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Ready, Neal Edward

Positions:

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1983

Ph.D. — University of California at Irvine

M.D. 1986

M.D. — Vanderbilt University

Medical Resident, Medicine

Brown University

Fellow In Hematology Oncology, Medicine

Brown University

Fellow In Hematology Oncology, Medicine

Tufts University

Grants:

AFT_31_ALLIANCE FOUNDATION TRIAL

Administered By
Duke Cancer Institute
AwardedBy
Alliance Foundation Trials, LLC
Role
Principal Investigator
Start Date
June 02, 2017
End Date
February 28, 2022

BMS CA209817

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
January 17, 2017
End Date
October 31, 2021

TOP 1501

Administered By
Duke Cancer Institute
AwardedBy
Merck
Role
Principal Investigator
Start Date
September 01, 2016
End Date
August 31, 2021

BMS451

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2021

TRINITY

Administered By
Duke Cancer Institute
AwardedBy
Stem CentRx, Inc.
Role
Principal Investigator
Start Date
March 01, 2016
End Date
February 28, 2021

CheckMate 568

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
February 01, 2016
End Date
January 31, 2021

BMS-227

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
November 01, 2015
End Date
October 31, 2020

Condor

Administered By
Duke Cancer Institute
AwardedBy
AstraZeneca LP
Role
Principal Investigator
Start Date
October 01, 2015
End Date
September 30, 2020

BMS CA 209-331-001 An Open label, Randomized Phase 3 Study of Nivolumab or Chemo

Administered By
Duke Cancer Institute
AwardedBy
The Bristol-Myers/Sanofi Pharmaceuticals, Inc. Partnership
Role
Principal Investigator
Start Date
July 01, 2015
End Date
June 30, 2020

A phase II, multi-center, single-arm, global study of MEDI4736 monotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN)

Administered By
Duke Cancer Institute
AwardedBy
AstraZeneca Pharmaceuticals, LP
Role
Principal Investigator
Start Date
April 01, 2015
End Date
March 31, 2020

A phase 1 / 2 multicenter study of BMS-986012 in subjects with relapsed/refractory small cell lung cnacer

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
August 01, 2014
End Date
July 31, 2019

A Phase I study to evaluate the saftey, phamocokinetics and pharmacodynamics of JNJ-42756493 a pan-fibroblat growth fact

Administered By
Duke Cancer Institute
AwardedBy
Janssen Research & Development, LLC
Role
Principal Investigator
Start Date
August 01, 2014
End Date
July 30, 2019

An open label, randomized phase 3 clincal trial of Nivolumab vs therapy of investigator's choice in recurrent or metasti

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
March 01, 2014
End Date
February 28, 2019

A phase II, multicenter, single-arm study of MPDL3280A in patients with advanced PD-L1_positive Locally advanced or Meta

Administered By
Duke Cancer Institute
AwardedBy
Genentech, Inc.
Role
Principal Investigator
Start Date
October 01, 2013
End Date
September 30, 2018

Phase I/II open label dose escalation study of the safety, pharmacokinetics, and preliminary efficacy of SCI6D6.5 as a s

Administered By
Duke Cancer Institute
AwardedBy
Stem CentRx, Inc.
Role
Principal Investigator
Start Date
October 01, 2013
End Date
September 30, 2018

Evaluation of Tumor Infiltrating Lymphocytes in Resected Non Small Cell Lung Cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Lung Cancer Initiative of North Carolina
Role
Mentor
Start Date
July 01, 2015
End Date
June 30, 2018

An open-label, randomized, phase 3 trial of Nivolumab vs Investigator's choice chemotherapy as first-line therapy ofr st

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
February 01, 2014
End Date
December 31, 2017

Abbvie M14-361

Administered By
Duke Cancer Institute
AwardedBy
AbbVie Inc.
Role
Principal Investigator
Start Date
September 01, 2015
End Date
January 25, 2017

Programs in Clinical Effectiveness of Cancer Pharmacogenomics

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 30, 2009
End Date
August 31, 2012

Refining and Validating Genomic Signatures in Lung Cancer

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
August 14, 2009
End Date
December 31, 2010
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Publications:

Long-Term Survival after Complete Surgical Resection and Adjuvant Immunotherapy for Distant Melanoma Metastases

© 2017 Society of Surgical Oncology Background: This phase III study was undertaken to evaluate the efficacy of an allogeneic whole-cell vaccine (Canvaxin™) plus bacillus Calmette-Guerin (BCG) after complete resection of stage IV melanoma. Methods: After complete resection of ≤5 distant metastases, patients were randomly assigned to BCG+Canvaxin (BCG/Cv) or BCG+placebo (BCG/Pl). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and immune response measured by skin test (ClinicalTrials.gov identifier: NCT00052156). Results: Beginning in May 1998, 496 patients were randomized. In April 2005, the Data Safety Monitoring Board recommended stopping enrollment due to a low probability of efficacy. At that time, median OS and 5-year OS rate were 38.6 months and 44.9%, respectively, for BCG/Pl versus 31.4 months and 39.6% in the BCG/Cv group (hazard ratio (HR), 1.18; p = 0.250). Follow-up was extended at several trial sites through March 2010. Median OS and 5-year and 10-year survival was 39.1 months, 43.3 and 33.3%, respectively, for BCG/Pl versus 34.9 months, 42.5 and 36.4%, in the BCG/Cv group (HR 1.053; p = 0.696). Median DFS, 5- and 10-year DFS were 7.6 months, 23.8 and 21.7%, respectively, for BCG/Pl versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG/Cv group (HR 0.882; p = 0.260). Positive DTH skin testing correlated with increased survival. Discussion: In this, the largest study of postsurgical adjuvant therapy for stage IV melanoma reported to date, BCG/Cv did not improve outcomes over BCG/placebo. Favorable long-term survival among study patients suggests that metastasectomy should be considered for selected patients with stage IV melanoma.

Authors
Faries, MB; Mozzillo, N; Kashani-Sabet, M; Thompson, JF; Kelley, MC; DeConti, RC; Lee, JE; Huth, JF; Wagner, J; Dalgleish, A; Pertschuk, D; Nardo, C; Stern, S; Elashoff, R; Gammon, G; Morton, DL; Thompson, JF; Smithers, M; Hughes, M; Coventry, BJ; Shapiro, J; McArthur, G; Buzaid, A; Miller, W; Schadendorf, D; Garbe, C; Kaatz, M; Peter, RU; Terheyden, P; Dalgleish, A; Redmond, P; Schneebaum, S; Mozzillo, N; Testori, A; Santinami, M; Hoekstra, HJ; McCrystal, M; Dummer, R; Kashani-Sabet, M et al.
MLA Citation
Faries, MB, Mozzillo, N, Kashani-Sabet, M, Thompson, JF, Kelley, MC, DeConti, RC, Lee, JE, Huth, JF, Wagner, J, Dalgleish, A, Pertschuk, D, Nardo, C, Stern, S, Elashoff, R, Gammon, G, Morton, DL, Thompson, JF, Smithers, M, Hughes, M, Coventry, BJ, Shapiro, J, McArthur, G, Buzaid, A, Miller, W, Schadendorf, D, Garbe, C, Kaatz, M, Peter, RU, Terheyden, P, Dalgleish, A, Redmond, P, Schneebaum, S, Mozzillo, N, Testori, A, Santinami, M, Hoekstra, HJ, McCrystal, M, Dummer, R, and Kashani-Sabet, M et al. "Long-Term Survival after Complete Surgical Resection and Adjuvant Immunotherapy for Distant Melanoma Metastases (Accepted)." Annals of Surgical Oncology (October 10, 2017): 1-10.
Source
scopus
Published In
Annals of Surgical Oncology
Publish Date
2017
Start Page
1
End Page
10
DOI
10.1245/s10434-017-6072-3

Pooled Analysis of Individual Patient Data on Concurrent Chemoradiotherapy for Stage III Non-Small-Cell Lung Cancer in Elderly Patients Compared With Younger Patients Who Participated in US National Cancer Institute Cooperative Group Studies.

Purpose Concurrent chemoradiotherapy is standard treatment for patients with stage III non-small-cell lung cancer. Elderly patients may experience increased rates of adverse events (AEs) or less benefit from concurrent chemoradiotherapy. Patients and Methods Individual patient data were collected from 16 phase II or III trials conducted by US National Cancer Institute-supported cooperative groups of concurrent chemoradiotherapy alone or with consolidation or induction chemotherapy for stage III non-small-cell lung cancer from 1990 to 2012. Overall survival (OS), progression-free survival, and AEs were compared between patients age ≥ 70 (elderly) and those younger than 70 years (younger). Unadjusted and adjusted hazard ratios (HRs) for survival time and CIs were estimated by single-predictor and multivariable frailty Cox models. Unadjusted and adjusted odds ratio (ORs) for AEs and CIs were obtained from single-predictor and multivariable generalized linear mixed-effect models. Results A total of 2,768 patients were classified as younger and 832 as elderly. In unadjusted and multivariable models, elderly patients had worse OS (HR, 1.20; 95% CI, 1.09 to 1.31 and HR, 1.17; 95% CI, 1.07 to 1.29, respectively). In unadjusted and multivariable models, elderly and younger patients had similar progression-free survival (HR, 1.01; 95% CI, 0.93 to 1.10 and HR, 1.00; 95% CI, 0.91 to 1.09, respectively). Elderly patients had a higher rate of grade ≥ 3 AEs in unadjusted and multivariable models (OR, 1.35; 95% CI, 1.07 to 1.70 and OR, 1.38; 95% CI, 1.10 to 1.74, respectively). Grade 5 AEs were significantly higher in elderly compared with younger patients (9% v 4%; P < .01). Fewer elderly compared with younger patients completed treatment (47% v 57%; P < .01), and more discontinued treatment because of AEs (20% v 13%; P < .01), died during treatment (7.8% v 2.9%; P < .01), and refused further treatment (5.8% v 3.9%; P = .02). Conclusion Elderly patients in concurrent chemoradiotherapy trials experienced worse OS, more toxicity, and had a higher rate of death during treatment than younger patients.

Authors
Stinchcombe, TE; Zhang, Y; Vokes, EE; Schiller, JH; Bradley, JD; Kelly, K; Curran, WJ; Schild, SE; Movsas, B; Clamon, G; Govindan, R; Blumenschein, GR; Socinski, MA; Ready, NE; Akerley, WL; Cohen, HJ; Pang, HH; Wang, X
MLA Citation
Stinchcombe, TE, Zhang, Y, Vokes, EE, Schiller, JH, Bradley, JD, Kelly, K, Curran, WJ, Schild, SE, Movsas, B, Clamon, G, Govindan, R, Blumenschein, GR, Socinski, MA, Ready, NE, Akerley, WL, Cohen, HJ, Pang, HH, and Wang, X. "Pooled Analysis of Individual Patient Data on Concurrent Chemoradiotherapy for Stage III Non-Small-Cell Lung Cancer in Elderly Patients Compared With Younger Patients Who Participated in US National Cancer Institute Cooperative Group Studies." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 35.25 (September 2017): 2885-2892.
PMID
28493811
Source
epmc
Published In
Journal of Clinical Oncology
Volume
35
Issue
25
Publish Date
2017
Start Page
2885
End Page
2892
DOI
10.1200/jco.2016.71.4758

Patterns of Failure After Surgery for Non-Small-cell Lung Cancer Invading the Chest Wall.

The patterns of failure after resection of non-small-cell lung cancer (NSCLC) invading the chest wall are not well documented, and the role of adjuvant radiation therapy (RT) is unclear, prompting the present analysis.The present institutional review board-approved study evaluated patients who had undergone surgery from 1995 to 2014 for localized NSCLC invading the chest wall. Patients with superior sulcus tumors were excluded. The clinical outcomes were estimated using the Kaplan-Meier method and compared using a log-rank test. The prognostic factors were assessed using a multivariate analysis, and the patterns of failure were scored.Seventy-four patients were evaluated. Most patients had undergone lobectomy or pneumonectomy (85%) with en bloc chest wall resection (80%) and had pathologically node negative findings (81%). The surgical margins were positive in 10 patients (14%) and most commonly involved the chest wall (7 of 10). Adjuvant treatment included RT in 21 (28%) and chemotherapy in 28 (38%). A total of 24 local recurrences developed. The chest wall was a component of local disease recurrence in 19 of 24 cases (79%). The local control rate at 5 years for the entire population was 60% (95% confidence interval, 46%-74%). The local control rate was 74% with adjuvant RT versus 55% without RT (P = .43). On multivariate analysis, only resection less than lobectomy or pneumonectomy was associated with worse local control. The overall survival rate was 38% with RT versus 34% without RT (P = .59).Positive surgical margins and local disease recurrence were common after resection of NSCLC invading the chest wall. The primary pattern of failure was local recurrence in the chest wall. Adjuvant RT was not associated with improved local control or survival.

Authors
Tandberg, DJ; Kelsey, CR; D'Amico, TA; Crawford, J; Chino, JP; Tong, BC; Ready, NE; Wright, A
MLA Citation
Tandberg, DJ, Kelsey, CR, D'Amico, TA, Crawford, J, Chino, JP, Tong, BC, Ready, NE, and Wright, A. "Patterns of Failure After Surgery for Non-Small-cell Lung Cancer Invading the Chest Wall." Clinical lung cancer 18.4 (July 2017): e259-e265.
PMID
27965012
Source
epmc
Published In
Clinical lung cancer
Volume
18
Issue
4
Publish Date
2017
Start Page
e259
End Page
e265
DOI
10.1016/j.cllc.2016.11.008

Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs.

mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities involved in mRNA degradation genes were found to be associated with cancer risks. Therefore, we systematically investigated the roles of genetic variants in the general mRNA degradation pathway in lung cancer risk.Meta-analyses were conducted using summary data from six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci.This pathway-based analysis included 6816 single nucleotide polymorphisms (SNP) in 68 genes in 14 463 lung cancer cases and 44 188 controls. In the single-locus analysis, we found that 20 SNPs were associated with lung cancer risk with a false discovery rate threshold of <0.05. Among the 11 newly identified SNPs in CNOT6, which were in high linkage disequilibrium, the rs2453176 with a RegulomDB score "1f" was chosen as the tagSNP for further analysis. We found that the rs2453176 T allele was significantly associated with lung cancer risk (odds ratio = 1.11, 95% confidence interval = 1.04-1.18) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association.The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk. © 2016 Wiley Periodicals, Inc.

Authors
Zhou, F; Wang, Y; Liu, H; Ready, N; Han, Y; Hung, RJ; Brhane, Y; McLaughlin, J; Brennan, P; Bickeböller, H; Rosenberger, A; Houlston, RS; Caporaso, N; Landi, MT; Brüske, I; Risch, A; Ye, Y; Wu, X; Christiani, DC; Goodman, G; Chen, C; Transdisciplinary Research in Cancer of the Lung (TRICL) Research Team, ; Amos, CI; Wei, Q
MLA Citation
Zhou, F, Wang, Y, Liu, H, Ready, N, Han, Y, Hung, RJ, Brhane, Y, McLaughlin, J, Brennan, P, Bickeböller, H, Rosenberger, A, Houlston, RS, Caporaso, N, Landi, MT, Brüske, I, Risch, A, Ye, Y, Wu, X, Christiani, DC, Goodman, G, Chen, C, Transdisciplinary Research in Cancer of the Lung (TRICL) Research Team, , Amos, CI, and Wei, Q. "Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs." Molecular carcinogenesis 56.4 (April 2017): 1227-1238.
PMID
27805284
Source
epmc
Published In
Molecular Carcinogenesis
Volume
56
Issue
4
Publish Date
2017
Start Page
1227
End Page
1238
DOI
10.1002/mc.22585

Phase II Study of Dasatinib in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer.

The Src pathway in activated in about one-third of non-small cell lung cancer (NSCLC) tumors. Dasatinib has Src-inhibitor activity. We examined the activity of dasatinib in 37 patients with advanced, previously treated NSCLC. Among the 29 patients who underwent pre-treatment biopsy for RNA biomarker analysis, 25 were treated with dasatinib 70 mg twice daily. There were no responses. Five patients discontinued treatment due to toxicity. Three patients had minor biopsy-related pneumothoraces. Given the lack of responses, no biomarkers were analyzed. Dasatinib 70 mg twice daily does not have activity nor is it well tolerated in unselected patients with advanced stage, previously treated NSCLC.

Authors
Kelley, MJ; Jha, G; Shoemaker, D; Herndon, JE; Gu, L; Barry, WT; Crawford, J; Ready, N
MLA Citation
Kelley, MJ, Jha, G, Shoemaker, D, Herndon, JE, Gu, L, Barry, WT, Crawford, J, and Ready, N. "Phase II Study of Dasatinib in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer." Cancer investigation 35.1 (January 2017): 32-35.
PMID
27911119
Source
epmc
Published In
Cancer Investigation (Informa)
Volume
35
Issue
1
Publish Date
2017
Start Page
32
End Page
35
DOI
10.1080/07357907.2016.1253710

Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study.

Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen.We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer.Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells).Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted.Stemcentrx Inc.

Authors
Rudin, CM; Pietanza, MC; Bauer, TM; Ready, N; Morgensztern, D; Glisson, BS; Byers, LA; Johnson, ML; Burris, HA; Robert, F; Han, TH; Bheddah, S; Theiss, N; Watson, S; Mathur, D; Vennapusa, B; Zayed, H; Lally, S; Strickland, DK; Govindan, R; Dylla, SJ; Peng, SL; Spigel, DR; SCRX16-001 investigators,
MLA Citation
Rudin, CM, Pietanza, MC, Bauer, TM, Ready, N, Morgensztern, D, Glisson, BS, Byers, LA, Johnson, ML, Burris, HA, Robert, F, Han, TH, Bheddah, S, Theiss, N, Watson, S, Mathur, D, Vennapusa, B, Zayed, H, Lally, S, Strickland, DK, Govindan, R, Dylla, SJ, Peng, SL, Spigel, DR, and SCRX16-001 investigators, . "Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study." The Lancet. Oncology 18.1 (January 2017): 42-51.
PMID
27932068
Source
epmc
Published In
The Lancet Oncology
Volume
18
Issue
1
Publish Date
2017
Start Page
42
End Page
51
DOI
10.1016/s1470-2045(16)30565-4

Quantifying the Dynamics of Field Cancerization in Tobacco-Related Head and Neck Cancer: A Multiscale Modeling Approach.

High rates of local recurrence in tobacco-related head and neck squamous cell carcinoma (HNSCC) are commonly attributed to unresected fields of precancerous tissue. Because they are not easily detectable at the time of surgery without additional biopsies, there is a need for noninvasive methods to predict the extent and dynamics of these fields. Here, we developed a spatial stochastic model of tobacco-related HNSCC at the tissue level and calibrated the model using a Bayesian framework and population-level incidence data from the Surveillance, Epidemiology, and End Results (SEER) registry. Probabilistic model analyses were performed to predict the field geometry at time of diagnosis, and model predictions of age-specific recurrence risks were tested against outcome data from SEER. The calibrated models predicted a strong dependence of the local field size on age at diagnosis, with a doubling of the expected field diameter between ages at diagnosis of 50 and 90 years, respectively. Similarly, the probability of harboring multiple, clonally unrelated fields at the time of diagnosis was found to increase substantially with patient age. On the basis of these findings, we hypothesized a higher recurrence risk in older than in younger patients when treated by surgery alone; we successfully tested this hypothesis using age-stratified outcome data. Further clinical studies are needed to validate the model predictions in a patient-specific setting. This work highlights the importance of spatial structure in models of epithelial carcinogenesis and suggests that patient age at diagnosis may be a critical predictor of the size and multiplicity of precancerous lesions. Cancer Res; 76(24); 7078-88. ©2016 AACR.

Authors
Ryser, MD; Lee, WT; Ready, NE; Leder, KZ; Foo, J
MLA Citation
Ryser, MD, Lee, WT, Ready, NE, Leder, KZ, and Foo, J. "Quantifying the Dynamics of Field Cancerization in Tobacco-Related Head and Neck Cancer: A Multiscale Modeling Approach." Cancer research 76.24 (December 2016): 7078-7088.
PMID
27913438
Source
epmc
Published In
Cancer Research
Volume
76
Issue
24
Publish Date
2016
Start Page
7078
End Page
7088
DOI
10.1158/0008-5472.can-16-1054

Toxicity of definitive and post-operative radiation following ipilimumab in non-small cell lung cancer.

To determine the feasibility and toxicity of radiation therapy, delivered either as definitive treatment or following surgery, following neo-adjuvant immune checkpoint inhibition for locally advanced NSCLC sixteen patients who received neo-adjuvant chemotherapy including ipilimumab as part of a phase II study were identified. Patients were analyzed by intent of radiation and toxicity graded based on CTCAE 4.0. There were seven patients identified who received definitive radiation and nine who received post-operative radiation. There was no grade 3 or greater toxicity in the definitive treatment group although one patient stopped treatment early due to back pain secondary to progression outside of the treatment field. In the post-operative treatment group, one patient required a one week break due to grade 2 odynophagia and no grade 3 or greater toxicity was observed. In this study of radiation as definitive or post-operative treatment following neo-adjuvant chemotherapy including ipilimumab for locally advanced NSCLC was feasible and well tolerated with limited toxicity.

Authors
Boyer, MJ; Gu, L; Wang, X; Kelsey, CR; Yoo, DS; Onaitis, MW; Dunphy, FR; Crawford, J; Ready, NE; Salama, JK
MLA Citation
Boyer, MJ, Gu, L, Wang, X, Kelsey, CR, Yoo, DS, Onaitis, MW, Dunphy, FR, Crawford, J, Ready, NE, and Salama, JK. "Toxicity of definitive and post-operative radiation following ipilimumab in non-small cell lung cancer." Lung cancer (Amsterdam, Netherlands) 98 (August 2016): 76-78.
PMID
27393510
Source
epmc
Published In
Lung Cancer
Volume
98
Publish Date
2016
Start Page
76
End Page
78
DOI
10.1016/j.lungcan.2016.05.014

Genetic variants in ABCG1 are associated with survival of nonsmall-cell lung cancer patients.

Cell membrane transporters and metabolic enzymes play a crucial role in the transportation of a wide variety of substrates that maintain homeostasis in biological processes. We explored associations between genetic variants in these genes and survival of nonsmall-cell lung cancer (NSCLC) patients by reanalyzing two datasets from published genome-wide association studies (GWASs). In the discovery by using the GWAS dataset of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, we evaluated associations of 1,245 single-nucleotide polymorphisms (SNPs) in genes of four transporter families and two metabolic enzyme families with survival of 1,185 NSCLC patients. We then performed a replication analysis in the Harvard University Lung Cancer study (LCS) with 984 NSCLC patients. Multivariate Cox proportional hazards regression and false discovery rate (FDR) corrections were performed to evaluate the associations. We identified that 21 genotyped SNPs in eight gene regions were significantly associated with survival with FDR ≤ 0.1 in the discovery dataset. Subsequently, we confirmed six SNPs, which were putative functional, in ABCG1 of the ATP-binding cassette transporter family in the replication dataset. In the pooled analysis, two tagging (at r(2)  > 0.8 for linkage disequilibrium with other replicated SNPs)/functional SNPs were independently associated with survival: rs225388 G > A [adjusted hazards ratio (HR) = 1.12, 95% confidence interval (CI) = 1.03-1.20, Ptrend  = 4.6 × 10(-3)] and rs225390 A > G (adjusted HR = 1.16, 95% CI = 1.07-1.25, Ptrend  = 3.8 × 10(-4) ). Our results indicated that genetic variants of ABCG1 may be predictors of survival of NSCLC patients.

Authors
Wang, Y; Liu, H; Ready, NE; Su, L; Wei, Y; Christiani, DC; Wei, Q
MLA Citation
Wang, Y, Liu, H, Ready, NE, Su, L, Wei, Y, Christiani, DC, and Wei, Q. "Genetic variants in ABCG1 are associated with survival of nonsmall-cell lung cancer patients." International journal of cancer 138.11 (June 2016): 2592-2601.
PMID
26757251
Source
epmc
Published In
International Journal of Cancer
Volume
138
Issue
11
Publish Date
2016
Start Page
2592
End Page
2601
DOI
10.1002/ijc.29991

Adaptive planning using positron emission tomography for locally advanced lung cancer: A feasibility study.

To evaluate the feasibility of adaptive planning using positron emission tomography-computed tomography (PET-CT) in locally advanced non-small cell lung cancer.Patients with locally advanced non-small cell lung cancer receiving definitive radiation therapy (RT) were eligible. Initial planning PET-CT was performed and a conventional RT plan (2 Gy/fraction to 60 Gy) was designed. A second planning PET-CT was obtained at ~50 Gy. Dose escalation to ~70 Gy for residual fludeoxyglucose-avid disease was pursued at the discretion of the treating oncologists. The primary endpoint was feasibility of adaptive planning using interim PET-CT. Normal tissue dose-volume parameters were calculated for both adaptive and simulated nonadaptive plans.From 2012 to 2014, 33 eligible patients were enrolled and underwent planning PET-CT, 3 of which were found to have new distant metastases. Of 30 patients who initiated RT, interim PET-CT was obtained in 29. This showed complete response in 2 patients, partial response/stable disease in 24, and new distant metastases in 3. Selective dose escalation was performed in 17 patients. For those receiving a boost, the median gross tumor volumes pre-RT and at ~50 Gy were 78 mL and 29 mL, respectively (P = .01). Reasons for no dose escalation were normal tissue constraints (n = 3), poorly defined residual disease (n = 2), acute toxicity (n = 1), and refusal of further therapy (n = 1). Adaptive planning compared with a simulated nonadaptive approach allowed for significant dose reductions to the lungs, heart, and esophagus (all P < .01).Adaptive planning using PET-CT was feasible and allows for significant dose reductions to normal tissues compared with traditional planning techniques.

Authors
Kelsey, CR; Christensen, JD; Chino, JP; Adamson, J; Ready, NE; Perez, BA
MLA Citation
Kelsey, CR, Christensen, JD, Chino, JP, Adamson, J, Ready, NE, and Perez, BA. "Adaptive planning using positron emission tomography for locally advanced lung cancer: A feasibility study." Practical radiation oncology 6.2 (March 2016): 96-104.
PMID
26723555
Source
epmc
Published In
Practical Radiation Oncology
Volume
6
Issue
2
Publish Date
2016
Start Page
96
End Page
104
DOI
10.1016/j.prro.2015.10.009

Positive Interaction between Prophylactic Cranial Irradiation and Maintenance Sunitinib for Untreated Extensive-Stage Small Cell Lung Cancer Patients After Standard Chemotherapy: A Secondary Analysis of CALGB 30504 (ALLIANCE).

Prophylactic cranial irradiation (PCI) has become a standard option for patients with extensive-stage small cell lung cancer (ES-SCLC). The Cancer and Leukemia Group B 30504 trial was a randomized phase II study of the effect of sunitinib versus placebo in ES-SCLC patients responding to platinum-based systemic therapy. The study required preenrollment brain imaging. PCI was provided at the discretion of treating physicians. We performed a secondary analysis of the Cancer and Leukemia Group B trial to determine the impact of PCI on patients with ES-SCLC.Fisher's exact test and the Wilcoxon rank-sum test were conducted to identify the differences between patients receiving PCI and patients not receiving PCI. Kaplan-Meier analyses described progression-free survival (PFS) and overall survival (OS) for patients in the PCI and non-PCI groups.A total of 85 patients received maintenance therapy (41 received placebo and 44 received sunitinib). Patient characteristics were balanced between the PCI and non-PCI groups. The patients receiving PCI plus sunitinib had a nonsignificant 2.7-month improvement in PFS (5.0 months versus 2.3 months, p = 0.14, hazard risk [HR] = 0.62, 95% confidence interval [CI]: 0.33-1.18) trending toward improved OS (8.9 months versus 5.4 months, p = 0.053, HR = 0.47, 95% CI: 0.22-1.03). PCI was associated with a trend toward improved median PFS (2.9 months versus 2.2 months, p = 0.096, HR = 0.69, 95% CI: 0.45-1.07) but not median OS (8.3 months in the PCI group versus 8.7 months in the non-PCI group, p = 0.76, HR = 1.07, 95% CI: 0.67-1.71). The patients receiving placebo had no improvement in PFS or OS with PCI.Trends toward improved PFS and OS were seen in patients receiving PCI and sunitinib, thus supporting the need for further prospective research evaluating the integration of maintenance systemic therapy and PCI for patients with ES-SCLC. Improved outcomes for patients with ES-SCLC after induction chemotherapy may require PCI, thoracic radiotherapy, and maintenance systemic therapy to achieve control of both intracranial and extracranial disease.

Authors
Salama, JK; Gu, L; Wang, X; Pang, HH; Bogart, JA; Crawford, J; Schild, SE; Vokes, EE; Ready, NE
MLA Citation
Salama, JK, Gu, L, Wang, X, Pang, HH, Bogart, JA, Crawford, J, Schild, SE, Vokes, EE, and Ready, NE. "Positive Interaction between Prophylactic Cranial Irradiation and Maintenance Sunitinib for Untreated Extensive-Stage Small Cell Lung Cancer Patients After Standard Chemotherapy: A Secondary Analysis of CALGB 30504 (ALLIANCE)." Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 11.3 (March 2016): 361-369.
PMID
26723241
Source
epmc
Published In
Journal of Thoracic Oncology
Volume
11
Issue
3
Publish Date
2016
Start Page
361
End Page
369
DOI
10.1016/j.jtho.2015.11.001

Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome.

Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS.The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79).Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel.ClinicalTrials.gov identifier: NCT00699998.

Authors
Roe, MT; Cyr, DD; Eckart, D; Schulte, PJ; Morse, MA; Blackwell, KL; Ready, NE; Zafar, SY; Beaven, AW; Strickler, JH; Onken, JE; Winters, KJ; Houterloot, L; Zamoryakhin, D; Wiviott, SD; White, HD; Prabhakaran, D; Fox, KAA; Armstrong, PW; Ohman, EM; TRILOGY ACS Investigators,
MLA Citation
Roe, MT, Cyr, DD, Eckart, D, Schulte, PJ, Morse, MA, Blackwell, KL, Ready, NE, Zafar, SY, Beaven, AW, Strickler, JH, Onken, JE, Winters, KJ, Houterloot, L, Zamoryakhin, D, Wiviott, SD, White, HD, Prabhakaran, D, Fox, KAA, Armstrong, PW, Ohman, EM, and TRILOGY ACS Investigators, . "Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome." European heart journal 37.4 (January 2016): 412-422.
PMID
26637834
Source
epmc
Published In
European Heart Journal (Elsevier)
Volume
37
Issue
4
Publish Date
2016
Start Page
412
End Page
422
DOI
10.1093/eurheartj/ehv611

Phase 1 Dose Escalation Study of Accelerated Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Lung Cancer.

To determine the maximum tolerated dose of radiation therapy (RT) given in an accelerated fashion with concurrent chemotherapy using intensity modulated RT.Patients with locally advanced lung cancer (non-small cell and small cell) with good performance status and minimal weight loss received concurrent cisplatin and etoposide with RT. Intensity modulated RT with daily image guidance was used to facilitate esophageal avoidance and delivered using 6 fractions per week (twice daily on Fridays with a 6-hour interval). The dose was escalated from 58 Gy to a planned maximum dose of 74 Gy in 4 Gy increments in a standard 3 + 3 trial design. Dose-limiting toxicity (DLT) was defined as acute grade 3-5 nonhematologic toxicity attributed to RT.A total of 24 patients were enrolled, filling all dose cohorts, all completing RT and chemotherapy as prescribed. Dose-limiting toxicity occurred in 1 patient at 58 Gy (grade 3 esophagitis) and 1 patient at 70 Gy (grade 3 esophageal fistula). Both patients with DLTs had large tumors (12 cm and 10 cm, respectively) adjacent to the esophagus. Three additional patients were enrolled at both dose cohorts without further DLT. In the final 74-Gy cohort, no DLTs were observed (0 of 6).Dose escalation and acceleration to 74 Gy with intensity modulated RT and concurrent chemotherapy was tolerable, with a low rate of grade ≥3 acute esophageal reactions.

Authors
Kelsey, CR; Das, S; Gu, L; Dunphy, FR; Ready, NE; Marks, LB
MLA Citation
Kelsey, CR, Das, S, Gu, L, Dunphy, FR, Ready, NE, and Marks, LB. "Phase 1 Dose Escalation Study of Accelerated Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Lung Cancer." International journal of radiation oncology, biology, physics 93.5 (December 2015): 997-1004.
PMID
26581138
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
93
Issue
5
Publish Date
2015
Start Page
997
End Page
1004
DOI
10.1016/j.ijrobp.2015.09.007

Surrogate clinical endpoints to predict overall survival in non-small cell lung cancer trials-are we in a new era?

Surrogate endpoints for clinical trials in oncology offer an alternative metric for measuring clinical benefit, allowing for shorter trial duration, smaller patient cohorts, and single arm design. The correlation of surrogate endpoints with overall survival (OS) in therapeutic studies is a central consideration to their validity. The Food and Drug Administration (FDA) recently published an analysis of fourteen clinical trials in advanced non-small cell lung cancer (NSCLC), and discovered a strong association between response rate and progression free survival. Furthermore, a correlation between response rate and OS is demonstrated when analyzing the experimental treatment arm separately, minimizing bias from patient crossover. We also highlight multiple, important considerations when using response as an endpoint in clinical trials involving NSCLC patients.

Authors
Clarke, JM; Wang, X; Ready, NE
MLA Citation
Clarke, JM, Wang, X, and Ready, NE. "Surrogate clinical endpoints to predict overall survival in non-small cell lung cancer trials-are we in a new era?." Translational lung cancer research 4.6 (December 2015): 804-808.
PMID
26798592
Source
epmc
Published In
Translational lung cancer research
Volume
4
Issue
6
Publish Date
2015
Start Page
804
End Page
808
DOI
10.3978/j.issn.2218-6751.2015.05.03

Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.

Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity.In this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non-small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival.Overall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab versus 39% (95% CI, 33 to 45) with docetaxel. With additional follow-up, the overall survival rate at 18 months was 39% (95% CI, 34 to 45) with nivolumab versus 23% (95% CI, 19 to 28) with docetaxel. The response rate was 19% with nivolumab versus 12% with docetaxel (P=0.02). Although progression-free survival did not favor nivolumab over docetaxel (median, 2.3 months and 4.2 months, respectively), the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel (19% and 8%, respectively). Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (≥1%, ≥5%, and ≥10%) of the PD-1 ligand. Treatment-related adverse events of grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as compared with 54% of those in the docetaxel group.Among patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy, overall survival was longer with nivolumab than with docetaxel. (Funded by Bristol-Myers Squibb; CheckMate 057 ClinicalTrials.gov number, NCT01673867.).

Authors
Borghaei, H; Paz-Ares, L; Horn, L; Spigel, DR; Steins, M; Ready, NE; Chow, LQ; Vokes, EE; Felip, E; Holgado, E; Barlesi, F; Kohlhäufl, M; Arrieta, O; Burgio, MA; Fayette, J; Lena, H; Poddubskaya, E; Gerber, DE; Gettinger, SN; Rudin, CM; Rizvi, N; Crinò, L; Blumenschein, GR; Antonia, SJ; Dorange, C; Harbison, CT; Graf Finckenstein, F; Brahmer, JR
MLA Citation
Borghaei, H, Paz-Ares, L, Horn, L, Spigel, DR, Steins, M, Ready, NE, Chow, LQ, Vokes, EE, Felip, E, Holgado, E, Barlesi, F, Kohlhäufl, M, Arrieta, O, Burgio, MA, Fayette, J, Lena, H, Poddubskaya, E, Gerber, DE, Gettinger, SN, Rudin, CM, Rizvi, N, Crinò, L, Blumenschein, GR, Antonia, SJ, Dorange, C, Harbison, CT, Graf Finckenstein, F, and Brahmer, JR. "Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer." The New England journal of medicine 373.17 (October 2015): 1627-1639.
PMID
26412456
Source
epmc
Published In
The New England journal of medicine
Volume
373
Issue
17
Publish Date
2015
Start Page
1627
End Page
1639
DOI
10.1056/nejmoa1507643

Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.

Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population.We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival.The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P=0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group.Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.).

Authors
Brahmer, J; Reckamp, KL; Baas, P; Crinò, L; Eberhardt, WEE; Poddubskaya, E; Antonia, S; Pluzanski, A; Vokes, EE; Holgado, E; Waterhouse, D; Ready, N; Gainor, J; Arén Frontera, O; Havel, L; Steins, M; Garassino, MC; Aerts, JG; Domine, M; Paz-Ares, L; Reck, M; Baudelet, C; Harbison, CT; Lestini, B; Spigel, DR
MLA Citation
Brahmer, J, Reckamp, KL, Baas, P, Crinò, L, Eberhardt, WEE, Poddubskaya, E, Antonia, S, Pluzanski, A, Vokes, EE, Holgado, E, Waterhouse, D, Ready, N, Gainor, J, Arén Frontera, O, Havel, L, Steins, M, Garassino, MC, Aerts, JG, Domine, M, Paz-Ares, L, Reck, M, Baudelet, C, Harbison, CT, Lestini, B, and Spigel, DR. "Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer." The New England journal of medicine 373.2 (July 2015): 123-135.
PMID
26028407
Source
epmc
Published In
The New England journal of medicine
Volume
373
Issue
2
Publish Date
2015
Start Page
123
End Page
135
DOI
10.1056/nejmoa1504627

Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study-CALGB 30504 (Alliance).

To evaluate the efficacy of maintenance sunitinib after chemotherapy for small-cell lung cancer (SCLC).The Cancer and Leukemia Group B 30504 trial was a randomized, placebo-controlled, phase II study that enrolled patients before chemotherapy (cisplatin 80 mg/m(2) or carboplatin area under the curve of 5 on day 1 plus etoposide 100 mg/m(2) per day on days 1 to 3 every 21 days for four to six cycles). Patients without progression were randomly assigned 1:1 to placebo or sunitinib 37.5 mg per day until progression. Cross-over after progression was allowed. The primary end point was progression-free survival (PFS) from random assignment for maintenance placebo versus sunitinib using a one-sided log-rank test with α = .15; 80 randomly assigned patients provided 89% power to detect a hazard ratio (HR) of 1.67.One hundred forty-four patients were enrolled; 138 patients received chemotherapy. Ninety-five patients were randomly assigned; 10 patients did not receive maintenance therapy (five on each arm). Eighty-five patients received maintenance therapy (placebo, n = 41; sunitinib, n = 44). Grade 3 adverse events with more than 5% incidence were fatigue (19%), decreased neutrophils (14%), decreased leukocytes (7%), and decreased platelets (7%) for sunitinib and fatigue (10%) for placebo; grade 4 adverse events were GI hemorrhage (n = 1) and pancreatitis, hypocalcemia, and elevated lipase (n = 1; all in same patient) for sunitinib and thrombocytopenia (n = 1) and hypernatremia (n = 1) for placebo. Median PFS on maintenance was 2.1 months for placebo and 3.7 months for sunitinib (HR, 1.62; 70% CI, 1.27 to 2.08; 95% CI, 1.02 to 2.60; one-sided P = .02). Median overall survival from random assignment was 6.9 months for placebo and 9.0 months for sunitinib (HR, 1.28; 95% CI, 0.79 to 2.10; one-sided P = .16). Three sunitinib and no placebo patients achieved complete response during maintenance. Ten (77%) of 13 patients evaluable after cross-over had stable disease on sunitinib (6 to 27 weeks).Maintenance sunitinib was safe and improved PFS in extensive-stage SCLC.

Authors
Ready, NE; Pang, HH; Gu, L; Otterson, GA; Thomas, SP; Miller, AA; Baggstrom, M; Masters, GA; Graziano, SL; Crawford, J; Bogart, J; Vokes, EE
MLA Citation
Ready, NE, Pang, HH, Gu, L, Otterson, GA, Thomas, SP, Miller, AA, Baggstrom, M, Masters, GA, Graziano, SL, Crawford, J, Bogart, J, and Vokes, EE. "Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study-CALGB 30504 (Alliance)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.15 (May 2015): 1660-1665.
PMID
25732163
Source
epmc
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015
Start Page
1660
End Page
1665
DOI
10.1200/jco.2014.57.3105

Accuracy of positron emission tomography in identifying hilar (N1) lymph node involvement in non-small cell lung cancer: Implications for stereotactic body radiation therapy

© 2015 American Society for Radiation Oncology. Purpose: To assess the efficacy of preoperative positron emission tomography (PET) to stage the ipsilateral hilum in resected non-small cell lung cancer (NSCLC). Methods and materials: All patients who underwent surgery for NSCLC between 1995 and 2008 were evaluated. Patients who underwent preoperative PET imaging at our institution and had hilar nodal sampling were included. Those whose primary tumors extended to the hilum or who received preoperative chemotherapy or radiation therapy were excluded. All PET studies were interpreted by an attending nuclear medicine radiologist and were scored as positive or negative in the hilum or peribronchial area based on visual analysis alone. A 2-sided Fisher exact test compared patient subgroups. Results: During the time interval, 1558 patients underwent surgery for NSCLC, of whom 484 were eligible for this analysis. The ipsilateral hilum was positive on preoperative PET in 107 patients. The median number of N1 lymph nodes sampled was 4 (range, 1-31). Positive ipsilateral N1 lymph nodes were identified pathologically in 91 patients (19%). Among the 91 patients with involved N1 lymph nodes, 40 were PET positive resulting in a sensitivity of 44%. Among 393 patients without pathologic involvement of hilar lymph nodes, 326 were PET negative resulting in a specificity of 83%. The positive predictive and negative predictive values were 37% and 86%, respectively. Conclusions: Positron emission tomography appears to have limitations in staging the ipsilateral hilar lymph nodes. Invasive sampling is appropriate if treatment would differ based on the nodal status.

Authors
Pepek, JM; Marks, LB; Berry, MF; Ready, NE; Gee, NG; Coleman, RE; D'Amico, TA; Crawford, J; Kelsey, CR
MLA Citation
Pepek, JM, Marks, LB, Berry, MF, Ready, NE, Gee, NG, Coleman, RE, D'Amico, TA, Crawford, J, and Kelsey, CR. "Accuracy of positron emission tomography in identifying hilar (N1) lymph node involvement in non-small cell lung cancer: Implications for stereotactic body radiation therapy." Practical Radiation Oncology 5.2 (March 1, 2015): 79-84.
Source
scopus
Published In
Practical Radiation Oncology
Volume
5
Issue
2
Publish Date
2015
Start Page
79
End Page
84
DOI
10.1016/j.prro.2014.05.002

Accuracy of positron emission tomography in identifying hilar (N1) lymph node involvement in non-small cell lung cancer: Implications for stereotactic body radiation therapy.

To assess the efficacy of preoperative positron emission tomography (PET) to stage the ipsilateral hilum in resected non-small cell lung cancer (NSCLC).All patients who underwent surgery for NSCLC between 1995 and 2008 were evaluated. Patients who underwent preoperative PET imaging at our institution and had hilar nodal sampling were included. Those whose primary tumors extended to the hilum or who received preoperative chemotherapy or radiation therapy were excluded. All PET studies were interpreted by an attending nuclear medicine radiologist and were scored as positive or negative in the hilum or peribronchial area based on visual analysis alone. A 2-sided Fisher exact test compared patient subgroups.During the time interval, 1558 patients underwent surgery for NSCLC, of whom 484 were eligible for this analysis. The ipsilateral hilum was positive on preoperative PET in 107 patients. The median number of N1 lymph nodes sampled was 4 (range, 1-31). Positive ipsilateral N1 lymph nodes were identified pathologically in 91 patients (19%). Among the 91 patients with involved N1 lymph nodes, 40 were PET positive resulting in a sensitivity of 44%. Among 393 patients without pathologic involvement of hilar lymph nodes, 326 were PET negative resulting in a specificity of 83%. The positive predictive and negative predictive values were 37% and 86%, respectively.Positron emission tomography appears to have limitations in staging the ipsilateral hilar lymph nodes. Invasive sampling is appropriate if treatment would differ based on the nodal status.

Authors
Pepek, JM; Marks, LB; Berry, MF; Ready, NE; Gee, NG; Coleman, RE; D'Amico, TA; Crawford, J; Kelsey, CR
MLA Citation
Pepek, JM, Marks, LB, Berry, MF, Ready, NE, Gee, NG, Coleman, RE, D'Amico, TA, Crawford, J, and Kelsey, CR. "Accuracy of positron emission tomography in identifying hilar (N1) lymph node involvement in non-small cell lung cancer: Implications for stereotactic body radiation therapy." Practical radiation oncology 5.2 (March 2015): 79-84.
PMID
25413417
Source
epmc
Published In
Practical Radiation Oncology
Volume
5
Issue
2
Publish Date
2015
Start Page
79
End Page
84
DOI
10.1016/j.prro.2014.05.002

Smoking history predicts for increased risk of second primary lung cancer: a comprehensive analysis.

BACKGROUND: Tobacco use is the most important risk factor for the development of lung cancer. The objective of the current study was to determine the effect of smoking on the development of second primary lung cancers (SPLCs) and other clinical outcomes after surgery for non-small cell lung cancer (NSCLC). METHODS: All patients who underwent surgery for NSCLC at the study institution from 1995 through 2008 were identified. Rates of SPLC were analyzed based on smoking status and pack-year exposure. Multivariate analysis was performed to determine risk factors for SPLC. Overall survival, local control, distant metastases, and postoperative mortality were also examined. RESULTS: A total of 1484 patients were identified, including 98 never-smokers. The incidence of SPLC at 3 years, 5 years, and 8 years was 5%, 8%, and 16%, respectively. Only 1 never-smoker developed an SPLC. On multivariate analysis, which was restricted to ever-smokers with pack-years as a continuous variable, smoking history was found to be the only independent risk factor for SPLC (hazard ratio, 1.08; 95% confidence interval, 1.02-1.16 [P = .031]), corresponding to an 8% increased risk per 10 pack-year exposure. There were no differences in rates of local control or distant metastases based on smoking status. There was a trend toward lower postoperative mortality in never-smokers compared with ever-smokers (0% vs 3.3%; P = .069). Overall survival was found to be significantly worse for current smokers compared with former and never-smokers. CONCLUSIONS: SPLCs are rare in never-smokers. Increasing tobacco exposure is associated with a higher risk of SPLC in patients with a history of smoking. Current smokers have an increased risk of mortality whereas former and never-smokers have comparable survival.

Authors
Boyle, JM; Tandberg, DJ; Chino, JP; D'Amico, TA; Ready, NE; Kelsey, CR
MLA Citation
Boyle, JM, Tandberg, DJ, Chino, JP, D'Amico, TA, Ready, NE, and Kelsey, CR. "Smoking history predicts for increased risk of second primary lung cancer: a comprehensive analysis." Cancer 121.4 (February 2015): 598-604.
PMID
25283893
Source
epmc
Published In
Cancer
Volume
121
Issue
4
Publish Date
2015
Start Page
598
End Page
604
DOI
10.1002/cncr.29095

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

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

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

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

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

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

Tumor acquisition for biomarker research in lung cancer.

The biopsy collection data from two lung cancer trials that required fresh tumor samples be obtained for microarray analysis were reviewed. In the trial for advanced disease, microarray data were obtained on 50 patient samples, giving an overall success rate of 60.2%. The majority of the specimens were obtained through CT-guided lung biopsies (N = 30). In the trial for early-stage patients, 28 tissue specimens were collected from excess tumor after surgical resection with a success rate of 85.7%. This tissue procurement program documents the feasibility in obtaining fresh tumor specimens prospectively that could be used for molecular testing.

Authors
Stevenson, M; Christensen, J; Shoemaker, D; Foster, T; Barry, WT; Tong, BC; Wahidi, M; Shofer, S; Datto, M; Ginsburg, G; Crawford, J; D'Amico, T; Ready, N
MLA Citation
Stevenson, M, Christensen, J, Shoemaker, D, Foster, T, Barry, WT, Tong, BC, Wahidi, M, Shofer, S, Datto, M, Ginsburg, G, Crawford, J, D'Amico, T, and Ready, N. "Tumor acquisition for biomarker research in lung cancer." Cancer investigation 32.6 (July 2014): 291-298.
PMID
24810245
Source
epmc
Published In
Cancer Investigation (Informa)
Volume
32
Issue
6
Publish Date
2014
Start Page
291
End Page
298
DOI
10.3109/07357907.2014.911880

Prognostic Validation of the Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Index in Inoperable Non-Small-Cell Lung Cancer

Authors
Denehy, L; Hornsby, WE; Herndon, JE; Thomas, S; Ready, NE; Granger, CL; Valera, L; Kenjale, AA; Eves, ND; Jones, LW
MLA Citation
Denehy, L, Hornsby, WE, Herndon, JE, Thomas, S, Ready, NE, Granger, CL, Valera, L, Kenjale, AA, Eves, ND, and Jones, LW. "Prognostic Validation of the Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Index in Inoperable Non-Small-Cell Lung Cancer." JOURNAL OF THORACIC ONCOLOGY 8.12 (December 2013): 1545-1550.
PMID
24389436
Source
wos-lite
Published In
Journal of Thoracic Oncology
Volume
8
Issue
12
Publish Date
2013
Start Page
1545
End Page
1550
DOI
10.1097/JTO.0000000000000032

Are discordant positron emission tomography and pathological assessments of the mediastinum in non-small cell lung cancer significant?

OBJECTIVE: Many patients with non-small cell lung cancer have positive mediastinal lymph nodes on preoperative positron emission tomography (PET) but do not have mediastinal involvement after surgery. The prognostic significance of this discordance was assessed. METHODS: This Institutional Review Board-approved study evaluated patients treated with upfront surgery at Duke Cancer Institute (Durham, NC) for non-small cell lung cancer from 1995 to 2008. Those staged with PET with pN0-1 disease after negative invasive mediastinal assessment were included. Mediastinal lymph nodes were scored as positive or negative based on visual analysis of the preoperative PET. Clinical outcomes of the PET-positive and PET-negative cohorts were estimated using the Kaplan-Meier method and compared using a log-rank test. Prognostic factors were assessed using a multivariate analysis. RESULTS: A total of 547 patients were assessed, of whom 105 (19%) were PET positive in the mediastinum. The median number of mediastinal lymph node stations sampled was 4 (range, 1-9). The 5-year risk of local recurrence was 26% in PET-positive versus 21% in PET-negative patients (P = .50). Patterns of local failure were similar between the 2 groups. Distant recurrence (35% vs 29%; P = .63) and overall survival (44% vs 54%; P = .52) were comparable for PET-positive and PET-negative patients. On multivariate analysis, a positive PET was not significant for local recurrence (hazard ratio [HR], 1; P = 1), distant recurrence (HR, 0.82; P = .42), or overall survival (HR, 1.08; P = .62). CONCLUSIONS: Patients with positive mediastinal lymph nodes on preoperative PET, but negative on histologic analysis, are not at increased risk of disease recurrence. Pathologic staging remains the standard.

Authors
Tandberg, DJ; Gee, NG; Chino, JP; D'Amico, TA; Ready, NE; Coleman, RE; Kelsey, CR
MLA Citation
Tandberg, DJ, Gee, NG, Chino, JP, D'Amico, TA, Ready, NE, Coleman, RE, and Kelsey, CR. "Are discordant positron emission tomography and pathological assessments of the mediastinum in non-small cell lung cancer significant?." J Thorac Cardiovasc Surg 146.4 (October 2013): 796-801.
PMID
23870158
Source
pubmed
Published In
Journal of Thoracic and Cardiovascular Surgery
Volume
146
Issue
4
Publish Date
2013
Start Page
796
End Page
801
DOI
10.1016/j.jtcvs.2013.05.027

Diabetes mellitus: A significant co-morbidity in the setting of lung cancer?

Authors
Washington, I; Chino, JP; Marks, LB; D'Amico, TA; Berry, MF; Ready, NE; Higgins, KA; Yoo, DS; Kelsey, CR
MLA Citation
Washington, I, Chino, JP, Marks, LB, D'Amico, TA, Berry, MF, Ready, NE, Higgins, KA, Yoo, DS, and Kelsey, CR. "Diabetes mellitus: A significant co-morbidity in the setting of lung cancer?." THORACIC CANCER 4.2 (May 2013): 123-130.
PMID
28920196
Source
wos-lite
Published In
Thoracic Cancer
Volume
4
Issue
2
Publish Date
2013
Start Page
123
End Page
130
DOI
10.1111/j.1759-7714.2012.00162.x

Small cell lung cancer: Clinical practice guidelines in oncology

Neuroendocrine tumors account for approximately 20% of lung cancers; most (≈15%) are small cell lung cancer (SCLC). These NCCN Clinical Practice Guidelines in Oncology for SCLC focus on extensive-stage SCLC because it occurs more frequently than limited-stage disease. SCLC is highly sensitive to initial therapy; however, most patients eventually die of recurrent disease. In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; however, long-term survival is rare. Most cases of SCLC are attributable to cigarette smoking; therefore, smoking cessation should be strongly promoted. Copyright © 2013, JNCCN-Journal of the National Comprehensive Cancer Network.

Authors
Kalemkerian, GP; Akerley, W; Bogner, P; Borghaei, H; Chow, LQM; Downey, RJ; Gandhi, L; Ganti, AKP; Govindan, R; Grecula, JC; Hayman, J; Heist, RS; Horn, L; Jahan, T; Koczywas, M; Jr, BWL; Merritt, RE; Moran, CA; Niell, HB; O'Malley, J; Patel, JD; Ready, N; Rudin, CM; Jr, CCW; Gregory, K; Hughes, M
MLA Citation
Kalemkerian, GP, Akerley, W, Bogner, P, Borghaei, H, Chow, LQM, Downey, RJ, Gandhi, L, Ganti, AKP, Govindan, R, Grecula, JC, Hayman, J, Heist, RS, Horn, L, Jahan, T, Koczywas, M, Jr, BWL, Merritt, RE, Moran, CA, Niell, HB, O'Malley, J, Patel, JD, Ready, N, Rudin, CM, Jr, CCW, Gregory, K, and Hughes, M. "Small cell lung cancer: Clinical practice guidelines in oncology." JNCCN Journal of the National Comprehensive Cancer Network 11.1 (2013): 78-98.
PMID
23307984
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
11
Issue
1
Publish Date
2013
Start Page
78
End Page
98

Are discordant positron emission tomography and pathological assessments of the mediastinum in non-small cell lung cancer significant?

Objective: Many patients with non-small cell lung cancer have positive mediastinal lymph nodes on preoperative positron emission tomography (PET) but do not have mediastinal involvement after surgery. The prognostic significance of this discordance was assessed. Methods: This Institutional Review Board-approved study evaluated patients treated with upfront surgery at Duke Cancer Institute (Durham, NC) for non-small cell lung cancer from 1995 to 2008. Those staged with PET with pN0-1 disease after negative invasive mediastinal assessment were included. Mediastinal lymph nodes were scored as positive or negative based on visual analysis of the preoperative PET. Clinical outcomes of the PET-positive and PET-negative cohorts were estimated using the Kaplan-Meier method and compared using a log-rank test. Prognostic factors were assessed using a multivariate analysis. Results: A total of 547 patients were assessed, of whom 105 (19%) were PET positive in the mediastinum. The median number of mediastinal lymph node stations sampled was 4 (range, 1-9). The 5-year risk of local recurrence was 26% in PET-positive versus 21% in PET-negative patients (P =.50). Patterns of local failure were similar between the 2 groups. Distant recurrence (35% vs 29%; P =.63) and overall survival (44% vs 54%; P =.52) were comparable for PET-positive and PET-negative patients. On multivariate analysis, a positive PET was not significant for local recurrence (hazard ratio [HR], 1; P = 1), distant recurrence (HR, 0.82; P =.42), or overall survival (HR, 1.08; P =.62). Conclusions: Patients with positive mediastinal lymph nodes on preoperative PET, but negative on histologic analysis, are not at increased risk of disease recurrence. Pathologic staging remains the standard. Copyright © 2013 by The American Association for Thoracic Surgery.

Authors
Tandberg, DJ; Gee, NG; Chino, JP; D'Amico, TA; Ready, NE; Coleman, RE; Kelsey, CR
MLA Citation
Tandberg, DJ, Gee, NG, Chino, JP, D'Amico, TA, Ready, NE, Coleman, RE, and Kelsey, CR. "Are discordant positron emission tomography and pathological assessments of the mediastinum in non-small cell lung cancer significant?." Journal of Thoracic and Cardiovascular Surgery 146.4 (2013): 796-801.
Source
scival
Published In
Journal of Thoracic and Cardiovascular Surgery
Volume
146
Issue
4
Publish Date
2013
Start Page
796
End Page
801
DOI
10.1016/j.jtcvs.2013.05.027

Lymphovascular invasion in non-small-cell lung cancer: implications for staging and adjuvant therapy.

BACKGROUND: Lymphovascular space invasion (LVI) is an established negative prognostic factor and an indication for postoperative radiation therapy in many malignancies. The purpose of this study was to evaluate LVI in patients with early-stage non-small-cell lung cancer, undergoing surgical resection. METHODS: All patients who underwent initial surgery for pT1-3N0-2 non-small-cell lung cancer at Duke University Medical Center from 1995 to 2008 were identified. A multivariate ordinal regression was used to assess the relationship between LVI and pathologic hilar and/or mediastinal lymph node (LN) involvement. A multivariate Cox regression analysis was used to evaluate the relationship of LVI and other clinical and pathologic factors on local failure (LF), freedom from distant metastasis (FFDM), and overall survival (OS). Kaplan-Meier methods were used to generate estimates of LF, FFDM, and OS in patients with and without LVI. RESULTS: One thousand five hundred and fifty-nine patients were identified. LVI was independently associated with the presence of regional LN involvement (p < 0.001) along with lobar (versus sublobar) resections (p < 0.001), and an open thoracotomy (versus video-assisted thoracoscopic surgery). LVI was not independently associated with LF on multivariate analysis (hazard ratio [HR] = 1.23, p = 0.25), but was associated with a lower FFDM (HR 1.52, p = 0.005) and OS (HR 1.26, p = 0.015). In addition, multivariate analysis showed that LVI was strongly associated with increased risk of developing distant metastases (HR = 1.75, p = 0.006) and death (HR = 1.53, p = 0.003) in adenocarcinomas but not in squamous carcinomas. CONCLUSIONS: LVI is associated with an increased risk of harboring regional LN involvement. LVI is also an adverse prognostic factor for the development of distant metastases and long-term survival.

Authors
Higgins, KA; Chino, JP; Ready, N; D'Amico, TA; Berry, MF; Sporn, T; Boyd, J; Kelsey, CR
MLA Citation
Higgins, KA, Chino, JP, Ready, N, D'Amico, TA, Berry, MF, Sporn, T, Boyd, J, and Kelsey, CR. "Lymphovascular invasion in non-small-cell lung cancer: implications for staging and adjuvant therapy." J Thorac Oncol 7.7 (July 2012): 1141-1147.
PMID
22617241
Source
pubmed
Published In
Journal of Thoracic Oncology
Volume
7
Issue
7
Publish Date
2012
Start Page
1141
End Page
1147
DOI
10.1097/JTO.0b013e3182519a42

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

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

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

Local failure in resected N1 lung cancer: implications for adjuvant therapy.

PURPOSE: To evaluate actuarial rates of local failure in patients with pathologic N1 non-small-cell lung cancer and to identify clinical and pathologic factors associated with an increased risk of local failure after resection. METHODS AND MATERIALS: All patients who underwent surgery for non-small-cell lung cancer with pathologically confirmed N1 disease at Duke University Medical Center from 1995-2008 were identified. Patients receiving any preoperative therapy or postoperative radiotherapy or with positive surgical margins were excluded. Local failure was defined as disease recurrence within the ipsilateral hilum, mediastinum, or bronchial stump/staple line. Actuarial rates of local failure were calculated with the Kaplan-Meier method. A Cox multivariate analysis was used to identify factors independently associated with a higher risk of local recurrence. RESULTS: Among 1,559 patients who underwent surgery during the time interval, 198 met the inclusion criteria. Of these patients, 50 (25%) received adjuvant chemotherapy. Actuarial (5-year) rates of local failure, distant failure, and overall survival were 40%, 55%, and 33%, respectively. On multivariate analysis, factors associated with an increased risk of local failure included a video-assisted thoracoscopic surgery approach (hazard ratio [HR], 2.5; p = 0.01), visceral pleural invasion (HR, 2.1; p = 0.04), and increasing number of positive N1 lymph nodes (HR, 1.3 per involved lymph node; p = 0.02). Chemotherapy was associated with a trend toward decreased risk of local failure that was not statistically significant (HR, 0.61; p = 0.2). CONCLUSIONS: Actuarial rates of local failure in pN1 disease are high. Further investigation of conformal postoperative radiotherapy may be warranted.

Authors
Higgins, KA; Chino, JP; Berry, M; Ready, N; Boyd, J; Yoo, DS; Kelsey, CR
MLA Citation
Higgins, KA, Chino, JP, Berry, M, Ready, N, Boyd, J, Yoo, DS, and Kelsey, CR. "Local failure in resected N1 lung cancer: implications for adjuvant therapy." Int J Radiat Oncol Biol Phys 83.2 (June 1, 2012): 727-733.
PMID
22208965
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
83
Issue
2
Publish Date
2012
Start Page
727
End Page
733
DOI
10.1016/j.ijrobp.2011.07.018

Stereotactic radiotherapy for malignancies involving the trigeminal and facial nerves.

Involvement of a cranial nerve caries a poor prognosis for many malignancies. Recurrent or residual disease in the trigeminal or facial nerve after primary therapy poses a challenge due to the location of the nerve in the skull base, the proximity to the brain, brainstem, cavernous sinus, and optic apparatus and the resulting complex geometry. Surgical resection caries a high risk of morbidity and is often not an option for these patients. Stereotactic radiosurgery and radiotherapy are potential treatment options for patients with cancer involving the trigeminal or facial nerve. These techniques can deliver high doses of radiation to complex volumes while sparing adjacent critical structures. In the current study, seven cases of cancer involving the trigeminal or facial nerve are presented. These patients had unresectable recurrent or residual disease after definitive local therapy. Each patient was treated with stereotactic radiation therapy using a linear accelerator based system. A multidisciplinary approach including neuroradiology and surgical oncology was used to delineate target volumes. Treatment was well tolerated with no acute grade 3 or higher toxicity. One patient who was reirradiated experienced cerebral radionecrosis with mild symptoms. Four of the seven patients treated had no evidence of disease after a median follow up of 12 months (range 2-24 months). A dosimetric analysis was performed to compare intensity modulated fractionated stereotactic radiation therapy (IM-FSRT) to a 3D conformal technique. The dose to 90% (D90) of the brainstem was lower with the IM-FSRT plan by a mean of 13.5 Gy. The D95 to the ipsilateral optic nerve was also reduced with IM-FSRT by 12.2 Gy and the D95 for the optic chiasm was lower with FSRT by 16.3 Gy. Treatment of malignancies involving a cranial nerve requires a multidisciplinary approach. Use of an IM-FSRT technique with a micro-multileaf collimator resulted in a lower dose to the brainstem, optic nerves and chiasm for each case examined.

Authors
Cuneo, KC; Zagar, TM; Brizel, DM; Yoo, DS; Hoang, JK; Chang, Z; Wang, Z; Yin, FF; Das, SK; Green, S; Ready, N; Bhatti, MT; Kaylie, DM; Becker, A; Sampson, JH; Kirkpatrick, JP
MLA Citation
Cuneo, KC, Zagar, TM, Brizel, DM, Yoo, DS, Hoang, JK, Chang, Z, Wang, Z, Yin, FF, Das, SK, Green, S, Ready, N, Bhatti, MT, Kaylie, DM, Becker, A, Sampson, JH, and Kirkpatrick, JP. "Stereotactic radiotherapy for malignancies involving the trigeminal and facial nerves." Technol Cancer Res Treat 11.3 (June 2012): 221-228.
PMID
22468993
Source
pubmed
Published In
Technology in cancer research & treatment
Volume
11
Issue
3
Publish Date
2012
Start Page
221
End Page
228
DOI
10.7785/tcrt.2012.500290

Treatment-induced changes in vocal cord mobility and subsequent local recurrence after organ preservation therapy for laryngeal carcinoma.

BACKGROUND: As multidisciplinary cancer treatment evolves, strategies to identify patients needing early resection/salvage are necessary. Some have suggested that vocal cord function after organ-preservation treatment may be an indicator. METHODS: A retrospective review was performed of patients presenting with fixed or impaired vocal cord function at a tertiary center. Local recurrence rates were examined in patients with and without improved/normal mobilization after treatment. RESULTS: Sixty-nine patients met the inclusion criteria, with 35 patients having vocal cord fixation and 34 patients with impaired mobility. After treatment, 44 patients had normalization of vocal cord function, while 25 patients did not, with 2-year local control rates of 70% and 77%, p = .23, respectively. No difference in local control was found between patients with normalized/improved cord function (n = 53) and those who remained the same/worsened (n = 16; p = .81). CONCLUSION: Therapy-induced changes in vocal cord mobility did not correlate with local recurrence. Other criteria are needed to identify patients most likely to benefit from early surgical resection/salvage after organ preservation.

Authors
Lee, WT; Yoo, DS; Puscas, L; Witsell, D; Cohen, SM; Fisher, SR; Scher, R; Broadwater, G; Ready, N; Brizel, DR; Esclamado, RM
MLA Citation
Lee, WT, Yoo, DS, Puscas, L, Witsell, D, Cohen, SM, Fisher, SR, Scher, R, Broadwater, G, Ready, N, Brizel, DR, and Esclamado, RM. "Treatment-induced changes in vocal cord mobility and subsequent local recurrence after organ preservation therapy for laryngeal carcinoma." Head Neck 34.6 (June 2012): 792-796.
PMID
21850701
Source
pubmed
Published In
Head & Neck: Journal for the Sciences & Specialties of the Head and Neck
Volume
34
Issue
6
Publish Date
2012
Start Page
792
End Page
796
DOI
10.1002/hed.21813

Retraction: characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma.

Authors
Stevenson, M; Mostertz, W; Acharya, CR; Kim, W; Walters, K; Barry, W; Higgins, K; Tuchman, SA; Crawford, J; Vlahovic, G; Ready, N; Onaitis, M; Potti, A
MLA Citation
Stevenson, M, Mostertz, W, Acharya, CR, Kim, W, Walters, K, Barry, W, Higgins, K, Tuchman, SA, Crawford, J, Vlahovic, G, Ready, N, Onaitis, M, and Potti, A. "Retraction: characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma." Clin Cancer Res 18.6 (March 15, 2012): 1818-.
PMID
22355011
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
18
Issue
6
Publish Date
2012
Start Page
1818
DOI
10.1158/1078-0432.CCR-12-0337

Prospective trial of synchronous bevacizumab, erlotinib, and concurrent chemoradiation in locally advanced head and neck cancer.

PURPOSE: We assessed the safety and efficacy of synchronous VEGF and epidermal growth factor receptor (EGFR) blockade with concurrent chemoradiation (CRT) in locally advanced head and neck cancer (HNC). EXPERIMENTAL DESIGN: Newly diagnosed patients with stage III/IV HNC received a 2-week lead-in of bevacizumab and/or erlotinib, followed by both agents with concurrent cisplatin and twice daily radiotherapy. Safety was assessed using Common Toxicity Criteria version 3.0. The primary efficacy endpoint was clinical complete response (CR) rate after CRT. RESULTS: Twenty-nine patients enrolled on study, with 27 completing therapy. Common grade III toxicities were mucositis (n = 14), dysphagia (n = 8), dehydration (n = 7), osteoradionecrosis (n = 3), and soft tissue necrosis (n = 2). Feeding tube placement was required in 79% but no patient remained dependent at 12-month posttreatment. Clinical CR after CRT was 96% [95% confidence interval (CI), 82%-100%]. Median follow-up was 46 months in survivors, with 3-year locoregional control and distant metastasis-free survival rates of 85% and 93%. Three-year estimated progression-free survival, disease-specific survival, and overall survival rates were 82%, 89%, and 86%, respectively. Dynamic contrast enhanced MRI (DCE-MRI) analysis showed that patients who had failed had lower baseline pretreatment median K(trans) values, with subsequent increases after lead-in therapy and 1 week of CRT. Patients who did not fail had higher median K(trans) values that decreased during therapy. CONCLUSIONS: Dual VEGF/EGFR inhibition can be integrated with CRT in locally advanced HNC, with efficacy that compares favorably with historical controls albeit with an increased risk of osteoradionecrosis. Pretreatment and early DCE-MRI may prospectively identify patients at high risk of failure.

Authors
Yoo, DS; Kirkpatrick, JP; Craciunescu, O; Broadwater, G; Peterson, BL; Carroll, MD; Clough, R; MacFall, JR; Hoang, J; Scher, RL; Esclamado, RM; Dunphy, FR; Ready, NE; Brizel, DM
MLA Citation
Yoo, DS, Kirkpatrick, JP, Craciunescu, O, Broadwater, G, Peterson, BL, Carroll, MD, Clough, R, MacFall, JR, Hoang, J, Scher, RL, Esclamado, RM, Dunphy, FR, Ready, NE, and Brizel, DM. "Prospective trial of synchronous bevacizumab, erlotinib, and concurrent chemoradiation in locally advanced head and neck cancer." Clin Cancer Res 18.5 (March 1, 2012): 1404-1414.
PMID
22253412
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
18
Issue
5
Publish Date
2012
Start Page
1404
End Page
1414
DOI
10.1158/1078-0432.CCR-11-1982

Weekly paclitaxel and carboplatin induction chemotherapy followed by concurrent chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck

OBJECTIVE: To perform a phase II trial evaluating dose dense induction chemotherapy for locally advanced head and neck cancer. PATIENTS AND METHODS: Thirty-five patients received 6 weekly doses of carboplatin (area under the curve=2) and paclitaxel (135 mg/m) followed by concurrent weekly paclitaxel (40 mg/m) and carboplatin (area under the curve=1) and daily radiation (66-72 Gy). RESULTS: There was 1 induction death from neutropenic sepsis and 1 sudden death during chemoradiotherapy. The overall response rate with induction was 79%. With >40 months of follow-up, the 36-month overall survival was 67% and squamous cell carcinoma of the head and neck survival 84%. Patients undergoing biopsy of the primary tumor site after the therapies had 17/18 (94%) pathologic complete response rate. The locoregional relapse rate was 40% (24 mo 28%) and distant relapse rate was 8% with only 1 distant site. CONCLUSIONS: Therapy was active but patients must be carefully selected and monitored. Compared with the historical controls, dose dense and intense induction chemotherapy decreased distant failure rate without compromising the locoregional control. Copyright © 2011 by Lippincott Williams & Wilkins.

Authors
Ready, NE; Rathore, R; Johnson, TT; Nadeem, A; Chougule, P; Ruhl, C; Radie-Keane, K; Theall, K; Wanebo, HJ; Marcello, J; Kennedy, T
MLA Citation
Ready, NE, Rathore, R, Johnson, TT, Nadeem, A, Chougule, P, Ruhl, C, Radie-Keane, K, Theall, K, Wanebo, HJ, Marcello, J, and Kennedy, T. "Weekly paclitaxel and carboplatin induction chemotherapy followed by concurrent chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck." American Journal of Clinical Oncology: Cancer Clinical Trials 35.1 (2012): 6-12.
PMID
21293244
Source
scival
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
35
Issue
1
Publish Date
2012
Start Page
6
End Page
12
DOI
10.1097/COC.0b013e3182019ee3

Cisplatin, irinotecan, and bevacizumab for untreated extensive-stage small-cell lung cancer: CALGB 30306, a phase II study.

PURPOSE: The efficacy of cisplatin, irinotecan, and bevacizumab was evaluated in patients with extensive-stage small-cell lung cancer (ES-SCLC). PATIENTS AND METHODS: Patients with ES-SCLC received cisplatin 30 mg/m(2) and irinotecan 65 mg/m(2) on days 1 and 8 plus bevacizumab 15 mg/kg on day 1 every 21 days for six cycles on this phase II study. The primary end point was to differentiate between 50% and 65% 12-month survival rates. RESULTS: Seventy-two patients were enrolled between March 2005 and April 2006; four patients canceled, and four were ineligible. Grade 3 or 4 toxicities included neutropenia (25%), all electrolyte (23%), diarrhea (16%), thrombocytopenia (10%), fatigue (10%), nausea (10%), hypertension (9%), anemia (9%), infection (7%), vascular access thrombosis (2%), stroke (2%), and bowel perforation (1%). Three deaths (5%) occurred on therapy as a result of pneumonitis (n = 1), stroke (n =1), and heart failure (n = 1). Complete response, partial response, and stable disease occurred in three (5%), 45 (70%), and 11 patients (17%), respectively. Progressive disease occurred in one patient (2%). Overall response rate was 75%. Median progression-free survival (PFS) was 7.0 months (95% CI, 6.4 to 8.4 months). Median overall survival (OS) was 11.6 months (95% CI, 10.5 to 15.1 months). Hypertension ≥ grade 1 was associated with improved OS after adjusting for performance status (PS) and age (hazard ratio [HR], 0.55; 95% CI, 0.31 to 0.97; P = .04). Lower vascular endothelial growth factor levels correlated with worse PFS after adjusting for age and PS (HR, 0.90; 95% CI, 0.83 to 0.99; P = .03). CONCLUSION: PFS and OS times were higher compared with US trials in ES-SCLC with the same chemotherapy. However, the primary end point of the trial was not met. Hypertension was associated with improved survival after adjusting for age and PS.

Authors
Ready, NE; Dudek, AZ; Pang, HH; Hodgson, LD; Graziano, SL; Green, MR; Vokes, EE
MLA Citation
Ready, NE, Dudek, AZ, Pang, HH, Hodgson, LD, Graziano, SL, Green, MR, and Vokes, EE. "Cisplatin, irinotecan, and bevacizumab for untreated extensive-stage small-cell lung cancer: CALGB 30306, a phase II study." J Clin Oncol 29.33 (November 20, 2011): 4436-4441.
PMID
21969504
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
33
Publish Date
2011
Start Page
4436
End Page
4441
DOI
10.1200/JCO.2011.35.6923

Persistent N2 disease after neoadjuvant chemotherapy for non-small-cell lung cancer.

OBJECTIVES: Patients achieving a mediastinal pathologic complete response with neoadjuvant chemotherapy have improved outcomes compared with patients with persistent N2 disease. How to best manage this latter group of patients is unknown, prompting a review of our institutional experience. METHODS: All patients who initiated neoadjuvant therapy for non-small-cell lung cancer from 1995 to 2008 were evaluated. The patients were excluded if they had received preoperative radiotherapy, had had a mediastinal pathologic complete response, or had evidence of disease progression after neoadjuvant chemotherapy. The clinical endpoints were calculated using the Kaplan-Meier product-limit method and compared using a log-rank test. RESULTS: A total of 28 patients were identified. The median follow-up period was 24 months. Several neoadjuvant chemotherapy regimens were used, most commonly carboplatin with vinorelbine (36%) or paclitaxel (32%). A partial response to chemotherapy was noted in 23 (82%) and stable disease was noted in 5 (18%) on postchemotherapy imaging. Resection was performed in 22 of 28 patients, consisting of lobectomy in 14, pneumonectomy in 2, and wedge/segmentectomy in 6 (21/22 R0, 1/22 R1). There were no postoperative deaths. Postoperative therapy (radiotherapy and/or additional chemotherapy) was administered to 12 patients (55%). The remaining 6 patients generally received definitive radiotherapy with or without additional chemotherapy. The overall and disease-free survival rate at 1, 3, and 5 years was 75%, 37%, and 37% and 50%, 23%, and 19%, respectively. The survival rate at 5 years was similar between patients undergoing resection (34%) and those receiving definitive radiotherapy with or without chemotherapy (40%; P = .73). CONCLUSIONS: Disease-free and overall survival was sufficiently high to warrant aggressive local therapy (surgery or radiotherapy) in patients with persistent N2 disease after neoadjuvant chemotherapy.

Authors
Higgins, KA; Chino, JP; Ready, N; Onaitis, MW; Berry, MF; D'Amico, TA; Kelsey, CR
MLA Citation
Higgins, KA, Chino, JP, Ready, N, Onaitis, MW, Berry, MF, D'Amico, TA, and Kelsey, CR. "Persistent N2 disease after neoadjuvant chemotherapy for non-small-cell lung cancer." J Thorac Cardiovasc Surg 142.5 (November 2011): 1175-1179.
PMID
22014344
Source
pubmed
Published In
Journal of Thoracic and Cardiovascular Surgery
Volume
142
Issue
5
Publish Date
2011
Start Page
1175
End Page
1179
DOI
10.1016/j.jtcvs.2011.07.059

How well does the new lung cancer staging system predict for local/regional recurrence after surgery?: A comparison of the TNM 6 and 7 systems.

INTRODUCTION: To evaluate how well the tumor, node, metastasis (TNM) 6 and TNM 7 staging systems predict rates of local/regional recurrence (LRR) after surgery alone for non-small cell lung cancer. METHODS: All patients who underwent surgery for non-small cell lung cancer at Duke between 1995 and 2005 were reviewed. Those undergoing sublobar resections, with positive margins or involvement of the chest wall, or those who received any chemotherapy or radiation therapy (RT) were excluded. Disease recurrence at the surgical margin, or within ipsilateral hilar and/or mediastinal lymph nodes, was considered as a LRR. Stage was assigned based on both TNM 6 and TNM 7. Rates of LRR were estimated using the Kaplan-Meier method. A Cox regression analysis evaluated the hazard ratio of LRR by stage within TNM 6 and TNM 7. RESULTS: A total of 709 patients were eligible for the analysis. Median follow-up was 32 months. For all patients, the 5-year actuarial risk of LRR was 23%. Conversion from TNM 6 to TNM 7 resulted in 21% stage migration (upstaging in 13%; downstaging in 8%). Five-year rates of LRR for stages IA, IB, IIA, IIB, and IIIA disease using TNM 6 were 16%, 26%, 43%, 35%, and 40%, respectively. Using TNM 7, corresponding rates were 16%, 23%, 37%, 39%, and 30%, respectively. The hazard ratios for LRR were statistically different for IA and IB in both TNM 6 and 7 but were also different for IB and IIA in TNM 7. CONCLUSIONS: LRR risk increases monotonically for stages IA to IIB in the new TNM 7 system. This information might be valuable when designing future studies of postoperative RT.

Authors
Pepek, JM; Chino, JP; Marks, LB; D'amico, TA; Yoo, DS; Onaitis, MW; Ready, NE; Hubbs, JL; Boyd, J; Kelsey, CR
MLA Citation
Pepek, JM, Chino, JP, Marks, LB, D'amico, TA, Yoo, DS, Onaitis, MW, Ready, NE, Hubbs, JL, Boyd, J, and Kelsey, CR. "How well does the new lung cancer staging system predict for local/regional recurrence after surgery?: A comparison of the TNM 6 and 7 systems." J Thorac Oncol 6.4 (April 2011): 757-761.
PMID
21325975
Source
pubmed
Published In
Journal of Thoracic Oncology
Volume
6
Issue
4
Publish Date
2011
Start Page
757
End Page
761
DOI
10.1097/JTO.0b013e31821038c0

Small cell lung cancer clinical practice guidelines in oncology

Authors
Kalemkerian, GP; Akerley, W; Rogner, P; Borghaei, H; Chow, L; Downey, RJ; Gandhi, L; Ganti, AKP; Govindan, R; Grecula, JC; Hayman, J; Heist, RS; Horn, L; Jahan, TM; Koczywas, M; Moran, CA; Niell, HD; O'Malley, J; Patel, JD; Ready, N; Rudin, CM; Jr, CCW
MLA Citation
Kalemkerian, GP, Akerley, W, Rogner, P, Borghaei, H, Chow, L, Downey, RJ, Gandhi, L, Ganti, AKP, Govindan, R, Grecula, JC, Hayman, J, Heist, RS, Horn, L, Jahan, TM, Koczywas, M, Moran, CA, Niell, HD, O'Malley, J, Patel, JD, Ready, N, Rudin, CM, and Jr, CCW. "Small cell lung cancer clinical practice guidelines in oncology." JNCCN Journal of the National Comprehensive Cancer Network 9.10 (2011): 1086-1113.
PMID
21975911
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
10
Publish Date
2011
Start Page
1086
End Page
1113

Selective organ preservation in operable locally advanced head and neck squamous cell carcinomas guided by primary site restaging biopsy: Long-term results of two sequential brown university oncology group chemoradiotherapy studies

Objectives. The long-term outcomes of selective organ preservation in operable, locally advanced head and neck cancers in two sequential chemoradiotherapy (CRT) protocols (HN-53, HN-67) are reported. Methods: A total of 65 patients were treated with CRT consisting of carboplatin (AUC = 1/week) and paclitaxel (60 or 40 mg/m 2/week) with radiation (1.8 Gy/day). After 5 weeks of CRT, if primary site biopsies were pathologically negative, then completion CRT to 67-72 Gy was done with neck dissection in node-positive cases. Alternatively, a positive rebiopsy required primary site resection and neck dissection followed by radiotherapy boost as deemed necessary. Results: Pathologic complete responses occurred in 71% patients who then completed CRT; the remaining 29% patients underwent primary site surgery. The 5-year and median overall survival were 47% and 57 months with no statistically significant differences between the two groups. Overall long-term failure rates were: 6% local, 6% regional, and 32% distant. Conclusions: This strategy of selective organ preservation was effective in 71% patients with CRT, whereas salvage surgery was required in the remainder. Long-term survival was equivalent in both treatment groups. © Society of Surgical Oncology 2011.

Authors
Wanebo, HJ; Rathore, R; Chougule, P; Disiena, MR; Koness, RJ; McRae, RG; Nigri, PT; Radie-Keane, K; Ready, N
MLA Citation
Wanebo, HJ, Rathore, R, Chougule, P, Disiena, MR, Koness, RJ, McRae, RG, Nigri, PT, Radie-Keane, K, and Ready, N. "Selective organ preservation in operable locally advanced head and neck squamous cell carcinomas guided by primary site restaging biopsy: Long-term results of two sequential brown university oncology group chemoradiotherapy studies." Annals of Surgical Oncology 18.12 (2011): 3479-3485.
PMID
21553142
Source
scival
Published In
Annals of Surgical Oncology
Volume
18
Issue
12
Publish Date
2011
Start Page
3479
End Page
3485
DOI
10.1245/s10434-011-1697-0

Pathologic response after neoadjuvant carboplatin and weekly paclitaxel for early-stage lung cancer: A Brown University Oncology Group phase II study

Pathologic complete response (pCR) to neoadjuvant chemotherapy is associated with improved survival in solid tumors. Southwest Oncology Group 9900 demonstrated a 9% pCR after three cycles of paclitaxel/carboplatin every 21 days. We evaluated pCR rate with intensive weekly paclitaxel in a phase II study. Methods: Patients with non-small cell lung cancer, stage IB to IIIA, were eligible and received carboplatin, area under the curve = 6, every 21 days ×3 and paclitaxel 80 mg/m 2 weekly ×9. Primary outcome was the pCR rate. Results: Twenty patients with clinical stage IB (n = 16), IIA (n = 1), IIB (n = 1), and IIIA (n = 2) were enrolled. Mean age was 65 years. Toxicity included grade 4 neutropenia in 1 (5%), grade 3 neutropenia in 3 (15%), grade 3 neuropathy in 1 (5%), and grade 3 nausea in 1 (5%). After neoadjuvant therapy, one patient refused surgery and one died of a nontreatment-related event. Eighteen patients underwent complete resection, 15 by lobectomy, and 3 by pneumonectomy. Pathology revealed 3 (17%) patients with pCR. The median follow-up is 67 months. For clinical stage IB (n = 16), the median overall survival has not been reached, and the 5-year overall survival is 69%. All patients with pCR (n = 3) remain alive and disease-free. Improved overall survival was seen in patients who were pathologically down-staged versus patients who were not, p = 0.05. Conclusions: Neoadjuvant chemotherapy with intensive weekly paclitaxel and carboplatin is well tolerated and does not increase surgical morbidity. This intense regimen achieves rates of pCR and survival that compares favorably with other reported induction regimens and merits further investigation. Copyright © 2011 by the International Association for the Study of Lung Cancer.

Authors
Ahmed, S; Birnbaum, AE; Safran, HP; Dipetrillo, TA; Aswad, BI; Ready, NE; Ng, T
MLA Citation
Ahmed, S, Birnbaum, AE, Safran, HP, Dipetrillo, TA, Aswad, BI, Ready, NE, and Ng, T. "Pathologic response after neoadjuvant carboplatin and weekly paclitaxel for early-stage lung cancer: A Brown University Oncology Group phase II study." Journal of Thoracic Oncology 6.8 (2011): 1432-1434.
PMID
21847062
Source
scival
Published In
Journal of Thoracic Oncology
Volume
6
Issue
8
Publish Date
2011
Start Page
1432
End Page
1434
DOI
10.1097/JTO.0b013e3182209043

Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer

Background: AT-101 is an inhibitor of Bcl-2 family proteins including Bcl-2, Bcl-xL, Mcl-1, and Bcl-w. In vivo and in vitro studies have exhibited broad activity of AT-101, including synergy with docetaxel in non-small cell lung cancer tumor models. Methods: We conducted a prospective, randomized (1:1), double-blind, placebo-controlled phase 2 study. Eligible patients must have received one prior chemotherapeutic regimen for advanced or metastatic non-small cell lung cancer and may also have received therapy with an epidermal growth factor receptor inhibitor. Patients received AT-101 (40 mg b.i.d. × 3 days) or placebo in combination with docetaxel (75 mg/m on day 1) every 21 days. The primary endpoint was progression-free survival (PFS) as determined by independent review; other endpoints include overall survival and PFS by investigator determination. Approximately 102 patients were planned to provide 70 events (80% power, hazard ratio [HR] of 0.6, one-sided alpha of 0.1). Results: One hundred six patients were assigned to treatment and 105 patients received at least one dose of AT-101 or placebo. Baseline factors were balanced between treatment groups: median age 59 years; 77% men, and 79% current or former smokers. Ninety-three percent of patients had distant metastatic disease at randomization and 56% squamous histology. The most frequently reported adverse events were fatigue (18%), anemia (18%), and dyspnea (18%). No statistically significant differences in serious adverse events were observed between AT-101 and placebo; grade 1/2 headaches appeared more frequently with AT-101 (9% versus 0%) and neutropenia was reported more frequently in the docetaxel plus placebo arm compared with docetaxel plus AT-101 (17% versus 8%). Unlike trials with continuous daily dosing of AT-101, no cases of small bowel obstruction were reported. The response rate and median PFS were not different between the arms by independent review, PFS 7.5 weeks for docetaxel plus AT-101 and 7.1 weeks for docetaxel plus placebo arms (HR, 1.04; p = 0.57). The median overall survival was 7.8 months for docetaxel plus AT-101 versus 5.9 months for docetaxel plus placebo (HR, 0.82; p = 0.21). Conclusions: The primary endpoint of improved PFS for AT-101 plus docetaxel was not met. AT-101 plus docetaxel was well tolerated with an adverse event profile indistinguishable from the base docetaxel regimen. AT-101 is the first oral, pan Bcl-2 family inhibitor to exhibit a possible survival benefit in a randomized study. Copyright © 2011 by the International Association for the Study of Lung Cancer.

Authors
Ready, N; Karaseva, NA; Orlov, SV; Luft, AV; Popovych, O; Holmlund, JT; Wood, BA; Leopold, L
MLA Citation
Ready, N, Karaseva, NA, Orlov, SV, Luft, AV, Popovych, O, Holmlund, JT, Wood, BA, and Leopold, L. "Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer." Journal of Thoracic Oncology 6.4 (2011): 781-785.
PMID
21289522
Source
scival
Published In
Journal of Thoracic Oncology
Volume
6
Issue
4
Publish Date
2011
Start Page
781
End Page
785
DOI
10.1097/JTO.0b013e31820a0ea6

Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial.

INTRODUCTION: This study evaluated the addition of gefitinib to sequential or concurrent chemoradiotherapy (CRT) in unresectable stage III non-small cell lung cancer. METHODS: Between May 2002 and April 2005, 63 patients were entered before the study closing early. All received two cycles paclitaxel 200 mg/m and carboplatin area under the curve 6 intravenous plus gefitinib 250 mg daily. Poor risk stratum 1 (> or =5% weight loss and/or performance status 2) received radiotherapy 200 cGy for 33 fractions (6600 cGy) and gefitinib 250 mg daily. Good-risk stratum 2 (performance status: 0-1 weight loss and <5%) received the same RT with gefitinib 250 mg daily and weekly paclitaxel 50 mg/m plus carboplatin AUC 2. Consolidation gefitinib until progression was started after all toxicities were grade < or =2. RESULTS: Acute high-grade infield toxicities were not clearly increased compared with historical CRT data. Poor-risk (N = 21) median progression-free survival was 13.4 months (95% confidence interval [CI]: 6.4-25.2) and median overall survival 19.0 months (95% CI: 9.9-28.4). Good-risk (N = 39) median progression-free survival was 9.2 months (95% CI: 6.7-12.2), and median overall survival was 13 months (95% CI: 8.5-17.2). Thirteen of 45 tumors analyzed had activating epidermal growth factor receptor (EGFR) mutations, and 2 of 13 also had T790M mutations. Seven tumors of 45 had KRAS mutations. There was no apparent survival difference with EGFR-activating mutations versus wild type or KRAS mutation versus wild type. CONCLUSIONS: Survival of poor-risk patients with wild type or mutated EGFR receiving sequential CRT with gefitinib was promising. Survival for good-risk patients receiving concurrent CRT plus gefitinib was disappointing even for tumors with activating EGFR mutations.

Authors
Ready, N; Jänne, PA; Bogart, J; Dipetrillo, T; Garst, J; Graziano, S; Gu, L; Wang, X; Green, MR; Vokes, EE; Cancer, Leukemia Group B, Chicago, IL,
MLA Citation
Ready, N, Jänne, PA, Bogart, J, Dipetrillo, T, Garst, J, Graziano, S, Gu, L, Wang, X, Green, MR, Vokes, EE, Cancer, Leukemia Group B, Chicago, and IL, . "Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial." J Thorac Oncol 5.9 (September 2010): 1382-1390.
PMID
20686428
Source
pubmed
Published In
Journal of Thoracic Oncology
Volume
5
Issue
9
Publish Date
2010
Start Page
1382
End Page
1390
DOI
10.1097/JTO.0b013e3181eba657

Carboplatin with weekly docetaxel and ifosfamide in advanced head and neck cancers: A phase i Brown University Oncology Group dose escalation study (HN-93)

Purpose: A phase I study was performed to determine the maximally tolerated dose of carboplatin, ifosfamide, and docetaxel in advanced head and neck cancers. Methods: Carboplatin (week 1) was administered with weekly docetaxel and ifosfamide for 3 weeks in an every 4-week cycle. Restaging was done after two cycles, while dose level escalation was done in cohorts of three patients. Results: Fifteen patients (recurrent/metastatic disease, n = 8; bulky locally advanced disease, n = 7) were enrolled. No dose-limiting toxicities were observed. Toxicities included grade 3 neutropenia and anemia (n = 2, each), and grade 2 thrombocytopenia (n = 3). The final level of carboplatin AUC = 6 (week 1) with docetaxel 30 mg/m2 per week and ifosfamide 1,000 mg/m 2 per week was chosen for further evaluation. Conclusions: This novel regimen of carboplatin with weekly docetaxel and ifosfamide has a favorable toxicity profile and is active in this setting. Phase II study results are awaited. © 2010 Springer-Verlag.

Authors
Rathore, R; Birnbaum, A; Rathore, B; Dipetrillo, T; Kennedy, T; Ready, N
MLA Citation
Rathore, R, Birnbaum, A, Rathore, B, Dipetrillo, T, Kennedy, T, and Ready, N. "Carboplatin with weekly docetaxel and ifosfamide in advanced head and neck cancers: A phase i Brown University Oncology Group dose escalation study (HN-93)." Cancer Chemotherapy and Pharmacology 66.6 (2010): 1013-1017.
PMID
20130878
Source
scival
Published In
Cancer Chemotherapy and Pharmacology
Volume
66
Issue
6
Publish Date
2010
Start Page
1013
End Page
1017
DOI
10.1007/s00280-010-1251-y

Cetuximab, paclitaxel, carboplatin, and radiation for head and neck cancer: A toxicity analysis

Objective: To determine the feasibility and toxicity of the addition of cetuximab to paclitaxel, carboplatin, and concurrent radiation for patients with head and neck cancer. Materials and Methods: Patients with stage III or IV locally advanced squamous cell cancer of the head and neck, without distant organ metastases, were eligible. Patients received 4 weeks of induction cetuximab followed by weekly cetuximab, paclitaxel, carboplatin, and concurrent radiation. Results: Thirty-two patients were assessable for chemoradiation toxicities. Grade 3 and grade 4 mucositis occurred in 53% and 16% of patients, respectively. Grade 3 and grade 4 radiation dermatitis occurred in 44% and 9% of patients, respectively. Grade 3/4 radiation dermatitis was associated with the use of intensity modulated radiation therapy (64% vs.14%, respectively, P < 0.0001). Grade 3 and grade 4 cetuximab associated acneiform rash developed in 6% and 3% of patients. Overall 21 patients (66%) had any grade 3 toxicity and 10 patients (31%) had any grade 4 toxicity. The percentages of the intended total dose delivered of carboplatin, cetuximab, paclitaxel, and radiation were 86%, 89%, 89%, and 96%, respectively. Conclusion: Cetuximab, when combined with paclitaxel, carboplatin and intensity modulated radiation therapy, increases dermatologic toxicity but does not increase mucosal toxicity as compared with previous Brown University Oncology Group studies of paclitaxel, carboplatin, and conventional radiation for patients with head and neck cancer. Copyright © 2010 by Lippincott Williams & Wilkins.

Authors
Birnbaum, A; Dipetrillo, T; Rathore, R; Anderson, E; Wanebo, H; Puthwala, Y; Joyce, D; Safran, H; Henderson, D; Kennedy, T; Ready, N; Sio, TT-W
MLA Citation
Birnbaum, A, Dipetrillo, T, Rathore, R, Anderson, E, Wanebo, H, Puthwala, Y, Joyce, D, Safran, H, Henderson, D, Kennedy, T, Ready, N, and Sio, TT-W. "Cetuximab, paclitaxel, carboplatin, and radiation for head and neck cancer: A toxicity analysis." American Journal of Clinical Oncology: Cancer Clinical Trials 33.2 (2010): 144-147.
PMID
19786848
Source
scival
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
33
Issue
2
Publish Date
2010
Start Page
144
End Page
147
DOI
10.1097/COC.0b013e3181979093

Characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma.

PURPOSE: Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities are the result of a common biological phenotype, such as regulatory pathways. EXPERIMENTAL DESIGN: Lung cancer cell lines with corresponding gene expression data and genes associated with an embryonic stem cell identity were used to develop a signature of embryonic stemness (ES) activity specific to lung adenocarcinoma. Biological characteristics were elucidated as a function of cancer biology/oncogenic pathway dysregulation. The ES signature was applied to three independent early-stage (I-IIIa) lung adenocarcinoma data sets with clinically annotated gene expression data. The relationship between the ES phenotype and cisplatin (current standard of care) sensitivity was evaluated. RESULTS: Pathway analysis identified specific regulatory networks [Ras (P = 0.0005), Myc (P = 0.0224), wound healing (P < 0.0001), chromosomal instability (P < 0.0001), and invasiveness (P < 0.0001)] associated with the ES phenotype. The prognostic relevance of the ES signature, as related to patient survival, was characterized in three cohorts [CALGB 9761 (n = 82; P = 0.0001), National Cancer Institute Director's Challenge Consortium (n = 442; P = 0.0002), and Duke (n = 45; P = 0.06)]. The ES signature was not prognostic in prostate, breast, or ovarian adenocarcinomas. Lung tumors (n = 569) and adenocarcinoma cell lines (n = 31) expressing the ES phenotype were more likely to be resistant to cisplatin (P < 0.0001 and P = 0.006, respectively). CONCLUSIONS: Lung adenocarcinomas that share a common gene expression pattern with normal human embryonic stem cells were associated with decreased survival, increased biological complexity, and increased likelihood of resistance to cisplatin. This indicates the aggressiveness of these tumors.

Authors
Stevenson, M; Mostertz, W; Acharya, C; Kim, W; Walters, K; Barry, W; Higgins, K; Tuchman, SA; Crawford, J; Vlahovic, G; Ready, N; Onaitis, M; Potti, A
MLA Citation
Stevenson, M, Mostertz, W, Acharya, C, Kim, W, Walters, K, Barry, W, Higgins, K, Tuchman, SA, Crawford, J, Vlahovic, G, Ready, N, Onaitis, M, and Potti, A. "Characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma." Clin Cancer Res 15.24 (December 15, 2009): 7553-7561.
PMID
19996213
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
24
Publish Date
2009
Start Page
7553
End Page
7561
DOI
10.1158/1078-0432.CCR-09-1939

Preoperative chemotherapy versus preoperative chemoradiotherapy for stage III (N2) non-small-cell lung cancer.

PURPOSE: To compare preoperative chemotherapy (ChT) and preoperative chemoradiotherapy (ChT-RT) in operable Stage III non-small-cell lung cancer. METHODS AND MATERIALS: This retrospective study analyzed all patients with pathologically confirmed Stage III (N2) non-small-cell lung cancer who initiated preoperative ChT or ChT-RT at Duke University between 1995 and 2006. Mediastinal pathologic complete response (pCR) rates were compared using a chi-square test. The actuarial overall survival, disease-free survival, and local control were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox regression analysis was also performed. RESULTS: A total of 101 patients who initiated preoperative therapy with planned resection were identified. The median follow-up was 20 months for all patients and 38 months for survivors. The mediastinal lymph nodes were reassessed after preoperative therapy in 88 patients (87%). Within this group, a mediastinal pCR was achieved in 35% after preoperative ChT vs. 65% after preoperative ChT-RT (p = 0.01). Resection was performed in 69% after ChT and 84% after ChT-RT (p = 0.1). For all patients, the overall survival, disease-free survival, and local control rate at 3 years was 40%, 27%, and 66%, respectively. No statistically significant differences were found in the clinical endpoints between the ChT and ChT-RT subgroups. On multivariate analysis, a mediastinal pCR was associated with improved disease-free survival (p = 0.03) and local control (p = 0.03), but not overall survival (p = 0.86). CONCLUSION: Preoperative ChT-RT was associated with higher mediastinal pCR rates but not improved survival.

Authors
Higgins, K; Chino, JP; Marks, LB; Ready, N; D'Amico, TA; Clough, RW; Kelsey, CR
MLA Citation
Higgins, K, Chino, JP, Marks, LB, Ready, N, D'Amico, TA, Clough, RW, and Kelsey, CR. "Preoperative chemotherapy versus preoperative chemoradiotherapy for stage III (N2) non-small-cell lung cancer." Int J Radiat Oncol Biol Phys 75.5 (December 1, 2009): 1462-1467.
PMID
19467798
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
75
Issue
5
Publish Date
2009
Start Page
1462
End Page
1467
DOI
10.1016/j.ijrobp.2009.01.069

Local recurrence after surgery for early stage lung cancer: an 11-year experience with 975 patients.

BACKGROUND: The objective of the current study was to evaluate the actuarial risk of local failure (LF) after surgery for stage I to II nonsmall cell lung cancer (NSCLC) and assess surgical and pathologic factors affecting this risk. METHODS: The records, including pertinent radiologic studies, of all patients who underwent surgery for T1 to T2, N0 to N1 NSCLC at Duke University between 1995 and 2005 were reviewed. Risks of disease recurrence were estimated using the Kaplan-Meier method. A multivariate Cox regression analysis assessed factors associated with LF in the entire cohort and a subgroup undergoing optimal surgery for stage IB to II disease. RESULTS: For all 975 consecutive patients, the 5-year actuarial risk of local and/or distant disease recurrence was 36%. First sites of failure were local only (25%), local and distant (29%), and distant only (46%). The 5-year actuarial risk of LF was 23%. On multivariate analysis, squamous/large cell histology (hazards ratio [HR], 1.98), stage > IA (HR, 2.02), and sublobar resections (HR, 1.99) were found to be independently associated with a higher risk of LF. For the subset of patients (n = 445) undergoing at least a lobectomy with negative surgical margins and currently considered for adjuvant chemotherapy (stage IB-II disease), the 5-year actuarial risk of LF was 27%. Within this subgroup, squamous/large cell histology (HR, 2.5) and lymphovascular space invasion (HR, 1.74) were associated with a higher risk of LF. The 5-year rate of LF was 13%, 32%, and 47%, respectively, with 0, 1, or 2 risk factors. CONCLUSIONS: Greater than half of disease recurrences after surgery for early stage NSCLC involved local sites. Pathologic factors may help to distinguish those patients at highest risk.

Authors
Kelsey, CR; Marks, LB; Hollis, D; Hubbs, JL; Ready, NE; D'Amico, TA; Boyd, JA
MLA Citation
Kelsey, CR, Marks, LB, Hollis, D, Hubbs, JL, Ready, NE, D'Amico, TA, and Boyd, JA. "Local recurrence after surgery for early stage lung cancer: an 11-year experience with 975 patients." Cancer 115.22 (November 15, 2009): 5218-5227.
PMID
19672942
Source
pubmed
Published In
Cancer
Volume
115
Issue
22
Publish Date
2009
Start Page
5218
End Page
5227
DOI
10.1002/cncr.24625

Langerhans cell histiocytosis following acute leukemia in an adult

Authors
Hirsh, R; Giri, D; Griffith, R; Stone, R; Ready, N
MLA Citation
Hirsh, R, Giri, D, Griffith, R, Stone, R, and Ready, N. "Langerhans cell histiocytosis following acute leukemia in an adult." American Journal of Hematology 84.10 (2009): 693-694.
PMID
19691100
Source
scival
Published In
American Journal of Hematology
Volume
84
Issue
10
Publish Date
2009
Start Page
693
End Page
694
DOI
10.1002/ajh.21490

Phase I and Pharmacokinetic study of gimatecan given orally once a week for 3 of 4 weeks in Patients with advanced solid tumors

Purpose: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of gimatecan, a lipophilic camptothecin analogue, administered orally once a week for 3 weeks. Experimental Design: Adult patients with advanced solid tumors with good performance status and adequate hematologic, hepatic, and renal function were eligible for the study. The plasma pharmacokinetics of the drug was characterized during the initial 28-day cycle. Results: A total of 33 patients were evaluated at 7 dose levels ranging from 0.27 to 3.20 mg/m 2/wk. Anemia, fatigue, neutropenia, nausea, and vomiting were the principal toxicities. DLTs experienced by 3 of 7 patients in dose level 7 (3.20 mg/m 2) were grade 2 hyperbilirubinemia and grade 3 to 4 fatigue. DLT (anorexia and nausea) occurred in only 1 of 11 patients evaluated at the MTD of 2.40 mg/m 2. There were no objective responses, although disease stabilization was observed in 4 patients. Gimatecan has a very long apparent biological haff-life (mean ± SD, 77 ± 37 h) and exists in plasma almost entirely as the pharmacologically active intact lactone form. At the MTD, mean peak concentrations of the drug in plasma ranged from 67 to 82 ng/mL for the 3 weekly doses and the mean concentration 7 days after dosing was 15 ± 18 ng/mL. Conclusions: Administration of gimatecan orally once a week at doses that are well tolerated provides continuous exposure to potentially effective plasma concentrations of the biologically active form of the drug. This regimen deserves further evaluation to define its antitumor activity in specific tumor types either alone or in combination with other agents. © 2009 American Association for Cancer Research.

Authors
Zhu, AX; Ready, N; Clark, JW; Safran, H; Amato, A; Salem, N; Pace, S; He, X; Zvereva, N; Lynch, TJ; Ryan, DP; Supko, JG
MLA Citation
Zhu, AX, Ready, N, Clark, JW, Safran, H, Amato, A, Salem, N, Pace, S, He, X, Zvereva, N, Lynch, TJ, Ryan, DP, and Supko, JG. "Phase I and Pharmacokinetic study of gimatecan given orally once a week for 3 of 4 weeks in Patients with advanced solid tumors." Clinical Cancer Research 15.1 (2009): 374-381.
PMID
19118068
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
1
Publish Date
2009
Start Page
374
End Page
381
DOI
10.1158/1078-0432.CCR-08-1024

Small cell lung cancer

Small cell lung cancer (SCLC) accounts for 15% of lung cancers. Nearly all cases of SCLC are attributable to cigarette smoking, and the remaining cases are presumably caused by environmental or genetic factors. Compared with non-small cell lung cancer, SCLC generally has a more rapid doubling time, a higher growth fraction, and earlier development of widespread metastases. SCLC is highly sensitive to initial chemotherapy and radiotherapy, but most patients eventually die from recurrent disease. These guidelines detail the management of SCLC from initial diagnosis and staging through treatment, and include information on supportive and palliative care. Important updates to the 2008 version include refined categories for performance status and the addition of topotecan as an option for patients who experience relapse. © Journal of the National Comprehensive Cancer Network 2008.

Authors
Kalemkerian, GP; Akerley, W; Downey, RJ; Ettinger, DS; Fossella, F; Grecula, JC; Jahan, T; Johnson, BE; Kessinger, A; Koczywas, M; Langer, CJ; Martins, R; Niell, HB; Pan, CC; Ramnath, N; Ready, N; Robert, F; Jr, CCW
MLA Citation
Kalemkerian, GP, Akerley, W, Downey, RJ, Ettinger, DS, Fossella, F, Grecula, JC, Jahan, T, Johnson, BE, Kessinger, A, Koczywas, M, Langer, CJ, Martins, R, Niell, HB, Pan, CC, Ramnath, N, Ready, N, Robert, F, and Jr, CCW. "Small cell lung cancer." JNCCN Journal of the National Comprehensive Cancer Network 6.3 (2008): 294-314.
PMID
18377848
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
6
Issue
3
Publish Date
2008
Start Page
294
End Page
314

Concurrent chemoradiotherapy with weekly paclitaxel and carboplatin for locally advanced head and neck cancer: Long-term follow-up of a Brown University Oncology Group phase II study (HN-53)

Background. A phase II study was conducted using concurrent paclitaxel, carboplatin, and external beam radiotherapy (RT) in patients with advanced head and neck cancer. Methods. Forty-three patients (stage III, n = 12; stage IV, n = 31) were treated with 8 cycles of weekly paclitaxel (60 mg/m2), carboplatin (area under the curve [AUC] = 1), and RT (1.8 Gy daily; total dose, 66-72 Gy). Patients with initially palpable lymph nodes underwent neck dissection. Results. The overall clinical response rate was 91% (65% complete, 26% partial). Severe mucositis occurred in 37 (90%) patients, necessitating hospitalization in 13 (31%) patients. With a median follow-up of 49 months, the locoregional and distant failure rates were 26% and 21%, respectively. Conclusions. Concurrent paclitaxel, carboplatin, and RT for advanced head and neck cancer results in high complete response rates. Long-term follow-up has revealed the curative potential of this regimen, though the doses used resulted in unacceptable toxicity. ©2007 Wiley Periodicals, Inc.

Authors
Chougule, PB; Akhtar, MS; Rathore, R; Koness, J; McRae, R; Nigri, P; Radie-Keane, K; Kennedy, T; Wanebo, HJ; Ready, N
MLA Citation
Chougule, PB, Akhtar, MS, Rathore, R, Koness, J, McRae, R, Nigri, P, Radie-Keane, K, Kennedy, T, Wanebo, HJ, and Ready, N. "Concurrent chemoradiotherapy with weekly paclitaxel and carboplatin for locally advanced head and neck cancer: Long-term follow-up of a Brown University Oncology Group phase II study (HN-53)." Head and Neck 30.3 (2008): 289-296.
PMID
17657799
Source
scival
Published In
Head & Neck: Journal for the Sciences & Specialties of the Head and Neck
Volume
30
Issue
3
Publish Date
2008
Start Page
289
End Page
296
DOI
10.1002/hed.20700

Phase I study of the farnesyltransferase inhibitor lonafarnib with weekly paclitaxel in patients with solid tumors.

PURPOSE: To establish the maximum tolerated dose of the farnesyltransferase inhibitor lonafarnib (Sarasar, Schering-Plough Corp., Kenilworth, NJ) in combination with weekly paclitaxel in patients with solid tumors. Tolerability, pharmacokinetics, safety, and dose-limiting toxicity were characterized. EXPERIMENTAL DESIGN: Patients were enrolled from January 2000 to May 2001. Lonafarnib was administered continuously orally twice daily at doses of 100, 125, and 150 mg in combination with paclitaxel at doses of 40, 60, or 80 mg/m(2) i.v. over 1 h weekly in 28-day cycles in a phase I design. Plasma samples for determinations of lonafarnib and paclitaxel concentrations were collected at selected time points. RESULTS: Twenty-seven patients were enrolled. The maximum tolerated dose (the dose level below where dose-limiting toxicity occurred and the recommended phase II dose) was lonafarnib 125 mg/m(2) twice daily and paclitaxel 80 mg/m(2) weekly. Dose-limiting toxicity was neutropenia with or without fever, which occurred in two of three patients treated at the lonafarnib 150 mg twice daily dose level. Diarrhea was a common side effect of lonafarnib but usually was mild to moderate in severity and could be controlled with standard medication without lonafarnib dose adjustment. Other reported adverse events included nausea, vomiting, fatigue, and taste changes. These adverse events were neither more frequent nor more severe than would be expected with paclitaxel alone. There were no apparent pharmacokinetic interactions between weekly paclitaxel and continuous twice-daily lonafarnib. CONCLUSIONS: The recommended dose of lonafarnib for phase II trials is 125 mg orally twice daily when combined with weekly paclitaxel 80 mg/m(2). The dose-limiting toxicity was neutropenia.

Authors
Ready, NE; Lipton, A; Zhu, Y; Statkevich, P; Frank, E; Curtis, D; Bukowski, RM
MLA Citation
Ready, NE, Lipton, A, Zhu, Y, Statkevich, P, Frank, E, Curtis, D, and Bukowski, RM. "Phase I study of the farnesyltransferase inhibitor lonafarnib with weekly paclitaxel in patients with solid tumors." Clin Cancer Res 13.2 Pt 1 (January 15, 2007): 576-583.
PMID
17255280
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
2 Pt 1
Publish Date
2007
Start Page
576
End Page
583
DOI
10.1158/1078-0432.CCR-06-1262

Image-guided percutaneous thermal ablation for the palliative treatment of chest wall masses

OBJECTIVES: To evaluate the palliative benefits of image-guided thermal ablation for the treatment of painful tumors affecting the chest wall. METHODS: Thirty-nine patients, median age 65 years, underwent percutaneous thermal ablation of 44 chest wall masses. Thirty-eight radiofrequency ablations (RFAs), 3 microwave ablations (MWAs), and 3 cryoablations were performed. Subjective pain reports at 1 week and 1 month postablation were scored from 0 to 4 based on a standard Likert pain relief scale, with 2 or higher representing clinically significant pain relief. RESULTS: Patients were followed for a median of 6 months. Overall, 31 of 44 procedures (70.5%) resulted in significant pain relief. Improvement followed 15 of 15 (100%) of ablations that were performed within 90 days of treatment with palliative external-beam radiation therapy (XRT), compared with 16 of 29 (55.2%) of the remaining procedures. Mean pain relief score at 1 month was 3.86 for the 15 combined procedures versus 1.96 for the 29 remaining procedures (P < 0.001). Local pain recurred after 5 of 31 positive responses (16.1%). Median survival was 11.2 ± 2.3 months for patients with significant pain relief and 4.3 ± 1.4 months for nonresponders (P < 0.001). Adverse events included a transient symptom "flare" (n = 5, 11.4%) and the exacerbation of a preexisting brachial plexopathy. CONCLUSIONS: Thermal ablation results in significant pain relief for the majority of patients and shows evidence of synergistic benefit when temporally combined with XRT. This minimally invasive technique appears to be a safe and durable alternative for the palliation of chest wall masses. © 2007 Lippincott Williams & Wilkins, Inc.

Authors
Grieco, CA; Simon, CJ; Mayo-Smith, WW; Dipetrillo, TA; Ready, NE; Dupuy, DE
MLA Citation
Grieco, CA, Simon, CJ, Mayo-Smith, WW, Dipetrillo, TA, Ready, NE, and Dupuy, DE. "Image-guided percutaneous thermal ablation for the palliative treatment of chest wall masses." American Journal of Clinical Oncology: Cancer Clinical Trials 30.4 (2007): 361-367.
PMID
17762436
Source
scival
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
30
Issue
4
Publish Date
2007
Start Page
361
End Page
367
DOI
10.1097/COC.0b013e318033e76a

A multi-center phase II study of weekly topotecan as second-line therapy for small cell lung cancer

Purpose: To determine the response rate, toxicity, failure free and overall survival of weekly topotecan in patients with relapsed small cell lung cancer who received one prior platinum based chemotherapy. Patients and methods: Twenty two patients with relapsed disease after response to one prior chemotherapy with or without radiotherapy and patients with relapse more than 90 days after their last therapy received topotecan 4 mg/m2 intravenous over 30 min on days 1,8,15; every 4 weeks (3 weeks on and 1 weeks off). Chemotherapy was given until disease progression or unacceptable toxicity. Results: Of 22 patients, none of the patients responded to weekly topotecan therapy. Four patients had stable disease. After a median follow up of 1 year, median time to progression was 6 weeks and median survival was 5 months. The common toxicities associated with this regimen were anemia, thrombocytopenia, fatigue, GI side effects and alopecia. Conclusion: Weekly topotecan was well tolerated but ineffective in this trial. Although commonly used, weekly regimen of topotecan should be used with caution in relapsed SCLC. © 2007 Elsevier Ireland Ltd. All rights reserved.

Authors
Shah, C; Ready, N; Perry, M; Kirshner, J; Gajra, A; Neuman, N; Garziano, S
MLA Citation
Shah, C, Ready, N, Perry, M, Kirshner, J, Gajra, A, Neuman, N, and Garziano, S. "A multi-center phase II study of weekly topotecan as second-line therapy for small cell lung cancer." Lung Cancer 57.1 (2007): 84-88.
PMID
17399850
Source
scival
Published In
Lung Cancer
Volume
57
Issue
1
Publish Date
2007
Start Page
84
End Page
88
DOI
10.1016/j.lungcan.2007.02.014

Percutaneous image-guided thermal ablation and radiation therapy: Outcomes of combined treatment for 41 patients with inoperable stage I/II non-small-cell lung cancer

PURPOSE: To evaluate the clinical outcomes in patients with early-stage non-small-cell lung cancer (NSCLC) after combined treatment with thermal ablation and radiation therapy (RT). MATERIALS AND METHODS: Forty-one patients with inoperable stage I/II NSCLC tumors underwent thermal ablation and RT at our institution between 1998 and 2005. Thirty-seven radiofrequency (RF) ablation procedures and four microwave ablation procedures were performed. Ablations were followed by standard-fraction external-beam RT within 90 days (n = 27) or postprocedural brachytherapy (n = 14). Survival and local recurrence were the primary endpoints evaluated by Kaplan-Meier analysis. RESULTS: The median follow-up was 19.5 months. The overall survival rates were 97.6% at 6 months, 86.8% at 1 year, 70.4% at 2 years, and 57.1% at 3 years. Patients with tumors smaller than 3 cm (n = 17) had an average survival time of 44.4 ± 5.4 months (SE). Patients with tumors 3 cm or larger (n = 24) had an average survival time of 34.6 ± 7.0 months (P = .08). Local recurrence occurred in 11.8% of tumors smaller than 3 cm after an average of 45.6 ± 4.1 months and in 33.3% of the larger tumors after an average of 34.0 ± 7.8 months (P = .03). Outcomes in the brachytherapy and RT groups did not differ significantly. Nine of 15 pneumothoraces required chest tube drainage (22.0%). CONCLUSIONS: Thermal ablation followed by RT for inoperable stage I/II NSCLC has a relatively low rate of complications that are easily managed. Combined therapy may result in an improved survival compared with either modality alone. © SIR, 2006.

Authors
Grieco, CA; Simon, CJ; Mayo-Smith, WW; DiPetrillo, TA; Ready, NE; Dupuy, DE
MLA Citation
Grieco, CA, Simon, CJ, Mayo-Smith, WW, DiPetrillo, TA, Ready, NE, and Dupuy, DE. "Percutaneous image-guided thermal ablation and radiation therapy: Outcomes of combined treatment for 41 patients with inoperable stage I/II non-small-cell lung cancer." Journal of Vascular and Interventional Radiology 17.7 (2006): 1117-1124.
PMID
16868164
Source
scival
Published In
JVIR: Journal of Vascular and Interventional Radiology
Volume
17
Issue
7
Publish Date
2006
Start Page
1117
End Page
1124
DOI
10.1097/01.RVI.0000228373.58498.6E

Phase II trial of weekly paclitaxel and gemcitabine for previously untreated, Stage IIIB-IV nonsmall cell lung cancer

BACKGROUND. The purpose of the current study was to evaluate the efficacy and tolerance of the noncisplatin-based combination of paclitaxel and gemcitabine administered weekly for patients with untreated metastatic nonsmall cell lung cancer (NSCLC). METHODS. Patients with Stage IIIB/IV or recurrent NSCLC, a performance status of 0-2, and no prior chemotherapy exposure were eligible. Patients received gemcitabine 1000 mg/m2 and paclitaxel 85 mg/m2 on Days 1, 8, 15, 22, 29, 36 of an 8-week cycle until progression. RESULTS. Thirty-nine eligible patients were enrolled. The median age was 66 years and 14 patients were ≥70 years old. Performance status was 2 in 13 (33%) and 29 patients (75%) had Stage IV. Five patients (12.8%) developed interstitial pneumonitis and 2 of these were responsive to steroid therapy. The overall response rate was 23.1%, with no complete responses. The median survival was 32 weeks and the 1-year survival was 32%. CONCLUSIONS. This regimen of weekly paclitaxel and gemcitabine has modest activity in advanced NSCLC. © 2006 American Cancer Society.

Authors
Akerley, W; Safran, H; Zaner, K; Ready, N; Mega, T; Kennedy, T
MLA Citation
Akerley, W, Safran, H, Zaner, K, Ready, N, Mega, T, and Kennedy, T. "Phase II trial of weekly paclitaxel and gemcitabine for previously untreated, Stage IIIB-IV nonsmall cell lung cancer." Cancer 107.5 (2006): 1050-1054.
PMID
16878327
Source
scival
Published In
Cancer
Volume
107
Issue
5
Publish Date
2006
Start Page
1050
End Page
1054
DOI
10.1002/cncr.22095

Radiofrequency ablation followed by conventional radiotherapy for medically inoperable stage I non-small cell lung cancer

Purpose: The standard treatment of stage I non-small cell lung cancer (NSCLC) is surgical resection. Some patients are poor surgical candidates due to severe comorbid medical conditions. Radiotherapy alone has historically been used in this patient population with limited success. Radiofrequency ablation (RFA) is an image-guided, thermally mediated ablative technique recently applied to lung tumors. Combination therapy with both these treatments has not been previously performed. We report our experience with combined CT-guided RFA and conventional radiotherapy in 24 medically inoperable patients with a minimum of 2-year study follow-up in surviving patients. Patients and methods: Twenty-four consecutive, medically inoperable patients with biopsy-proven, stage I NSCLC were treated with CT-guided RFA followed by radiotherapy to a dose of 66 Gy. RFA was performed with a single or cluster cool-tip F electrode; 21 patients were staged before therapy using fluorodeoxyglucose-positron emission tomography. Results: There were 14 women and 10 men (median age, 76 years; range, 58 to 85 years). The histologic subtypes were squamous cell (n = 13), adenocarcinoma (n = 5), and undifferentiated (n = 6). All patients received MFA followed by three-dimensional conformal radiotherapy. There were no treatment-related deaths or grade 3/4 toxicities. Pneumothorax requiring chest tubes developed in three patients (12.5%). At a mean follow-up period of 26.7 months (range, 6 to 65 months), 14 patients (58.3%) died, with cumulative survival rates of 50% and 39% at the end of 2 years and 5 years, respectively. Ten of the deaths were cancer related. Two patients had local recurrence (8.3%), while nine patients had systemic metastatic disease. Three patients died of respiratory failure with no evidence of active disease, and one patient died of a cerebrovascular accident at 18-month follow-up. Pleural effusions developed after treatment in six patients (25%), which proved to be malignant in one patient. Conclusion: RFA followed by conventional radiotherapy is feasible in this population of medically inoperable stage I NSCLC patients. Procedural complication rates are low, and no additional major toxicities were seen despite the addition of RFA. Local control and survival rates appear to be better than with radiotherapy alone.

Authors
Dupuy, DE; DiPetrillo, T; Gandhi, S; Ready, N; Ng, T; Donat, W; Mayo-Smith, WW
MLA Citation
Dupuy, DE, DiPetrillo, T, Gandhi, S, Ready, N, Ng, T, Donat, W, and Mayo-Smith, WW. "Radiofrequency ablation followed by conventional radiotherapy for medically inoperable stage I non-small cell lung cancer." Chest 129.3 (2006): 738-745.
PMID
16537876
Source
scival
Published In
Chest
Volume
129
Issue
3
Publish Date
2006
Start Page
738
End Page
745
DOI
10.1378/chest.129.3.738

A low rate of central nervous system progression in a phase II trial of outpatient chemobiologic therapy with cisplatin, temozolomide, interleukin-2, and interferon alfa 2-B for metastatic malignant melanoma

The objective of this study was to evaluate an outpatient chemobiotherapy regimen for metastatic melanoma that included an agent with central nervous system (CNS) antitumor activity. Patients without prior therapy for metastatic disease received 20 mg/m2 cisplatin intravenously on days 1 through 4, 100 mg/m2 temozolomide orally on days 1 through 5, concurrent with 5 MIU/m2 interferon alfa 2-B subcutaneously on days 1 through 5 and 10 MIU/m2 interleukin-2 subcutaneously on days 1 and 6 MIU/m2 subcutaneously on days 2 through 4. Treatment was given every 21 days to a maximum of 6 cycles. Twenty-four patients were enrolled. Significant toxicities included grade 3 or 4 nausea/vomiting in 8 (33%) and electrolyte abnormalities in 9 (38%). There were no episodes of febrile neutropenia or treatment-related deaths. Of 21 evaluable patients, responses were 6 progressive disease, 10 stable disease (SD), 3 partial remission (PR), and 2 complete remission (CR) (response rate 5 of 21 = 24%). Four patients with SD or PR had prolonged survivals (23, 24, 37+, and 39 months). The 2 patients with clinical or pathologic CR had durable remissions (42+ and 46+ months). Median survival based on intent to treat was 291 days. Of 21 evaluable patients, 3 progressed initially in the CNS and none of the 5 patients achieving PR/CR progressed initially in the CNS. This regimen had significant morbidity but was safely delivered in the outpatient setting. Objective responses, prolonged stable disease, and durable remissions indicate activity. There was a lower-than-expected rate of initial CNS progression. Copyright © 2005 by Lippincott Williams & Wilkins.

Authors
Ready, N; Aronson, F; Wanebo, H; Kennedy, T
MLA Citation
Ready, N, Aronson, F, Wanebo, H, and Kennedy, T. "A low rate of central nervous system progression in a phase II trial of outpatient chemobiologic therapy with cisplatin, temozolomide, interleukin-2, and interferon alfa 2-B for metastatic malignant melanoma." American Journal of Clinical Oncology: Cancer Clinical Trials 28.5 (2005): 479-484.
PMID
16199988
Source
scival
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
28
Issue
5
Publish Date
2005
Start Page
479
End Page
484
DOI
10.1097/01.coc.0000164006.72694.1b

Inhibition of the epidermal growth factor receptor in combined modality treatment for locally advanced non-small cell lung cancer

Epidermal growth factor receptor 1 (EGFR1) is a 170-kd glycoprotein that plays many roles in the growth of non-small cell lung cancer (NSCLC). There are four known receptors in the EGFR family. Binding of a ligand such as epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-α) causes EGFR to undergo a conformational change leading to autophosphorylation of EGFR and activation of the EGFR growth factor pathway. The protein products of the genes that are then expressed increase cell proliferation and angiogenesis and inhibit programmed cell death. EGFR is expressed in 40% to 80% of NSCLC. EGFR tyrosine kinase activity can be inhibited by antibody therapy, such as cetuximab, against the extracellular domain of EGFR or small-molecule therapy, such as gefitinib or erlotinib that blocks the adenosine triphosphate (ATP) binding site of the cytoplasmic domain. Both forms of EGFR inhibition have single-agent antitumor activity against previously treated NSCLC. Interestingly, EGFR expression does not correlate with response to EGFR inhibition therapy. Increased likelihood of responding to small-molecule therapy is associated with female gender, never smoking, adenocarcinoma, and acquired mutations of the EGFR ATP binding site in tumor cells. In previously treated NSCLC, the small-molecule erlotinib improved both quality of life and median survival as a single agent compared with best supportive care. Southwest Oncology Group 0023 is a large, phase III, randomized trial comparing concurrent chemoradiotherapy and consolidation docetaxel with or without maintenance small-molecule therapy with gefitinib. There is also strong preclinical evidence that EGFR inhibition is additive or synergistic with radiotherapy in NSCLC. In locally advanced head and neck cancer, the addition of cetuximab antibody therapy to radiation increased median survival from 28 to 54 months. Cancer and Leukemia Group B 30106 and a multi-institutional Australian phase I trial have shown that gefitinib can be added to concurrent chemoradiotherapy for stage III NSCLC without excessive toxicity. A phase I trial at the University of Chicago (Chicago, IL) has evaluated erlotinib with concurrent chemoradiotherapy in stage III NSCLC. Radiation Therapy Oncology Group 0324 is an on going phase II trial studying cetuximab and concurrent chemoradiotherapy in stage III NSCLC. © 2005 Elsevier Inc. All rights reserved.

Authors
Ready, N
MLA Citation
Ready, N. "Inhibition of the epidermal growth factor receptor in combined modality treatment for locally advanced non-small cell lung cancer." Seminars in Oncology 32.SUPPL. 3 (2005): S35-S41.
PMID
16015534
Source
scival
Published In
Seminars in Oncology
Volume
32
Issue
SUPPL. 3
Publish Date
2005
Start Page
S35
End Page
S41
DOI
10.1053/j.seminoncol.2005.03.008

Gefitinib therapy for non-small cell lung cancer

Gefitinib is a small molecule that specifically inhibits the tyrosine kinase activity of the epidermat growth factor receptor (EGFR) type 1 by interfering with the adenosine triphosphate (ATP) binding site. At doses that maximally inhibit EGFR tyrosine kinase activity chosen for phase II trials, the most common side effects of gefitinib are low-grade rash or diarrhea. An infrequent but serious side effect of gefitinib is interstitial lung disease (ILD). The Iressa dose evaluation for advanced lung cancer phase II trials (IDEAL 1 and IDEAL 2) of single agent gefitinib, 250 or 500 mg orally per day in pretreated patients with non-small cell lung cancer (NSCLC), found about 20% of patients on IDEAl-1 and 10% of patients on IDEAL-2 had major objective responses and improvement of symptoms. The data from the IDEAL trials and the extensive experience from the 21,000 patients treated on the expanded access program, suggests that the patients who have a major objective response probably have a significant survival benefit in addition to palliative benefit. In addition, approximately 40% of patients on the IDEAL trials experienced improvement in symptoms. Gefitinib was approved for third line treatment of NSCLC. Gefitinib is effective, safe, and well-tolerated single-agent therapy in previously treated NSCLC. Although there have been no direct comparisons, the small molecule inhibitors of EGFR gefitinib and erlotinib appear to have similar efficacy. Erlotinib has been shown to produce a survival advantage compared to best supportive care in an unselected group of previously treated patients with NSCLC. Until similar trials are completed comparing gefitinib to best supportive care, there is a similar survival advantage for gefitinib. Nonsmokers, women, and patients with adenocarcinoma, are more likely to have major objective responses than other patients. Bronchioalveolar lung cancer is a subtype of NSCLC that is more likely to respond to gefitinib. Several groups have now reported that most, but not all, tumors experiencing a major objective response to gefitinib have mutations associated with the ATP-binding site of EGFR. It is reasonable to move gefitinib in to second-line therapy for patients who are known to have a tumor that is more likety to respond to gefitinib. Also, I would treat such patients with gefitinib as first-line therapy on an appropriate clinical trial approved by the Institutional Review Board (IRB). Outside of a clinical trial, patients with advanced disease should initially be treated with a combination of doublet chemotherapy. There is strong evidence that there is no benefit to concurrent chemotherapy and gefitinib. Gefitinib should not be given concurrently with cytotoxic chemotherapy as initial treatment for NSCLC. Sequential therapy combining chemotherapy and gefitinib in advanced disease or as adjuvant therapy should only be done in the context of a clinical trial approved by the IRB. There is preclinical evidence suggesting that gefitinib is a radiosensitizer. Early results from trials combining radiation, or chemoradiotherapy with gefitinib have shown that these combinations are without excessive additive toxicity. There is no proven clinical benefit for concurrent Gefitinib and radiation. Gefitinib should only be given with radiation as part of an appropriate clinical trial approved by the IRB. Copyright © 2005 by Current Science Inc.

Authors
Birnbaum, A; Ready, N
MLA Citation
Birnbaum, A, and Ready, N. "Gefitinib therapy for non-small cell lung cancer." Current Treatment Options in Oncology 6.1 (2005): 75-81.
PMID
15610717
Source
scival
Published In
Current Treatment Options in Oncology
Volume
6
Issue
1
Publish Date
2005
Start Page
75
End Page
81

Consensus report IASLC workshop Bruges, September 2002: Pretreatment minimal staging for non-small cell lung cancer

Authors
Postmus, PE; Rocmans, P; Asamura, H; Ball, D; Belderbos, J; Cappello, M; Jassem, J; Novello, S; Pass, H; Passlick, B; Pirker, R; Ready, N; Sause, W; Scagliotti, G; Vansteenkiste, J; Westeel, V; Zandwijk, NV
MLA Citation
Postmus, PE, Rocmans, P, Asamura, H, Ball, D, Belderbos, J, Cappello, M, Jassem, J, Novello, S, Pass, H, Passlick, B, Pirker, R, Ready, N, Sause, W, Scagliotti, G, Vansteenkiste, J, Westeel, V, and Zandwijk, NV. "Consensus report IASLC workshop Bruges, September 2002: Pretreatment minimal staging for non-small cell lung cancer." Lung Cancer 42.2 SUPPL. (2003): S3-S6.
PMID
14708514
Source
scival
Published In
Lung Cancer
Volume
42
Issue
2 SUPPL.
Publish Date
2003
Start Page
S3
End Page
S6
DOI
10.1016/S0169-5002(03)00296-4

Management of unresectable non-small cell carcinoma of the lung (NSCLC)

Authors
Cox, JD; Chevalier, TL; Arriagada, R; Choy, H; Curran, WJ; Fukuoka, M; Harper, P; Komaki, R; Pechoux, CL; Lievens, Y; Rami-Porta, R; Ready, N; Sause, W; Stuschke, M; Thatcher, N
MLA Citation
Cox, JD, Chevalier, TL, Arriagada, R, Choy, H, Curran, WJ, Fukuoka, M, Harper, P, Komaki, R, Pechoux, CL, Lievens, Y, Rami-Porta, R, Ready, N, Sause, W, Stuschke, M, and Thatcher, N. "Management of unresectable non-small cell carcinoma of the lung (NSCLC)." Lung Cancer 42.2 SUPPL. (2003): S15-S16.
PMID
14708518
Source
scival
Published In
Lung Cancer
Volume
42
Issue
2 SUPPL.
Publish Date
2003
Start Page
S15
End Page
S16
DOI
10.1016/S0169-5002(03)00298-8

Induction or consolidation systemic therapy in the multimodality treatment of unresectable locally advanced non-small cell lung cancer

Chemoradiotherapy has been shown to improve survival over radiation alone for unresectable locally advanced non-small cell lung cancer (NSCLC). Large randomized trials comparing sequential to concomitant platinum based chemoradiotherapy have demonstrated improved median survival times in favor of concomitant treatment. Recent phase II trials have evaluated the integration of advanced radiotherapy techniques, novel chemotherapy combinations, induction chemotherapy, and consolidation chemotherapy with concomitant chemoradiotherapy. On-going or recently completed phase III trials are evaluating whether the promising regimens from phase II studies are superior to concomitant chemoradiotherapy alone. Molecular therapies now need to be integrated with chemoradiotherapy. © 2003 Elsevier Ireland Ltd. All rights reserved.

Authors
Ready, NE; Vokes, EE
MLA Citation
Ready, NE, and Vokes, EE. "Induction or consolidation systemic therapy in the multimodality treatment of unresectable locally advanced non-small cell lung cancer." Lung Cancer 42.2 SUPPL. (2003): S65-S69.
PMID
14611917
Source
scival
Published In
Lung Cancer
Volume
42
Issue
2 SUPPL.
Publish Date
2003
Start Page
S65
End Page
S69
DOI
10.1016/S0169-5002(03)00306-4

Elective lymph node dissection for melanoma laid to rest yet again

Authors
Ready, N; Weinstock, MA
MLA Citation
Ready, N, and Weinstock, MA. "Elective lymph node dissection for melanoma laid to rest yet again." Archives of Dermatology 139.9 (2003): 1203-1204.
Source
scival
Published In
Archives of Dermatology
Volume
139
Issue
9
Publish Date
2003
Start Page
1203
End Page
1204
DOI
10.1001/archderm.139.9.1203

Adjuvant High-Dose Interferon Therapy for High-Risk Melanoma

Authors
Ready, N; Weinstock, MA
MLA Citation
Ready, N, and Weinstock, MA. "Adjuvant High-Dose Interferon Therapy for High-Risk Melanoma." Archives of Dermatology 139.12 (2003): 1635-1637.
PMID
14676083
Source
scival
Published In
Archives of Dermatology
Volume
139
Issue
12
Publish Date
2003
Start Page
1635
End Page
1637
DOI
10.1001/archderm.139.12.1635

A phase I study of a weekly schedule of paclitaxel and carboplatin in patients with advanced carcinoma

BACKGROUND. We conducted a Phase I study of weekly paclitaxel (P) and carboplatin (C) in patients with advanced malignancies to determine the maximum tolerated dose (MTD) of this combination. METHODS. Dose levels were escalated independently for patients with and without previous chemotherapy exposure and advanced malignancies. Both agents were administered weekly for 6 weeks followed by a 2-week break per cycle. P, escalated to tolerance starting at 135 mg/m2 per week, and C, fixed dose at area under the curve (AUC) = 2 mg/mL/min, were administered to groups of three or six patients. Doses were modified for granulocyte counts less than 1800/μL or for neurotoxicity greater than Grade 1. MTD was defined as the highest dose level at which less than 50% of patients developed unacceptable toxicity and received more than 80% of the intended dose during the first cycle. Dose levels were escalated until these conditions were exceeded. RESULTS. Twenty-seven patients (12 patients with previous chemotherapy exposure and 15 chemotherapy-naive patients) were examined for toxicity. Dose escalation was halted due to neutropenia and/or Grade 2/3 neuropathy in both arms. The MTD was P = 135/C = 2 for patients with previous chemotherapy exposure and P = 150/C = 2 for chemotherapy-naive patients. CONCLUSIONS. The combination of P and C administered on a weekly schedule permits a two to threefoldenhancement of P dose intensity with full doses of C. Phase II trials of this regimen in patients with various malignancies are being evaluated to determine efficacy and tolerance. © 2002 American Cancer Society.

Authors
Akerley, W; Rathore, R; Ready, N; Leone, L; Sikov, W; Safran, H; Kennedy, T
MLA Citation
Akerley, W, Rathore, R, Ready, N, Leone, L, Sikov, W, Safran, H, and Kennedy, T. "A phase I study of a weekly schedule of paclitaxel and carboplatin in patients with advanced carcinoma." Cancer 95.9 (2002): 2000-2005.
PMID
12404295
Source
scival
Published In
Cancer
Volume
95
Issue
9
Publish Date
2002
Start Page
2000
End Page
2005
DOI
10.1002/cncr.10902

Update in non-small cell lung cancer.

Authors
Moore, T; Ready, N
MLA Citation
Moore, T, and Ready, N. "Update in non-small cell lung cancer." Medicine and health, Rhode Island 85.1 (2002): 7-9.
PMID
11824158
Source
scival
Published In
Medicine and health, Rhode Island
Volume
85
Issue
1
Publish Date
2002
Start Page
7
End Page
9

Surgical resection is necessary to maximize tumor control in function-preserving, aggressive chemoradiation protocols for advanced squamous cancer of the head and neck (stage III and IV)

Background: The role of surgery in aggressive chemoradiation protocols for advanced head and neck cancer has been questioned because of the quoted high clinical response rates in many series. Methods: The role of surgical resection was examined in an aggressive neoadjuvant protocol of weekly paclitaxel, carboplatin, and radiation for stage III and IV with completion of radiation to 72 Gy if biopsy at the primary site was negative after administration of 45 Gy. Of 43 patients enrolled, 38 completed the protocol. The clinical response was 100% (including 18 complete and 20 partial responses). Results: The complete pathologic response (negative primary site biopsy at 45 Gy) was 25 of 38 (66%). Of patients who presented with N1 to N3 nodes, neck dissection revealed residual nodal metastases in 22%. Surgical resection of the primary site was required in 13 patients, including 5 with larynx cancer and 2 with base of tongue cancers. Four patients had resection with reconstruction for advanced mandible floor of mouth cancer, and one had resection of nasal-maxillary cancer. Functional resection was performed in 9 of 12 patients. The median progression free and overall survival was 64% and 68%, respectively, at median follow-up of 50 months. Nine patients developed recurrence (three local and six distant). There were no failures in the neck. Salvage surgery was performed in one patient with local and one with distant disease. Conclusions: Surgical resection is an essential component of aggressive chemoradiation protocols to ensure tumor control at the primary site and in the neck.

Authors
Wanebo, H; Chougule, P; Ready, N; Safran, H; Ackerley, W; Koness, RJ; McRae, R; Nigri, P; Leone, L; Radie-Keane, K; Reiss, P; Kennedy, T
MLA Citation
Wanebo, H, Chougule, P, Ready, N, Safran, H, Ackerley, W, Koness, RJ, McRae, R, Nigri, P, Leone, L, Radie-Keane, K, Reiss, P, and Kennedy, T. "Surgical resection is necessary to maximize tumor control in function-preserving, aggressive chemoradiation protocols for advanced squamous cancer of the head and neck (stage III and IV)." Annals of Surgical Oncology 8.8 (2001): 644-650.
PMID
11569779
Source
scival
Published In
Annals of Surgical Oncology
Volume
8
Issue
8
Publish Date
2001
Start Page
644
End Page
650
DOI
10.1245/aso.2001.8.8.644

Preoperative paclitaxel, carboplatin, and radiation therapy in advanced head and neck cancer (stage III and IV)

Preoperative chemotherapy and chemoradiation protocols are generally associated with high clinical response rates but limited pathologic responses for large primary tumors. We have initiated a prospective phase II study of weekly paclitaxel and carboplatin plus concurrent, fractionated external- beam radiation, followed by organ-preserving or function-restorative surgery (when applicable to maximize locoregional tumor control). Operable patients staged by triple endoscopy received a percutaneous gastrostomy and vigorous dental and nutritional support during therapy. Paclitaxel 60 mg/m2 and carboplatin at an area under the concentration-time curve of 1 were administered weekly with radiation therapy 45 Gy, with repeat biopsy of the primary site at 5 weeks. Patients with a positive biopsy had definitive surgery within 4 to 5 weeks. Patients with a negative biopsy received 3 additional weeks of radiation therapy, to a total close of 72 Gy plus paclitaxel and carboplatin. Forty-three patients were enrolled, including 33 men and 10 women ranging in age from 37 to 81 years. Fourteen patients had stage III disease, 19 patients had stage IVA disease, and 10 patients had stage IVB disease. Sites of disease included the floor of the mouth (n = 8), tongue (n = 8), oropharynx (n = 5), hypopharynx (n = 4), larynx (n = 12), palate-tonsil (n = 2), unknown primary (n = 3), and nasal cavity (n = 1). Of 38 patients evaluable for primary response (two patients had unknown primary tumor, two patients failed to complete the chemoradiation protocol, and one patient was evaluable for toxicity only), 18 patients had a complete clinical response and 20 patients had a partial response; the overall clinical response rate was 100%. A pathologic clinical response at the primary site occurred in 25 of these 38 patients (66%), who subsequently received completion radiation (67 to 72 Gy). After induction chemoradiation, 36 patients with N1-N3 nodes had neck dissection; seven had positive nodes (19%). Fourteen patients had residual cancer at the primary site at the time of the repeat biopsy. Sites of the lesions were the floor of the mouth/mandible (n = 4), nasal cavity/maxilla (n = 2), base of tongue (n = 2), and larynx (n = 6). All were resected with function-preserving reconstruction (two patients required total laryngectomy and one patient refused surgery). At a median follow-up of more than 16 months, progression-free and overall survival rates were 64% and 68%, respectively. Preoperative paclitaxel, carboplatin, and radiation was associated with a high clinical response rate at the primary site and a high level of organ preservation or functional restoration, if ablation was performed.

Authors
Wanebo, HJ; Chougule, P; Ready, N; Koness, RJ; Akerley, W; McRae, R; Nigri, P; Leone, L; Webber, B; Safran, H
MLA Citation
Wanebo, HJ, Chougule, P, Ready, N, Koness, RJ, Akerley, W, McRae, R, Nigri, P, Leone, L, Webber, B, and Safran, H. "Preoperative paclitaxel, carboplatin, and radiation therapy in advanced head and neck cancer (stage III and IV)." Seminars in Radiation Oncology 9.2 SUPPL. 1 (1999): 77-84.
PMID
10210544
Source
scival
Published In
Seminars in Radiation Oncology
Volume
9
Issue
2 SUPPL. 1
Publish Date
1999
Start Page
77
End Page
84

Chemoradiotherapy for advanced inoperable head and neck cancer: A phase II study

The beneficial effects of chemotherapy in patients with advanced head and neck cancer remain controversial in terms of survival, but have shown some promise in improving locoregional control and quality of life. In an effort to improve locoregional control and survival, a prospective phase II study was initiated using paclitaxel and carboplatin with concurrent conventional fractionated external-beam radiotherapy. Paclitaxel and carboplatin have both shown excellent radiosensitization through two discrete mechanisms, cell blockage in G2/M phase and inhibition of DNA repair, respectively. Patients were stratified as either operable or inoperable. This report pertains to the inoperable patient group, who received eight cycles of weekly paclitaxel (60 mg/m2), carboplatin [area under the concentration- time curve of 1) with conventional radiotherapy (72 Gy). Chemoradiotherapy was followed by neck dissection for those patients who presented with clinically palpable lymph nodes. Thirty-three patients were enrolled in this group (23 men and 10 women with a median age of 56 years). Eleven patients (33%) had stage III disease; 22 (67%), stage IV disease. The median follow- up period was 14 months. Clinical complete response occurred in 20 patients (60%) and partial response occurred in 10 [30%), for an overall response rate of 90%. Following completion of therapy, 18 patients have undergone biopsy at the primary tumor site and 17 were negative. Eight of the 16 patients with clinically palpable neck nodes at presentation underwent neck dissection; five (63%) had negative nodes. Mucositis was the most common toxicity. Grade 3 or 4 mucositis occurred in 30 of the 33 (90%) patients. Other grade 3 or 4 toxicities included skin (22%), candidiasis (19%), neutropenia (9%), and dehydration (6%). One patient with laryngeal carcinoma who had pathologic complete response developed cartilage necrosis and is undergoing hyperbaric oxygen therapy. Survival data are early but encouraging. Concurrent paclitaxel, carboplatin, and external-beam radiotherapy yielded excellent clinical and pathologic responses. Mucositis remains, the most common and significant morbidity. The study will continue for necessary accrual.

Authors
Chougule, PB; Akhtar, MS; Akerley, W; Ready, N; Safran, H; McRae, R; Nigri, P; Bellino, J; Koness, J; Radie-Keane, K; Wanebo, H
MLA Citation
Chougule, PB, Akhtar, MS, Akerley, W, Ready, N, Safran, H, McRae, R, Nigri, P, Bellino, J, Koness, J, Radie-Keane, K, and Wanebo, H. "Chemoradiotherapy for advanced inoperable head and neck cancer: A phase II study." Seminars in Radiation Oncology 9.2 SUPPL. 1 (1999): 58-63.
PMID
10210541
Source
scival
Published In
Seminars in Radiation Oncology
Volume
9
Issue
2 SUPPL. 1
Publish Date
1999
Start Page
58
End Page
63

Post transfusion non-cardiogenic pulmonary edema in a patient with chemotherapy-related hemolytic uremic syndrome.

Authors
Kluger, NJ; Cummings, FJ; Ready, NE; Sweeney, JD; Weitberg, AB
MLA Citation
Kluger, NJ, Cummings, FJ, Ready, NE, Sweeney, JD, and Weitberg, AB. "Post transfusion non-cardiogenic pulmonary edema in a patient with chemotherapy-related hemolytic uremic syndrome." Medicine and health, Rhode Island 81.7 (1998): 235-236.
PMID
9689787
Source
scival
Published In
Medicine and health, Rhode Island
Volume
81
Issue
7
Publish Date
1998
Start Page
235
End Page
236

Concurrent paclitaxel, carboplatin, and radiotherapy in advanced head and neck cancers: A phase II study - Preliminary results

Radiotherapy or surgery alone for advanced head and neck cancer generally yields poor results. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin have both shown excellent radiosensitization through two discrete mechanisms, namely, blocking the cell cycle in the G2/M phase and inhibiting DNA repair. In an effort to improve locoregional control and survival, a prospective phase II study was initiated using paclitaxel 60 mg/m2 and carboplatin (area under the concentration- time curve of 1), each given as a single dose weekly with concurrent conventional fractionated external beam radiotherapy. Patients were stratified into two groups: operable and inoperable/unresectable. The operable and inoperable groups received 5 weeks (45 Gy) and 8 weeks (72 Gy) of chemoradiotherapy, respectively. Patients in the operable group were evaluated with repeat biopsies from the primary site after 5 weeks. Those with a positive biopsy underwent surgery; those with a negative biopsy received 3 additional weeks of chemoradiotherapy. Thirty-four patients were entered in the operable group (28 men and six women; 40 to 71 years of age; 12 stage III and 22 stage IV). Of 26 evaluable patients, 19 (73%) had a complete clinical response (95% confidence interval [CI], 52% to 88%) and six (23%) had a partial response (95% CI, 9% to 44%), for a total clinical response rate of 96% (95% CI, 80% to 100%). A pathologic complete response at the primary site (two had an unknown primary site) occurred in 17 of 24 (71%) patients (95% CI, 49% to 87%). Of 20 patients with NI-3 nodes who underwent neck dissection, 17 (85%) had pathologically negative lymph nodes. Seven patients with residual tumor at the primary site were resected (oral cavity, three; maxilla, one; base of tongue, one; and larynx, two). Grades 3 and 4 mucositis were seen in 19 (73%) patients; mucositis was the most common and significant morbidity. Accrual for the inoperable group continues. Concomitant paclitaxel, carboplatin, and external beam radiotherapy yielded excellent clinical responses, but produced significant grade 3/4 toxicity. In the operable group, the majority of responders had a complete pathologic response. These preliminary findings will be assessed in terms of response duration, organ preservation, and long-term survival.

Authors
Chougule, P; Wanebo, H; Akerley, W; McRae, R; Nigri, P; Leone, L; Safran, H; Ready, N; Koness, RJ; Radie-Keane, K; Cole, B
MLA Citation
Chougule, P, Wanebo, H, Akerley, W, McRae, R, Nigri, P, Leone, L, Safran, H, Ready, N, Koness, RJ, Radie-Keane, K, and Cole, B. "Concurrent paclitaxel, carboplatin, and radiotherapy in advanced head and neck cancers: A phase II study - Preliminary results." Seminars in Oncology 24.6 SUPPL. 19 (1997): S19-57-S19-61-.
PMID
9427268
Source
scival
Published In
Seminars in Oncology
Volume
24
Issue
6 SUPPL. 19
Publish Date
1997
Start Page
S19-57-S19-61

Preoperative chemoradiation coupled with aggressive resection as needed ensures near total control in advanced head and neck cancer

BACKGROUND: Preoperative chemotherapy or chemoradiation protocols are generally associated with high clinical response rates, but limited pathologic responses for large primary tumors, we have initiated a prospective phase II study of weekly paclitaxel 60 mg/M2, and carboplatin (AUC of 1) plus concurrent fractionated external beam radiation (45 Gy) followed by organ-preserving (or function restorative) surgery when applicable to maximize local-regional tumor control. PATIENTS AND METHODS: Operable patients staged by triple endoscopy received a percutaneous endoscopic gastrostomy and vigorous dental and nutritional support during therapy. Weekly paclitaxel 60 mg/M2, carboplatin (AUC of 1), and radiation 45 Gy were given with rebiopsy of the primary site at 5 weeks. Patients with positive biopsy had definitive surgery in 4 to 5 weeks. Patients with negative biopsy-results received 3 additional weeks of radiation, to a total dose of 72 Gy plus carboplatin and paclitaxel. RESULTS: The 35 patients were 29 men and 6 women, aged 40 to 71 years, with stage III (12) or stage IV (23) cancer. The site of the cancer was oral cavity, 10; base of tongue, 3; oropharynx, 3; hypopharynx, 4; larynx, 12 (glottic, 6; supraglottic, 6), unknown primary, 2; other, nasal cavity, 1. Of 34 evaluable patients, 16 (47%) had a complete clinical response (CR) and 18 (53%) had a partial response (PR); total clinical response rate was 100%. A pathologic CR at the primary site occurred in 23 of 34 patients (68%; 2 had an unknown primary) who went on to completion radiation at 67 to 72 Gy. After induction chemoradiation 21 patients with N1-3 nodes had neck dissection; 6 (31%) had positive nodes. Twelve patients had residual cancer at the primary site at time of rebiopsy: mandible, 4; maxilla, 1; base of tongue, 2; larynx, 4; floor of mouth, 1; and nasal cavity, 1. All were resected with function- preserving reconstruction. At median follow-up of > 12 months, progression- free and overall survivals were 71% and 83%, respectively. CONCLUSION: Preoperative treatment with paclitaxel, carboplatin, and radiation is associated with high CR at the primary site and a high level of organ preservation or functional restoration if ablation is done.

Authors
Wanebo, HJ; Chougule, P; III, WLA; Koness, RJ; McRae, R; Nigri, P; Leone, L; Ready, N; Safran, H; Webber, B; Cole, B
MLA Citation
Wanebo, HJ, Chougule, P, III, WLA, Koness, RJ, McRae, R, Nigri, P, Leone, L, Ready, N, Safran, H, Webber, B, and Cole, B. "Preoperative chemoradiation coupled with aggressive resection as needed ensures near total control in advanced head and neck cancer." American Journal of Surgery 174.5 (1997): 518-522.
PMID
9374228
Source
scival
Published In
The American Journal of Surgery
Volume
174
Issue
5
Publish Date
1997
Start Page
518
End Page
522
DOI
10.1016/S0002-9610(97)00167-0

P-selectin induces the expression of tissue factor on monocytes

P-selectin on activated platelets and stimulated endothelial cells mediates cell adhesion with monocytes and neutrophils. Since activated platelets induce tissue factor on mononuclear leukocytes, we examined the effect of P-selectin on the expression of tissue factor activity in monocytes. Purified P-selectin stimulated tissue factor expression on mononuclear leukocytes in a dose-dependent manner. Chinese hamster ovary (CHO) cells expressing P-selectin stimulated tissue factor procoagulant activity in purified monocytes, whereas untransfected CHO cells and CHO cells expressing E-selectin did not. Anti-P-selectin antibodies inhibited the effects of purified P-selectin and CHO cells expressing P-selectin on monocytes. Incubation of CHO cells expressing P-selectin with monocytes leads to development of tissue factor mRNA in monocytes and to the expression of tissue factor antigen on the monocyte surface. These results indicate that P- selectin upregulates the expression of tissue factor on monocytes as well as mediates the binding of platelets and endothelial cells with monocytes and neutrophils. The binding of P-selectin of monocytes in the area of vascular injury may be a component of a mechanism that initiates thrombosis.

Authors
Celi, A; Pellegrini, G; Lorenzet, R; Blasi, AD; Ready, N; Furie, BC; Furie, B
MLA Citation
Celi, A, Pellegrini, G, Lorenzet, R, Blasi, AD, Ready, N, Furie, BC, and Furie, B. "P-selectin induces the expression of tissue factor on monocytes." Proceedings of the National Academy of Sciences of the United States of America 91.19 (1994): 8767-8771.
PMID
7522321
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
91
Issue
19
Publish Date
1994
Start Page
8767
End Page
8771
DOI
10.1073/pnas.91.19.8767

Treatment choices in chronic myelogenous leukemia

Chemotherapy with hydroxyurea may be a primary treatment modality in those patients over age 50 who cannot receive a bone marrow transplant and in whom α-interferon therapy could prove to be unacceptably toxic.

Authors
Ready, N; Freeman, NJ; Carvalho, A
MLA Citation
Ready, N, Freeman, NJ, and Carvalho, A. "Treatment choices in chronic myelogenous leukemia." Hospital Practice 27.9 A (1992): 95-98+101.
PMID
1522171
Source
scival
Published In
Hospital Practice
Volume
27
Issue
9 A
Publish Date
1992
Start Page
95
End Page
98+101

Development of fast singing muscles in a katydid.

In males of the katydid Neoconocephalus robustus, mesothoracic wings are used in flight (wing stroke frequence = 20 Hz) and stridulation (200 Hz), while the metathoracic wings are used in flight alone. Most mesothoracic wing muscles produce much briefer isometric twitches than metathoracic counterparts. The mesothoracic first tergocoxal muscle (TCX1) has a twitch duration (onset to 50% relaxation, 35 degrees C) of 6-8 ms and the metathoracic TXC1 a twitch duration of 12-15 ms. The TCX1 muscles from animals one and two instars from adulthood produce twitches similar in duration to those of the adult metathoracic TCX1. The twitch duration of the mesothoracic TCX1 acquires its adult brevity gradually over the first 5 days of adult life. Both TCX1 muscles increase greatly in size and mitochondrial content around the time of the terminal molt. During this period the mesothoracic TCX1 develops narrower myofibrils and a smaller ratio of fibril volume to sarcoplasmic reticulum volume than is characteristic of the metathoracic TCX1. Changes in the ultrastructure of the mesothoracic TCX1 precede changes in contraction kinetics around the time of the terminal molt so that there is not a strict correlation between muscle structure and performance during the period of rapid growth.

Authors
Ready, NE
MLA Citation
Ready, NE. "Development of fast singing muscles in a katydid." The Journal of experimental zoology 238.1 (1986): 43-54.
PMID
3711818
Source
scival
Published In
The Journal of experimental zoology
Volume
238
Issue
1
Publish Date
1986
Start Page
43
End Page
54

Growth and development of flight muscle in the locust (Schistocerca nitens, Thunberg)

The isometric contraction kinetics, ultrastructure, and growth of locust flight muscle that is derived from body wall muscle (metathoracic dorsal longitudinal muscle) and from limb muscle (second metathoracic tergocoxal muscle) were studied during the last three nymphal instars and in the adult 2 weeks past the terminal molt. Two distinct developmental patterns were found that correlated with use during nymphal life. The second tergocoxal muscle (TC2) is used from the time of hatching as a coxal remoter. As such, its contraction kinetics and ultrastructure are characteristic of fast, phasic muscle, which predisposes it to use in the adult as a wing levator. In contrast, the dorsal longitudinal muscle (DLM) is nonfunctional during nymphal life; contraction kinetics and ultrastructure characteristic of fast, phasic muscle develop gradually in late nymphal life until the adult kinetics are attained 2 weeks past the terminal molt. Although growth in both of these muscles occurs as the result of increases in fiber number and cross-sectional area, there are differences in the manner in which this growth is achieved. In the TC2, there is a continuous increase in fiber number through the last three nymphal instars. In contrast, in the DML, the increase in fiber number is nearly complete by two molts before adulthood.

Authors
Mizisin, AP; Ready, NE
MLA Citation
Mizisin, AP, and Ready, NE. "Growth and development of flight muscle in the locust (Schistocerca nitens, Thunberg)." Journal of Experimental Zoology 237.1 (1986): 45-55.
Source
scival
Published In
Journal of Experimental Zoology
Volume
237
Issue
1
Publish Date
1986
Start Page
45
End Page
55

Structural and functional development of cricket wing muscles

The sizes of the unifunctional dorsal longitudinal (DLM) and bifunctional subalar (SA) metathoracic flight muscles of the cricket Teleogryllus oceanicus increase by more than an order of magnitude between the second instar before the terminal molt and the tenth day of adult life. During the same development period isometric twitch duration (onset to 50% relaxation, 25° C varies little, while muscle mitochondrial content increased by a factor of ten as measured by stereological analysis of electron micrographs and citrate synthase activity (μmoles citrate.min-1.gm protein-1, 25°C). The wing muscles of adults have abundant sarcoplasmic reticulum (SR), narrow myofibrils, and a high volume density of mitochondria. At two molts from adulthood muscles that will later be used in flight behavior also have narrow myofibrils and abundant SR, but unlike muscles at later stages, nymphal muscles have a low volume density of mitochondria. At the terminal molt muscles have at least as much SR as is seen in muscles at the tenth day of adult life, and the myofibrils are also more narrow at the earlier stage. Since there is significant variation in muscle structure and little change in twitch duration during late development, the efficacy of the SR in releasing and resequestering CA2+ is seemingly lower in muscles at the terminal molt, a time of rapid muscle growth.

Authors
Ready, NE; Najm, RE
MLA Citation
Ready, NE, and Najm, RE. "Structural and functional development of cricket wing muscles." Journal of Experimental Zoology 233.1 (1985): 3550--.
Source
scival
Published In
Journal of Experimental Zoology
Volume
233
Issue
1
Publish Date
1985
Start Page
3550-

Structural and functional development of cricket ring muscles.

The sizes of the unifunctional dorsal longitudinal (DLM) and bifunctional subalar (SA) metathoracic flight muscles of the cricket Teleogryllus oceanicus increase by more than an order of magnitude between the second instar before the terminal molt and the tenth day of adult life. During the same developmental period isometric twitch duration (onset to 50% relaxation, 25 degrees C) varies little, while muscle mitochondrial content increased by a factor of ten as measured by stereological analysis of electron micrographs and citrate synthase activity (mumoles citrate . min-1 . gm protein-1, 25 degrees C). The wing muscles of adults have abundant sarcoplasmic reticulum (SR), narrow myofibrils, and a high volume density of mitochondria. At two molts from adulthood muscles that will later be used in flight behavior also have narrow myofibrils and abundant SR, but unlike muscles at later stages, nymphal muscles have a low volume density of mitochondria. At the terminal molt muscles have at least as much SR as is seen in muscles at the tenth day of adult life, and the myofibrils are also more narrow at the earlier stage. Since there is significant variation in muscle structure and little change in twitch duration during late development, the efficacy of the SR in releasing and resequestering CA2+ is seemingly lower in muscles at the terminal molt, a time of rapid muscle growth.

Authors
Ready, NE; Najm, RE
MLA Citation
Ready, NE, and Najm, RE. "Structural and functional development of cricket ring muscles." Journal of Experimental Zoology 233.1 (1985): 35-50.
PMID
3973549
Source
scival
Published In
Journal of Experimental Zoology
Volume
233
Issue
1
Publish Date
1985
Start Page
35
End Page
50

Flight muscle development in a hemimetabolous insect

Authors
Ready, NE; Josephson, RK
MLA Citation
Ready, NE, and Josephson, RK. "Flight muscle development in a hemimetabolous insect." Journal of Experimental Zoology 220.1 (March 1, 1982): 49-56.
Source
crossref
Published In
Journal of Experimental Zoology
Volume
220
Issue
1
Publish Date
1982
Start Page
49
End Page
56
DOI
10.1002/jez.1402200107

Salt and water balance in the polychaete Nereis virens

1. 1. Nereis virens is a large and common estuarine and coastal nereid polychaete of the North Atlantic Ocean, frequently used in physiological experiments. 2. 2. N. virens is euryhaline, surviving from about 5%o (15% SW) to over 100% SW. 3. 3. N. virens is slightly hyperosmotic at all salinities, with a modest increment in coelomic fluid hyperosmoticity when adapted to salinities below 25% SW. 4. 4. There is only very limited hyperregulation of Na+ and Cl+ in worms adapted to low salinities; K+ is strongly hyperionic at all salinities. 5. 5. pH of coelomic fluid increases as the salinity of the medium declines. 6. 6. Volume regulation is moderately well developed, but declines in animals maintained in salinities below 25% SW. © 1982.

Authors
Oglesby, LC; Mangum, CP; Heacox, AE; Ready, NE
MLA Citation
Oglesby, LC, Mangum, CP, Heacox, AE, and Ready, NE. "Salt and water balance in the polychaete Nereis virens." Comparative Biochemistry and Physiology -- Part A: Physiology 73.1 (1982): 15-19.
Source
scival
Published In
Comparative Biochemistry and Physiology, A: Comparative Physiology
Volume
73
Issue
1
Publish Date
1982
Start Page
15
End Page
19
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