emerson, E; Neff, N; Vaught, JL; Murakata, C; Djakiew, D; Lamb, J; Bova, S; George, D; Isaacs, JT
MLA Citation
Dionne, CA, Camoratto, AM, Jani, JP, Emerson, E, Neff, N, Vaught, JL, Murakata, C, Djakiew, D, Lamb, J, Bova, S, George, D, and Isaacs, JT. "Cell cycle-independent death of prostate adenocarcinoma is induced by the trk tyrosine kinase inhibitor CEP-751 (KT6587)." Clinical Cancer Research 4.8 (1998): 1887-1898.
PMID
9717816
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
4
Issue
8
Publish Date
1998
Start Page
1887
End Page
1898

Splenosis presenting as a mass on digital rectal examination

Authors
Dockery, WD; George, DJ; Rodriguez, R
MLA Citation
Dockery, WD, George, DJ, and Rodriguez, R. "Splenosis presenting as a mass on digital rectal examination." Journal of Urology 158.6 (1997): 2244--.
PMID
9366362
Source
scival
Published In
The Journal of Urology
Volume
158
Issue
6
Publish Date
1997
Start Page
2244-
DOI
10.1016/S0022-5347(01)68217-X

Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate

Prostate cancer is the second most common cause of death from cancer in U.S. men, and advanced, hormone-refractory disease is characterized by painful osteoblastic bone metastases. Endothelin-1, more commonly known as a potent vasoconstrictor, is a normal ejaculate protein that also stimulates osteoblasts. We show here that plasma immunoreactive endothelin concentrations are significantly elevated in men with metastatic prostate cancer and that every human prostate cancer cell line tested produces endothelin-1 messenger RNA and secretes immunoreactive endothelin. Exogenous endothelin-1 is a prostate cancer mitogen in vitro and increases alkaline phosphatase activity in new bone formation, indicating that ectopic endothelin-1 may be a mediator of the osteoblastic response of bone to metastatic prostate cancer.

Authors
Nelson, JB; Hedican, SP; George, DJ; Reddi, AH; Piantadosi, S; Eisenberger, MA; Simons, JW
MLA Citation
Nelson, JB, Hedican, SP, George, DJ, Reddi, AH, Piantadosi, S, Eisenberger, MA, and Simons, JW. "Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate." Nature Medicine 1.9 (1995): 944-949.
PMID
7585222
Source
scival
Published In
Nature Medicine
Volume
1
Issue
9
Publish Date
1995
Start Page
944
End Page
949

Membrane association of the myristoylated alanine-rich C kinase substrate (MARCKS) protein appears to involve myristate-dependent binding in the absence of a myristoyl protein receptor.

The myristoylated alanine-rich C kinase substrate, or MARCKS protein, has been implicated in several cellular processes, yet its physiological function remains unknown. We have studied the molecular basis of its membrane association in a cell-free system in order to help elucidate its regulation and function. First, we showed that the MARCKS protein incorporated [3H]myristate when its mRNA was translated in vitro in reticulocyte lysates. The myristoylated protein bound rapidly to freshly fractionated cell membranes, while a nonmyristoylated mutant associated to a much lesser extent (< 15% of wild type). To determine whether this binding was due to a specific cytoplasmic-face protein "receptor," as is seen with pp60v-src, we pretreated the membranes in several ways. Prior treatment of membranes with heat (100 degrees C for 3 min) or trypsin did not affect subsequent MARCKS binding. Binding was markedly decreased in 50 mM EDTA, 0.5 M NaCl, or 1.0% Triton X-100; it was restored to normal after removal of the NaCl and EDTA but was still decreased after removal of the Triton X-100. These findings argued against the existence of a protein receptor for the MARCKS protein on cellular membranes. Finally, MARCKS protein phosphorylated in vitro with protein kinase C bound to the cell membranes to the same extent as the nonphosphorylated protein; this binding was also unaffected by an excess of a synthetic peptide corresponding to the phosphorylation site domain of the protein. We conclude that, at least in this in vitro system, the membrane association of the MARCKS protein is primarily dependent on the amino-terminal myristate moiety and does not appear to involve a specific cytoplasmic-face protein receptor.

Authors
George, DJ; Blackshear, PJ
MLA Citation
George, DJ, and Blackshear, PJ. "Membrane association of the myristoylated alanine-rich C kinase substrate (MARCKS) protein appears to involve myristate-dependent binding in the absence of a myristoyl protein receptor." J Biol Chem 267.34 (December 5, 1992): 24879-24885.
PMID
1332970
Source
pubmed
Published In
The Journal of biological chemistry
Volume
267
Issue
34
Publish Date
1992
Start Page
24879
End Page
24885

Dissociation of thymidine incorporation and transferrin receptor expression from cell growth and c-myc accumulation in α-interferon-treated cells

α-Interferon is capable of altering the pattern of growth of both normal and neoplastic cells, but the pathways essential to sensitivity and resistance to α-interferon are unknown. To explore the growth inhibition induced by α-interferon, we examined the interferon-sensitive cell line Daudi and the resistant cell line HL-60. In Daudi, α-interferon induced a fall in c-myc mRNA accumulation at 24 h, inhibited tritiated thymidine ([3H]Thd) uptake at 48-72 h, and inhibited proliferation at 72-96 h. The half-life of c-myc mRNA was shortened from 31 to 13 min by α-interferon treatment. In HL-60, no alteration in c-myc accumulation or cell growth was observed, but [3H]Thd uptake was inhibited by 49%. Exogenous thymidine partially reversed the effects of α-interferon on [3H]Thd incorporation. The number of transferrin receptors, as measured by immunofluorescence, was unaffected by α-interferon in both cell lines. We conclude that the growth inhibitory effects of α-interferon are neither dependent upon inhibition of thymidine metabolism nor on expression of the transferrin receptor, but may be linked to control of c-myc.

Authors
Meadows, LM; George, DJ; Kaufman, RE
MLA Citation
Meadows, LM, George, DJ, and Kaufman, RE. "Dissociation of thymidine incorporation and transferrin receptor expression from cell growth and c-myc accumulation in α-interferon-treated cells." Journal of Biological Response Modifiers 9.2 (1990): 212-220.
PMID
2187953
Source
scival
Published In
Journal of Biological Response Modifiers
Volume
9
Issue
2
Publish Date
1990
Start Page
212
End Page
220
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