| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Tumor Biology |
Departments of Radiation Oncology [K. K. A.], Experimental Radiation Oncology [X. T., L. M.], Anatomical Pathology Services Cytology [H-Z. Z.], and Pathology–Patient Care [R. K.] and Radiation Therapy Oncology Group [B. A. B.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Department of Pathology, LDS Hospital, University of Utah School of Medicine, Salt Lake City, Utah 84143 [E. H. H.]; and Department of Radiation Oncology, University of California, San Francisco, California 94143 [K. K. F.]
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1REFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1REFERENCES |
|---|
Advances in the understanding of the molecular biology of HNSCC have opened many new research directions. Increasing effort has been directed toward developing molecular targeted therapies or searching for molecular markers that are useful either in predicting treatment outcome or in selecting patients for specific molecular targeted therapies based on particular tumor characteristics. Three recently published review articles (4, 5, 6)
summarize the current status of the search for prognosis-predictive biomarkers. Although none of the studies has identified convincing data to warrant routine clinical application of any marker, encouraging leads have been generated for a number of molecules including p53, EGFR and one of its ligands, TGF-
, and cyclin D1 (6)
.
We undertook a correlative biomarker study on a relatively large, prospective series of patients with advanced HNSCC enrolled in a Phase III trial of the RTOG and randomized to the standard therapy arm, i.e., conventionally fractionated radiotherapy (70 Gy in 7 weeks). The results revealed that EGFR expression was not correlated with disease stage at presentation or other known clinical prognostic variables. However, correlative analysis showed that EGFR expression was a strong prognostic indicator for OS and DFS and was highly predictive for the probability of LR relapse but not for distant metastasis. Our results suggest that quantitative EGFR IHC assay should be valuable for selecting patients for different currently available therapy modalities or enrollment into trials testing novel therapies targeting EGFR or its downstream signaling pathways.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1REFERENCES |
|---|
Radiotherapy records of each patient, including simulation and verification portal films, total dose, number of fractions, and elapsed treatment days relative to the protocol prescription were verified by the two radiation oncology study co-chairs with the assistance of the RTOG staff. Follow-up assessment of LR control and (when indicated) systemic spread took place around 4 weeks after completion of treatment and then every 3 months for the first 1–1.5 years, every 4 months from 18 months through 3 years, biannually in years 3–5, and annually thereafter. The median follow-up for surviving patients was 41.2 months at the time of analysis.
The current study population consisted of 155 of 268 (58%) patients (30% had stage III disease, and 66% had stage IV disease) randomized to the conventional radiotherapy (70 Gy in 7 weeks) arm and had sufficiently large pretreatment paraffin-embedded biopsy specimens for cutting additional slides for IHC assay. The distribution of patient and tumor characteristics and the treatment outcome of the study population were compared with those of the remaining 113 non-study group to detect the presence of potential systematic differences.
EGFR Immunohistochemical Assay.
The paraffin sections were dewaxed and hydrated in a graded series of alcohol, followed by blockage in 3% H2O2/methanol for 5 min and enzymatic digestion with 0.02% (w/v) protease type XXIV for 2 min at room temperature. The slides were incubated for 1 h with mouse monoclonal antibodies that react to the peptide backbone of the extracellular domain of the EGFR molecule (31G7; Zymed Laboratories, Inc.) diluted 1:50 in dilution buffer at room temperature. Subsequently, the slides were rinsed for 2 min in PBS (pH 7.6) for three times and incubated with Dako’s Mouse EnVision+ Peroxidase System for 30 min. The peroxidase-catalyzed product was visualized with the BioGenex DAB Chromogen Kit. The sections were finally lightly counterstained with Mayer’s hematoxylin (Sigma Chemical Co.) for 15 s, rinsed, intensified, dehydrated, and mounted for quantitative analysis.
Interassay consistency was monitored by inclusion of positive and negative controls with each batch of staining. These consisted of sections of a high EGFR-expressing lung cancer stained with primary antibody and isotype-matched irrelevant antibody, respectively. Each batch of 24 slides thus contained a positive control, a negative control, and slides of 22 cases. Measurements were normalized to these controls (negative control = 0, positive control = 100%).
Quantitation of EGFR Expression.
The magnitude of EGFR expression was measured by computerized quantitative image analysis using a SAMBA 4000 Cell Image Analysis System (SAMBA Technologies, Meylan, France) without knowledge of clinical data. The image analyzer is a PC-based integrated system for densitometric, morphometric, and colorimetric analysis of cells and tissues. It consists of a Zeiss microscope with x10, x20, and x40 objectives and a Sony 960MD 3-chip charge-coupled device camera interfaced with a Power Spec computer (Micro Center Co., Houston, TX) equipped with a Matrox Meteor digitizer board (Matrox Electronic Systems Ltd., Dorval, Quebec, Canada).
Light and camera settings were standardized, resulting in average background values of 210 ± 5 (mean ± SD, scale 0–255 from black to white) for the red, green, and blue channels. Images were captured using x20 objective. Background subtraction was automatically performed on every tissue after storing an empty field of the slide. Analysis was performed after transformation of the red-green-blue information to hue-saturation-intensity information. The SAMBA software (Immuno-Analysis Version 4.22) enables the operator, after evaluating several fields on control slides, to set an intensity threshold value for the best discrimination between tissue and background. Separation between the hematoxylin counterstain (blue) and the DAB immunostaining (brown) was achieved by setting a proper threshold on the hue value. The threshold for DAB-positive hues was obtained by evaluating several fields on positive and negative control slides for optimal separation between blue- and brown-stained areas. Stromal components were removed from the analysis by interactive cut and paste techniques.
Parameters measured were MOD (MOD = the mean of optical densities measured over the labeled areas within the structure, proportional to the mean stain concentration), SI (SI = the proportion of stained area relative to the total area of the structures), and QS (QS = MOD x SI/100). Averaging the quantitative computerized image analysis data obtained from nine fields of each section yielded these parameters. These parameters with or without subtraction of a paired negative control slide (isotype-matched irrelevant antibody) were correlated with clinical outcome data.
Data Analysis.
The parameters of EGFR expression were sent to the RTOG Statistical Unit for incorporation into the study data set for performing correlative analysis. To determined whether the study population is representative for the whole group, the known clinical prognostic profile and outcome end points of patients with successful EGFR assay were first compared with those of patients with no or insufficient specimens. The magnitude and distribution of pretreatment EGFR expression were then assessed using various descriptive statistics (mean, median, and so forth) along with their association with the known tumor- and patient-related prognostic variables and RPA (8)
for survival and LR control. Finally, the magnitude and distribution of pretreatment EGFR expression were correlated with the OS, DFS, and pattern of relapse (LR recurrence and distant metastasis).
Statistical Method.
Comparisons of baseline characteristics were done using the Pearson 
2 test (9)
, with the exception of age, which was performed with a t test. OS and DFS were estimated using the Kaplan-Meier method (10)
and compared by the log-rank test (11)
. Time to LR control and distant metastases were estimated by the method of cumulative incidence (12)
and tested with Gray’s test (13)
. Multivariate analysis was performed using the Cox proportional hazards model (14)
.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1REFERENCES |
|---|
and 2
show that there was no significant difference between the groups in the distribution of known clinical prognostic indicators of survival and LR control, i.e., KPS, age, T stage, N stage, combined stage grouping, and RPA classes. There was, however, some imbalance in the distribution by gender and primary tumor site, i.e., the study group had relatively more women and more patients with supraglottic cancer but fewer patients with oropharyngeal carcinoma. Table 3
shows that there was no difference between the two groups in treatment outcome end points, i.e., OS, DFS, LR control, and distant metastasis rates.
|
|
|
and 2
show that HNSCCs had a wide range of EGFR expression [i.e., the MOD varied from 0.2 to 66.0 (median, 24.0), SI varied from 0.3 to 97.0 (median, 80.7), and QS varied from 0.01 to 69.9 (median, 23.8)]. Of the 155 tumors examined, 148 (95%) had detectable EGFR expression. There was a relatively strong but nonlinear correlation between MOD and SI (correlation coefficient, 0.79).
|
|
reveals that there was no correlation between EGFR expression and the known clinical prognostic indicators, i.e., T stage, N stage, stage grouping, and RPA classes for survival and LR control. However, as shown in Fig. 3
and Table 5
, the level of EGFR expression, quantified either with or without subtraction of negative controls, had highly significant correlation with the OS, DFS, and LR control rates, but not with the incidence of distant metastasis. Patients with higher (>median MOD) EGFR-expressing HNSCCs had highly significantly poorer OS and DFS (Fig. 3, A and B)
and lower LR control (Fig. 3C)
than those with lower EGFR-expressing cancer. In contrast, EGFR expression had no influence on the incidence of distant metastasis (Fig. 3D)
. Significant correlations, although slightly less robust than MOD, were also observed between SI and QS and the OS, DFS, and LR relapse rates (Table 5)
. In multivariate analyses (Table 6)
, EGFR MOD came out as a strong independent prognostic factor for OS and DFS and as the strongest predictor for LR control.
|
|
|
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1REFERENCES |
|---|
/protein kinase-, and signal transducer and activator-3 pathways (16
, 17)
. Activation of these pathways ultimately leads to transcription of other genes responsible for cell growth, differentiation, and death. However, how these downstream pathways regulate radiation sensitivity is not well understood and is the subject of investigation in many laboratories. A study using the DU145 prostate carcinoma cell line, for example, showed that after irradiation these cells become dependent on MAPK activation for cell cycle progression and that MAPK inhibition results in cell cycle arrest at the G2-M-phase transition, which is accompanied by cell death when MAPK inhibition is sustained (18)
. Another study revealed that EGFR blockade leads to redistribution of DNA-PK from the nucleus to the cytosol, resulting in reduced radiation-induced DNA damage repair and thus radiation sensitization, detectable through the classical split-dose experiment (19)
.
The EGFR pathways attracted the attention of head and neck cancer investigators because the majority of HNSCCs have elevated expression of EGFR and its ligand, TGF-. For example, Grandis and Tweardy (20)
found a mean 69-fold (range, 0.3–690) EGFR mRNA increase and a 5-fold (range, 0.1–19.9) TGF- mRNA elevation in 91% and 87.5%, respectively, of 24 HNSCCs assessed relative to mRNA levels in normal mucosa. The corresponding magnitudes of increase in EGFR and TGF- proteins, determined by IHC (MOD), were 1.7-fold (P = 0.005) and 1.9-fold (0.006), respectively (21)
. The nature of the protein overexpression is thought to result from enhanced transcription with no apparent change in mRNA stability (20)
, although gene amplification has also been observed (22)
.
Three teams of investigators explored the potential prognostic significance of EGFR expression in patients with laryngeal carcinomas treated with radiotherapy (23 , 24) or surgery (25) . The studies of Miyaguchi et al. (23) and Wen et al. (24) yielded conflicting results in relatively small series of patients with early laryngeal carcinomas (T1–2) receiving various radiation doses. The lower radiation dose range administered (24) may be considered substandard by current norm and, therefore may have accounted for the rather poor overall outcome. Maurizi et al. (25) determined the EGFR expression by radioligand receptor assay on frozen tumor samples in 140 patients with T1–4 laryngeal carcinomas with or without palpable nodes who underwent conservative (n = 67) or radical (n = 73) laryngectomy alone. The median EGFR value in this series was 8.4 fmol mg-1 protein but ranged from 0 to 169.9 fmol mg-1 protein. Multivariate analysis revealed that T stage and EGFR level were the most important independent prognostic factors for relapse-free survival and OS. Unfortunately, the pattern of failure was not addressed in this study.
More recently, Grandis et al. (26)
determined the expression of EGFR and TGF- proteins by IHC in 91 patients with various stages (T14N0–1) and sites of HNSCC all treated with surgical resection and followed by radiotherapy in 56 patients and chemotherapy in 16 patients. Analysis of IHC data and treatment outcome using a proportional hazard model revealed that the combination of EGFR or TGF- level with lymph node stage was the strongest predictor of cause-specific survival. The combination of EGFR level with lymph node stage was found to be as strong a predictor as the triple combination of EGFR level plus TGF- level plus lymph node stage. The exclusion of the EGFR level from the model resulted in a statistically significant reduction in the predictive power. This study also did not address the effects of protein expression on the pattern of relapse of the index cancer.
We performed a quantitative IHC study using antibodies predominantly recognizing the membrane-associated extracellular domain of the EGFR molecule (see Fig. 1
) in a larger series of representative patients enrolled in a prospective clinical trial and treated with a consistent radiation regimen alone. The results showed that advanced, predominantly stage III-IV HNSCC had a wide range of EGFR expression, which did not correlate with the tumor or nodal stage, other established prognostic combined stage groupings (AJCC or RPA), or patient performance status. Correlative analysis showed that EGFR expression was a strong, independent prognostic indicator of OS and DFS.
Analysis of the patterns of relapse in this series revealed a new, clinically relevant finding that EGFR expression was a robust predictor for LR relapse but not for distant metastasis. This observation provides compelling clinical evidence in support of experimental data showing that EGFR expression is the strongest and most consistent indicator of cellular radioresistance in vitro (27)
and that there is a close relationship between EGFR overexpression and tumor radioresistance in vivo (28
, 29)
. Multivariate analysis (Table 6)
of the current data revealed that EGFR expression was even a stronger predictor of LR control than T stage. Furthermore, Table 7
shows that its addition to T stage improves the predictive power for LR control. Because the incidence of LR relapse is much higher than that of distant metastasis, this finding suggests that patients with EGFR-overexpressing tumor would benefit more from the development of more effective LR therapy. Work aimed at assessing the impact of EGFR expression on the relapse pattern of patients treated with novel radiation regimens or with radiation plus concurrent chemotherapy is in progress.
|
Therapeutic approaches targeting EGFR signaling pathway either alone or in combination with radiation or cytotoxic agents are being intensively investigated. Strategies that are in various stages of development include blockade of the extracellular receptor domain (19
, 30, 31, 32, 33, 34, 35)
, inhibition of the intracellular tyrosine kinase activity [reviewed by Fry (36)
and Noonberg and Benz (37)
], inhibition of receptor production by antisense approaches (32
, 38)
, expression of a truncated dominant-negative EGFR mutant (39)
, and so on. For example, anti-EGFR antibody, C225, in combination with chemotherapy or radiation, is being addressed in Phase III clinical trials, and many small-molecule tyrosine kinase inhibitors are in Phase I-II clinical testing. Data presented in Fig. 3C
suggest that tumor radiation sensitization through inhibition of EGFR signaling, when successful in humans, could yield a therapeutic gain by increasing the LR control rate in patients with EGFR-overexpressing HNSCC. The nonlinear correlation between MOD (a measure of EGFR density of individual malignant cells) and SI (reflecting the proportion of malignant cells expressing EGFR) raised a question regarding how to define EGFR overexpression. Data presented in Fig. 2
show that the natural break points might be around the median values for both MOD and SI because below the median MOD, there is a wide variation in SI, and above the median, >80% of malignant cells express EGFR in most tumors. Fig. 4
shows that additional cutoff points below or above the median value did not improve the prediction of the risk of LR relapse. The ongoing studies in other cohorts of patients will hopefully refine the cutoff values for use in future trials. Nevertheless, because many types of antibodies are available and some variability in assay techniques exists, an individual laboratory needs to perform assay calibration until a validated standardized kit becomes available. Meanwhile, using SI of 80% as a cutoff point would be a reasonable strategy.
|
|
Appendix 1 |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1REFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 Supported by Grants CA84415 and CA06294, awarded by the National Cancer Institute, supplemented by the Texas Tobacco Settlement Funds and Gilbert H. Fletcher Chair. 
2 To whom requests for reprints should be addressed, at Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 97, Houston, TX 77030. Phone: (713) 792-3400; Fax: (713) 794-5573; E-mail: kianang{at}mail.mdanderson.org
3 The abbreviations used are: HNSCC, head and neck squamous cell carcinoma; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; DAB, 3,3'-diaminobenzidine; MOD, mean optical density; SI, staining index; QS, quick score; RPA, recursive partitioning analysis; OS, overall survival; DFS, disease-free survival; LR, local-regional; TGF, transforming growth factor; RTOG, Radiation Therapy Oncology Group; AJCC, American Joint Committee on Cancer; MAPK, mitogen-activated protein kinase; KPS, Karnofsky Performance Scale; DNA-PK, DNA-dependent protein kinase.
Received 6/10/02. Accepted 10/14/02.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1REFERENCES |
|---|
and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res., 53: 3579-3584, 1993. and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck. Cancer (Phila.), 78: 1284-1292, 1996.[Medline]
in early laryngeal cancer treated with radiotherapy. Laryngoscope, 106: 884-888, 1996.[Medline]
and EGFR protein in head and neck squamous cell carcinoma and patient survival. J. Natl. Cancer Inst., 90: 824-832, 1998.This article has been cited by other articles:
|
|
 |
|
  L. J. Wirth, A. M. Allen, M. R. Posner, R. I. Haddad, Y. Li, J. R. Clark, P. M. Busse, A. W. Chan, L. A. Goguen, C. M. Norris, et al. Phase I dose-finding study of paclitaxel with panitumumab, carboplatin and intensity-modulated radiotherapy in patients with locally advanced squamous cell cancer of the head and neck Ann. Onc., November 5, 2009; (2009) mdp477v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Egloff, M. E. Rothstein, R. Seethala, J. M. Siegfried, J. R. Grandis, and L. P. Stabile Cross-Talk between Estrogen Receptor and Epidermal Growth Factor Receptor in Head and Neck Squamous Cell Carcinoma Clin. Cancer Res., November 1, 2009; 15(21): 6529 - 6540. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. XU, G. CAI, W. YE, X. WANG, Y. LI, P. ZHAO, A. ZHANG, R. ZHANG, and B. CAO Molecular Imaging Application of Radioiodinated Anti-EGFR Human Fab to EGFR-overexpressing Tumor Xenografts Anticancer Res, October 1, 2009; 29(10): 4005 - 4011. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hama, Y. Yuza, Y. Saito, J. O-uchi, S. Kondo, M. Okabe, H. Yamada, T. Kato, H. Moriyama, S. Kurihara, et al. Prognostic Significance of Epidermal Growth Factor Receptor Phosphorylation and Mutation in Head and Neck Squamous Cell Carcinoma Oncologist, September 1, 2009; 14(9): 900 - 908. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Tolmachev Reply: Molecular Imaging of EGFR: It's Time to Go Beyond Receptor Expression J. Nucl. Med., July 1, 2009; 50(7): 1196 - 1196. [Full Text] [PDF]
|
|
|
|
|
|
H. Schoder, M. Fury, N. Lee, and D. Kraus PET Monitoring of Therapy Response in Head and Neck Squamous Cell Carcinoma J. Nucl. Med., May 1, 2009; 50(Suppl_1): 74S - 88S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. W. Stewart, E. E.W. Cohen, L. Licitra, C. M.L. Van Herpen, C. Khorprasert, D. Soulieres, P. Vodvarka, D. Rischin, A. M. Garin, F. R. Hirsch, et al. Phase III Study of Gefitinib Compared With Intravenous Methotrexate for Recurrent Squamous Cell Carcinoma of the Head and Neck J. Clin. Oncol., April 10, 2009; 27(11): 1864 - 1871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. T. Wolf Tradition, Teamwork, and Tailored Treatment: Surgical Oncology in the Genomic Era Arch Otolaryngol Head Neck Surg, April 1, 2009; 135(4): 337 - 341. [Full Text] [PDF]
|
|
|
|
 |
|
 V Martin, L Mazzucchelli, and M Frattini An overview of the epidermal growth factor receptor fluorescence in situ hybridisation challenge in tumour pathology J. Clin. Pathol., April 1, 2009; 62(4): 314 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Y. Lai, P. Koppikar, S. M. Thomas, E. E. Childs, A. M. Egloff, R. R. Seethala, B. F. Branstetter, W. E. Gooding, A. Muthukrishnan, J. M. Mountz, et al. Intratumoral Epidermal Growth Factor Receptor Antisense DNA Therapy in Head and Neck Cancer: First Human Application and Potential Antitumor Mechanisms J. Clin. Oncol., March 10, 2009; 27(8): 1235 - 1242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Harrington, I. A. El-Hariry, C. S. Holford, A. Lusinchi, C. M. Nutting, D. Rosine, M. Tanay, E. Deutsch, J. Matthews, C. D'Ambrosio, et al. Phase I Study of Lapatinib in Combination With Chemoradiation in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck J. Clin. Oncol., March 1, 2009; 27(7): 1100 - 1107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C M West, L Joseph, and S Bhana Epidermal growth factor receptor-targeted therapy Br. J. Radiol., October 1, 2008; 81(Special_Issue_1): S36 - S44. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. I. Haddad and D. M. Shin Recent Advances in Head and Neck Cancer N. Engl. J. Med., September 11, 2008; 359(11): 1143 - 1154. [Full Text] [PDF]
|
|
|
|
|
|
K. K. Ang Multidisciplinary Management of Locally Advanced SCCHN: Optimizing Treatment Outcomes Oncologist, August 1, 2008; 13(8): 899 - 910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. M. G. Agra, A. L. Carvalho, C. A. L. Pinto, E. P. Martins, J. G. Filho, F. A. Soares, and L. P. Kowalski Biological Markers and Prognosis in Recurrent Oral Cancer After Salvage Surgery Arch Otolaryngol Head Neck Surg, July 1, 2008; 134(7): 743 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Koppikar, S.-H. Choi, A. M. Egloff, Q. Cai, S. Suzuki, M. Freilino, H. Nozawa, S. M. Thomas, W. E. Gooding, J. M. Siegfried, et al. Combined Inhibition of c-Src and Epidermal Growth Factor Receptor Abrogates Growth and Invasion of Head and Neck Squamous Cell Carcinoma Clin. Cancer Res., July 1, 2008; 14(13): 4284 - 4291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Melancon, W. Lu, Z. Yang, R. Zhang, Z. Cheng, A. M. Elliot, J. Stafford, T. Olson, J. Z. Zhang, and C. Li In vitro and in vivo targeting of hollow gold nanoshells directed at epidermal growth factor receptor for photothermal ablation therapy Mol. Cancer Ther., June 1, 2008; 7(6): 1730 - 1739. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Boehm, M. Sen, R. Seethala, W. E. Gooding, M. Freilino, S. M. Y. Wong, S. Wang, D. E. Johnson, and J. R. Grandis Combined Targeting of Epidermal Growth Factor Receptor, Signal Transducer and Activator of Transcription-3, and Bcl-XL Enhances Antitumor Effects in Squamous Cell Carcinoma of the Head and Neck Mol. Pharmacol., June 1, 2008; 73(6): 1632 - 1642. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A Bonner and J. J Caudell Combining Radiation with Biological Agents: Focus on the Inhibition of Epidermal Growth Factor Receptor Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 423 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Seethala, W. E. Gooding, P. N. Handler, B. Collins, Q. Zhang, J. M. Siegfried, and J. R. Grandis Immunohistochemical Analysis of Phosphotyrosine Signal Transducer and Activator of Transcription 3 and Epidermal Growth Factor Receptor Autocrine Signaling Pathways in Head and Neck Cancers and Metastatic Lymph Nodes Clin. Cancer Res., March 1, 2008; 14(5): 1303 - 1309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Choi and J.N. Myers Molecular Pathogenesis of Oral Squamous Cell Carcinoma: Implications for Therapy Journal of Dental Research, January 1, 2008; 87(1): 14 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Roda, T. Joshi, J. P. Butchar, J. W. McAlees, A. Lehman, S. Tridandapani, and W. E. Carson III The Activation of Natural Killer Cell Effector Functions by Cetuximab-Coated, Epidermal Growth Factor Receptor Positive Tumor Cells is Enhanced By Cytokines Clin. Cancer Res., November 1, 2007; 13(21): 6419 - 6428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Riesterer, L. Milas, and K. K. Ang Use of Molecular Biomarkers for Predicting the Response to Radiotherapy With or Without Chemotherapy J. Clin. Oncol., September 10, 2007; 25(26): 4075 - 4083. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Elser, L. L. Siu, E. Winquist, M. Agulnik, G. R. Pond, S. F. Chin, P. Francis, R. Cheiken, J. Elting, A. McNabola, et al. Phase II Trial of Sorafenib in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck or Nasopharyngeal Carcinoma J. Clin. Oncol., August 20, 2007; 25(24): 3766 - 3773. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. V. Karamouzis, J. R. Grandis, and A. Argiris Therapies Directed Against Epidermal Growth Factor Receptor in Aerodigestive Carcinomas JAMA, July 4, 2007; 298(1): 70 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Forastiere and B. A. Burtness Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer--More Insights, but More Questions J. Clin. Oncol., June 1, 2007; 25(16): 2152 - 2155. [Full Text] [PDF]
|
|
|
|
|
|
S. Temam, H. Kawaguchi, A. K. El-Naggar, J. Jelinek, H. Tang, D. D. Liu, W. Lang, J.-P. Issa, J. J. Lee, and L. Mao Epidermal Growth Factor Receptor Copy Number Alterations Correlate With Poor Clinical Outcome in Patients With Head and Neck Squamous Cancer J. Clin. Oncol., June 1, 2007; 25(16): 2164 - 2170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Vermorken, J. Trigo, R. Hitt, P. Koralewski, E. Diaz-Rubio, F. Rolland, R. Knecht, N. Amellal, A. Schueler, and J. Baselga Open-Label, Uncontrolled, Multicenter Phase II Study to Evaluate the Efficacy and Toxicity of Cetuximab As a Single Agent in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Who Failed to Respond to Platinum-Based Therapy J. Clin. Oncol., June 1, 2007; 25(16): 2171 - 2177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. L. Siu, D. Soulieres, E. X. Chen, G. R. Pond, S. F. Chin, P. Francis, L. Harvey, M. Klein, W. Zhang, J. Dancey, et al. Phase I/II Trial of Erlotinib and Cisplatin in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: A Princess Margaret Hospital Phase II Consortium and National Cancer Institute of Canada Clinical Trials Group Study J. Clin. Oncol., June 1, 2007; 25(16): 2178 - 2183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Curran, J. Giralt, P. M. Harari, K. K. Ang, R. B. Cohen, M. S. Kies, J. Jassem, J. Baselga, E. K. Rowinsky, N. Amellal, et al. Quality of Life in Head and Neck Cancer Patients After Treatment With High-Dose Radiotherapy Alone or in Combination With Cetuximab J. Clin. Oncol., June 1, 2007; 25(16): 2191 - 2197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Y. Feng, C. A. Lopez, D. P. Normolle, S. Varambally, X. Li, P. Y. Chun, M. A. Davis, T. S. Lawrence, and M. K. Nyati Effect of Epidermal Growth Factor Receptor Inhibitor Class in the Treatment of Head and Neck Cancer with Concurrent Radiochemotherapy In vivo Clin. Cancer Res., April 15, 2007; 13(8): 2512 - 2518. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cruz, A Ocana, E Del Barco, and A Pandiella Targeting receptor tyrosine kinases and their signal transduction routes in head and neck cancer Ann. Onc., March 1, 2007; 18(3): 421 - 430. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S-H. Ou, J. Zell, A Ziogas, and H Anton-Culver Epidemiology of nasopharyngeal carcinoma in the United States: improved survival of Chinese patients within the keratinizing squamous cell carcinoma histology Ann. Onc., January 1, 2007; 18(1): 29 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Sok, F. M. Coppelli, S. M. Thomas, M. N. Lango, S. Xi, J. L. Hunt, M. L. Freilino, M. W. Graner, C. J. Wikstrand, D. D. Bigner, et al. Mutant Epidermal Growth Factor Receptor (EGFRvIII) Contributes to Head and Neck Cancer Growth and Resistance to EGFR Targeting Clin. Cancer Res., September 1, 2006; 12(17): 5064 - 5073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Tijink, D. Neri, C. R. Leemans, M. Budde, L. M. Dinkelborg, M. Stigter-van Walsum, L. Zardi, and G. A.M.S. van Dongen Radioimmunotherapy of Head and Neck Cancer Xenografts Using 131I-Labeled Antibody L19-SIP for Selective Targeting of Tumor Vasculature J. Nucl. Med., July 1, 2006; 47(7): 1127 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P P Dendy and P Wardman Hypoxia in biology and medicine: the legacy of L H Gray. Br. J. Radiol., July 1, 2006; 79(943): 545 - 549. [Full Text] [PDF]
|
|
|
|
|
|
K. Erjala, M. Sundvall, T. T. Junttila, N. Zhang, M. Savisalo, P. Mali, J. Kulmala, J. Pulkkinen, R. Grenman, and K. Elenius Signaling via ErbB2 and ErbB3 Associates with Resistance and Epidermal Growth Factor Receptor (EGFR) Amplification with Sensitivity to EGFR Inhibitor Gefitinib in Head and Neck Squamous Cell Carcinoma Cells. Clin. Cancer Res., July 1, 2006; 12(13): 4103 - 4111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bourhis, F. Rivera, R. Mesia, A. Awada, L. Geoffrois, C. Borel, Y. Humblet, A. Lopez-Pousa, R. Hitt, M. E. Vega Villegas, et al. Phase I/II Study of Cetuximab in Combination With Cisplatin or Carboplatin and Fluorouracil in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck J. Clin. Oncol., June 20, 2006; 24(18): 2866 - 2872. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Brizel and R. Esclamado Concurrent Chemoradiotherapy for Locally Advanced, Nonmetastatic, Squamous Carcinoma of the Head and Neck: Consensus, Controversy, and Conundrum J. Clin. Oncol., June 10, 2006; 24(17): 2612 - 2617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bernier, J. B. Vermorken, and W. M. Koch Adjuvant Therapy in Patients With Resected Poor-Risk Head and Neck Cancer J. Clin. Oncol., June 10, 2006; 24(17): 2629 - 2635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E.W. Cohen Role of Epidermal Growth Factor Receptor Pathway-Targeted Therapy in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck J. Clin. Oncol., June 10, 2006; 24(17): 2659 - 2665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. R. Cardenes, E. G. Chiorean, J. DeWitt, M. Schmidt, and P. Loehrer Locally advanced pancreatic cancer: current therapeutic approach. Oncologist, June 1, 2006; 11(6): 612 - 623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Conley Treatment of Advanced Head and Neck Cancer: What Lessons Have We Learned? J. Clin. Oncol., March 1, 2006; 24(7): 1023 - 1025. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kong, P. Leboucher, R. Leek, V. Calleja, S. Winter, A. Harris, P. J. Parker, and B. Larijani Prognostic value of an activation state marker for epidermal growth factor receptor in tissue microarrays of head and neck cancer. Cancer Res., March 1, 2006; 66(5): 2834 - 2843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhu, H. J. Belmont, S. Price-Schiavi, B. Liu, H.-i. Lee, M. Fernandez, R. L. Wong, J. Builes, P. R. Rhode, and H. C. Wong Visualization of p53264-272/HLA-A*0201 Complexes Naturally Presented on Tumor Cell Surface by a Multimeric Soluble Single-Chain T Cell Receptor. J. Immunol., March 1, 2006; 176(5): 3223 - 3232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Bonner, P. M. Harari, J. Giralt, N. Azarnia, D. M. Shin, R. B. Cohen, C. U. Jones, R. Sur, D. Raben, J. Jassem, et al. Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the Head and Neck N. Engl. J. Med., February 9, 2006; 354(6): 567 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-H. Yang, W.-C. Chiang, T.-Y. Chou, S.-Y. Chang, P.-M. Chen, S.-C. Teng, and K.-J. Wu Increased NBS1 Expression Is a Marker of Aggressive Head and Neck Cancer and Overexpression of NBS1 Contributes to Transformation Clin. Cancer Res., January 15, 2006; 12(2): 507 - 515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Erovic, M. Pelzmann, M. Ch. Grasl, J. Pammer, G. Kornek, W. Brannath, E. Selzer, and D. Thurnher Mcl-1, Vascular Endothelial Growth Factor-R2, and 14-3-3{sigma} Expression Might Predict Primary Response against Radiotherapy and Chemotherapy in Patients with Locally Advanced Squamous Cell Carcinomas of the Head and Neck Clin. Cancer Res., December 15, 2005; 11(24): 8632 - 8636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Burtness, M. A. Goldwasser, W. Flood, B. Mattar, and A. A. Forastiere Phase III Randomized Trial of Cisplatin Plus Placebo Compared With Cisplatin Plus Cetuximab in Metastatic/Recurrent Head and Neck Cancer: An Eastern Cooperative Oncology Group Study J. Clin. Oncol., December 1, 2005; 23(34): 8646 - 8654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E.W. Cohen, M. W. Lingen, L. E. Martin, P. L. Harris, B. W. Brannigan, S. M. Haserlat, R. A. Okimoto, D. C. Sgroi, S. Dahiya, B. Muir, et al. Response of Some Head and Neck Cancers to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors May Be Linked to Mutation of ERBB2 rather than EGFR Clin. Cancer Res., November 15, 2005; 11(22): 8105 - 8108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Bentzen, B. M. Atasoy, F. M. Daley, S. Dische, P. I. Richman, M. I. Saunders, K. R. Trott, and G. D. Wilson Epidermal Growth Factor Receptor Expression in Pretreatment Biopsies From Head and Neck Squamous Cell Carcinoma As a Predictive Factor for a Benefit From Accelerated Radiation Therapy in a Randomized Controlled Trial J. Clin. Oncol., August 20, 2005; 23(24): 5560 - 5567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Herbst, M. Arquette, D. M. Shin, K. Dicke, E. E. Vokes, N. Azarnia, W. K. Hong, and M. S. Kies Phase II Multicenter Study of the Epidermal Growth Factor Receptor Antibody Cetuximab and Cisplatin for Recurrent and Refractory Squamous Cell Carcinoma of the Head and Neck J. Clin. Oncol., August 20, 2005; 23(24): 5578 - 5587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Baselga, J. M. Trigo, J. Bourhis, J. Tortochaux, H. Cortes-Funes, R. Hitt, P. Gascon, N. Amellal, A. Harstrick, and A. Eckardt Phase II Multicenter Study of the Antiepidermal Growth Factor Receptor Monoclonal Antibody Cetuximab in Combination With Platinum-Based Chemotherapy in Patients With Platinum-Refractory Metastatic and/or Recurrent Squamous Cell Carcinoma of the Head and Neck J. Clin. Oncol., August 20, 2005; 23(24): 5568 - 5577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Psyrri, Z. Yu, P. M. Weinberger, C. Sasaki, B. Haffty, R. Camp, D. Rimm, and B. A. Burtness Quantitative Determination of Nuclear and Cytoplasmic Epidermal Growth Factor Receptor Expression in Oropharyngeal Squamous Cell Cancer by Using Automated Quantitative Analysis Clin. Cancer Res., August 15, 2005; 11(16): 5856 - 5862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Chinnaiyan, S. Huang, G. Vallabhaneni, E. Armstrong, S. Varambally, S. A. Tomlins, A. M. Chinnaiyan, and P. M. Harari Mechanisms of Enhanced Radiation Response following Epidermal Growth Factor Receptor Signaling Inhibition by Erlotinib (Tarceva) Cancer Res., April 15, 2005; 65(8): 3328 - 3335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. W. Park, M. N. Younes, S. A. Jasser, O. G. Yigitbasi, G. Zhou, C. D. Bucana, B. N. Bekele, and J. N. Myers AEE788, a Dual Tyrosine Kinase Receptor Inhibitor, Induces Endothelial Cell Apoptosis in Human Cutaneous Squamous Cell Carcinoma Xenografts in Nude Mice Clin. Cancer Res., March 1, 2005; 11(5): 1963 - 1973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhang, D. J. Park, B. Lu, D. Y. Yang, M. Gordon, S. Groshen, J. Yun, O. A. Press, D. Vallbohmer, K. Rhodes, et al. Epidermal Growth Factor Receptor Gene Polymorphisms Predict Pelvic Recurrence in Patients with Rectal Cancer Treated with Chemoradiation Clin. Cancer Res., January 15, 2005; 11(2): 600 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Harari Promising new advances in head and neck radiotherapy Ann. Onc., January 1, 2005; 16(suppl_6): vi13 - vi19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bourhis New approaches to enhance chemotherapy in SCCHN Ann. Onc., January 1, 2005; 16(suppl_6): vi20 - vi24. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Vokes Current treatments and promising investigations in a multidisciplinary setting Ann. Onc., January 1, 2005; 16(suppl_6): vi25 - vi30. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Ang Concurrent Radiation Chemotherapy for Locally Advanced Head and Neck Carcinoma: Are We Addressing Burning Subjects? J. Clin. Oncol., December 1, 2004; 22(23): 4657 - 4659. [Full Text] [PDF]
|
|
|
|
|
|
D. L. Schwartz, J. Rajendran, B. Yueh, M. D. Coltrera, M. LeBlanc, J. Eary, and K. Krohn FDG-PET Prediction of Head and Neck Squamous Cell Cancer Outcomes Arch Otolaryngol Head Neck Surg, December 1, 2004; 130(12): 1361 - 1367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. H. Kalish, R. A. Kwong, I. E. Cole, R. M. Gallagher, R. L. Sutherland, and E. A. Musgrove Deregulated Cyclin D1 Expression Is Associated with Decreased Efficacy of the Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Gefitinib in Head and Neck Squamous Cell Carcinoma Cell Lines Clin. Cancer Res., November 15, 2004; 10(22): 7764 - 7774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Schechter, R. E. Wendt III, D. J. Yang, A. Azhdarinia, W. D. Erwin, A. M. Stachowiak, L. D. Broemeling, E. E. Kim, J. D. Cox, D. A. Podoloff, et al. Radiation Dosimetry of 99mTc-Labeled C225 in Patients with Squamous Cell Carcinoma of the Head and Neck J. Nucl. Med., October 1, 2004; 45(10): 1683 - 1687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Dominguez-Escrig, J. D. Kelly, D. E. Neal, S. M. King, and B. R. Davies Evaluation of the Therapeutic Potential of the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Gefitinib in Preclinical Models of Bladder Cancer Clin. Cancer Res., July 15, 2004; 10(14): 4874 - 4884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E.W. Cohen, M. W. Lingen, and E. E. Vokes The Expanding Role of Systemic Therapy in Head and Neck Cancer J. Clin. Oncol., May 1, 2004; 22(9): 1743 - 1752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ke, X. Wen, M. Gurfinkel, C. Charnsangavej, S. Wallace, E. M. Sevick-Muraca, and C. Li Near-Infrared Optical Imaging of Epidermal Growth Factor Receptor in Breast Cancer Xenografts Cancer Res., November 15, 2003; 63(22): 7870 - 7875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q.-T. Le and A. J. Giaccia Therapeutic Exploitation of the Physiological and Molecular Genetic Alterations in Head and Neck Cancer Clin. Cancer Res., October 1, 2003; 9(12): 4287 - 4295. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
median versus MOD > median) and OS (A), DFS (B), LR relapse (C), and distant metastasis (D).