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Brizel, David Manfield

Overview:

Head and neck cancer has constituted both my principal clinical and research foci since I came to Duke University in 1987. I designed and led a single institution phase 3 randomized clinical trial, initiated in 1989, which was one of the first in the world to demonstrate that radiotherapy and concurrent chemotherapy (CRT) was more efficacious than radiotherapy alone (RT) for treating locally advanced head and neck cancer. CRT has since been established as the non-surgical standard of care for locally advanced head and neck cancer. Reduction of treatment-induced toxicity has also been a major interest of mine because more intensive therapeutic regimens improve efficacy but also increase morbidity. I was the principal investigator of the pivotal multinational randomized trial of amifostine in head and neck cancer, which established proof of principle for pharmacologic radioprotection and led to FDA approval of this drug for protection against radiation induced xerostomia in the treatment of head and neck cancer in 1999. I have also investigated role of recombinant human keratinocyte growth factor KGF in the amelioration of mucositis in both preclinical and clinical settings.
I have an ongoing commitment to the study of in situ tumor physiology and biology. I was one of the initial investigators to initiate direct measurement of tumor oxygenation in humans on a systematic basis. This work revealed a prognostic relationship between tumor hypoxia and local-regional failure and survival in head and neck. Parallel studies of tumor oxygenation in soft tissue sarcomas resulted in the first published literature to demonstrate that hypoxia at a primary tumor site was associated with a significant increase in the risk of subsequent distant metastatic recurrence after completion of treatment. We have also demonstrated that elevated lactate concentrations in head and neck cancer primary tumors is associated with an increased risk of metastatic failure in patients undergoing primary surgical therapy for head and neck cancer.
These interests and accomplishments provide the foundation for my present efforts, which are devoted to the development of functional metabolic imaging, both MRI and PET. We are using imaging to characterize the inherent, non-treatment induced variability of several physiologic and metabolic parameters in both tumors and normal tissues and to measure treatment induced changes in them. The long- term intent is to improve our abilities to predict treatment outcome, to better understand the relationships between physical dose delivery and the risk of toxicity, and to choose more customized treatment strategies for our patients that will increase the chances of cure and decrease the risks of serious side effects



Positions:

Leonard Prosnitz Professor of Radiation Oncology

Radiation Oncology
School of Medicine

Professor of Radiation Oncology

Radiation Oncology
School of Medicine

Professor in Surgery

Surgery, Head and Neck Surgery and Communication Sciences
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1983

M.D. — Northwestern University

Grants:

NCI National Clinical Trials Network U10 (Year 4)

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 14, 2014
End Date
February 28, 2019

BMX-001 as a Radio-Protector in Head and Neck Cancer Therapy Phase I and Phase II

Administered By
Radiation Oncology
AwardedBy
BioMimetix Pharmaceutical, Inc.
Role
Principal Investigator
Start Date
March 01, 2017
End Date
May 08, 2018

Digital tomosynthesis: a new paradigm for radiation treatment verification

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 11, 2007
End Date
July 31, 2009

Measurement of Hypoxia in Non-Small Cell Lung Carcinoma

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
April 01, 2002
End Date
March 31, 2006

Hyperglycemia and Oxygen Breathing in Head & Neck Cancer

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2000
End Date
March 31, 2004

Predicting Human Tumor Response by 31p MRS

Administered By
Radiology, Neuroradiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 21, 1995
End Date
February 28, 2001

Hyperthermia And Perfusion Effects In Cancer Therapy

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
August 01, 1997
End Date
July 31, 1999

Hyperthermia And Perfusion Effects In Cancer Therapy

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 29, 1995
End Date
July 31, 1999

Hyperthermia And Perfusion Effects In Cancer Therapy

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
June 01, 1987
End Date
July 31, 1999

Heat & Radiation Effects On Tumor Microcirculation

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
May 01, 1997
End Date
April 30, 1999

Effects Of Heat And Radiation On Tumor

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
May 01, 1996
End Date
April 30, 1999

Hyperthermia And Perfusion Effects In Cancer Therapy

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
June 01, 1993
End Date
May 31, 1995
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Publications:

Immunotherapy of head and neck cancer: Emerging clinical trials from a National Cancer Institute Head and Neck Cancer Steering Committee Planning Meeting.

Recent advances have permitted successful therapeutic targeting of the immune system in head and neck squamous cell carcinoma (HNSCC). These new immunotherapeutic targets and agents are being rapidly adopted by the oncologic community and hold considerable promise. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issue of how to further investigate the use of immunotherapy in patients with HNSCC. The goals of the meeting were to consider phase 2 or 3 trial designs primarily in 3 different patient populations: those with previously untreated, human papillomavirus-initiated oropharyngeal cancers; those with previously untreated, human papillomavirus-negative HNSCC; and those with recurrent/metastatic HNSCC. In addition, a separate committee was formed to develop integrative biomarkers for the clinical trials. The meeting started with an overview of key immune components and principles related to HNSCC, including immunosurveillance and immune escape. Four clinical trial concepts were developed at the meeting integrating different immunotherapies with existing standards of care. These designs were presented for implementation by the head and neck committees of the National Cancer Institute-funded National Clinical Trials Network. This article summarizes the proceedings of this Clinical Trials Planning Meeting, the purpose of which was to facilitate the rigorous development and design of randomized phase 2 and 3 immunotherapeutic trials in patients with HNSCC. Although reviews usually are published immediately after the meeting is held, this report is unique because there are now tangible clinical trial designs that have been funded and put into practice and the studies are being activated to accrual. Cancer 2016. © 2016 American Cancer Society.

Authors
Bauman, JE; Cohen, E; Ferris, RL; Adelstein, DJ; Brizel, DM; Ridge, JA; O'Sullivan, B; Burtness, BA; Butterfield, LH; Carson, WE; Disis, ML; Fox, BA; Gajewski, TF; Gillison, ML; Hodge, JW; Le, Q-T; Raben, D; Strome, SE; Lynn, J; Malik, S
MLA Citation
Bauman, JE, Cohen, E, Ferris, RL, Adelstein, DJ, Brizel, DM, Ridge, JA, O'Sullivan, B, Burtness, BA, Butterfield, LH, Carson, WE, Disis, ML, Fox, BA, Gajewski, TF, Gillison, ML, Hodge, JW, Le, Q-T, Raben, D, Strome, SE, Lynn, J, and Malik, S. "Immunotherapy of head and neck cancer: Emerging clinical trials from a National Cancer Institute Head and Neck Cancer Steering Committee Planning Meeting." Cancer (December 2016).
PMID
27906454
Source
epmc
Published In
Cancer
Publish Date
2016
DOI
10.1002/cncr.30449

Pathology-based staging for HPV-positive squamous carcinoma of the oropharynx.

The rapid worldwide rise in incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has generated studies confirming this disease as an entity distinct from traditional OPSCC. Based on pathology, surgical studies have revealed prognosticators specific to HPV-positive OPSCC. The current AJCC/UICC staging and pathologic nodal (pN)-classification do not differentiate for survival, demonstrating the need for new, HPV-specific OPSCC staging. The objective of this study was to define a pathologic staging system specific to HPV-positive OPSCC.Data were assembled from a surgically-managed, p16-positive OPSCC cohort (any T, any N, M0) of 704 patients from five cancer centers. Analysis was performed for (a) the AJCC/UICC pathologic staging, (b) newly published clinical staging for non-surgically managed HPV-positive OPSCC, and (c) a novel, pathology-based, "HPVpath" staging system that combines features of the primary tumor and nodal metastases.A combination of AJCC/UICC pT-classification and pathology-confirmed metastatic node count (⩽4 versus ⩾5) yielded three groups: stages I (pT1-T2, ⩽4 nodes), II (pT1-T2, ⩾5 nodes; pT3-T4, ⩽4 nodes), and III (pT3-T4, ⩾5 nodes), with incrementally worse prognosis (Kaplan-Meier overall survival of 90%, 84% and 48% respectively). Existing AJCC/UICC pathologic staging lacked prognostic definition. Newly published HPV-specific clinical stagings from non-surgically managed patients, although prognostic, showed lower precision for this surgically managed cohort.Three loco-regional "HPVpath" stages are identifiable for HPV-positive OPSCC, based on a combination of AJCC/UICC primary tumor pT-classification and metastatic node count. A workable, pathologic staging system is feasible to establish prognosis and guide adjuvant therapy decisions in surgically-managed HPV-positive OPSCC.

Authors
Haughey, BH; Sinha, P; Kallogjeri, D; Goldberg, RL; Lewis, JS; Piccirillo, JF; Jackson, RS; Moore, EJ; Brandwein-Gensler, M; Magnuson, SJ; Carroll, WR; Jones, TM; Wilkie, MD; Lau, A; Upile, NS; Sheard, J; Lancaster, J; Tandon, S; Robinson, M; Husband, D; Ganly, I; Shah, JP; Brizel, DM; O'Sullivan, B; Ridge, JA; Lydiatt, WM
MLA Citation
Haughey, BH, Sinha, P, Kallogjeri, D, Goldberg, RL, Lewis, JS, Piccirillo, JF, Jackson, RS, Moore, EJ, Brandwein-Gensler, M, Magnuson, SJ, Carroll, WR, Jones, TM, Wilkie, MD, Lau, A, Upile, NS, Sheard, J, Lancaster, J, Tandon, S, Robinson, M, Husband, D, Ganly, I, Shah, JP, Brizel, DM, O'Sullivan, B, Ridge, JA, and Lydiatt, WM. "Pathology-based staging for HPV-positive squamous carcinoma of the oropharynx." Oral oncology 62 (November 2016): 11-19.
PMID
27865363
Source
epmc
Published In
Oral Oncology
Volume
62
Publish Date
2016
Start Page
11
End Page
19
DOI
10.1016/j.oraloncology.2016.09.004

Prognostic value of midtreatment FDG-PET in oropharyngeal cancer.

Prognostic metabolic imaging indices are needed for risk stratification for patients with locally advanced oropharyngeal cancer.We retrospectively examined pretreatment and midtreatment fluorodeoxyglucose-positron emission tomography (FDG-PET) parameters in patients with locally advanced oropharyngeal cancer who were treated with definitive chemoradiation.A total of 74 patients were evaluated. Pretreatment metabolic tumor volume (MTV) using threshold of 50% standardized uptake value (SUV) maximum (MTV50% ) was associated with progression-free survival (PFS; p = .003; hazard ratio [HR] = 1.57 per 10 cc; 95% confidence interval [CI] = 1.17-2.11) and overall survival (OS; p = .01; HR = 1.36 per 10 cc; 95% CI = 1.07-1.74). Midtreatment MTV using a threshold of SUV 2.0 (MTV2.0 ) was associated with PFS (p < .001; HR = 1.24 per 10 cc; 95% CI = 1.10-1.39) and OS (p = .009; HR = 1.21 per 10 cc; 95% CI = 1.05-1.39). Nodal total lesion glycolysis (TLG) velocity >5% decrease/week was associated with improved PFS (p = .04; HR = 0.37; 95% CI = 0.15-0.95).Metabolic response during chemoradiation is associated with survival in locally advanced oropharyngeal cancer and may aid with risk-adapting treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38: First-1478, 2016.

Authors
Pollom, EL; Song, J; Durkee, BY; Aggarwal, S; Bui, T; von Eyben, R; Li, R; Brizel, DM; Loo, BW; Le, Q-T; Hara, WY
MLA Citation
Pollom, EL, Song, J, Durkee, BY, Aggarwal, S, Bui, T, von Eyben, R, Li, R, Brizel, DM, Loo, BW, Le, Q-T, and Hara, WY. "Prognostic value of midtreatment FDG-PET in oropharyngeal cancer." Head & neck 38.10 (October 2016): 1472-1478.
PMID
27043927
Source
epmc
Published In
Head & Neck: Journal for the Sciences & Specialties of the Head and Neck
Volume
38
Issue
10
Publish Date
2016
Start Page
1472
End Page
1478
DOI
10.1002/hed.24454

Oxygen and Perfusion Kinetics in Response to Fractionated Radiation Therapy in FaDu Head and Neck Cancer Xenografts Are Related to Treatment Outcome.

To test whether oxygenation kinetics correlate with the likelihood for local tumor control after fractionated radiation therapy.We used diffuse reflectance spectroscopy to noninvasively measure tumor vascular oxygenation and total hemoglobin concentration associated with radiation therapy of 5 daily fractions (7.5, 9, or 13.5 Gy/d) in FaDu xenografts. Spectroscopy measurements were obtained immediately before each daily radiation fraction and during the week after radiation therapy. Oxygen saturation and total hemoglobin concentration were computed using an inverse Monte Carlo model.First, oxygenation kinetics during and after radiation therapy, but before tumor volumes changed, were associated with local tumor control. Locally controlled tumors exhibited significantly faster increases in oxygenation after radiation therapy (days 12-15) compared with tumors that recurred locally. Second, within the group of tumors that recurred, faster increases in oxygenation during radiation therapy (day 3-5 interval) were correlated with earlier recurrence times. An area of 0.74 under the receiver operating characteristic curve was achieved when classifying the local control tumors from all irradiated tumors using the oxygen kinetics with a logistic regression model. Third, the rate of increase in oxygenation was radiation dose dependent. Radiation doses ≤9.5 Gy/d did not initiate an increase in oxygenation, whereas 13.5 Gy/d triggered significant increases in oxygenation during and after radiation therapy.Additional confirmation is required in other tumor models, but these results suggest that monitoring tumor oxygenation kinetics could aid in the prediction of local tumor control after radiation therapy.

Authors
Hu, F; Vishwanath, K; Salama, JK; Erkanli, A; Peterson, B; Oleson, JR; Lee, WT; Brizel, DM; Ramanujam, N; Dewhirst, MW
MLA Citation
Hu, F, Vishwanath, K, Salama, JK, Erkanli, A, Peterson, B, Oleson, JR, Lee, WT, Brizel, DM, Ramanujam, N, and Dewhirst, MW. "Oxygen and Perfusion Kinetics in Response to Fractionated Radiation Therapy in FaDu Head and Neck Cancer Xenografts Are Related to Treatment Outcome." International journal of radiation oncology, biology, physics 96.2 (October 2016): 462-469.
PMID
27598811
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Issue
2
Publish Date
2016
Start Page
462
End Page
469
DOI
10.1016/j.ijrobp.2016.06.007

Immunotherapy and Checkpoint Inhibitors in Recurrent and Metastatic Head and Neck Cancer.

Immune surveillance is well recognized as an important mechanism to prevent development or progression of head and neck cancers. Head and neck cancer cells can escape the immune system through multiple mechanisms including development of tolerance in T cells and inhibition of T-cell-related pathways, generally referred to as checkpoint inhibitors. This article highlights advances in immuno-oncology treatment approaches in recurrent and metastatic head and neck squamous cell carcinoma. Clinical trials are discussed in detail, with an emphasis on response dynamics, oncologic efficacy, safety, and tolerability of checkpoint inhibitors. In addition, developing concepts and ongoing studies in this setting are also reviewed.

Authors
Hashemi-Sadraei, N; Sikora, AG; Brizel, DM
MLA Citation
Hashemi-Sadraei, N, Sikora, AG, and Brizel, DM. "Immunotherapy and Checkpoint Inhibitors in Recurrent and Metastatic Head and Neck Cancer." American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Meeting 35 (January 2016): e277-e282.
PMID
27249733
Source
epmc
Published In
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting
Volume
35
Publish Date
2016
Start Page
e277
End Page
e282
DOI
10.14694/edbk_157801

Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model.

To test the effects of a novel Mn porphyrin oxidative stress modifier, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE), for its radioprotective and radiosensitizing properties in normal tissue versus tumor, respectively.Murine oral mucosa and salivary glands were treated with a range of radiation doses with or without MnBuOE to establish the dose-effect curves for mucositis and xerostomia. Radiation injury was quantified by intravital near-infrared imaging of cathepsin activity, assessment of salivation, and histologic analysis. To evaluate effects of MnBuOE on the tumor radiation response, we administered the drug as an adjuvant to fractionated radiation of FaDu xenografts. Again, a range of radiation therapy (RT) doses was administered to establish the radiation dose-effect curve. The 50% tumor control dose values with or without MnBuOE and dose-modifying factor were determined.MnBuOE protected normal tissue by reducing RT-mediated mucositis, xerostomia, and fibrosis. The dose-modifying factor for protection against xerostomia was 0.77. In contrast, MnBuOE increased tumor local control rates compared with controls. The dose-modifying factor, based on the ratio of 50% tumor control dose values, was 1.3. Immunohistochemistry showed that MnBuOE-treated tumors exhibited a significant influx of M1 tumor-associated macrophages, which provides mechanistic insight into its radiosensitizing effects in tumors.MnBuOE widens the therapeutic margin by decreasing the dose of radiation required to control tumor, while increasing normal tissue resistance to RT-mediated injury. This is the first study to quantitatively demonstrate the magnitude of a single drug's ability to radioprotect normal tissue while radiosensitizing tumor.

Authors
Ashcraft, KA; Boss, M-K; Tovmasyan, A; Roy Choudhury, K; Fontanella, AN; Young, KH; Palmer, GM; Birer, SR; Landon, CD; Park, W; Das, SK; Weitner, T; Sheng, H; Warner, DS; Brizel, DM; Spasojevic, I; Batinic-Haberle, I; Dewhirst, MW
MLA Citation
Ashcraft, KA, Boss, M-K, Tovmasyan, A, Roy Choudhury, K, Fontanella, AN, Young, KH, Palmer, GM, Birer, SR, Landon, CD, Park, W, Das, SK, Weitner, T, Sheng, H, Warner, DS, Brizel, DM, Spasojevic, I, Batinic-Haberle, I, and Dewhirst, MW. "Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model." International journal of radiation oncology, biology, physics 93.4 (November 2015): 892-900.
PMID
26530759
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
93
Issue
4
Publish Date
2015
Start Page
892
End Page
900
DOI
10.1016/j.ijrobp.2015.07.2283

Semiautomated head-and-neck IMRT planning using dose warping and scaling to robustly adapt plans in a knowledge database containing potentially suboptimal plans.

Prior work by the authors and other groups has studied the creation of automated intensity modulated radiotherapy (IMRT) plans of equivalent quality to those in a patient database of manually created clinical plans; those database plans provided guidance on the achievable sparing to organs-at-risk (OARs). However, in certain sites, such as head-and-neck, the clinical plans may not be sufficiently optimized because of anatomical complexity and clinical time constraints. This could lead to automated plans that suboptimally exploit OAR sparing. This work investigates a novel dose warping and scaling scheme that attempts to reduce effects of suboptimal sparing in clinical database plans, thus improving the quality of semiautomated head-and-neck cancer (HNC) plans.Knowledge-based radiotherapy (KBRT) plans for each of ten "query" patients were semiautomatically generated by identifying the most similar "match" patient in a database of 103 clinical manually created patient plans. The match patient's plans were adapted to the query case by: (1) deforming the match beam fluences to suit the query target volume and (2) warping the match primary/boost dose distribution to suit the query geometry and using the warped distribution to generate query primary/boost optimization dose-volume constraints. Item (2) included a distance scaling factor to improve query OAR dose sparing with respect to the possibly suboptimal clinical match plan. To further compensate for a component plan of the match case (primary/boost) not optimally sparing OARs, the query dose volume constraints were reduced using a dose scaling factor to be the minimum from either (a) the warped component plan (primary or boost) dose distribution or (b) the warped total plan dose distribution (primary + boost) scaled in proportion to the ratio of component prescription dose to total prescription dose. The dose-volume constraints were used to plan the query case with no human intervention to adjust constraints during plan optimization.KBRT and original clinical plans were dosimetrically equivalent for parotid glands (mean/median doses), spinal cord, and brainstem (maximum doses). KBRT plans significantly reduced larynx median doses (21.5 ± 6.6 Gy to 17.9 ± 3.9 Gy), and oral cavity mean (32.3 ± 6.2 Gy to 28.9 ± 5.4 Gy) and median (28.7 ± 5.7 Gy to 23.2 ± 5.3 Gy) doses. Doses to ipsilateral parotid gland, larynx, oral cavity, and brainstem were lower or equivalent in the KBRT plans for the majority of cases. By contrast, KBRT plans generated without the dose warping and dose scaling steps were not significantly different from the clinical plans.Fast, semiautomatically generated HNC IMRT plans adapted from existing plans in a clinical database can be of equivalent or better quality than manually created plans. The reductions in OAR doses in the semiautomated plans, compared to the clinical plans, indicate that the proposed dose warping and scaling method shows promise in mitigating the impact of suboptimal clinical plans.

Authors
Schmidt, M; Lo, JY; Grzetic, S; Lutzky, C; Brizel, DM; Das, SK
MLA Citation
Schmidt, M, Lo, JY, Grzetic, S, Lutzky, C, Brizel, DM, and Das, SK. "Semiautomated head-and-neck IMRT planning using dose warping and scaling to robustly adapt plans in a knowledge database containing potentially suboptimal plans." Medical physics 42.8 (August 2015): 4428-4434.
PMID
26233173
Source
epmc
Published In
Medical physics
Volume
42
Issue
8
Publish Date
2015
Start Page
4428
End Page
4434
DOI
10.1118/1.4923174

Head and Neck Cancers, Version 1.2015.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (H&N) Cancers. These Insights describe the different types of particle therapy that may be used to treat H&N cancers, in contrast to traditional radiation therapy (RT) with photons (x-ray). Research is ongoing regarding the different types of particle therapy, including protons and carbon ions, with the goals of reducing the long-term side effects from RT and improving the therapeutic index. For the 2015 update, the NCCN H&N Cancers Panel agreed to delete recommendations for neutron therapy for salivary gland cancers, because of its limited availability, which has decreased over the past 2 decades; the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

Authors
Pfister, DG; Spencer, S; Brizel, DM; Burtness, B; Busse, PM; Caudell, JJ; Cmelak, AJ; Colevas, AD; Dunphy, F; Eisele, DW; Foote, RL; Gilbert, J; Gillison, ML; Haddad, RI; Haughey, BH; Hicks, WL; Hitchcock, YJ; Jimeno, A; Kies, MS; Lydiatt, WM; Maghami, E; McCaffrey, T; Mell, LK; Mittal, BB; Pinto, HA; Ridge, JA; Rodriguez, CP; Samant, S; Shah, JP; Weber, RS; Wolf, GT; Worden, F; Yom, SS; McMillian, N; Hughes, M
MLA Citation
Pfister, DG, Spencer, S, Brizel, DM, Burtness, B, Busse, PM, Caudell, JJ, Cmelak, AJ, Colevas, AD, Dunphy, F, Eisele, DW, Foote, RL, Gilbert, J, Gillison, ML, Haddad, RI, Haughey, BH, Hicks, WL, Hitchcock, YJ, Jimeno, A, Kies, MS, Lydiatt, WM, Maghami, E, McCaffrey, T, Mell, LK, Mittal, BB, Pinto, HA, Ridge, JA, Rodriguez, CP, Samant, S, Shah, JP, Weber, RS, Wolf, GT, Worden, F, Yom, SS, McMillian, N, and Hughes, M. "Head and Neck Cancers, Version 1.2015." Journal of the National Comprehensive Cancer Network : JNCCN 13.7 (July 2015): 847-856.
PMID
26150579
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
13
Issue
7
Publish Date
2015
Start Page
847
End Page
856

Current status of clinical trials in head and neck cancer 2014.

INTRODUCTION: The last few years have seen significant increase in the number of available clinical trials in head and neck cancer. It has been difficult to stay abreast of these efforts because multiple cooperative groups and institutions are engaged in their recruitment. This review presents the state of the art of available clinical trials organized around major research themes. DATA SOURCES: Published literature, published cooperative group monographs, expert review. REVIEW METHODS: Initial themes in head and neck cancer clinical trial development were first identified along with examples. Opinions from an international panel of multidisciplinary experts were then solicited. RESULTS/DISCUSSION: Current major themes of head and neck clinical trials centered on 5 major themes: (1) recognition of human papillomavirus oropharynx cancer and optimal treatment strategies, (2) defining the role of transoral surgery in head and neck cancer treatment, (3) improving postoperative adjuvant treatment, (4) investigation of rare malignancies, and (5) the importance of biomarker-driven, innovative, and targeted therapy investigation. CONCLUSIONS: A number of exciting clinical trials are currently in development or accrual with the potential for tremendous impact and improvement of the treatment of head and neck cancer. IMPLICATIONS FOR PRACTICE: Awareness by practicing otolaryngologists and trainees of these current themes will be essential for study accrual, success, and improvement in the care of head and neck cancer.

Authors
Liu, JC; Ridge, JA; Brizel, DM; O'Sullivan, B; Cohen, EW; Mann, BS; Adelstein, DJ
MLA Citation
Liu, JC, Ridge, JA, Brizel, DM, O'Sullivan, B, Cohen, EW, Mann, BS, and Adelstein, DJ. "Current status of clinical trials in head and neck cancer 2014." Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery 152.3 (March 2015): 410-417.
PMID
25605695
Source
epmc
Published In
Otolaryngology - Head and Neck Surgery
Volume
152
Issue
3
Publish Date
2015
Start Page
410
End Page
417
DOI
10.1177/0194599814566595

Different strokes for different folks: new paradigms for staging oropharynx cancer.

Authors
Brizel, DM
MLA Citation
Brizel, DM. "Different strokes for different folks: new paradigms for staging oropharynx cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.8 (March 2015): 817-818.
PMID
25667276
Source
epmc
Published In
Journal of Clinical Oncology
Volume
33
Issue
8
Publish Date
2015
Start Page
817
End Page
818
DOI
10.1200/jco.2014.60.1757

Head and neck cancers, version 1.2015 featured updates to the NCCN guidelines

© JNCCN-Journal of the National Comprehensive Cancer Network.These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (H&N) Cancers. These Insights describe the different types of particle therapy that may be used to treat H&N cancers, in contrast to traditional radiation therapy (RT) with photons (x-ray). Research is ongoing regarding the different types of particle therapy, including protons and carbonions, with the goals of reducing the long-term side effects from RT and improving the therapeutic index. For the 2015 update, the NCCN H&N Cancers Panel agreed to delete recommendations for neutron therapy for salivary gland cancers, because of its limited availability, which has decreased over the past 2 decades; the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

Authors
Pfister, DG; Spencer, S; Brizel, DM; Burtness, B; Busse, PM; Caudell, JJ; Cmelak, AJ; Colevas, AD; Dunphy, F; Eisele, DW; Foote, RL; Gilbert, J; Gillison, ML; Haddad, RI; Haughey, BH; Hicks, WL; Hitchcock, YJ; Jimeno, A; Kies, MS; Lydiatt, WM; Maghami, E; McCaffrey, T; Mell, LK; Mittal, BB; Pinto, HA; Ridge, JA; Rodriguez, CP; Samant, S; Shah, JP; Weber, RS; Wolf, GT; Worden, F; Yom, SS; McMillian, N; Hughes, M
MLA Citation
Pfister, DG, Spencer, S, Brizel, DM, Burtness, B, Busse, PM, Caudell, JJ, Cmelak, AJ, Colevas, AD, Dunphy, F, Eisele, DW, Foote, RL, Gilbert, J, Gillison, ML, Haddad, RI, Haughey, BH, Hicks, WL, Hitchcock, YJ, Jimeno, A, Kies, MS, Lydiatt, WM, Maghami, E, McCaffrey, T, Mell, LK, Mittal, BB, Pinto, HA, Ridge, JA, Rodriguez, CP, Samant, S, Shah, JP, Weber, RS, Wolf, GT, Worden, F, Yom, SS, McMillian, N, and Hughes, M. "Head and neck cancers, version 1.2015 featured updates to the NCCN guidelines." JNCCN Journal of the National Comprehensive Cancer Network 13.7 (January 1, 2015): 847-856.
Source
scopus
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
13
Issue
7
Publish Date
2015
Start Page
847
End Page
856

Diffusion-weighted imaging for head and neck squamous cell carcinoma: quantifying repeatability to understand early treatment-induced change.

OBJECTIVE: The purpose of this study was to define baseline variability of apparent diffusion coefficient (ADC) on diffusion-weighted MR imaging (DWI) in patients with head and neck squamous cell carcinoma (HNSCC) and to compare it with early treatment-induced ADC change. SUBJECTS AND METHODS: Patients with American Joint Committee on Cancer stages III and IV HNSCC were imaged with two baseline DWI examinations 1 week apart and a third DWI examination during the 2nd week of curative-intent chemoradiation therapy. Mean ADC was measured in the primary tumor and largest lymph node for each patient on the three DWI scans. Mean baseline percentage differences (%∆ADC) were compared with intratreatment change. The repeatability coefficient for baseline %∆ADC was calculated and compared with intratreatment %∆ADC. Repeatability was also assessed with Bland-Altman plots and the intraclass correlation coefficient (ICC). RESULTS: Sixteen patients underwent double baseline imaging, with 14 also undergoing intratreatment imaging. Baseline nodal disease ADC could be measured in 16 patients, but ADC in primary tumors could only be measured in five patients. The nodal mean (SD) baseline %∆ADC was 8% (± 7%), which was significantly different compared with intratreatment changes of 32% (± 31%) (p = 0.01). Baseline ICC was 0.86 for nodal disease and 0.99 for primary tumor (excellent correlation). The calculated repeatability coefficient for baseline nodal ADC was 15%. No patients had decreases in intratreatment ADC of more than 15%. CONCLUSION: Baseline ADC variability for HNSCC is less than intratreatment ADC change for nodal disease. Assessment of response should consider intrinsic baseline variability.

Authors
Hoang, JK; Choudhury, KR; Chang, J; Craciunescu, OI; Yoo, DS; Brizel, DM
MLA Citation
Hoang, JK, Choudhury, KR, Chang, J, Craciunescu, OI, Yoo, DS, and Brizel, DM. "Diffusion-weighted imaging for head and neck squamous cell carcinoma: quantifying repeatability to understand early treatment-induced change." AJR. American journal of roentgenology 203.5 (November 2014): 1104-1108.
PMID
25341151
Source
epmc
Published In
AJR. American journal of roentgenology
Volume
203
Issue
5
Publish Date
2014
Start Page
1104
End Page
1108
DOI
10.2214/ajr.14.12838

Head and neck cancers, Version 2.2014. Clinical practice guidelines in oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers focuses on glottic laryngeal cancer, which is the most common type of laryngeal cancer and has an excellent cure rate. The lymphatic drainage of the glottis is sparse, and early stage primaries rarely spread to regional nodes. Because hoarseness is an early symptom, most glottic laryngeal cancer is early stage at diagnosis. Updates to these guidelines for 2014 include revisions to "Principles of Radiation Therapy" for each site and "Principles of Surgery," and the addition of a new section on "Principles of Dental Evaluation and Management."

Authors
Pfister, DG; Spencer, S; Brizel, DM; Burtness, B; Busse, PM; Caudell, JJ; Cmelak, AJ; Colevas, AD; Dunphy, F; Eisele, DW; Gilbert, J; Gillison, ML; Haddad, RI; Haughey, BH; Hicks, WL; Hitchcock, YJ; Jimeno, A; Kies, MS; Lydiatt, WM; Maghami, E; Martins, R; McCaffrey, T; Mell, LK; Mittal, BB; Pinto, HA; Ridge, JA; Rodriguez, CP; Samant, S; Schuller, DE; Shah, JP; Weber, RS; Wolf, GT; Worden, F; Yom, SS; McMillian, NR; Hughes, M
MLA Citation
Pfister, DG, Spencer, S, Brizel, DM, Burtness, B, Busse, PM, Caudell, JJ, Cmelak, AJ, Colevas, AD, Dunphy, F, Eisele, DW, Gilbert, J, Gillison, ML, Haddad, RI, Haughey, BH, Hicks, WL, Hitchcock, YJ, Jimeno, A, Kies, MS, Lydiatt, WM, Maghami, E, Martins, R, McCaffrey, T, Mell, LK, Mittal, BB, Pinto, HA, Ridge, JA, Rodriguez, CP, Samant, S, Schuller, DE, Shah, JP, Weber, RS, Wolf, GT, Worden, F, Yom, SS, McMillian, NR, and Hughes, M. "Head and neck cancers, Version 2.2014. Clinical practice guidelines in oncology." Journal of the National Comprehensive Cancer Network : JNCCN 12.10 (October 2014): 1454-1487.
PMID
25313184
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
12
Issue
10
Publish Date
2014
Start Page
1454
End Page
1487

Phase II multicenter trial of Caphosol for the reduction of mucositis in patients receiving radiation therapy for head and neck cancer.

We conducted a phase II multicenter study evaluating Caphosol in patients receiving head and neck radiation (H/N RT) +/- chemotherapy or biologic sensitizer.The primary endpoint of the study tested the rate of functional mucositis (WHO grade > or equal to 2) with the hypothesis that <75% of patients would develop > or equal to 2 mucositis with Caphosol compared with a historical rate of >90%. New methods were applied with higher than historic rigor. 5 Institutions were included in this study: Moffitt Cancer Center (MCC), MD Anderson Cancer Center (MDACC), Duke University Cancer Center (DUCC), University of Florida (UF) and Temple University Cancer Center (TUCC). Caphosol was taken by patients at least 4 times a day and up to 10 times per day commencing with day 1 of RT and for a total duration of 8 weeks after completion of RT. Detailed questionnaires were completed weekly by patients and a unique algorithm was used to generate the WHO grade of mucositis.98 Patients were enrolled in the study. 59/98 (60%) patients were evaluable for the primary endpoint giving us 80% power. All evaluable patients experienced WHO grade > or equal to 2 mucositis and the trial failed to reject the null hypothesis. > or equal to 2 mucositis rates at weeks 2, 4, 6, 11 and 15 were as follows: 45%, 90%, 98%, 71%, 50%.We were unable to demonstrate that Caphosol significantly reduced WHO grade 2 or higher mucositis below a 90% historic rate. We are not surprised with this finding given our rigorous methodology in grading.

Authors
Rao, NG; Trotti, A; Kim, J; Schell, MJ; Zhao, X; Amdur, RJ; Brizel, DM; Chambers, MS; Caudell, JJ; Miyamoto, C; Rosenthal, DI
MLA Citation
Rao, NG, Trotti, A, Kim, J, Schell, MJ, Zhao, X, Amdur, RJ, Brizel, DM, Chambers, MS, Caudell, JJ, Miyamoto, C, and Rosenthal, DI. "Phase II multicenter trial of Caphosol for the reduction of mucositis in patients receiving radiation therapy for head and neck cancer." Oral oncology 50.8 (August 2014): 765-769.
PMID
24954065
Source
epmc
Published In
Oral Oncology
Volume
50
Issue
8
Publish Date
2014
Start Page
765
End Page
769
DOI
10.1016/j.oraloncology.2014.06.001

Comprehensive population-averaged arterial input function for dynamic contrast-enhanced vmagnetic resonance imaging of head and neck cancer.

PURPOSE: To generate a population-averaged arterial input function (PA-AIF) for quantitative analysis of dynamic contrast-enhanced MRI data in head and neck cancer patients. METHODS AND MATERIALS: Twenty patients underwent dynamic contrast-enhanced MRI during concurrent chemoradiation therapy. Imaging consisted of 2 baseline scans 1 week apart (B1/B2) and 1 scan after 1 week of chemoradiation therapy (Wk1). Regions of interest (ROIs) in the right and left carotid arteries were drawn on coronal images. Plasma concentration curves of all ROIs were averaged and fit to a biexponential decay function to obtain the final PA-AIF (AvgAll). Right-sided and left-sided ROI plasma concentration curves were averaged separately to obtain side-specific AIFs (AvgRight/AvgLeft). Regions of interest were divided by time point to obtain time-point-specific AIFs (AvgB1/AvgB2/AvgWk1). The vascular transfer constant (Ktrans) and the fractional extravascular, extracellular space volume (Ve) for primaries and nodes were calculated using the AvgAll AIF, the appropriate side-specific AIF, and the appropriate time-point-specific AIF. Median Ktrans and Ve values derived from AvgAll were compared with those obtained from the side-specific and time-point-specific AIFs. The effect of using individual AIFs was also investigated. RESULTS: The plasma parameters for AvgAll were a1,2 = 27.11/17.65 kg/L, m1,2 = 11.75/0.21 min(-1). The coefficients of repeatability (CRs) for AvgAll versus AvgLeft were 0.04 min(-1) for Ktrans and 0.02 for Ve. For AvgAll versus AvgRight, the CRs were 0.08 min(-1) for Ktrans and 0.02 for Ve. When AvgAll was compared with AvgB1/AvgB2/AvgWk1, the CRs were slightly higher: 0.32/0.19/0.78 min(-1), respectively, for Ktrans; and 0.07/0.08/0.09 for Ve. Use of a PA-AIF was not significantly different from use of individual AIFs. CONCLUSION: A PA-AIF for head and neck cancer was generated that accounts for differences in right carotid artery versus left carotid artery, day-to-day fluctuations, and early treatment-induced changes. The small CRs obtained for Ktrans and Ve indicate that side-specific AIFs are not necessary. However, a time-point-specific AIF may improve pharmacokinetic accuracy.

Authors
Onxley, JD; Yoo, DS; Muradyan, N; MacFall, JR; Brizel, DM; Craciunescu, OI
MLA Citation
Onxley, JD, Yoo, DS, Muradyan, N, MacFall, JR, Brizel, DM, and Craciunescu, OI. "Comprehensive population-averaged arterial input function for dynamic contrast-enhanced vmagnetic resonance imaging of head and neck cancer." International journal of radiation oncology, biology, physics 89.3 (July 2014): 658-665.
PMID
24929169
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
89
Issue
3
Publish Date
2014
Start Page
658
End Page
665
DOI
10.1016/j.ijrobp.2014.03.006

Incidence and risk factors of significant carotid artery stenosis in asymptomatic survivors of head and neck cancer after radiotherapy

Background The incidence and risk factors of carotid artery stenosis in asymptomatic patients after head and neck radiation therapy (RT) are unknown. Methods This retrospective study reviewed asymptomatic patients treated with RT for head and neck cancer from 2000 to 2009 who underwent screening carotid ultrasound. Results Two hundred twenty-four patients were included, the majority of whom had stage III to IV disease and received cisplatin-based chemotherapy. Median time from RT completion to last carotid ultrasound was 3 years. Actuarial rate of carotid artery stenosis at 4 years was 14% (95% confidence interval [CI], 4% to 22%). Multivariate analysis revealed that carotid artery stenosis was associated with Framingham risk factors (hazard ratio [HR], 1.6 per factor; 95% CI, 1.2-2.2; p =.003). Among 135 patients treated with intensity-modulated radiation therapy (IMRT), the HR for carotid artery stenosis was 1.4 for every 10 Gy increase in mean RT dose to the carotid bulb plus 2 cm (95% CI, 0.8-2.4; p =.35). Conclusion Prevention and screening programs should be considered for head and neck cancer survivors given the high risk of carotid artery stenosis. Copyright © 2013 Wiley Periodicals, Inc.

Authors
Dorth, JA; Patel, PR; Broadwater, G; Brizel, DM
MLA Citation
Dorth, JA, Patel, PR, Broadwater, G, and Brizel, DM. "Incidence and risk factors of significant carotid artery stenosis in asymptomatic survivors of head and neck cancer after radiotherapy." Head and Neck 36.2 (February 1, 2014): 215-219.
Source
scopus
Published In
Head & Neck: Journal for the Sciences & Specialties of the Head and Neck
Volume
36
Issue
2
Publish Date
2014
Start Page
215
End Page
219
DOI
10.1002/hed.23280

Incidence and risk factors of significant carotid artery stenosis in asymptomatic survivors of head and neck cancer after radiotherapy.

BACKGROUND: The incidence and risk factors of carotid artery stenosis in asymptomatic patients after head and neck radiation therapy (RT) are unknown. METHODS: This retrospective study reviewed asymptomatic patients treated with RT for head and neck cancer from 2000 to 2009 who underwent screening carotid ultrasound. RESULTS: Two hundred twenty-four patients were included, the majority of whom had stage III to IV disease and received cisplatin-based chemotherapy. Median time from RT completion to last carotid ultrasound was 3 years. Actuarial rate of carotid artery stenosis at 4 years was 14% (95% confidence interval [CI], 4% to 22%). Multivariate analysis revealed that carotid artery stenosis was associated with Framingham risk factors (hazard ratio [HR], 1.6 per factor; 95% CI, 1.2-2.2; p = .003). Among 135 patients treated with intensity-modulated radiation therapy (IMRT), the HR for carotid artery stenosis was 1.4 for every 10 Gy increase in mean RT dose to the carotid bulb plus 2 cm (95% CI, 0.8-2.4; p = .35). CONCLUSION: Prevention and screening programs should be considered for head and neck cancer survivors given the high risk of carotid artery stenosis.

Authors
Dorth, JA; Patel, PR; Broadwater, G; Brizel, DM
MLA Citation
Dorth, JA, Patel, PR, Broadwater, G, and Brizel, DM. "Incidence and risk factors of significant carotid artery stenosis in asymptomatic survivors of head and neck cancer after radiotherapy." Head Neck 36.2 (February 2014): 215-219.
PMID
23554082
Source
pubmed
Published In
Head & Neck: Journal for the Sciences & Specialties of the Head and Neck
Volume
36
Issue
2
Publish Date
2014
Start Page
215
End Page
219
DOI
10.1002/hed.23280

Phase II multicenter trial of Caphosol for the reduction of mucositis in patients receiving radiation therapy for head and neck cancer

Purpose We conducted a phase II multicenter study evaluating Caphosol in patients receiving head and neck radiation (H/N RT) +/- chemotherapy or biologic sensitizer. Materials/Methods The primary endpoint of the study tested the rate of functional mucositis (WHO grade > or equal to 2) with the hypothesis that <75% of patients would develop > or equal to 2 mucositis with Caphosol compared with a historical rate of >90%. New methods were applied with higher than historic rigor. 5 Institutions were included in this study: Moffitt Cancer Center (MCC), MD Anderson Cancer Center (MDACC), Duke University Cancer Center (DUCC), University of Florida (UF) and Temple University Cancer Center (TUCC). Caphosol was taken by patients at least 4 times a day and up to 10 times per day commencing with day 1 of RT and for a total duration of 8 weeks after completion of RT. Detailed questionnaires were completed weekly by patients and a unique algorithm was used to generate the WHO grade of mucositis. Results 98 Patients were enrolled in the study. 59/98 (60%) patients were evaluable for the primary endpoint giving us 80% power. All evaluable patients experienced WHO grade > or equal to 2 mucositis and the trial failed to reject the null hypothesis. > or equal to 2 mucositis rates at weeks 2, 4, 6, 11 and 15 were as follows: 45%, 90%, 98%, 71%, 50%. Conclusion We were unable to demonstrate that Caphosol significantly reduced WHO grade 2 or higher mucositis below a 90% historic rate. We are not surprised with this finding given our rigorous methodology in grading. © 2014 Elsevier Ltd. All rights reserved.

Authors
Rao, NG; Trotti, A; Kim, J; Schell, MJ; Zhao, X; Amdur, RJ; Brizel, DM; Chambers, MS; Caudell, JJ; Miyamoto, C; Rosenthal, DI
MLA Citation
Rao, NG, Trotti, A, Kim, J, Schell, MJ, Zhao, X, Amdur, RJ, Brizel, DM, Chambers, MS, Caudell, JJ, Miyamoto, C, and Rosenthal, DI. "Phase II multicenter trial of Caphosol for the reduction of mucositis in patients receiving radiation therapy for head and neck cancer." Oral Oncology 50.8 (January 1, 2014): 765-769.
Source
scopus
Published In
Oral Oncology
Volume
50
Issue
8
Publish Date
2014
Start Page
765
End Page
769
DOI
10.1016/j.oraloncology.2014.06.001

Head and neck cancers, version 2.2013. Featured updates to the NCCN guidelines.

These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org).

Authors
Pfister, DG; Ang, K-K; Brizel, DM; Burtness, BA; Busse, PM; Caudell, JJ; Cmelak, AJ; Colevas, AD; Dunphy, F; Eisele, DW; Gilbert, J; Gillison, ML; Haddad, RI; Haughey, BH; Hicks, WL; Hitchcock, YJ; Kies, MS; Lydiatt, WM; Maghami, E; Martins, R; McCaffrey, T; Mittal, BB; Pinto, HA; Ridge, JA; Samant, S; Schuller, DE; Shah, JP; Spencer, S; Weber, RS; Wolf, GT; Worden, F; Yom, SS; McMillian, NR; Hughes, M; National Comprehensive Cancer Network,
MLA Citation
Pfister, DG, Ang, K-K, Brizel, DM, Burtness, BA, Busse, PM, Caudell, JJ, Cmelak, AJ, Colevas, AD, Dunphy, F, Eisele, DW, Gilbert, J, Gillison, ML, Haddad, RI, Haughey, BH, Hicks, WL, Hitchcock, YJ, Kies, MS, Lydiatt, WM, Maghami, E, Martins, R, McCaffrey, T, Mittal, BB, Pinto, HA, Ridge, JA, Samant, S, Schuller, DE, Shah, JP, Spencer, S, Weber, RS, Wolf, GT, Worden, F, Yom, SS, McMillian, NR, Hughes, M, and National Comprehensive Cancer Network, . "Head and neck cancers, version 2.2013. Featured updates to the NCCN guidelines." J Natl Compr Canc Netw 11.8 (August 2013): 917-923.
PMID
23946171
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
11
Issue
8
Publish Date
2013
Start Page
917
End Page
923

Using FDG-PET to measure early treatment response in head and neck squamous cell carcinoma: quantifying intrinsic variability in order to understand treatment-induced change.

BACKGROUND AND PURPOSE: Quantification of both baseline variability and intratreatment change is necessary to optimally incorporate functional imaging into adaptive therapy strategies for HNSCC. Our aim was to define the baseline variability of SUV on FDG-PET scans in patients with head and neck squamous cell carcinoma and to compare it with early treatment-induced SUV change. MATERIALS AND METHODS: Patients with American Joint Committee on Cancer stages III-IV HNSCC were imaged with 2 baseline PET/CT scans and a third scan after 1-2 weeks of curative-intent chemoradiation. SUVmax and SUVmean were measured in the primary tumor and most metabolically active nodal metastasis. Repeatability was assessed with Bland-Altman plots. Mean percentage differences (%ΔSUV) in baseline SUVs were compared with intratreatment %ΔSUV. The repeatability coefficient for baseline %ΔSUV was compared with intratreatment %ΔSUV. RESULTS: Seventeen patients had double-baseline imaging, and 15 of these patients also had intratreatment scans. Bland-Altman plots showed excellent baseline agreement for nodal metastases SUVmax and SUVmean, but not primary tumor SUVs. The mean baseline %ΔSUV was lowest for SUVmax in nodes (7.6% ± 5.2%) and highest for SUVmax in primary tumor (12.6% ± 9.2%). Corresponding mean intratreatment %ΔSUVmax was 14.5% ± 21.6% for nodes and 15.2% ± 22.4% for primary tumor. The calculated RC for baseline nodal SUVmax and SUVmean were 10% and 16%, respectively. The only patient with intratreatment %ΔSUV above these RCs was 1 of 2 patients with residual disease after CRT. CONCLUSIONS: Baseline SUV variability for HNSCC is less than intratreatment change for SUV in nodal disease. Evaluation of early treatment response should be measured quantitatively in nodal disease rather than the primary tumor, and assessment of response should consider intrinsic baseline variability.

Authors
Hoang, JK; Das, SK; Choudhury, KR; Yoo, DS; Brizel, DM
MLA Citation
Hoang, JK, Das, SK, Choudhury, KR, Yoo, DS, and Brizel, DM. "Using FDG-PET to measure early treatment response in head and neck squamous cell carcinoma: quantifying intrinsic variability in order to understand treatment-induced change." AJNR Am J Neuroradiol 34.7 (July 2013): 1428-1433.
PMID
23391836
Source
pubmed
Published In
American Journal of Neuroradiology
Volume
34
Issue
7
Publish Date
2013
Start Page
1428
End Page
1433
DOI
10.3174/ajnr.A3412

Contemporary radiotherapy in head and neck cancer: balancing chance for cure with risk for complication.

Radiotherapy plays an integral role in the management of most patients with cancers of the head and neck. Better understanding of radiobiology and radiation physics has allowed radiation oncologists to enhance the tumoricidal effects of radiation and reduce the severity of normal tissue toxicities. This article reviews the biologic foundation of head and neck radiotherapy, the physical principles and technological innovations that enable delivery of highly conformal radiation, the acute and late complications of radiation-based treatments, and the clinical evidence supporting contemporary practice.

Authors
Cabrera, AR; Yoo, DS; Brizel, DM
MLA Citation
Cabrera, AR, Yoo, DS, and Brizel, DM. "Contemporary radiotherapy in head and neck cancer: balancing chance for cure with risk for complication." Surg Oncol Clin N Am 22.3 (July 2013): 579-598. (Review)
PMID
23622081
Source
pubmed
Published In
Surgical Oncology Clinics of North America
Volume
22
Issue
3
Publish Date
2013
Start Page
579
End Page
598
DOI
10.1016/j.soc.2013.02.001

Radiation induces aerobic glycolysis through reactive oxygen species.

BACKGROUND AND PURPOSE: Although radiation induced reoxygenation has been thought to increase radiosensitivity, we have shown that its associated oxidative stress can have radioprotective effects, including stabilization of the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1 is known to regulate many of the glycolytic enzymes, thereby promoting aerobic glycolysis, which is known to promote treatment resistance. Thus, we hypothesized that reoxygenation after radiation would increase glycolysis. We previously showed that blockade of oxidative stress using a superoxide dismutase (SOD) mimic during reoxygenation can downregulate HIF-1 activity. Here we tested whether concurrent use of this drug with radiotherapy would reduce the switch to a glycolytic phenotype. MATERIALS AND METHODS: 40 mice with skin fold window chambers implanted with 4T1 mammary carcinomas were randomized into (1) no treatment, (2) radiation alone, (3) SOD mimic alone, and (4) SOD mimic with concurrent radiation. All mice were imaged on the ninth day following tumor implantation (30 h following radiation treatment) following injection of a fluorescent glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG). Hemoglobin saturation was measured by using hyperspectral imaging to quantify oxygenation state. RESULTS: Mice treated with radiation showed significantly higher 2-NBDG fluorescence compared to controls (p=0.007). Hemoglobin saturation analysis demonstrated reoxygenation following radiation, coinciding with the observed increase in glycolysis. The concurrent use of the SOD mimic with radiation demonstrated a significant reduction in 2-NBDG fluorescence compared to effects seen after radiation alone, while having no effect on reoxygenation. CONCLUSIONS: Radiation induces an increase in tumor glucose demand approximately 30 h following therapy during reoxygenation. The use of an SOD mimic can prevent the increase in aerobic glycolysis when used concurrently with radiation, without preventing reoxygenation.

Authors
Zhong, J; Rajaram, N; Brizel, DM; Frees, AE; Ramanujam, N; Batinic-Haberle, I; Dewhirst, MW
MLA Citation
Zhong, J, Rajaram, N, Brizel, DM, Frees, AE, Ramanujam, N, Batinic-Haberle, I, and Dewhirst, MW. "Radiation induces aerobic glycolysis through reactive oxygen species." Radiother Oncol 106.3 (March 2013): 390-396.
PMID
23541363
Source
pubmed
Published In
Radiotherapy and Oncology
Volume
106
Issue
3
Publish Date
2013
Start Page
390
End Page
396
DOI
10.1016/j.radonc.2013.02.013

Experimental radiotherapy Radiation induces aerobic glycolysis through reactive oxygen species

Background and purpose Although radiation induced reoxygenation has been thought to increase radiosensitivity, we have shown that its associated oxidative stress can have radioprotective effects, including stabilization of the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1 is known to regulate many of the glycolytic enzymes, thereby promoting aerobic glycolysis, which is known to promote treatment resistance. Thus, we hypothesized that reoxygenation after radiation would increase glycolysis. We previously showed that blockade of oxidative stress using a superoxide dismutase (SOD) mimic during reoxygenation can downregulate HIF-1 activity. Here we tested whether concurrent use of this drug with radiotherapy would reduce the switch to a glycolytic phenotype. Materials and methods 40 mice with skin fold window chambers implanted with 4T1 mammary carcinomas were randomized into (1) no treatment, (2) radiation alone, (3) SOD mimic alone, and (4) SOD mimic with concurrent radiation. All mice were imaged on the ninth day following tumor implantation (30 h following radiation treatment) following injection of a fluorescent glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2- deoxyglucose (2-NBDG). Hemoglobin saturation was measured by using hyperspectral imaging to quantify oxygenation state. Results Mice treated with radiation showed significantly higher 2-NBDG fluorescence compared to controls (p = 0.007). Hemoglobin saturation analysis demonstrated reoxygenation following radiation, coinciding with the observed increase in glycolysis. The concurrent use of the SOD mimic with radiation demonstrated a significant reduction in 2-NBDG fluorescence compared to effects seen after radiation alone, while having no effect on reoxygenation. Conclusions Radiation induces an increase in tumor glucose demand approximately 30 h following therapy during reoxygenation. The use of an SOD mimic can prevent the increase in aerobic glycolysis when used concurrently with radiation, without preventing reoxygenation. © 2013 Elsevier Ireland Ltd. All rights reserved.

Authors
Zhong, J; Rajaram, N; Brizel, DM; Frees, AE; Ramanujam, N; Batinic-Haberle, I; Dewhirst, MW
MLA Citation
Zhong, J, Rajaram, N, Brizel, DM, Frees, AE, Ramanujam, N, Batinic-Haberle, I, and Dewhirst, MW. "Experimental radiotherapy Radiation induces aerobic glycolysis through reactive oxygen species." Radiotherapy and Oncology 106.3 (2013): 390-396.
Source
scival
Published In
Radiotherapy & Oncology
Volume
106
Issue
3
Publish Date
2013
Start Page
390
End Page
396
DOI
10.1016/j.radonc.2013.02.013

Transoral resection of pharyngeal cancer: summary of a National Cancer Institute Head and Neck Cancer Steering Committee Clinical Trials Planning Meeting, November 6-7, 2011, Arlington, Virginia.

Recent advances now permit resection of many pharyngeal tumors through the open mouth, an approach that can greatly reduce the morbidity of surgical exposure. These transoral techniques are being rapidly adopted by the surgical community and hold considerable promise. On November 6-7, 2011, the National Cancer Institute sponsored a Clinical Trials Planning Meeting to address how to further investigate the use of transoral surgery, both in the good prognosis human papillomavirus (HPV)-initiated oropharyngeal cancers, and in those with HPV-unrelated disease. The proceedings of this meeting are summarized.

Authors
Adelstein, DJ; Ridge, JA; Brizel, DM; Holsinger, FC; Haughey, BH; O'Sullivan, B; Genden, EM; Beitler, JJ; Weinstein, GS; Quon, H; Chepeha, DB; Ferris, RL; Weber, RS; Movsas, B; Waldron, J; Lowe, V; Ramsey, S; Manola, J; Yueh, B; Carey, TE; Bekelman, JE; Konski, AA; Moore, E; Forastiere, A; Schuller, DE; Lynn, J; Ullmann, CD
MLA Citation
Adelstein, DJ, Ridge, JA, Brizel, DM, Holsinger, FC, Haughey, BH, O'Sullivan, B, Genden, EM, Beitler, JJ, Weinstein, GS, Quon, H, Chepeha, DB, Ferris, RL, Weber, RS, Movsas, B, Waldron, J, Lowe, V, Ramsey, S, Manola, J, Yueh, B, Carey, TE, Bekelman, JE, Konski, AA, Moore, E, Forastiere, A, Schuller, DE, Lynn, J, and Ullmann, CD. "Transoral resection of pharyngeal cancer: summary of a National Cancer Institute Head and Neck Cancer Steering Committee Clinical Trials Planning Meeting, November 6-7, 2011, Arlington, Virginia." Head Neck 34.12 (December 2012): 1681-1703.
PMID
23015475
Source
pubmed
Published In
Head & Neck: Journal for the Sciences & Specialties of the Head and Neck
Volume
34
Issue
12
Publish Date
2012
Start Page
1681
End Page
1703
DOI
10.1002/hed.23136

Predictive and prognostic role of functional imaging of head and neck squamous cell carcinomas.

Predicting radiotherapy (RT) treatment response and eventual locoregional disease control is an important component of the ongoing effort to improve the therapeutic ratio in the management of head and neck squamous cell carcinomas. The development of clinically useful predictive and prognostic imaging biomarkers has been limited by significant tumor heterogeneity in both the tumor and its microenvironment. Various advanced imaging techniques have been evaluated in the head and neck squamous cell carcinoma patient, which now offer a strategy to identify and quantify this heterogeneity, characterizing the tumor at baseline and its response to RT. The most promising of these techniques include dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), DCE computed tomography, diffusion-weighted MRI, and (18)F-fluoromisonidazole positron emission tomography (PET) all relying on the spatiotemporal quantification of a contrast agent within a region of interest that can be further analyzed by various pharmacokinetic models. Despite the small study populations, several consistent observations have been reported that warrant further validation. Features associated with a favorable RT response include tumors with an effective vasculature characterized by rapid and high influx rates of the contrast agent and its effective clearance with little or no regions of hypoxia. (18)F-deoxyglucose-PET imaging remains an active area of investigation with the metabolic tumor volume parameter appearing to offer potential predictive value. Characterizing changes during a course of RT may offer greater predictive value. Both DCE-MRI and diffusion-weighted MRI can identify physiological changes within the first 1-2 weeks of treatment that are correlated with long-term clinical outcome. Identifying persistent hypoxia with (18)F-fluoromisonidazole-PET during a course of RT suggests an increased risk of relapse. Whether this is due to an inability to favorably remodel the tumor's vasculature has not been clearly demonstrated to date. Future research goals include the need to further validate these promising imaging biomarkers especially in larger cohorts of patients, characterizing the optimal threshold cutoffs and to refine the predictive value by incorporating the assessments of early tumor responses to therapy that offer the potential for increased specificity because it reflects the biological stress responses.

Authors
Quon, H; Brizel, DM
MLA Citation
Quon, H, and Brizel, DM. "Predictive and prognostic role of functional imaging of head and neck squamous cell carcinomas." Semin Radiat Oncol 22.3 (July 2012): 220-232. (Review)
PMID
22687947
Source
pubmed
Published In
Seminars in Radiation Oncology
Volume
22
Issue
3
Publish Date
2012
Start Page
220
End Page
232
DOI
10.1016/j.semradonc.2012.03.007

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

Development and clinical evaluation of a three-dimensional cone-beam computed tomography estimation method using a deformation field map.

PURPOSE: To develop a three-dimensional (3D) cone-beam computed tomography (CBCT) estimation method using a deformation field map, and to evaluate and optimize the efficiency and accuracy of the method for use in the clinical setting. METHODS AND MATERIALS: We propose a method to estimate patient CBCT images using prior information and a deformation model. Patients' previous CBCT data are used as the prior information, and the new CBCT volume to be estimated is considered as a deformation of the prior image volume. The deformation field map is solved by minimizing deformation energy and maintaining new projection data fidelity using a nonlinear conjugate gradient method. This method was implemented in 3D form using hardware acceleration and multi-resolution scheme, and it was evaluated for different scan angles, projection numbers, and scan directions using liver, lung, and prostate cancer patient data. The accuracy of the estimation was evaluated by comparing the organ volume difference and the similarity between estimated CBCT and the CBCT reconstructed from fully sampled projections. RESULTS: Results showed that scan direction and number of projections do not have significant effects on the CBCT estimation accuracy. The total scan angle is the dominant factor affecting the accuracy of the CBCT estimation algorithm. Larger scan angles yield better estimation accuracy than smaller scan angles. Lung cancer patient data showed that the estimation error of the 3D lung tumor volume was reduced from 13.3% to 4.3% when the scan angle was increased from 60° to 360° using 57 projections. CONCLUSIONS: The proposed estimation method is applicable for 3D DTS, 3D CBCT, four-dimensional CBCT, and four-dimensional DTS image estimation. This method has the potential for significantly reducing the imaging dose and improving the image quality by removing the organ distortion artifacts and streak artifacts shown in images reconstructed by the conventional Feldkamp-Davis-Kress (FDK) algorithm.

Authors
Ren, L; Chetty, IJ; Zhang, J; Jin, J-Y; Wu, QJ; Yan, H; Brizel, DM; Lee, WR; Movsas, B; Yin, F-F
MLA Citation
Ren, L, Chetty, IJ, Zhang, J, Jin, J-Y, Wu, QJ, Yan, H, Brizel, DM, Lee, WR, Movsas, B, and Yin, F-F. "Development and clinical evaluation of a three-dimensional cone-beam computed tomography estimation method using a deformation field map." Int J Radiat Oncol Biol Phys 82.5 (April 1, 2012): 1584-1593.
PMID
21477945
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
82
Issue
5
Publish Date
2012
Start Page
1584
End Page
1593
DOI
10.1016/j.ijrobp.2011.02.002

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

Dynamic contrast-enhanced MRI in head-and-neck cancer: the impact of region of interest selection on the intra- and interpatient variability of pharmacokinetic parameters.

PURPOSE: Dynamic contrast-enhanced (DCE) MRI-extracted parameters measure tumor microvascular physiology and are usually calculated from an intratumor region of interest (ROI). Optimal ROI delineation is not established. The valid clinical use of DCE-MRI requires that the variation for any given parameter measured within a tumor be less than that observed between tumors in different patients. This work evaluates the impact of tumor ROI selection on the assessment of intra- and interpatient variability. METHOD AND MATERIALS: Head and neck cancer patients received initial targeted therapy (TT) treatment with erlotinib and/or bevacizumab, followed by radiotherapy and concurrent cisplatin with synchronous TT. DCE-MRI data from Baseline and the end of the TT regimen (Lead-In) were analyzed to generate the vascular transfer function (K(trans)), the extracellular volume fraction (v(e)), and the initial area under the concentration time curve (iAUC(1 min)). Four ROI sampling strategies were used: whole tumor or lymph node (Whole), the slice containing the most enhancing voxels (SliceMax), three slices centered in SliceMax (Partial), and the 5% most enhancing contiguous voxels within SliceMax (95Max). The average coefficient of variation (aCV) was calculated to establish intrapatient variability among ROI sets and interpatient variability for each ROI type. The average ratio between each intrapatient CV and the interpatient CV was calculated (aRCV). RESULTS: Baseline primary/nodes aRCVs for different ROIs not including 95Max were, for all three MR parameters, in the range of 0.14-0.24, with Lead-In values between 0.09 and 0.2, meaning a low intrapatient vs. interpatient variation. For 95Max, intrapatient CVs approximated interpatient CVs, meaning similar data dispersion and higher aRCVs (0.6-1.27 for baseline) and 0.54-0.95 for Lead-In. CONCLUSION: Distinction between different patient's primary tumors and/or nodes cannot be made using 95Max ROIs. The other three strategies are viable and equivalent for using DCE-MRI to measure head and neck cancer physiology.

Authors
Craciunescu, OI; Yoo, DS; Cleland, E; Muradyan, N; Carroll, MD; MacFall, JR; Barboriak, DP; Brizel, DM
MLA Citation
Craciunescu, OI, Yoo, DS, Cleland, E, Muradyan, N, Carroll, MD, MacFall, JR, Barboriak, DP, and Brizel, DM. "Dynamic contrast-enhanced MRI in head-and-neck cancer: the impact of region of interest selection on the intra- and interpatient variability of pharmacokinetic parameters." Int J Radiat Oncol Biol Phys 82.3 (March 1, 2012): e345-e350.
PMID
21985945
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
82
Issue
3
Publish Date
2012
Start Page
e345
End Page
e350
DOI
10.1016/j.ijrobp.2011.05.059

Mucosal melanoma of the head and neck.

Authors
Pfister, DG; Ang, K-K; Brizel, DM; Burtness, B; Cmelak, AJ; Colevas, AD; Dunphy, F; Eisele, DW; Gilbert, J; Gillison, ML; Haddad, RI; Haughey, BH; Hicks, WL; Hitchcock, YJ; Kies, MS; Lydiatt, WM; Maghami, E; Martins, R; McCaffrey, T; Mittal, BB; Pinto, HA; Ridge, JA; Samant, S; Sanguineti, G; Schuller, DE; Shah, JP; Spencer, S; Trotti, A; Weber, RS; Wolf, G; Worden, F; National Comprehensive Cancer Network,
MLA Citation
Pfister, DG, Ang, K-K, Brizel, DM, Burtness, B, Cmelak, AJ, Colevas, AD, Dunphy, F, Eisele, DW, Gilbert, J, Gillison, ML, Haddad, RI, Haughey, BH, Hicks, WL, Hitchcock, YJ, Kies, MS, Lydiatt, WM, Maghami, E, Martins, R, McCaffrey, T, Mittal, BB, Pinto, HA, Ridge, JA, Samant, S, Sanguineti, G, Schuller, DE, Shah, JP, Spencer, S, Trotti, A, Weber, RS, Wolf, G, Worden, F, and National Comprehensive Cancer Network, . "Mucosal melanoma of the head and neck." J Natl Compr Canc Netw 10.3 (March 2012): 320-338.
PMID
22393194
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
10
Issue
3
Publish Date
2012
Start Page
320
End Page
338

Analysis of pretreatment FDG-PET SUV parameters in head-and-neck cancer: tumor SUVmean has superior prognostic value.

PURPOSE: To evaluate the prognostic significance of different descriptive parameters in head-and-neck cancer patients undergoing pretreatment [F-18] fluoro-D-glucose-positron emission tomography (FDG-PET) imaging. PATIENTS AND METHODS: Head-and-neck cancer patients who underwent FDG-PET before a course of curative intent radiotherapy were retrospectively analyzed. FDG-PET imaging parameters included maximum (SUV(max)), and mean (SUV(mean)) standard uptake values, and total lesion glycolysis (TLG). Tumors and lymph nodes were defined on co-registered axial computed tomography (CT) slices. SUV(max) and SUV(mean) were measured within these anatomic regions. The relationships between pretreatment SUV(max), SUV(mean), and TLG for the primary site and lymph nodes were assessed using a univariate analysis for disease-free survival (DFS), locoregional control (LRC), and distant metastasis-free survival (DMFS). Kaplan-Meier survival curves were generated and compared via the log-rank method. SUV data were analyzed as continuous variables. RESULTS: A total of 88 patients was assessed. Two-year OS, LRC, DMFS, and DFS for the entire cohort were 85%, 78%, 81%, and 70%, respectively. Median SUV(max) for the primary tumor and lymph nodes was 15.4 and 12.2, respectively. Median SUV(mean) for the primary tumor and lymph nodes was 7 and 5.2, respectively. Median TLG was 770. Increasing pretreatment SUV(mean) of the primary tumor was associated with decreased disease-free survival (p = 0.01). Neither SUV(max) in the primary tumor or lymph nodes nor TLG was prognostic for any of the clinical endpoints. Patients with pretreatment tumor SUV(mean) that exceeded the median value (7) of the cohort demonstrated inferior 2-year DFS relative to patients with SUV(mean) ≤ the median value of the cohort, 58% vs. 82%, respectively, p = 0.03. CONCLUSION: Increasing SUV(mean) in the primary tumor was associated with inferior DFS. Although not routinely reported, pretreatment SUV(mean) may be a useful prognostic FDG-PET parameter and should be further evaluated prospectively.

Authors
Higgins, KA; Hoang, JK; Roach, MC; Chino, J; Yoo, DS; Turkington, TG; Brizel, DM
MLA Citation
Higgins, KA, Hoang, JK, Roach, MC, Chino, J, Yoo, DS, Turkington, TG, and Brizel, DM. "Analysis of pretreatment FDG-PET SUV parameters in head-and-neck cancer: tumor SUVmean has superior prognostic value." Int J Radiat Oncol Biol Phys 82.2 (February 1, 2012): 548-553.
PMID
21277108
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
82
Issue
2
Publish Date
2012
Start Page
548
End Page
553
DOI
10.1016/j.ijrobp.2010.11.050

FDG-PET assessment of the effect of head and neck radiotherapy on parotid gland glucose metabolism.

PURPOSE: Functional imaging with [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) provides the opportunity to define the physiology of the major salivary glands before and after radiation therapy. The goal of this retrospective study was to identify the radiation dose-response relationship of parotid gland glucose metabolism in patients with head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Forty-nine adults with HNSCC were identified who had curative intent intensity-modulated radiation therapy (IMRT) and FDG-PET imaging before and after treatment. Using a graphical user interface, contours were delineated for the parotid glands on axial CT slices while all authors were blinded to paired PET slices. Average and maximal standard uptake values (SUV) were measured within these anatomic regions. Changes in SUV and volume after radiation therapy were correlated with parotid gland dose-volume histograms from IMRT plans. RESULTS: The average parotid gland volume was 30.7 mL and contracted 3.9 ± 1.9% with every increase of 10 Gy in mean dose (p = 0.04). However, within the first 3 months after treatment, there was a uniform reduction of 16.5% ± 7.3% regardless of dose. The average SUV(mean) of the glands was 1.63 ± 0.48 pretreatment and declined by 5.2% ± 2.5% for every increase of 10 Gy in mean dose (p = 0.04). The average SUV(max) was 4.07 ± 2.85 pretreatment and decreased in a sigmoid manner with mean dose. A threshold of 32 Gy for mean dose existed, after which SUV(max) declined rapidly. CONCLUSION: Radiation dose responses of the parotid glands can be measured by integrated CT/FDG-PET scans. Retrospective analysis showed sigmoidal declines in the maximum metabolism but linear declines in the average metabolism of the glands with dose. Future studies should correlate this decline in FDG uptake with saliva production to improve treatment planning.

Authors
Roach, MC; Turkington, TG; Higgins, KA; Hawk, TC; Hoang, JK; Brizel, DM
MLA Citation
Roach, MC, Turkington, TG, Higgins, KA, Hawk, TC, Hoang, JK, and Brizel, DM. "FDG-PET assessment of the effect of head and neck radiotherapy on parotid gland glucose metabolism." Int J Radiat Oncol Biol Phys 82.1 (January 1, 2012): 321-326.
PMID
21030160
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
82
Issue
1
Publish Date
2012
Start Page
321
End Page
326
DOI
10.1016/j.ijrobp.2010.08.055

Effect of amifostine on survival among patients treated with radiotherapy: a meta-analysis of individual patient data.

PURPOSE: Controversy exists regarding whether or not amifostine might reduce the efficacy of cancer treatment. The aim of this meta-analysis was to evaluate the impact of amifostine on overall survival (OS) and progression-free survival (PFS) in patients treated with radiotherapy or chemoradiotherapy. MATERIAL AND METHODS: Updated data from individual patients with non-small-cell lung cancer, head and neck squamous cell carcinoma, and pelvic cancer treated with radiotherapy or chemoradiotherapy and randomly assigned to amifostine or not were included. The primary end point was OS. RESULTS: Twenty-two randomized trials (2279 patients) were potentially eligible. Data were available for 16 trials (1554 patients), but four trials (435 patients) were excluded after data checking. Ultimately 12 trials and 1119 patients were analyzed. A total of 431 patients were treated with radiotherapy alone (three trials), and 688 patients were treated with chemoradiotherapy (nine trials). Thirty-three percent of patients had lung cancers, 65% had head and neck cancers, and 2% had pelvic carcinomas. Ninety-one percent of patients had locally advanced disease (early stage, 9%). Median follow-up was 5.2 years. The hazard ratio (HR) of death was 0.98 (95% CI, 0.84 to 1.14; P = .78). On the basis of 11 trials (1091 patients), the HR of progression, relapse, or death was 1.05 (95% CI, 0.90 to 1.22; P = .53). The tests for heterogeneity were not significant (P ≥ .73), and there was no significant variation of treatment effect according to sex, age, tumor site, stage, histology, locoregional treatment, or type of administration for either end point. CONCLUSION: Amifostine did not reduce OS and PFS in patients treated with radiotherapy or chemoradiotherapy.

Authors
Bourhis, J; Blanchard, P; Maillard, E; Brizel, DM; Movsas, B; Buentzel, J; Langendijk, JA; Komaki, R; Swan Leong, S; Levendag, P; Pignon, JP
MLA Citation
Bourhis, J, Blanchard, P, Maillard, E, Brizel, DM, Movsas, B, Buentzel, J, Langendijk, JA, Komaki, R, Swan Leong, S, Levendag, P, and Pignon, JP. "Effect of amifostine on survival among patients treated with radiotherapy: a meta-analysis of individual patient data." J Clin Oncol 29.18 (June 20, 2011): 2590-2597.
PMID
21576630
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
18
Publish Date
2011
Start Page
2590
End Page
2597
DOI
10.1200/JCO.2010.33.1454

Head and neck cancers.

Authors
Pfister, DG; Ang, K-K; Brizel, DM; Burtness, BA; Cmelak, AJ; Colevas, AD; Dunphy, F; Eisele, DW; Gilbert, J; Gillison, ML; Haddad, RI; Haughey, BH; Hicks, WL; Hitchcock, YJ; Kies, MS; Lydiatt, WM; Maghami, E; Martins, R; McCaffrey, T; Mittal, BB; Pinto, HA; Ridge, JA; Samant, S; Sanguineti, G; Schuller, DE; Shah, JP; Spencer, S; Trotti, A; Weber, RS; Wolf, GT; Worden, F; National Comprehensive Concer Network,
MLA Citation
Pfister, DG, Ang, K-K, Brizel, DM, Burtness, BA, Cmelak, AJ, Colevas, AD, Dunphy, F, Eisele, DW, Gilbert, J, Gillison, ML, Haddad, RI, Haughey, BH, Hicks, WL, Hitchcock, YJ, Kies, MS, Lydiatt, WM, Maghami, E, Martins, R, McCaffrey, T, Mittal, BB, Pinto, HA, Ridge, JA, Samant, S, Sanguineti, G, Schuller, DE, Shah, JP, Spencer, S, Trotti, A, Weber, RS, Wolf, GT, Worden, F, and National Comprehensive Concer Network, . "Head and neck cancers." J Natl Compr Canc Netw 9.6 (June 1, 2011): 596-650. (Review)
PMID
21636536
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
6
Publish Date
2011
Start Page
596
End Page
650

Controversies in the locoregional management of head and neck cancer.

Head and neck cancer (HNC) is a heterogeneous combination of various sites and types of disease. This manuscript elaborates on 3 important and current issues: the emerging role of human papilloma virus (HPV) in oropharyngeal cancer (OPC), current considerations in systemic therapy for advanced disease, and evolving treatment of the neck. Exogenous carcinogens, most notably tobacco, have classically been implicated in the development of HNC. A large increase in the incidence of OPC has occurred in the past few decades, predominantly in nontobacco users, and is caused by HPV. This disease is unique in many respects and presents an opportunity for novel therapeutic approaches. Because the prognosis for HPV-related HNC is better, regardless of whether surgery or radiation is used as the primary therapy, the reduction of treatment-related morbidity has assumed increasing importance and provides unique opportunities and challenges for de-escalation of therapies. Radiotherapy (RT) and concurrent cisplatin is the most commonly used nonsurgical platform for locally advanced disease. New data suggest that viable alternatives exist to the typical 3 cycles of bolus high-dose cisplatin. The role of RT and concurrent taxanes remains less understood. Similarly, the value of integrating epidermal growth factor inhibition and concurrent chemoradiation is under continuing investigation. The use of PET scanning is changing the traditional use of adjuvant neck dissection after RT or chemoradiation. Recent data support the use of surgery in the presence of a positive posttreatment PET, and observation in the setting of a negative posttreatment scan.

Authors
Brizel, DM; Lydiatt, W; Colevas, AD
MLA Citation
Brizel, DM, Lydiatt, W, and Colevas, AD. "Controversies in the locoregional management of head and neck cancer." J Natl Compr Canc Netw 9.6 (June 1, 2011): 653-662. (Review)
PMID
21636537
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
6
Publish Date
2011
Start Page
653
End Page
662

Head and neck cancer as a model for advances in imaging prognosis, early assessment, and posttherapy evaluation.

Novel noninvasive functional imaging methods are necessary to predict therapeutic outcome and thereby improve the ability to properly select patients for treatment with both conventional and targeted therapies, to better evaluate therapeutic effectiveness during the early phases of treatment, and to enhance a priori risk assessment for treatment induced toxicity. Functional metabolic imaging typically involves pretreatment baseline magnetic resonance imaging (MRI) and/or positron emission tomographic (PET) scans and performance of subsequent scans during and/or after treatment. Imaging parameter changes are routinely attributed to the intervening therapy and clinical outcomes subsequently correlated with these changes. The physiologic parameter(s) that best correlate with clinical outcome and the relative utility of MRI versus PET are unknown, however. Furthermore, tumor vascular physiology and metabolic parameters are heterogeneous and dynamic processes. Large daily fluctuations often occur in the absence of treatment. The magnitude of this temporal variability is not established for MRI or for PET. Routine and meaningful clinical application of functional imaging requires understanding and quantification of the intrinsic variability of the underlying biologic processes and a demonstration that treatment-induced changes exceed intrinsic temporal variation.

Authors
Brizel, DM
MLA Citation
Brizel, DM. "Head and neck cancer as a model for advances in imaging prognosis, early assessment, and posttherapy evaluation." Cancer J 17.3 (May 2011): 159-165. (Review)
PMID
21610469
Source
pubmed
Published In
Cancer Journal
Volume
17
Issue
3
Publish Date
2011
Start Page
159
End Page
165
DOI
10.1097/PPO.0b013e31821e8a09

Head and neck cancers: Clinical practice guidelines in oncology

Authors
Pfister, DG; Ang, K-K; Brizel, DM; Burtness, BA; Cmelak, AJ; Colevas, AD; Dunphy, F; Eisele, DW; Gilbert, J; Gillison, ML; Haddad, RI; Haughey, BH; Jr, WLH; Hitchcock, YJ; Kies, MS; Lydiatt, WM; Maghami, E; Martins, R; McCaffrey, T; Mittal, BB; Pinto, HA; Ridge, JA; Samant, S; Sanguineti, G; Schuller, DE; Shah, JP; Spencer, S; III, AT; Weber, RS; Wolf, GT; Worden, F
MLA Citation
Pfister, DG, Ang, K-K, Brizel, DM, Burtness, BA, Cmelak, AJ, Colevas, AD, Dunphy, F, Eisele, DW, Gilbert, J, Gillison, ML, Haddad, RI, Haughey, BH, Jr, WLH, Hitchcock, YJ, Kies, MS, Lydiatt, WM, Maghami, E, Martins, R, McCaffrey, T, Mittal, BB, Pinto, HA, Ridge, JA, Samant, S, Sanguineti, G, Schuller, DE, Shah, JP, Spencer, S, III, AT, Weber, RS, Wolf, GT, and Worden, F. "Head and neck cancers: Clinical practice guidelines in oncology." JNCCN Journal of the National Comprehensive Cancer Network 9.6 (2011): 596-650.
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
6
Publish Date
2011
Start Page
596
End Page
650

The role of adaptive and functional imaging modalities in radiation therapy: approach and application from a radiation oncology perspective.

The field of radiation oncology relies heavily on imaging modalities. From initial consultation to treatment completion, images are used to guide nearly every step of the patient encounter. Technological advances in diagnostic radiology continue to be readily incorporated into clinical practice, with adaptive and functional studies able to extract and display ever more physical and novel biological data about patients and their tumors. At the same time, no imaging technique can address all the uncertainties inherent in cancer therapy. The application, interpretation, and limitations of various imaging modalities are discussed from a radiation oncology perspective.

Authors
Yoo, DS; Wong, TZ; Brizel, DM
MLA Citation
Yoo, DS, Wong, TZ, and Brizel, DM. "The role of adaptive and functional imaging modalities in radiation therapy: approach and application from a radiation oncology perspective." Semin Ultrasound CT MR 31.6 (December 2010): 444-461. (Review)
PMID
21147372
Source
pubmed
Published In
Seminars in Ultrasound, CT and MRI
Volume
31
Issue
6
Publish Date
2010
Start Page
444
End Page
461
DOI
10.1053/j.sult.2010.10.002

Dynamic contrast enhanced-MRI in head and neck cancer patients: variability of the precontrast longitudinal relaxation time (T10).

PURPOSE: Calculation of the precontrast longitudinal relaxation times (T10) is an integral part of the Tofts-based pharmacokinetic (PK) analysis of dynamic contrast enhanced-magnetic resonance images. The purpose of this study was to investigate the interpatient and over time variability of T10 in head and neck primary tumors and involved nodes and to determine the median T10 for primary and nodes (T10(p,n)). The authors also looked at the implication of using voxel-based T10 values versus region of interest (ROI)-based T10 on the calculated values for vascular permeability (K(trans)) and extracellular volume fraction (v(e)). METHODS: Twenty head and neck cancer patients receiving concurrent chemoradiation and molecularly targeted agents on a prospective trial comprised the study population. Voxel-based T10's were generated using a gradient echo sequence on a 1.5 T MR scanner using the variable flip angle method with two flip angles [J. A. Brookes et al., "Measurement of spin-lattice relaxation times with FLASH for dynamic MRI of the breast," Br. J. Radiol. 69, 206-214 (1996)]. The voxel-based T10, K(trans), and v(e) were calculated using iCAD's (Nashua, NH) software. The mean T10's in muscle and fat ROIs were calculated (T10(m,f)). To assess reliability of ROI drawing, T10(p,n) values from ROIs delineated by 2 users (A and B) were calculated as the average of the T10's for 14 patients. For a subset of three patients, the T10 variability from baseline to end of treatment was also investigated. The K(trans) and v(e) from primary and node ROIs were calculated using voxel-based T10 values and T10(p,n) and differences reported. RESULTS: The calculated T10 values for fat and muscle are within the range of values reported in literature for 1.5 T, i.e., T10(m) = 0.958 s and T10(f) = 0.303 s. The average over 14 patients of the T10's based on drawings by users A and B were T10(pA) = 0.804 s, T10(nA) = 0.760 s, T10(pB) = 0.849 s, and T10(nB) = 0.810 s. The absolute percentage difference between K(trans) and v(e) calculated with voxel-based T10 versus T10(p,n) ranged from 6% to 81% and from 2% to 24%, respectively. CONCLUSIONS: There is a certain amount of variability in the median T10 values between patients, but the differences are not significant. There were also no statistically significant differences between the T10 values for primary and nodes at baseline and the subsequent time points (p = 0.94 Friedman test). Voxel-based T10 calculations are essential when quantitative Tofts-based PK analysis in heterogeneous tumors is needed. In the absence of T10 mapping capability, when a relative, qualitative analysis is deemed sufficient, a value of T10(p,n) = 0.800 s can be used as an estimate for T10 for both the primary tumor and the affected nodes in head and neck cancers at all the time points considered.

Authors
Craciunescu, O; Brizel, D; Cleland, E; Yoo, D; Muradyan, N; Carroll, M; Barboriak, D; MacFall, J
MLA Citation
Craciunescu, O, Brizel, D, Cleland, E, Yoo, D, Muradyan, N, Carroll, M, Barboriak, D, and MacFall, J. "Dynamic contrast enhanced-MRI in head and neck cancer patients: variability of the precontrast longitudinal relaxation time (T10)." Med Phys 37.6 (June 2010): 2683-2692.
PMID
20632579
Source
pubmed
Published In
Medical physics
Volume
37
Issue
6
Publish Date
2010
Start Page
2683
End Page
2692
DOI
10.1118/1.3427487

Clinical practice guidance for radiotherapy planning after induction chemotherapy in locoregionally advanced head-and-neck cancer.

PURPOSE: The use of induction chemotherapy (IC) for locoregionally advanced head-and-neck cancer is increasing. The response to IC often causes significant alterations in tumor volume and location and shifts in normal anatomy. Proper determination of the radiotherapy (RT) targets after IC becomes challenging, especially with the use of conformal and precision RT techniques. Therefore, a consensus conference was convened to discuss issues related to RT planning and coordination of care for patients receiving IC. METHODS AND MATERIALS: Ten participants with special expertise in the various aspects of integration of IC and RT for the treatment of locoregionally advanced head-and-neck cancer, including radiation oncologists, medical oncologists, and a medical physicist, participated. The individual members were assigned topics for focused, didactic presentations. Discussion was encouraged after each presentation, and recommendations were formulated. RESULTS: Recommendations and guidelines emerged that emphasize up-front evaluation by all members of the head-and-neck management team, high-quality baseline and postinduction planning scans with the patient in the treatment position, the use of preinduction target volumes, and the use of full-dose RT, even in the face of a complete response. CONCLUSION: A multidisciplinary approach is strongly encouraged. Although these recommendations were provided primarily for patients treated with IC, many of these same principles apply to concurrent chemoradiotherapy without IC. A rapid response during RT is quite common, requiring the development of two or more plans in a sizeable fraction of patients, and suggesting the need for similar guidance in the rapidly evolving area of adaptive RT.

Authors
Salama, JK; Haddad, RI; Kies, MS; Busse, PM; Dong, L; Brizel, DM; Eisbruch, A; Tishler, RB; Trotti, AM; Garden, AS
MLA Citation
Salama, JK, Haddad, RI, Kies, MS, Busse, PM, Dong, L, Brizel, DM, Eisbruch, A, Tishler, RB, Trotti, AM, and Garden, AS. "Clinical practice guidance for radiotherapy planning after induction chemotherapy in locoregionally advanced head-and-neck cancer." Int J Radiat Oncol Biol Phys 75.3 (November 1, 2009): 725-733.
PMID
19362781
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
75
Issue
3
Publish Date
2009
Start Page
725
End Page
733
DOI
10.1016/j.ijrobp.2008.11.059

Mucositis-related morbidity and resource utilization in head and neck cancer patients receiving radiation therapy with or without chemotherapy.

The objective of this study was to estimate health care-resource utilization in head and neck cancer (HNC) patients. This was a prospective, longitudinal, multicenter, noninterventional study of mucositis in patients receiving radiation with or without chemotherapy for HNC. Mouth and throat soreness and functional impairment were measured using the Oral Mucositis Weekly Questionnaire-HNC. Resource utilization data were obtained from patient interviews and recorded from the patient's medical chart. Seventy-five patients were enrolled from six centers. Fifty (67%) patients received concurrent chemoradiation therapy; 34 (45%) received intensity-modulated radiation therapy. Over the course of treatment, 57 (76%) patients reported severe mouth and throat soreness. Pain and functional impairment because of mouth and throat soreness increased during the course of therapy despite the use of opioid analgesics in 64 (85%) of the patients. Complications of radiation therapy resulted in increased patient visits to physicians, nurses, and nutritionists. Thirty-eight (51%) patients had a feeding tube placed. Twenty-eight patients (37%) were hospitalized, five of whom were hospitalized twice; of the 33 admissions, 10 (30%) were designated as secondary to mucositis by their treating physician. Mean length of hospitalization was 4.9 days (range: 1-16). This study demonstrates that mucositis-related pain and functional impairment is associated with increased use of costly health resources. Effective treatments to reduce the pain and functional impairment of oral mucositis are needed in this patient population.

Authors
Murphy, BA; Beaumont, JL; Isitt, J; Garden, AS; Gwede, CK; Trotti, AM; Meredith, RF; Epstein, JB; Le, Q-T; Brizel, DM; Bellm, LA; Wells, N; Cella, D
MLA Citation
Murphy, BA, Beaumont, JL, Isitt, J, Garden, AS, Gwede, CK, Trotti, AM, Meredith, RF, Epstein, JB, Le, Q-T, Brizel, DM, Bellm, LA, Wells, N, and Cella, D. "Mucositis-related morbidity and resource utilization in head and neck cancer patients receiving radiation therapy with or without chemotherapy." J Pain Symptom Manage 38.4 (October 2009): 522-532.
PMID
19608377
Source
pubmed
Published In
Journal of Pain and Symptom Management
Volume
38
Issue
4
Publish Date
2009
Start Page
522
End Page
532
DOI
10.1016/j.jpainsymman.2008.12.004

Paraganglioma of the head and neck: long-term local control with radiotherapy.

OBJECTIVES: Paragangliomas are rare neuroendocrine neoplasms of the head and neck. Treatment strategies include resection, definitive external beam radiation therapy (EBRT), stereotactic radiosurgery (SRS), or observation alone. Due to their rarity and indolent clinical behavior, the optimal management for long-term control is unknown. METHODS: This Institutional Review Board-approved retrospective study identified all paragangliomas of the head and neck treated with definitive fractionated radiotherapy at Duke University Medical Center from 1963 to 2005 with minimum 2-year follow-up. Local control (LC) was calculated using the Kaplan-Meier method. RESULTS: Thirty-one patients were identified and treated with EBRT (median dose: 54 Gy, range: 38-65 Gy). Twelve patients were treated with megavoltage photon; 19 were treated with either cobalt-60 or cesium-137. Fourteen (45%) had undergone resection preceding radiation. Median follow-up was 9 years (range: 2-35 years), with 10 patients having greater than 15-year follow-up. LC at 5, 10, and 15 years was 96%, 90%, and 90%, respectively. There were no failures in the group treated with megavoltage photons, although this was not statistically significant (P = 0.28). There was no difference in LC between salvage radiation therapy (RT) used after surgical failure and definitive RT alone (10-year LC, 73% vs. 100%, respectively, P = 0.31). The incidence of acute toxicity greater than grade 2 was 3%, and there were no late toxicities greater than grade 2. CONCLUSIONS: RT is an effective and well-tolerated treatment for paragangliomas of the head and neck.

Authors
Chino, JP; Sampson, JH; Tucci, DL; Brizel, DM; Kirkpatrick, JP
MLA Citation
Chino, JP, Sampson, JH, Tucci, DL, Brizel, DM, and Kirkpatrick, JP. "Paraganglioma of the head and neck: long-term local control with radiotherapy." Am J Clin Oncol 32.3 (June 2009): 304-307.
PMID
19433962
Source
pubmed
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
32
Issue
3
Publish Date
2009
Start Page
304
End Page
307
DOI
10.1097/COC.0b013e318187dd94

Targeting the future in head and neck cancer.

Authors
Brizel, DM
MLA Citation
Brizel, DM. "Targeting the future in head and neck cancer." Lancet Oncol 10.3 (March 2009): 204-205. (Letter)
PMID
19261251
Source
pubmed
Published In
The Lancet Oncology
Volume
10
Issue
3
Publish Date
2009
Start Page
204
End Page
205
DOI
10.1016/S1470-2045(09)70051-8

Head and neck cancer. Introduction.

Authors
Brizel, DM
MLA Citation
Brizel, DM. "Head and neck cancer. Introduction." Semin Radiat Oncol 19.1 (January 2009): 1-2.
PMID
19028338
Source
pubmed
Published In
Seminars in Radiation Oncology
Volume
19
Issue
1
Publish Date
2009
Start Page
1
End Page
2
DOI
10.1016/j.semradonc.2008.09.001

Induction chemotherapy: to use or not to use? That is the question.

The intensification of radiation, induction chemotherapy, and concomitant chemoradiotherapy has been extensively investigated over the past 2 decades for the nonsurgical management of locally advanced, nonmetastatic squamous cell head and neck cancer (HNC). Concurrent chemoradiation has emerged as the standard of care, with the majority of its benefit resulting from improvements in locoregional disease control. Distant failure has become a more prominent problem in conjunction with these improvements. Concurrent chemotherapy provides suboptimal adjuvant treatment for distant disease. Multiagent induction chemotherapy holds more promise especially with the use of taxane-based regimens. Induction chemotherapy followed by concurrent chemoradiation (sequential chemoradiation) is now under investigation. The rationale and evidence supporting the choice to use or not to use a sequential program are discussed.

Authors
Brizel, DM; Vokes, EE
MLA Citation
Brizel, DM, and Vokes, EE. "Induction chemotherapy: to use or not to use? That is the question." Semin Radiat Oncol 19.1 (January 2009): 11-16. (Review)
PMID
19028340
Source
pubmed
Published In
Seminars in Radiation Oncology
Volume
19
Issue
1
Publish Date
2009
Start Page
11
End Page
16
DOI
10.1016/j.semradonc.2008.09.003

Introduction

Authors
Brizel, DM
MLA Citation
Brizel, DM. "Introduction." Seminars in Radiation Oncology 19.1 (2009): 1-2.
Source
scival
Published In
Seminars in Radiation Oncology
Volume
19
Issue
1
Publish Date
2009
Start Page
1
End Page
2
DOI
10.1016/j.semradonc.2008.09.001

Phase II study of palifermin and concurrent chemoradiation in head and neck squamous cell carcinoma.

PURPOSE: Acute mucositis is a dose-limiting toxicity of concurrent chemoradiotherapy regimens for locally advanced head and neck cancer. Palifermin (a recombinant human keratinocyte growth factor; DeltaN23-KGF) stimulates the proliferation and differentiation of mucosal epithelium to reduce mucositis in patients receiving intensive therapy for hematologic cancers. This study assessed the efficacy and safety of palifermin in patients receiving concurrent chemoradiotherapy for advanced head and neck squamous cell carcinoma. PATIENTS AND METHODS: In a phase II trial, standard radiotherapy was delivered in daily 2-Gy fractions to 70 Gy, or hyperfractionated radiotherapy was delivered in 1.25-Gy fractions twice daily to 72 Gy, over 7 weeks. Chemotherapy included cisplatin 20 mg/m(2) for 4 days and continuous-infusion fluorouracil 1,000 mg/m(2)/d for 4 days on weeks 1 and 5 of irradiation. Patients were randomly assigned 2:1 to palifermin 60 microg/kg or placebo once weekly for 10 doses. A follow-up trial evaluated long-term survival. RESULTS: Sixty-seven patients received palifermin and 32 received placebo. The median duration of grade >or= 2 mucositis was 6.5 and 8.1 weeks in the palifermin and placebo groups, respectively (P = .157). Palifermin appeared to reduce mucositis, dysphagia, and xerostomia during hyperfractionated radiotherapy (n = 40) but not standard radiation therapy (n = 59). Adverse events were similar between treatment groups. Palifermin did not alter tumor response or survival. CONCLUSION: Ten once-weekly doses of palifermin at 60 microg/kg were well tolerated. Most patients completed treatment, but palifermin did not reduce the morbidity of concurrent chemotherapy and radiotherapy. Future studies should evaluate higher palifermin doses with longer and more standardized assessment of acute mucositis.

Authors
Brizel, DM; Murphy, BA; Rosenthal, DI; Pandya, KJ; Glück, S; Brizel, HE; Meredith, RF; Berger, D; Chen, M-G; Mendenhall, W
MLA Citation
Brizel, DM, Murphy, BA, Rosenthal, DI, Pandya, KJ, Glück, S, Brizel, HE, Meredith, RF, Berger, D, Chen, M-G, and Mendenhall, W. "Phase II study of palifermin and concurrent chemoradiation in head and neck squamous cell carcinoma." J Clin Oncol 26.15 (May 20, 2008): 2489-2496.
PMID
18487568
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008
Start Page
2489
End Page
2496
DOI
10.1200/JCO.2007.13.7349

Preoperative radiotherapy and bevacizumab for angiosarcoma of the head and neck: two case studies.

BACKGROUND: Angiosarcoma of the face is a vascular tumor with poor local control and short median survival despite standard treatment. Bevacizumab is a humanized monoclonal antibody to vascular endothelial growth factor (VEGF), which can inhibit tumor growth. It is synergistic with radiotherapy in gastrointestinal malignancies. Given the vascular nature of angiosarcoma and the need for better treatment of this disease, we investigated the concurrent use of bevacizumab with preoperative radiotherapy for head and neck angiosarcoma. METHODS: Two patients diagnosed with angiosarcoma of the nose were treated preoperatively with bevacizumab (5-10 mg/kg) and concurrent radiotherapy (50 Gy), followed by resection of the tumor bed. RESULTS: Both patients had a complete pathologic response with no residual disease. Neither has developed recurrence, with follow-up of 8.5 months and 2.1 years. CONCLUSIONS: The neoadjuvant combination of bevacizumab and radiation therapy is promising and should be further studied in the setting of vascular malignancies.

Authors
Koontz, BF; Miles, EF; Rubio, MAD; Madden, JF; Fisher, SR; Scher, RL; Brizel, DM
MLA Citation
Koontz, BF, Miles, EF, Rubio, MAD, Madden, JF, Fisher, SR, Scher, RL, and Brizel, DM. "Preoperative radiotherapy and bevacizumab for angiosarcoma of the head and neck: two case studies." Head Neck 30.2 (February 2008): 262-266.
PMID
17685450
Source
pubmed
Published In
Head & Neck: Journal for the Sciences & Specialties of the Head and Neck
Volume
30
Issue
2
Publish Date
2008
Start Page
262
End Page
266
DOI
10.1002/hed.20674

Head and neck cancers

Authors
Forastiere, AA; Ang, K-K; Brizel, D; Brockstein, BE; Burtness, BA; Cmelak, AJ; Colevas, AD; Dunphy, F; Eisele, DW; Goepfert, H; Jr, WLH; Kies, MS; Lydiatt, WM; Maghami, E; Martins, R; McCaffrey, T; Mittal, BB; Pfister, DG; Pinto, HA; Posner, MR; Ridge, JA; Samant, S; Schuller, DE; Shah, JP; Spencer, S; III, AT; Weber, RS; Wolf, GT; Worden, F
MLA Citation
Forastiere, AA, Ang, K-K, Brizel, D, Brockstein, BE, Burtness, BA, Cmelak, AJ, Colevas, AD, Dunphy, F, Eisele, DW, Goepfert, H, Jr, WLH, Kies, MS, Lydiatt, WM, Maghami, E, Martins, R, McCaffrey, T, Mittal, BB, Pfister, DG, Pinto, HA, Posner, MR, Ridge, JA, Samant, S, Schuller, DE, Shah, JP, Spencer, S, III, AT, Weber, RS, Wolf, GT, and Worden, F. "Head and neck cancers." JNCCN Journal of the National Comprehensive Cancer Network 6.7 (2008): 646-695.
PMID
18691457
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
6
Issue
7
Publish Date
2008
Start Page
646
End Page
695

NCCN task force report: Prevention and management of mucositis in cancer care

Oral mucositis (OM) has emerged as a common cause of dose delays and interruptions of cancer therapies such as multicycle chemotherapy, myeloablative chemotherapy, and radiotherapy with or without concurrent chemotherapy of head and neck cancer. Research into both preventive and management strategies has lagged behind research into the common cancer treatment-related morbidities of nausea, vomiting, and cytopenias. This disparity is related to the complex risk assessment of multifactorial patient and treatment factors and different techniques of rating mucositis. In addition, relatively few clinical trials have focused on mucositis as a specific outcome. Currently, the only effective preventive strategies include the use of palifermin to prevent OM in the setting of hematopoietic stem cell transplantation and oral cryotherapy used in conjunction with bolus 5-FU, melphalan, or edatrexate. For the most part, managing OM relies on supportive care and symptom palliation. However, OM is a common problem associated with significant patient morbidity and increased resource use. The magnitude of the problem demands innovative approaches based on expert judgment as evidence accumulates to support specific recommendations. To improve this situation, the NCCN convened a multidisciplinary task force to address key issues. This report integrates expert judgment with a review of key literature on risk assessment, prevention, and treatment strategies, and provides recommendations for the overall management of OM. © Journal of the National Comprehensive Cancer Network.

Authors
Bensinger, W; Schubert, M; Ang, K-K; Brizel, D; Brown, E; Eilers, JG; Elting, L; Mittal, BB; Schattner, MA; Spielberger, R; Treister, NS; III, AMT
MLA Citation
Bensinger, W, Schubert, M, Ang, K-K, Brizel, D, Brown, E, Eilers, JG, Elting, L, Mittal, BB, Schattner, MA, Spielberger, R, Treister, NS, and III, AMT. "NCCN task force report: Prevention and management of mucositis in cancer care." JNCCN Journal of the National Comprehensive Cancer Network 6.SUPPL. 1 (2008): S1-S21.
PMID
18289497
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
6
Issue
SUPPL. 1
Publish Date
2008
Start Page
S1
End Page
S21

Radioprotective effects of amifostine on acute and chronic esophageal injury in rodents.

PURPOSE: This study was performed to evaluate the protective benefit of amifostine against esophageal injury from fractionated radiation in a rodent model. METHODS: Fractionated or sham esophageal irradiation was administered to Fisher-344 rats for 5 consecutive daily fractions of 9 Gy using 150 kV X-rays. Animals received an intraperitoneal injection of amifostine or placebo 30 min before each fraction. Histopathologic analyses for mucosal thickness, submucosal collagen deposition, activation of macrophages, oxidative stress and expression/activation of integrinalphavbeta6 and transforming growth factor (TGF)-beta were performed 5 days and 10 weeks after irradiation. RESULTS: Pre-RT mean mucosal thickness was 35 microm in both the placebo and the amifostine groups. Five days post-RT, mean mucosal thicknesses were 30 microm in the placebo group versus 37 microm in the amifostine group (p = 0.024). At 10 weeks post-RT, the group receiving amifostine experienced a significant decrease in tunica muscularis damage (p = 0.002), submucosal collagen deposition (p = 0.027), and macrophage accumulation (p = 0.026) when compared with the placebo group. The levels of immunoreactivity for oxidative stress, TGF-beta, and integrinalphavbeta6 were significantly decreased 10 weeks post-RT in the group receiving amifostine treatment compared with placebo group. CONCLUSIONS: This study demonstrates that amifostine given before each radiation fraction protects against acute and chronic esophageal injury in a rodent model. Protection of the mucosal epithelium integrity by amifostine prevents integrinalphavbeta6 expression which reduces TGF-beta activation and subsequent development of chronic esophageal injury in this model. Further investigation is necessary to determine the clinical relevance of these findings.

Authors
Vujaskovic, Z; Thrasher, BA; Jackson, IL; Brizel, MB; Brizel, DM
MLA Citation
Vujaskovic, Z, Thrasher, BA, Jackson, IL, Brizel, MB, and Brizel, DM. "Radioprotective effects of amifostine on acute and chronic esophageal injury in rodents." Int J Radiat Oncol Biol Phys 69.2 (October 1, 2007): 534-540.
PMID
17869666
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
69
Issue
2
Publish Date
2007
Start Page
534
End Page
540
DOI
10.1016/j.ijrobp.2007.05.062

On-board patient positioning for head-and-neck IMRT: comparing digital tomosynthesis to kilovoltage radiography and cone-beam computed tomography.

PURPOSE: High-precision intensity-modulated radiotherapy demands high patient positioning accuracy. On-board digital tomosynthesis (DTS) provides three-dimensional (3D) image guidance for daily positioning with a lower imaging dose, faster acquisition, and more geometric flexibility than 3D cone-beam computed tomography (CBCT). This clinical study evaluated DTS as a daily imaging technique for patient positioning and compared the results with 3D CBCT and two-dimensional (2D) radiography. METHODS AND MATERIALS: Head and neck cancer patients undergoing intensity-modulated radiotherapy were studied. For each session, the patient was positioned using laser marks. On-board imaging data sets, including 2D kilovoltage radiographs, DTS, and CBCT, were obtained to measure the daily patient positioning variations. The mean and standard deviations of the positioning variations in the translational and rotational directions were calculated. The positioning differences among 2D radiography, DTS, and CBCT were analyzed. RESULTS: Image data sets were collected from 65 treatment fractions for 10 patients. The systematic patient positioning variation was <0.10 cm and 1.0 degrees one dimensionally. The random variations were 0.27-0.34 cm in the translational and 0.93 degrees -1.99 degrees in the rotational direction. The mean vector isocenter variation was 0.48 cm. DTS with 40 degrees and 20 degrees scan angles in the coronal or sagittal directions yielded the same results for patient positioning. DTS performance was comparable to that of CBCT, with positioning differences of <0.1 cm and 0.5 degrees . The positioning difference between 2D radiography and DTS was approximately 0.1 cm and 0.2 cm in the vertical/longitudinal and lateral directions. CONCLUSION: Our results have demonstrated that DTS is a comparable 3D imaging technique to CBCT for daily patient positioning of head-and-neck patients as determined by manual registration of bony anatomy.

Authors
Wu, QJ; Godfrey, DJ; Wang, Z; Zhang, J; Zhou, S; Yoo, S; Brizel, DM; Yin, F-F
MLA Citation
Wu, QJ, Godfrey, DJ, Wang, Z, Zhang, J, Zhou, S, Yoo, S, Brizel, DM, and Yin, F-F. "On-board patient positioning for head-and-neck IMRT: comparing digital tomosynthesis to kilovoltage radiography and cone-beam computed tomography." Int J Radiat Oncol Biol Phys 69.2 (October 1, 2007): 598-606.
PMID
17869673
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
69
Issue
2
Publish Date
2007
Start Page
598
End Page
606
DOI
10.1016/j.ijrobp.2007.05.045

Pharmacologic approaches to radiation protection.

The concept of the therapeutic ratio (TR) is central to understanding the rationale for using radioprotectors. The TR relates tumor control probabilities and normal tissue complication probabilities to one another. An ideal radioprotector will reduce the latter without compromising the former. It should also be minimally toxic itself. Radioprotective strategies can be classified under the categories of protection, mitigation, and treatment. Protectors are administered before radiotherapy (RT) and are designed to prevent radiation-induced injury. Amifostine is the prototype drug. Mitigants are administered after RT but before the phenotypic expression of injury and are intended to ameliorate injury. Palifermin can be considered as the prototype mitigant. Treatment is a strategy that is predominantly palliative and supportive in nature. Pharmacologic radioprotective strategies should be integrated with physical strategies such as intensity-modulated radiotherapy to realize their maximum clinical potential.

Authors
Brizel, DM
MLA Citation
Brizel, DM. "Pharmacologic approaches to radiation protection." J Clin Oncol 25.26 (September 10, 2007): 4084-4089. (Review)
PMID
17827457
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
26
Publish Date
2007
Start Page
4084
End Page
4089
DOI
10.1200/JCO.2007.11.5816

How much radiation is the chemotherapy worth in advanced head and neck cancer?

PURPOSE: To estimate the radiotherapeutic dose equivalence of chemoradiotherapy in head and neck cancer. METHODS: The biologic equivalent dose (BED) of radiotherapy in nine trials of standard and five trials of modified fractionated radiotherapy with or without chemotherapy was calculated using the linear-quadratic formulation. Data from Radiation Therapy Oncology Group (RTOG) study 90-03 were used to calculate the relationship (S) between increase in locoregional control (LRC) and increase in BED with modified vs. standard fractionated radiotherapy. The increase in LRC with chemoradiotherapy vs. radiotherapy alone, the BED of the radiotherapy-alone arms, and the "S" value were used to calculate the BED contribution from chemotherapy and the total BED of chemoradiotherapy from each study. RESULTS: From RTOG 90-03, a 1% increase in BED yields a 1.1% increase in LRC. The mean BED of standard fractioned radiotherapy was 60.2 Gy(10) and 66 Gy(10) for modified fractionation. The mean BED of standard fractionated chemoradiotherapy was 71 Gy(10) (10.8 Gy(10) contributed by chemotherapy). The mean BED of modified fractionated chemoradiotherapy was 76 Gy(10) (10.4 Gy(10) contributed by chemotherapy). CONCLUSIONS: Chemotherapy increases BED by approximately 10 Gy(10) in standard and modified fractionated radiotherapy, equivalent to a dose escalation of 12 Gy in 2 Gy daily or 1.2 Gy twice daily. Such an escalation could not be safely achieved by increasing radiation dose alone.

Authors
Kasibhatla, M; Kirkpatrick, JP; Brizel, DM
MLA Citation
Kasibhatla, M, Kirkpatrick, JP, and Brizel, DM. "How much radiation is the chemotherapy worth in advanced head and neck cancer?." Int J Radiat Oncol Biol Phys 68.5 (August 1, 2007): 1491-1495.
PMID
17674979
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
68
Issue
5
Publish Date
2007
Start Page
1491
End Page
1495
DOI
10.1016/j.ijrobp.2007.03.025

The potential role of intrinsic hypoxia markers as prognostic variables in cancer.

Tumor hypoxia is related to tumor progression and therapy resistance, which leads to poor patient outcome. It has been suggested that measuring the hypoxic status of a tumor helps to predict patient outcome and to select more targeted treatment. However, current methods using needle electrodes or exogenous markers have limitations due to their invasiveness or necessity for preinjection. Recent studies showed that hypoxia-regulated genes could be alternatively used as endogenous hypoxia markers. This is a review of 15 hypoxia-regulated genes, including hypoxia-inducible factor-1 and its targets, and their correlation with tumor hypoxia and patient outcome from 213 studies. Though most of the studies showed significance of these genes in predicting prognosis, there was no definitive prognostic and hypoxia marker. In conclusion, this review suggests the need for further studies with standardized methods to examine gene expression, as well as the use of multiple gene expressions.

Authors
Moon, EJ; Brizel, DM; Chi, J-TA; Dewhirst, MW
MLA Citation
Moon, EJ, Brizel, DM, Chi, J-TA, and Dewhirst, MW. "The potential role of intrinsic hypoxia markers as prognostic variables in cancer." Antioxid Redox Signal 9.8 (August 2007): 1237-1294. (Review)
PMID
17571959
Source
pubmed
Published In
Antioxidants & Redox Signaling
Volume
9
Issue
8
Publish Date
2007
Start Page
1237
End Page
1294
DOI
10.1089/ars.2007.1623

A Phase II trial of subcutaneous amifostine and radiation therapy in patients with head-and-neck cancer.

PURPOSE: Intravenous amifostine 200 mg/m2 reduces xerostomia in head-and-neck cancer patients. This Phase II study evaluated subcutaneous (s.c.) amifostine in a similar patient population. PATIENTS AND METHODS: Patients received amifostine 500 mg, administered as two 250-mg s.c. injections 60 min before once-daily radiation for head-and-neck cancer (50-70 Gy in 5-7 weeks). The primary endpoint was the incidence of > or =Grade 2 acute xerostomia. RESULTS: Fifty-four patients received s.c. amifostine and radiotherapy. The incidence of > or =Grade 2 acute xerostomia was 56% (95% CI, 43-69%) and the incidence of > or =Grade 2 late xerostomia at 1 year was 45% (95% CI, 29-61%). The incidence of acute xerostomia was lower than reported previously with no amifostine in a controlled study; rates of acute xerostomia were similar between s.c. and i.v. amifostine in the two studies. The rate of late xerostomia with s.c. amifostine was intermediate between rates for i.v. amifostine and no amifostine, and not statistically significantly different from either historical control. Grades 1-2 nausea and emesis were the most common amifostine-related adverse events. Grade 3 amifostine-related adverse events reported by >1 patient included: dehydration (11%); rash (6%); and weight decrease, mucositis, dyspnea, and allergic reaction (each 4%). Seven patients (13%) had serious cutaneous adverse events outside the injection site. One-year rates of locoregional control, progression-free survival, and overall survival were 78%, 75%, and 85%, respectively. CONCLUSIONS: Subcutaneous amifostine provides a well-tolerated yet simpler alternative to i.v. amifostine for reducing acute xerostomia in head-and-neck cancer patients.

Authors
Anné, PR; Machtay, M; Rosenthal, DI; Brizel, DM; Morrison, WH; Irwin, DH; Chougule, PB; Estopinal, NC; Berson, A; Curran, WJ
MLA Citation
Anné, PR, Machtay, M, Rosenthal, DI, Brizel, DM, Morrison, WH, Irwin, DH, Chougule, PB, Estopinal, NC, Berson, A, and Curran, WJ. "A Phase II trial of subcutaneous amifostine and radiation therapy in patients with head-and-neck cancer." Int J Radiat Oncol Biol Phys 67.2 (February 1, 2007): 445-452.
PMID
17141978
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
67
Issue
2
Publish Date
2007
Start Page
445
End Page
452
DOI
10.1016/j.ijrobp.2006.08.044

Multiple etiologies of tumor hypoxia require multifaceted solutions.

Authors
Dewhirst, MW; Navia, IC; Brizel, DM; Willett, C; Secomb, TW
MLA Citation
Dewhirst, MW, Navia, IC, Brizel, DM, Willett, C, and Secomb, TW. "Multiple etiologies of tumor hypoxia require multifaceted solutions." Clin Cancer Res 13.2 Pt 1 (January 15, 2007): 375-377.
PMID
17255256
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
375
End Page
377
DOI
10.1158/1078-0432.CCR-06-2629

Concomitant chemoradiotherapy

Authors
Vokes, EE; Brizel, DM; Lawrence, TS
MLA Citation
Vokes, EE, Brizel, DM, and Lawrence, TS. "Concomitant chemoradiotherapy." Journal of Clinical Oncology 25.26 (2007): 4031-4032.
Source
scival
Published In
Journal of Clinical Oncology
Volume
25
Issue
26
Publish Date
2007
Start Page
4031
End Page
4032
DOI
10.1200/JCO.2007.13.8073

Longitudinal evaluation of the oral mucositis weekly questionnaire-head and neck cancer, a patient-reported outcomes questionnaire

BACKGROUND. Quality-of-life instruments that measure specific functional consequences of mucositis are needed to assess the efficacy of therapeutic interventions targeted against mucositis and to guide patient care. The authors undertook a prospective, multicenter, observational study to assess the validity, reliability, and feasibility of a new instrument, the Oral Mucositis Weekly Questionnaire-Head and Neck Cancer (OMWQ-HN). The OMWQ-HN is a patient-reported outcome questionnaire that measures the symptoms of mucositis, including mouth and throat soreness (MTS), and their impact on patient well-being and function. METHODS. The OMWQ-HN, along with the Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN), was administered 5 times over an approximately 6-week period to patients with head and neck cancer (HNC) who were receiving radiation therapy with or without chemotherapy. Information on supportive care measures also was collected. RESULTS. Seventy-five patients were enrolled and completed 93% of scheduled assessments (100% at baseline). The OMWQ-HN demonstrated good test-retest reliability (correlation coefficient, 0.80-0.89). Cross-sectional analyses to assess validity showed that OMWQ-HN scores were different across levels of pain, with those in the worst pain category reporting the highest OMWQ-HN scores. Strong correlations were observed between OMWQ-HN and FACT-HN. Patients experienced increases in MTS, which corresponded with a steady decline in function. MTS scores were highest in the patients who were taking opioid analgesics, suggesting that mucositis pain continued despite standard pain therapy. CONCLUSIONS. The current results indicated that the OMWQ-HN is a valid, reliable, and feasible instrument for assessing the impact of mucositis on patients who are receiving radiation therapy with or without chemotherapy for HNC. © 2007 American Cancer Society.

Authors
Epstein, JB; Beaumont, JL; Gwede, CK; Murphy, B; Garden, AS; Meredith, R; Le, Q-T; Brizel, D; Isitt, J; Cella, D
MLA Citation
Epstein, JB, Beaumont, JL, Gwede, CK, Murphy, B, Garden, AS, Meredith, R, Le, Q-T, Brizel, D, Isitt, J, and Cella, D. "Longitudinal evaluation of the oral mucositis weekly questionnaire-head and neck cancer, a patient-reported outcomes questionnaire." Cancer 109.9 (2007): 1914-1922.
PMID
17377917
Source
scival
Published In
Cancer
Volume
109
Issue
9
Publish Date
2007
Start Page
1914
End Page
1922
DOI
10.1002/cncr.22620

Oral mucositis-related morbidity and resource utilization in a prospective study of head and neck cancer patients

Authors
Isitt, J; Murphy, BA; Beaumont, JL; Garden, AS; Gwede, CK; Trotti, A; Meredith, RF; Epstein, JB; Le, Q; Brizel, QLDM; Bellm, LA; Wells, N; Cella, D
MLA Citation
Isitt, J, Murphy, BA, Beaumont, JL, Garden, AS, Gwede, CK, Trotti, A, Meredith, RF, Epstein, JB, Le, Q, Brizel, QLDM, Bellm, LA, Wells, N, and Cella, D. "Oral mucositis-related morbidity and resource utilization in a prospective study of head and neck cancer patients." Journal of Supportive Oncology 5.4 SUPPL. 2 (2007): 54-55.
Source
scival
Published In
The Journal of Supportive Oncology
Volume
5
Issue
4 SUPPL. 2
Publish Date
2007
Start Page
54
End Page
55

Concurrent chemoradiotherapy for locally advanced, nonmetastatic, squamous carcinoma of the head and neck: consensus, controversy, and conundrum.

Radiotherapy and concurrent chemotherapy (CRT) is superior to radiotherapy alone for the treatment of locally advanced, nonmetastatic squamous carcinoma of the head and neck (HNC). Three issues affect the use of CRT as primary treatment for advanced HNC. The first issue is the definition of advanced stage and the initial therapeutic choice of surgery or CRT and the role of post-CRT neck dissection. Function preservation considerations should guide the choice between surgery and CRT for patients with resectable disease. Fluorodeoxyglucose-positron emission tomography scanning may identify patients who require adjuvant neck dissection. The second issue is optimization of radiotherapy and chemotherapy schedules. Ideally, concurrent chemotherapy should be incorporated into radiotherapy (RT) regimens that would constitute optimal therapy were RT to be administered as single-modality treatment. Modified fractionation schemes constitute optimal single-modality RT. Platinum schedules other than bolus dosing every 3 to 4 weeks are effective and may be less toxic. The third issue is integration of biologically targeted therapy into CRT treatment programs. Epidermal growth factor receptor blockade enhances the effectiveness of RT alone. Its role and that of angiogenic blockade in CRT are under investigation.

Authors
Brizel, DM; Esclamado, R
MLA Citation
Brizel, DM, and Esclamado, R. "Concurrent chemoradiotherapy for locally advanced, nonmetastatic, squamous carcinoma of the head and neck: consensus, controversy, and conundrum." J Clin Oncol 24.17 (June 10, 2006): 2612-2617. (Review)
PMID
16763273
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
17
Publish Date
2006
Start Page
2612
End Page
2617
DOI
10.1200/JCO.2005.05.2829

Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor.

To test the hypothesis that temporal variations in microvessel red cell flux cause unstable oxygen levels in tumor interstitium, extravascular oxygenation of R3230Ac mammary tumors grown in skin-fold window chambers was measured using recessed tip polarographic microelectrodes. Red cell fluxes in microvessels surrounding pO2 measurement locations were measured using fluorescently labeled red cells. Temporal pO2 instability was observed in all experiments. Median pO2 was inversely related to radial distance from microvessels. Transient fluctuations above and below 10 mm Hg were consistently seen, except in one experiment near the oxygen diffusion distance limit (140 microm) where pO2 fluctuations were <2 mm Hg and median pO2 was <5 mm Hg. Vascular stasis was not seen in these experiments. These results show that fluctuations in red cell flux, as opposed to vascular stasis, can cause temporal variations in pO2 that extend from perivascular regions to the maximum oxygen diffusion distance.

Authors
Lanzen, J; Braun, RD; Klitzman, B; Brizel, D; Secomb, TW; Dewhirst, MW
MLA Citation
Lanzen, J, Braun, RD, Klitzman, B, Brizel, D, Secomb, TW, and Dewhirst, MW. "Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor." Cancer Res 66.4 (February 15, 2006): 2219-2223.
PMID
16489024
Source
pubmed
Published In
Cancer Research
Volume
66
Issue
4
Publish Date
2006
Start Page
2219
End Page
2223
DOI
10.1158/0008-5472.CAN-03-2958

The effect of darbepoetin alfa on growth, oxygenation and radioresponsiveness of a breast adenocarcinoma.

Tumor hypoxia is associated with poor clinical outcome in a variety of tumors, including cervical, head/neck and breast cancer. Administration of erythropoietic factors has been suggested as a means of improving tumor oxygenation (pO2). This study randomized rats to treatment with low-dose or high-dose darbepoetin alfa or a placebo to determine the effect of darbepoetin alfa on the pO2, growth and response to radiation therapy of R3230 mammary adenocarcinoma. Rats received 3 microg/kg (high dose) or 0.2 microg/kg (low dose) darbepoetin alfa or placebo for eight doses prior to either (1) pO2 measurement and pimonidazole staining or (2) irradiation or sham irradiation on post-transplant day 20. In the animals randomized to radiation treatment, placebo or darbepoetin alfa administration at a reduced dose was continued for 9 weeks or until the tumor diameter exceeded 15 mm (defined as failure for survival analysis). Treatment with high-dose and low-dose darbepoetin alfa produced hematocrits of 68 and 56% compared to 44 and 45% in their respective control groups (both P < 10(-5)). At 18 days post-transplant, tumor volume was not different for either darbepoetin alfa group compared to the placebo group. Tumor oxygenation, as measured by the fraction of pO2 measurement <10 mmHg and the intensity of pimonidazole staining, was significantly improved in the high-dose group (P = 0.046 and 0.03, respectively, compared with controls) but not in the low-dose group. Growth delay curves after irradiation did not differ significantly for high- or low-dose darbepoetin alfa compared to placebo. In this nonanemic animal model of mammary adenocarcinoma, darbepoetin alfa does not significantly alter tumor growth or radioresponsiveness, even though it improves oxygenation when administered at high doses.

Authors
Kirkpatrick, JP; Hardee, ME; Snyder, SA; Peltz, CM; Zhao, Y; Brizel, DM; Dewhirst, MW; Blackwell, KL
MLA Citation
Kirkpatrick, JP, Hardee, ME, Snyder, SA, Peltz, CM, Zhao, Y, Brizel, DM, Dewhirst, MW, and Blackwell, KL. "The effect of darbepoetin alfa on growth, oxygenation and radioresponsiveness of a breast adenocarcinoma." Radiat Res 165.2 (February 2006): 192-201.
PMID
16518899
Source
pubmed
Published In
Radiation Research
Volume
165
Issue
2
Publish Date
2006
Start Page
192
End Page
201

Influence of intravenous amifostine on xerostomia, tumor control, and survival after radiotherapy for head-and- neck cancer: 2-year follow-up of a prospective, randomized, phase III trial.

PURPOSE: To evaluate chronic xerostomia and tumor control 18 and 24 months after initial treatment with amifostine in a randomized controlled trial of patients with head-and-neck cancer; at 12 months after radiotherapy (RT), amifostine had been shown to reduce xerostomia without changing tumor control. METHODS AND MATERIALS: Adults with head-and-neck cancer who underwent once-daily RT for 5-7 weeks (total dose, 50-70 Gy) received either open-label amifostine (200 mg/m2 i.v.) 15-30 min before each fraction of radiation (n = 150) or RT alone (control; n = 153). RESULTS: Amifostine administration was associated with a reduced incidence of Grade > or =2 xerostomia over 2 years of follow-up (p = 0.002), an increase in the proportion of patients with meaningful (>0.1 g) unstimulated saliva production at 24 months (p = 0.011), and reduced mouth dryness scores on a patient benefit questionnaire at 24 months (p < 0.001). Locoregional control rate, progression-free survival, and overall survival were not significantly different between the amifostine group and the control group. CONCLUSIONS: Amifostine administration during head-and-neck RT reduces the severity and duration of xerostomia 2 years after treatment and does not seem to compromise locoregional control rates, progression-free survival, or overall survival.

Authors
Wasserman, TH; Brizel, DM; Henke, M; Monnier, A; Eschwege, F; Sauer, R; Strnad, V
MLA Citation
Wasserman, TH, Brizel, DM, Henke, M, Monnier, A, Eschwege, F, Sauer, R, and Strnad, V. "Influence of intravenous amifostine on xerostomia, tumor control, and survival after radiotherapy for head-and- neck cancer: 2-year follow-up of a prospective, randomized, phase III trial." Int J Radiat Oncol Biol Phys 63.4 (November 15, 2005): 985-990.
PMID
16253773
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
63
Issue
4
Publish Date
2005
Start Page
985
End Page
990
DOI
10.1016/j.ijrobp.2005.07.966

Recent progress in defining mechanisms and potential targets for prevention of normal tissue injury after radiation therapy.

The ability to optimize treatments for cancer on the basis of relative risks for normal tissue injury has important implications in oncology, because higher doses of radiation might, in some diseases, improve both local control and survival. To achieve this goal, a thorough understanding of the molecular mechanisms responsible for radiation-induced toxicity will be essential. Recent research has demonstrated that ionizing radiation triggers a series of genetic and molecular events, which might lead to chronic persistent alterations in the microenvironment and an aberrant wound-healing response. Disrupted epithelial-stromal cell communication might also be important. With the application of a better understanding of fundamental biology to clinical practice, new approaches to treating and preventing normal tissue injury can focus on correcting these disturbed molecular processes.

Authors
Anscher, MS; Chen, L; Rabbani, Z; Kang, S; Larrier, N; Huang, H; Samulski, TV; Dewhirst, MW; Brizel, DM; Folz, RJ; Vujaskovic, Z
MLA Citation
Anscher, MS, Chen, L, Rabbani, Z, Kang, S, Larrier, N, Huang, H, Samulski, TV, Dewhirst, MW, Brizel, DM, Folz, RJ, and Vujaskovic, Z. "Recent progress in defining mechanisms and potential targets for prevention of normal tissue injury after radiation therapy." Int J Radiat Oncol Biol Phys 62.1 (May 1, 2005): 255-259.
PMID
15850930
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
62
Issue
1
Publish Date
2005
Start Page
255
End Page
259
DOI
10.1016/j.ijrobp.2005.01.040

Pretreatment anemia is correlated with the reduced effectiveness of radiation and concurrent chemotherapy in advanced head and neck cancer.

PURPOSE: Pretreatment anemia is an adverse prognostic variable in squamous cell head-and-neck cancer (HNC) patients treated with radiotherapy (RT) alone. Tumor hypoxia is an adverse parameter for treatment with RT alone or with RT and concurrent chemotherapy (CCT). Tumor hypoxia is more prevalent in patients who present with pretreatment hemoglobin (Hgb) concentrations less than 13 g/dL. RT/CCT improves survival over RT alone in advanced HNC, and its use is becoming more widespread. This study was performed to evaluate whether pretreatment Hgb less than 13 g/dL was correlated with treatment outcome in patients with advanced HNC treated with a uniform regimen of RT/CCT. METHODS AND MATERIALS: The study population consisted of patients with AJCC Stage III or IV, M0 HNC who were treated with 70 to 72.5 Gy accelerated hyperfractionated RT (1.25 Gy b.i.d.) and CCT consisting of 2 cycles of CDDP (12-20 mg/m(2)/d x 5 days) and continuous infusion 5-FU (600 mg/m(2)/d x 5 days) during Week 1 and Week 6. A planned break in RT occurred during Week 4. These patients were enrolled on the experimental arm of a prospective randomized trial that compared this regimen to hyperfractionated irradiation alone from 1990 to 1996. RT/CCT was delivered as standard therapy from 1996 to 2000. The primary endpoint was failure-free survival (FFS). Secondary endpoints included local-regional control and overall survival. RESULTS: One hundred and fifty-nine patients were treated from 1990 to 2000. The median (25-75%) pretreatment Hgb was 13.6 (12.2-13.5) g/dL. Hgb was 13 g/dL or higher in 105 patients and less than 13 g/dL in 54 patients. Primary tumor sites included oropharynx (43%), hypopharynx/larynx (36%), oral cavity (9%), and nasopharynx (6%). Seventy-eight percent of the patients with Hgb 13 g/dL or higher and 92% of the patients with Hgb less than 13 g/dL had a primary tumor stage of T3 or T4 (p = 0.01). Node-positive disease was present in 74 of 105 (70%) of patients with Hgb 13 g/dL or higher patients and in 36/54 (67%) of patients with Hgb less than 13 g/dL patients. Median follow-up of surviving patients was 42 months (range, 4-128 months). Five-year FFS was 75% for patients with Hgb 13 g/dL or higher vs. 50% for patients with Hgb less than 13 g/dL had a (p < 0.01). A total of 49 failures occurred in both patient cohorts. The median (25-75%) decrease in Hgb during RT/CCT was 2.2 (1.3-3.1) g/dL, both in patients who failed and in those who remained disease-free. CONCLUSION: Pretreatment Hgb less than 13 g/dL is correlated with adverse outcomes in advanced HNC patients treated with RT/CCT. Whether anemia actually causes poor outcomes remains unknown. The therapeutic effect of anemia correction is being evaluated in prospective trials.

Authors
Prosnitz, RG; Yao, B; Farrell, CL; Clough, R; Brizel, DM
MLA Citation
Prosnitz, RG, Yao, B, Farrell, CL, Clough, R, and Brizel, DM. "Pretreatment anemia is correlated with the reduced effectiveness of radiation and concurrent chemotherapy in advanced head and neck cancer." Int J Radiat Oncol Biol Phys 61.4 (March 15, 2005): 1087-1095.
PMID
15752888
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
61
Issue
4
Publish Date
2005
Start Page
1087
End Page
1095
DOI
10.1016/j.ijrobp.2004.07.710

Relation between pO2, 31P magnetic resonance spectroscopy parameters and treatment outcome in patients with high-grade soft tissue sarcomas treated with thermoradiotherapy.

PURPOSE: In a prior study, the combination of (31)P magnetic resonance spectroscopy (MRS)-based intracellular pH (pHi) and T2 relaxation time was highly predictive of the pathologic complete response (pCR) rate in a small series of patients with soft tissue sarcomas (STSs) treated with thermoradiotherapy. Changes in the magnetic resonance metabolite ratios and pO(2) were related to the pCR rate. Hypoxia also correlated with a greater likelihood for the development of metastases. Because of the limited number of patients in the prior series, we initiated this study to determine whether the prior observations were repeatable and whether (31)P MRS lipid-related resonances were related to a propensity for metastasis. METHODS AND MATERIALS: Patients with high-grade STSs were enrolled in an institutional review board-approved Phase II thermoradiotherapy trial. All tumors received daily external beam radiotherapy (1.8-2.0 Gy, five times weekly) to a total dose of 30-50 Gy. Hyperthermia followed radiotherapy by <1 h and was given two times weekly. Tumors were resected 4-6 weeks after radiotherapy completion. The MRS/MRI parameters included (31)P metabolite ratios, pHi, and T2 relaxation time. The median pO(2) and hypoxic fraction were determined using pO(2) histography. Comparisons between experimental endpoints and the pCR rate and metastasis-free and overall survival were made. RESULTS: Of 35 patients, 21 and 28 had reportable pretreatment MRS/MRI and pO(2) data, respectively. The cutpoints for a previously tested receiver operating curve for a pCR were T2 = 100 and pHi = 7.3. In the current series, few tumors fell below the cutpoints so validation was not possible. The phosphodiester (PDE)/inorganic phosphate (Pi) ratio and hypoxic fraction correlated inversely with the pCR rate in the current series (Spearman correlation coefficient -0.51, p = 0.017; odds ratio of percentage of necrosis > or =95% = 0.01 for a 1% increase in the hypoxic fraction; Wald p = 0.036). The pretreatment phosphomonoester (PME)/Pi ratio also correlated inversely with the pCR rate (odds ratio of percentage of necrosis > or =95% = 0.06 for pretreatment PME/Pi ratio >0.8 vs. < or =0.8, Wald p = 0.023). The pretreatment PME/PDE ratio correlated strongly with metastasis-free survival and overall survival (p = 0.012 and hazard ratio = 5.8, and p = 0.038 and hazard ratio = 6.75, respectively). CONCLUSION: The dual parameter model containing pHi and T2 to predict the pCR in STSs treated with thermoradiotherapy was not verified. However, other parameters were statistically significant, including the PDE/Pi ratio and hypoxic fraction. These relationships may have interfered with our ability to obtain the pCR rate predicted by thermal doses achieved in these patients. The relationship between the PME/PDE ratio and metastasis-free and overall survival was provocative, but requires additional study to verify its predictive capability. Currently, 50% of all STS patients with high-grade tumors develop distant metastasis even when excellent local control is achieved. Parameters that could help select for patients who need adjuvant chemotherapy could have significant clinical benefit.

Authors
Dewhirst, MW; Poulson, JM; Yu, D; Sanders, L; Lora-Michiels, M; Vujaskovic, Z; Jones, EL; Samulski, TV; Powers, BE; Brizel, DM; Prosnitz, LR; Charles, HC
MLA Citation
Dewhirst, MW, Poulson, JM, Yu, D, Sanders, L, Lora-Michiels, M, Vujaskovic, Z, Jones, EL, Samulski, TV, Powers, BE, Brizel, DM, Prosnitz, LR, and Charles, HC. "Relation between pO2, 31P magnetic resonance spectroscopy parameters and treatment outcome in patients with high-grade soft tissue sarcomas treated with thermoradiotherapy." Int J Radiat Oncol Biol Phys 61.2 (February 1, 2005): 480-491.
PMID
15667971
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
61
Issue
2
Publish Date
2005
Start Page
480
End Page
491
DOI
10.1016/j.ijrobp.2004.06.211

Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study

Purpose: To analyze the relationship between pre-treatment measurements of tumor oxygen tension (pO2) and survival in advanced head and neck cancer. Patients and methods: Eppendorf pO2 measurements in 397 patients from seven centers were analyzed using the fraction of pO2 values ≤2.5 mmHg (HP2.5), ≤5 mmHg (HP5) and median tumor pO2 (mmHg) as descriptors. All patients had intended curative radiation therapy alone or as pre- or post-operative radiotherapy or radio-chemotherapy according to the practice at each center. Results: The degree of hypoxia varied between tumors with an overall median tumor pO2=9 mmHg (range 0-62 mmHg), a median HP2.5=19% (range 0-97%) and HP 5=38%, (range 0-100%). By quadratic regression median tumor pO 2 correlated with Hb (2P=0.026, n=357), while HP2.5 or HP5 did not. HP2.5 above the population median was the only parameter that associated with poor overall survival (Kaplan Meier analysis, P=0.006). In a multivariate Cox Proportional Hazards analysis, stratified according to institution HP2.5 was by far the most statistically significant factor in explaining the variability in survival. After adjusting for HP2.5, clinical stage, radiation dose and surgery hemoglobin concentration was not significant in the model. The prognostic model shows that the 5-year survival is almost constant for HP2.5 values in the range from 0 to 20%, whereas the 5-year survival approaches 0% in the most hypoxic tumors. Conclusion: This study provides evidence that tumor hypoxia is associated with a poor prognosis in patients with advanced head and neck cancer. © 2005 Elsevier Ireland Ltd. All rights reserved.

Authors
Nordsmark, M; Bentzen, SM; Rudat, V; Brizel, D; Lartigau, E; Stadler, P; Becker, A; Adam, M; Molls, M; Dunst, J; Terris, DJ; Overgaard, J
MLA Citation
Nordsmark, M, Bentzen, SM, Rudat, V, Brizel, D, Lartigau, E, Stadler, P, Becker, A, Adam, M, Molls, M, Dunst, J, Terris, DJ, and Overgaard, J. "Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study." Radiotherapy and Oncology 77.1 (2005): 18-24.
PMID
16098619
Source
scival
Published In
Radiotherapy & Oncology
Volume
77
Issue
1
Publish Date
2005
Start Page
18
End Page
24
DOI
10.1016/j.radonc.2005.06.038

Head and neck cancers: Clinical practice guidelines

The NCCN Head and Neck Cancers guidelines address tumors arising in the lip, oral cavity, oropharynx, hypopharynx, glottic and supraglottic larynx, paranasal (ethmoid and maxillary) sinuses, nasopharynx, and salivary glands, as well as occult primary cancer. Approximately 39,250 new cases of oral cavity, pharyngeal, and laryngeal cancers will occur in 2005, which accounts for about 3% of new cancer cases in the United States. An estimated 11,090 deaths from head and neck (H&N) cancers will occur in 2005. Alcohol and tobacco abuse are common etiologic factors in cancers of the oral cavity, oropharynx, hypopharynx, and larynx. Moreover, because the entire aerodigestive tract epithelium may be exposed to these carcinogens, patients with H&N cancer are at risk for developing second primary neoplasms of the H&N, lung, and esophagus. © Journal of the National Comprehensive Cancer Network.

Authors
Forastiere, AA; Ang, K; Brizel, D; Brockstein, BE; Dunphy, F; Eisele, DW; Goepfert, H; Jr, WLH; Kies, MS; Lydiatt, WM; Maghami, E; McCaffrey, T; Mittal, BB; Pfister, DG; Pinto, HA; Posner, MR; Ridge, JA; Samant, S; Schuller, DE; Shah, JP; Spencer, S; III, AT; III, RHW; Wolf, GT; Worden, F; Yueh, B
MLA Citation
Forastiere, AA, Ang, K, Brizel, D, Brockstein, BE, Dunphy, F, Eisele, DW, Goepfert, H, Jr, WLH, Kies, MS, Lydiatt, WM, Maghami, E, McCaffrey, T, Mittal, BB, Pfister, DG, Pinto, HA, Posner, MR, Ridge, JA, Samant, S, Schuller, DE, Shah, JP, Spencer, S, III, AT, III, RHW, Wolf, GT, Worden, F, and Yueh, B. "Head and neck cancers: Clinical practice guidelines." JNCCN Journal of the National Comprehensive Cancer Network 3.3 (2005): 316-391.
PMID
16002004
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
3
Issue
3
Publish Date
2005
Start Page
316
End Page
391

The protective effect of recombinant human keratinocyte growth factor on radiation-induced pulmonary toxicity in rats.

PURPOSE: Radiation-induced lung toxicity is a significant dose-limiting side effect of radiotherapy for thoracic tumors. Recombinant human keratinocyte growth factor (rHuKGF) has been shown to be a mitogen for type II pneumocytes. The purpose of this study was to determine whether rHuKGF prevents or ameliorates the severity of late lung damage from fractionated irradiation in a rat model. METHODS AND MATERIALS: Female Fisher 344 rats were irradiated to the right hemithorax with a dose of 40 Gy/5 fractions/5 days. rHuKGF at dose of 5 mg/kg or 15 mg/kg was given via a single intravenous injection 10 min after the last fraction of irradiation. Animals were followed for 6 months after irradiation. RESULTS: The breathing rate increased beginning at 6 weeks and reached a peak at 14 weeks after irradiation. The average breathing frequencies in the irradiated groups with rHuKGF (5 mg/kg and 15 mg/kg) treatment were significantly lower than that in the group receiving radiation without rHuKGF (116.5 +/- 1.0 and 115.2 +/- 0.8 vs 123.5 +/- 1.2 breaths/min, p < 0.01). The severity of lung fibrosis and the level of immunoreactivity of integrin alphavbeta6, TGFbeta1, type II TGFbeta receptor, Smad3, and phosphorylated Smad2/3 were significantly decreased only in the group receiving irradiation plus high-dose rHuKGF treatment compared with irradiation plus vehicle group, suggesting a dose response for the effect of rHuKGF. CONCLUSIONS: This study is the first to demonstrate that rHuKGF treatment immediately after irradiation protects against late radiation-induced pulmonary toxicity. These results suggest that restoration of the integrity of the pulmonary epithelium via rHuKGF stimulation may downregulate the TGF-beta-mediated fibrosis pathway. These data also support the use of rHuKGF in a clinical trial designed to prevent radiation-induced lung injury.

Authors
Chen, L; Brizel, DM; Rabbani, ZN; Samulski, TV; Farrell, CL; Larrier, N; Anscher, MS; Vujaskovic, Z
MLA Citation
Chen, L, Brizel, DM, Rabbani, ZN, Samulski, TV, Farrell, CL, Larrier, N, Anscher, MS, and Vujaskovic, Z. "The protective effect of recombinant human keratinocyte growth factor on radiation-induced pulmonary toxicity in rats." Int J Radiat Oncol Biol Phys 60.5 (December 1, 2004): 1520-1529.
PMID
15590184
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
60
Issue
5
Publish Date
2004
Start Page
1520
End Page
1529
DOI
10.1016/j.ijrobp.2004.07.729

Is there a role for selective neck dissection after chemoradiation for head and neck cancer?

Authors
Robbins, KT; Ferlito, A; Suárez, C; Brizel, DM; Bradley, PJ; Pellitteri, PK; Clayman, GL; Kowalski, LP; Genden, EM; Rinaldo, A
MLA Citation
Robbins, KT, Ferlito, A, Suárez, C, Brizel, DM, Bradley, PJ, Pellitteri, PK, Clayman, GL, Kowalski, LP, Genden, EM, and Rinaldo, A. "Is there a role for selective neck dissection after chemoradiation for head and neck cancer?." J Am Coll Surg 199.6 (December 2004): 913-916.
PMID
15555975
Source
pubmed
Published In
Journal of The American College of Surgeons
Volume
199
Issue
6
Publish Date
2004
Start Page
913
End Page
916
DOI
10.1016/j.jamcollsurg.2004.08.022

Tumor-dependent kinetics of partial pressure of oxygen fluctuations during air and oxygen breathing.

The primary purpose of this study was to examine the kinetics of partial pressure of oxygen (pO2) fluctuations in fibrosarcoma (FSA) and 9L tumors under air and O2 breathing conditions. The overall hypothesis was that key factors relating to oxygen tension fluctuations would vary between the two tumor types and as a function of the oxygen content of the breathing gas. To assist in the interpretation of the temporal data, spatial pO2 distributions were measured in 10 FSA and 8 9L tumors transplanted into the subcutis of the hind leg of Nembutal-anesthetized (50 mg/kg) Fischer 344 rats. Recessed-tip oxygen microelectrodes were inserted into the tumor, and linear pO2 measurements were recorded in 50-microm steps along a 3-mm path, and blood pressure was simultaneously measured via femoral arterial access. Additionally, pO2 was measured at a single location for 90 to 120 minutes in FSA (n=11) or 9L tumors (n=12). Rats were switched from air to 100% O2 breathing after 45 minutes. Temporal pO2 records were evaluated for their potential radiobiological significance by assessing the number of times they crossed a 10-mm-Hg threshold. In addition, the data were subjected to Fourier analysis for air and O2 breathing. FSA and 9L tumors had spatial median pO2 measurements of 4 and 1 mm Hg, respectively. 9L had more low pO2 measurements < or =2.5 mm Hg than did FSA, whereas between 2.5 and 10 mm Hg this pattern was reversed. Pimonidazole staining patterns in FSA and 9L tumors supported these results. Temporal pO2 instability was observed in all experiments during air and O2 breathing. Threshold analyses indicated that the 10 mm Hg threshold was crossed 2 to 5 times per hour, independent of tumor type. However, the magnitude of 9L pO2 fluctuations was approximately eight times greater than FSA fluctuations, as assessed with Fourier transform analysis (Wilcoxon, P < 0.005). O2 breathing significantly increased median pO2 in FSA from 3 to 8 mm Hg (P < 0.005) and caused a significant increase in frequency and magnitude of pO2 fluctuations. One hundred percent O2 breathing had no effect on 9L tumor pO2, and it decreased the magnitude of pO2 fluctuations with borderline significance. These results show that these two tumors differ significantly with respect to spatial and temporal oxygenation conditions under air and O2 breathing. Fluctuations of pO2 of the type reported herein are predicted to significantly affect radiotherapy response and could be a source for genetic instability, increased angiogenesis, and metastases.

Authors
Cárdenas-Navia, LI; Yu, D; Braun, RD; Brizel, DM; Secomb, TW; Dewhirst, MW
MLA Citation
Cárdenas-Navia, LI, Yu, D, Braun, RD, Brizel, DM, Secomb, TW, and Dewhirst, MW. "Tumor-dependent kinetics of partial pressure of oxygen fluctuations during air and oxygen breathing." Cancer Res 64.17 (September 1, 2004): 6010-6017.
PMID
15342381
Source
pubmed
Published In
Cancer Research
Volume
64
Issue
17
Publish Date
2004
Start Page
6010
End Page
6017
DOI
10.1158/0008-5472.CAN-03-0947

Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer.

PURPOSE: The purpose of this research was to evaluate toxicity, response, and changes in oxygenation (pO(2)) in patients with locally advanced breast cancer (LABC) treated with concurrent taxol, hyperthermia (HT), and radiation therapy (RT) followed by mastectomy. EXPERIMENTAL DESIGN: Eighteen patients with LABC were enrolled from October 1995 through February 1999. Treatment consisted of taxol (175 mg/m(2)) given every 3 weeks for three cycles. Radiation therapy included the breast and regional nodes with a dose of 50 Gy, followed by a boost to 60-65 Gy for those not undergoing surgery. Mastectomy was performed for patients deemed resectable after this neoadjuvant program. HT was administered twice per week. Oxygenation was measured before the first HT treatment and 24 h after the first HT treatment. RESULTS: Fifteen of 18 patients responded, 6 with a clinical complete response, 9 with a partial clinical response, and 3 nonresponders. Thirteen underwent mastectomy with 3 pathological complete responses. Tumor hypoxia was present in 8 of 13 patients (pO(2) = 4.7 +/- 1.2 mmHg). Five patients had well-oxygenated tumors (pO(2) = 27.6 +/- 7.8 mmHg). Patients with well-oxygenated tumors before treatment as well as those with significant reoxygenation had a favorable clinical response. Tumor reoxygenation appeared to be temperature dependent and associated with the lower thermal doses. CONCLUSIONS: This novel therapeutic program resulted in a high response rate in patients with LABC. Hyperthermia may offer a strategy for improving tumor reoxygenation with consequent treatment response. However, the effect of hyperthermia on tumor reoxygenation appears to depend on thermal dose and requires additional investigation.

Authors
Jones, EL; Prosnitz, LR; Dewhirst, MW; Marcom, PK; Hardenbergh, PH; Marks, LB; Brizel, DM; Vujaskovic, Z
MLA Citation
Jones, EL, Prosnitz, LR, Dewhirst, MW, Marcom, PK, Hardenbergh, PH, Marks, LB, Brizel, DM, and Vujaskovic, Z. "Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer." Clin Cancer Res 10.13 (July 1, 2004): 4287-4293.
PMID
15240513
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
13
Publish Date
2004
Start Page
4287
End Page
4293
DOI
10.1158/1078-0432.CCR-04-0133

Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer.

PURPOSE: Neck dissection has traditionally played an important role in the treatment of patients with squamous cell carcinoma of the head and neck who present with regionally advanced neck disease (N2-N3). Radiotherapy and concurrent chemotherapy improves overall survival in advanced head-and-neck cancer compared with radiotherapy alone. The necessity for postchemoradiation neck dissection is controversial. The intent of this report was to define the value of neck dissection in this patient population better. METHODS AND MATERIALS: Patients with locally advanced squamous carcinoma of the head and neck who also presented with nodal disease and underwent hyperfractionated radiotherapy and concurrent cisplatin/5-fluorouracil chemotherapy constituted the study population. Adjuvant modified neck dissection (MND) was planned 6 to 8 weeks after completion of chemoradiation in those patients who had a biopsy-proven pathologically complete response at the primary tumor site, irrespective of the clinical/radiographic neck response. A cohort of patients underwent electrode assessment of tumor oxygenation. Pathologic findings from the MND were used to compute the negative and positive predictive values and overall accuracy of the clinical/radiographic response (cCR). Regional control, failure-free survival, and survival were compared according to whether patients actually underwent MND. RESULTS: A total of 154 patients received concurrent chemoradiation. Of these, 108 presented with nodal disease: N1, n = 30; and N2-N3, n = 78. MND was performed in 65 (60%) of 108 patients, including 13 (43%) of 30 with Stage N1 and 52 (66%) of 78 with Stage N2-N3. For N1 patients, the negative predictive value of a cCR, positive predictive value of less than a cCR, and the overall accuracy for clinical response was 92%, 100%, and 92%, respectively. For N2-N3 patients, the corresponding values were 74%, 44%, and 60%. Patients with poorly oxygenated tumors were more likely to have residual disease at MND. The median follow-up was 4 years. The 4-year disease-free survival rate was 70% for N1 patients, irrespective of the clinical response or whether MND was performed. The 4-year disease-free survival rate was 75% for N2-N3 patients who had a cCR and underwent MND vs. 53% for patients who had a cCR but did not undergo MND (p = 0.08). The 4-year overall survival rate was 77% vs. 50% for these two groups of patients (p = 0.04). CONCLUSION: The clinical and pathologic responses in the neck correlated poorly with one another for patients with N2-N3 neck disease undergoing concurrent chemoradiation for advanced head-and-neck cancer. MND still appears to confer a disease-free survival and overall survival advantage with acceptably low morbidity. Tumor oxygenation assessment may be useful in selecting patients who are especially prone to have residual disease. Better tools need to be developed to determine prospectively whether this procedure is required for individual patients.

Authors
Brizel, DM; Prosnitz, RG; Hunter, S; Fisher, SR; Clough, RL; Downey, MA; Scher, RL
MLA Citation
Brizel, DM, Prosnitz, RG, Hunter, S, Fisher, SR, Clough, RL, Downey, MA, and Scher, RL. "Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer." Int J Radiat Oncol Biol Phys 58.5 (April 1, 2004): 1418-1423.
PMID
15050318
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
58
Issue
5
Publish Date
2004
Start Page
1418
End Page
1423
DOI
10.1016/j.ijrobp.2003.09.004

Assessment and management of cutaneous reactions with amifostine administration: Findings of the ethyol (amifostine) cutaneous treatment advisory panel (ECTAP)

Purpose To review reports of severe skin reactions during amifostine treatment. Methods and material The expert panel reviewed postmarketing reports of skin reactions and discussed strategies for evaluation and management. Results Between 1994 and April 2002, 35 events were classified as severe skin reactions worldwide: erythema multiforme (8), Stevens-Johnson syndrome (10), toxic epidermal necrolysis (11), toxicoderma (3), and bullae (3). Unadjusted incidences were 6-9 per 10,000 radiotherapy patients and 0.8-1 per 10,000 chemotherapy patients. In 10 patients (29%) amifostine was continued after cutaneous signs and symptoms appeared. Conclusions Practical recommendations for practicing clinicians were developed. Cutaneous evaluation for rash, ulceration, or lesions - particularly on lips/mucosa, palmar/plantar surfaces, and the trunk - should be performed before amifostine administration. Reactions can be classified as local injection site/radiation port reactions or non-injection site reactions; and non-injection site reactions with associated fever or constitutional symptoms must be differentiated from radiation-induced dermatitis or cutaneous reaction with another etiology. Amifostine should be permanently discontinued for severe skin reactions or reactions associated with constitutional symptoms not known to be due to any other etiology. Increased physician awareness, proper patient management, monitoring before administration, and early intervention/discontinuation for non-injection site reactions may reduce the incidence of cutaneous reactions and enhance amifostine safety. © 2004 Elsevier Inc.

Authors
Boccia, R; Anné, PR; Bourhis, J; Brizel, D; Daly, C; III, NH; Hymes, S; Koukourakis, M; Kozloff, M; Turner, M; Wasserman, T
MLA Citation
Boccia, R, Anné, PR, Bourhis, J, Brizel, D, Daly, C, III, NH, Hymes, S, Koukourakis, M, Kozloff, M, Turner, M, and Wasserman, T. "Assessment and management of cutaneous reactions with amifostine administration: Findings of the ethyol (amifostine) cutaneous treatment advisory panel (ECTAP)." International Journal of Radiation Oncology Biology Physics 60.1 (2004): 302-309.
PMID
15337569
Source
scival
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
60
Issue
1
Publish Date
2004
Start Page
302
End Page
309
DOI
10.1016/j.ijrobp.2004.02.026

Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer

Authors
Jones, EL; Prosnitz, LR; Dewhirst, MW; Marcom, PK; Hardenbergh, PH; Marks, LB; Brizel, DM; Vujaskovic, Z; Buchholz, TA
MLA Citation
Jones, EL, Prosnitz, LR, Dewhirst, MW, Marcom, PK, Hardenbergh, PH, Marks, LB, Brizel, DM, Vujaskovic, Z, and Buchholz, TA. "Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer." Women's Oncology Review 4.3 (2004): 221-222.
Source
scival
Published In
Women's Oncology Review
Volume
4
Issue
3
Publish Date
2004
Start Page
221
End Page
222
DOI
10.1080/14733400400012958

Human recombinant erythropoietin significantly improves tumor oxygenation independent of its effects on hemoglobin.

Tumor oxygenation is known to be an important predictive/prognostic marker in a variety of tumors, including cervix, head/neck, sarcoma, non-small cell of the lung, and breast. Tumor oxygenation is influenced by many interactions, including oxygen delivery (angiogenesis, permeability, and HgB) and consumption (metabolic and growth rates). This study randomized 30 nonanemic, female Fischer 344 rats into three treatment arms to examine the effects of recombinant human erythropoietin (EPO) on R3230 rodent mammary carcinoma oxygenation. The three treatment arms were: (a) placebo; (b) EPO after tumor implantation (2000 units/kg/SQdose, M/W/F for six doses); and (c) EPO before tumor implantation (2000 units/kg/SQdose, M/W/F for six doses). Tumors were implanted in the hindflank, and in vivo oxygenation was measured at day 22 after implantation using the Oxylite system (Oxford Optronix, Oxford, England). An average of 180 measurements/animal were performed. On day 22, median tumor volume was 399 mm(3) (range: 65-950 mm(3)), and no differences in tumor volume were seen between treatment arms. Mean hematocrit was equal between arms at therapy initiation but were significantly higher for both arms receiving EPO at day 22 (placebo versus Arm B versus Arm C; Wilcoxon P = 0.052). EPO-treated tumors had significantly less hypoxic measurements when compared with either the placebo or those receiving EPO before implantation. These data confirm that tumor oxygenation in nonanemic individuals may be improved through the administration of EPO, and this improvement appears to be independent of HgB effects.

Authors
Blackwell, KL; Kirkpatrick, JP; Snyder, SA; Broadwater, G; Farrell, F; Jolliffe, L; Brizel, DM; Dewhirst, MW
MLA Citation
Blackwell, KL, Kirkpatrick, JP, Snyder, SA, Broadwater, G, Farrell, F, Jolliffe, L, Brizel, DM, and Dewhirst, MW. "Human recombinant erythropoietin significantly improves tumor oxygenation independent of its effects on hemoglobin." Cancer Res 63.19 (October 1, 2003): 6162-6165.
PMID
14559797
Source
pubmed
Published In
Cancer Research
Volume
63
Issue
19
Publish Date
2003
Start Page
6162
End Page
6165

Ultrasound guided pO2 measurement of breast cancer reoxygenation after neoadjuvant chemotherapy and hyperthermia treatment.

The objective of this study was to determine whether neoadjuvant chemotherapy in combination with hyperthermia (HT) would improve oxygenation in locally advanced breast tumours. The study describes a new optimized ultrasound guided technique of pO2 measurement using Eppendorf polarographic oxygen probes in 18 stage IIB-III breast cancer patients. Prior to treatment, tumour hypoxia (median pO2<10 mmHg) was present in 11/18 patients (average median pO2=3.2 mmHg). Seven patients had well oxygenated tumours (median pO2 of 48.3 mmHg). Eight patients with hypoxic tumours prior to treatment had a significant improvement (p=0.0008) in tumour pO2 after treatment (pO2 increased to 19.2 mmHg). In three patients, tumours remained hypoxic (average median pO2=4.5 mmHg). The advantages of the ultrasound guided pO2 probe are in the accuracy of the Eppendorf electrode placement in tumour tissue, the ability to monitor electrode movement through the tumour tissue during the measurement and the ability to avoid electrode placement near or in large blood vessels by using colour Doppler imaging. The results of this preliminary study suggest that the combination of neoadjuvant chemotherapy and hyperthermia improves oxygenation in locally advanced breast tumours that are initially hypoxic.

Authors
Vujaskovic, Z; Rosen, EL; Blackwell, KL; Jones, EL; Brizel, DM; Prosnitz, LR; Samulski, TV; Dewhirst, MW
MLA Citation
Vujaskovic, Z, Rosen, EL, Blackwell, KL, Jones, EL, Brizel, DM, Prosnitz, LR, Samulski, TV, and Dewhirst, MW. "Ultrasound guided pO2 measurement of breast cancer reoxygenation after neoadjuvant chemotherapy and hyperthermia treatment." Int J Hyperthermia 19.5 (September 2003): 498-506.
PMID
12944165
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
19
Issue
5
Publish Date
2003
Start Page
498
End Page
506
DOI
10.1080/0265673031000121517

Effect of longitudinal oxygen gradients on effectiveness of manipulation of tumor oxygenation.

The purpose of this study was to test the hypothesis that longitudinal O(2) gradients in tumor affect response to manipulation of oxygenation. Previously we showed that pO(2) is higher on the fascial than the tumor surface of the R3230Ac rat mammary carcinoma when growing in a dorsal skin-fold window chamber, reflecting a longitudinal oxygen gradient. Magnetic resonance angiography verified prior results: the fascial surface has arterioles and higher vascular density than tumor; and the tumor surface has no arterioles. Phosphorescence lifetime imaging was used to measure each surface hypoxic percentage (HP; percentage of pixels < 10 mm Hg) before and after administration of mannitol or glucose (1 g/kg, i.v.) followed by O(2) breathing. The fascial surface had a smaller HP (median = 2.72%) than tumor (median = 27.94%; P = 0.0002) at baseline. HP on the fascial surface was positively correlated with HP on the tumor surface (P = 0.0067). HP decreased on the fascial surface after either sugar + O(2) (mannitol P = 0.03; glucose P = 0.06; combined P = 0.002), but HP did not change on the tumor surface. Therefore, the tumor surface is refractory to improvement in pO(2) with this method. Additional refinements may be needed to improve pO(2) of analogous regions in larger tumors; mechanism-driven suggestions are provided.

Authors
Erickson, K; Braun, RD; Yu, D; Lanzen, J; Wilson, D; Brizel, DM; Secomb, TW; Biaglow, JE; Dewhirst, MW
MLA Citation
Erickson, K, Braun, RD, Yu, D, Lanzen, J, Wilson, D, Brizel, DM, Secomb, TW, Biaglow, JE, and Dewhirst, MW. "Effect of longitudinal oxygen gradients on effectiveness of manipulation of tumor oxygenation." Cancer Res 63.15 (August 1, 2003): 4705-4712.
PMID
12907653
Source
pubmed
Published In
Cancer Research
Volume
63
Issue
15
Publish Date
2003
Start Page
4705
End Page
4712

Does amifostine have a role in chemoradiation treatment?

For many years, scientists have been investigating use of drugs to protect normal tissue from injury during radiation therapy, thereby increasing the amount of radiation that can be safely administered to patients. Despite the introduction of modern shielding techniques, dose modulation, and tissue-volume mapping, a small amount of normal tissue surrounding the target volume is inevitably irradiated during treatment, which can lead to severe side-effects. The most recent chemical radioprotector to become available clinically is amifostine. On the basis of efficacy data from a phase III randomised trial in patients with head and neck cancer, which showed reduced acute and chronic xerostomia with preserved antitumour response, some institutions are now adding amifostine to their chemoradiation regimens. However, much controversy surrounds the use of this drug. Some investigators are worried that radioprotectors may stop tumour tissue responding to radiation and therefore reduce treatment effectiveness. Moreover, amifostine opponents argue that the evidence is insufficient to justify routine use of this drug. In this Debate, David Brizel, who worked on the phase III amifostine efficacy study, and Jens Overgaard, a vehement opponent of amifostine therapy, provide thought-provoking arguments for two opposing perspectives on this contentious issue.

Authors
Brizel, DM; Overgaard, J
MLA Citation
Brizel, DM, and Overgaard, J. "Does amifostine have a role in chemoradiation treatment?." Lancet Oncol 4.6 (June 2003): 378-381.
PMID
12788413
Source
pubmed
Published In
The Lancet Oncology
Volume
4
Issue
6
Publish Date
2003
Start Page
378
End Page
381

A mathematical model of tumor oxygen and glucose mass transport and metabolism with complex reaction kinetics.

Hypoxia imparts radioresistance to tumors, and various approaches have been developed to enhance oxygenation, thereby improving radiosensitivity. This study explores the influence of kinetic and physical factors on substrate metabolism in a tumor model, based on a Krogh cylinder. In tissue, aerobic metabolism is assumed to depend on glucose and oxygen, represented by the product of Michaelis-Menten expressions. For the base case, an inlet pO(2) of 40 mmHg, a hypoxic limit of 5 mmHg, and a tissue/capillary radius ratio of 10 are used. For purely aerobic metabolism, a hypoxic fraction of 0.16 and volume-average pO(2) of 8 mmHg are calculated. Reducing the maximum oxygen rate constant by 9%, decreasing the tissue cylinder radius by 5%, or increasing the capillary radius by 8% abolishes the hypoxic fraction. When a glycolytic term is added, concentration profiles are similar to the base case. Using a distribution of tissue/capillary radius ratios increases the hypoxic fraction and reduces sensitivity to the oxygen consumption rate, compared to the case with a single tissue/capillary radius ratio. This model demonstrates that hypoxia is quite sensitive to metabolic rate and geometric factors. It also predicts quantitatively the effects of inhibited oxygen metabolism and enhanced mass transfer on tumor oxygenation.

Authors
Kirkpatrick, JP; Brizel, DM; Dewhirst, MW
MLA Citation
Kirkpatrick, JP, Brizel, DM, and Dewhirst, MW. "A mathematical model of tumor oxygen and glucose mass transport and metabolism with complex reaction kinetics." Radiat Res 159.3 (March 2003): 336-344.
PMID
12600236
Source
pubmed
Published In
Radiation Research
Volume
159
Issue
3
Publish Date
2003
Start Page
336
End Page
344

M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis.

BACKGROUND: The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis. METHODS: M6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months. RESULTS: M6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/IGF2R loss of heterozygosity. CONCLUSIONS: This study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy.

Authors
Jamieson, TA; Brizel, DM; Killian, JK; Oka, Y; Jang, H-S; Fu, X; Clough, RW; Vollmer, RT; Anscher, MS; Jirtle, RL
MLA Citation
Jamieson, TA, Brizel, DM, Killian, JK, Oka, Y, Jang, H-S, Fu, X, Clough, RW, Vollmer, RT, Anscher, MS, and Jirtle, RL. "M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis." BMC Cancer 3 (February 13, 2003): 4-.
PMID
12589712
Source
pubmed
Published In
BMC Cancer
Volume
3
Publish Date
2003
Start Page
4

The prevention and treatment of radiotherapy-induced xerostomia

Efforts to reduce the severity of postradiotherapy xerostomia include the use of salivary substitutes to gain symptomatic relief, salivary gland stimulants, agents delivered to protect the glands during radiotherapy (RT), and physical means to partially spare the major salivary glands from RT while adequately irradiating tumor targets. These means include advanced RT treatment planning and salivary tissue transfer to nonirradiated areas. The relative potential gain from each of these strategies is discussed in this article. The combination of partial salivary gland sparing and radiation protectors/stimulants may provide additive or synergistic gains in reducing the severity of xerostomia. © 2003 Elsevier Inc. All rights reserved.

Authors
Eisbruch, A; Rhodus, N; Rosenthal, D; Murphy, B; Rasch, C; Sonis, S; Scarantino, C; Brizel, D
MLA Citation
Eisbruch, A, Rhodus, N, Rosenthal, D, Murphy, B, Rasch, C, Sonis, S, Scarantino, C, and Brizel, D. "The prevention and treatment of radiotherapy-induced xerostomia." Seminars in Radiation Oncology 13.3 (2003): 302-308.
PMID
12903018
Source
scival
Published In
Seminars in Radiation Oncology
Volume
13
Issue
3
Publish Date
2003
Start Page
302
End Page
308
DOI
10.1016/S1053-4296(03)00027-4

How should we measure and report radiotherapy-induced xerostomia?

Xerostomia is commonly measured and graded using objective measures of major salivary gland output and observer-rated toxicity grading. The separation between the different grades is somewhat ambiguous in the current toxicity grading systems. We propose a new grading system based primarily on the functional deficits associated with xerostomia. Salivary flow rates have been added as a criterion to the grading system, notwithstanding the weak correlation reported in most studies between the symptoms and objective functional measures. In addition to the observer-rated toxicity grading, recording of patient-reported quality of life, using validated instruments, is encouraged. © 2003 Elsevier Inc. All rights reserved.

Authors
Eisbruch, A; Rhodus, N; Rosenthal, D; Murphy, B; Rasch, C; Sonis, S; Scarantino, C; Brizel, D
MLA Citation
Eisbruch, A, Rhodus, N, Rosenthal, D, Murphy, B, Rasch, C, Sonis, S, Scarantino, C, and Brizel, D. "How should we measure and report radiotherapy-induced xerostomia?." Seminars in Radiation Oncology 13.3 (2003): 226-234.
PMID
12903012
Source
scival
Published In
Seminars in Radiation Oncology
Volume
13
Issue
3
Publish Date
2003
Start Page
226
End Page
234
DOI
10.1016/S1053-4296(03)00033-X

M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis

Background: The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis. Methods: M6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months. Results: M6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/ IGF2R loss of heterozygosity. Conclusions: This study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy.© 2003 Jamieson et al; licensee BioMed Central Ltd.

Authors
Jamieson, TA; Brizel, DM; Killian, JK; Oka, Y; Jang, H-S; Fu, X; Clough, RW; Vollmer, RT; Anscher, MS; Jirtle, RL
MLA Citation
Jamieson, TA, Brizel, DM, Killian, JK, Oka, Y, Jang, H-S, Fu, X, Clough, RW, Vollmer, RT, Anscher, MS, and Jirtle, RL. "M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis." BMC Cancer 3 (2003).
Source
scival
Published In
BMC Cancer
Volume
3
Publish Date
2003
DOI
10.1186/1471-2407-3-4

Assessment of the protective effect of amifostine on radiation-induced pulmonary toxicity.

The objective of this study was to assess the radioprotective effects of amifostine in the rat model of radiation-induced lung injury using fractionated doses of radiation, to determine whether amifostine given before irradiation protects tumor from radiation cytotoxicity, and to determine whether changes in plasma levels of transforming growth factor (TGF)-beta correlate with radioprotective effect of amifostine. R3230 AC mammary adenocarcinoma was transplanted on the right posterior chest wall of female Fisher-344 rats. Both tumor-bearing and non-tumor-bearing animals were irradiated to the tumor or right lung using 4 MV photons and fractionated dose of 35 Gy/5 fractions/5 days. Animals with tumors and those without were randomized into 4 groups, respectively (8 to 10 rats per group), to receive (1) radiation alone; (2) radiation + amifostine; (3) amifostine alone; (4) sham radiation. Amifostine (150 mg/kg) was given intraperitoneally 30 minutes before each fraction of irradiation. The tumor size was measured twice a week. Breathing rate was assessed every 2 weeks. TGF-beta levels in plasma were assessed monthly after treatment. Six months after irradiation, animals were euthanized and lung tissue was processed for hydroxyproline content analysis. A significant increase in breathing frequency started 9 weeks after irradiation in animals that received radiation only. In the radiation + amifostine group, there was both a delay and a significantly lower peak in breathing frequency (P < .001). Hydroxyproline content was higher in the radiation-alone group than in rats given amifostine prior to radiation (P < .05). The TGF-beta levels in plasma showed an increase from 1 to 3 months after radiation, peaking at 2 months in the rats with (2.80 +/- 0.23) or without (5.32 +/- 1.21) amifostine compared to sham irradiation. TGF-beta levels were significantly lower at 1 to 3 months in rats receiving amifostine plus radiation versus those receiving radiation alone. Tumor growth delay and regrowth rate after radiation were not different between radiation-alone and radiation + amifostine groups. This study confirms the protective effect of amifostine in reducing radiation-induced pulmonary toxicity. No tumor protection was demonstrated after fractionated radiotherapy. The reduction in pulmonary injury with amifostine in paralleling lower plasma levels of TGF-beta, suggesting that monitoring plasma levels of this cytokine may reflect the efficacy of an intervention aimed at preventing radiation-induced lung injury.

Authors
Vujaskovic, Z; Feng, QF; Rabbani, ZN; Samulski, TV; Anscher, MS; Brizel, DM
MLA Citation
Vujaskovic, Z, Feng, QF, Rabbani, ZN, Samulski, TV, Anscher, MS, and Brizel, DM. "Assessment of the protective effect of amifostine on radiation-induced pulmonary toxicity." Exp Lung Res 28.7 (October 2002): 577-590.
PMID
12396250
Source
pubmed
Published In
Experimental Lung Research (Informa)
Volume
28
Issue
7
Publish Date
2002
Start Page
577
End Page
590
DOI
10.1080/01902140290096791

Radioprotection of lungs by amifostine is associated with reduction in profibrogenic cytokine activity.

Radiation-induced pulmonary toxicity causes significant morbidity and mortality in patients irradiated for lung cancer, breast cancer, lymphoma or thymoma. Amifostine is an important drug in the emerging field of cytoprotection. Recent advances in our understanding of the mechanism of radiation-induced injury at the molecular and cellular levels have stimulated interest in the development of effective radioprotective strategies. Accumulation of macrophages with associated production of reactive oxygen species (ROS) and production and activation of cytokines is a key process involved in the pathophysiology of radiation injury in the lung. The purpose of this study was to determine whether the mechanism of radioprotection by amifostine includes reduction in both macrophage activity and the expression and activation of profibrogenic cytokines. Our results demonstrated a reduction in both functional and histological radiation-induced lung injury by amifostine. In addition, this study is the first to demonstrate that amifostine given prior to irradiation reduced both the accumulation of macrophages and the expression/activation of lung tissue Tgfb1 which was followed by the reduction of plasma Tgfb1 levels during the development of radiation-induced lung injury. Future studies are needed to determine whether administration of amifostine both during and after radiotherapy may further increase its radioprotective effect.

Authors
Vujaskovic, Z; Feng, Q-F; Rabbani, ZN; Anscher, MS; Samulski, TV; Brizel, DM
MLA Citation
Vujaskovic, Z, Feng, Q-F, Rabbani, ZN, Anscher, MS, Samulski, TV, and Brizel, DM. "Radioprotection of lungs by amifostine is associated with reduction in profibrogenic cytokine activity." Radiat Res 157.6 (June 2002): 656-660.
PMID
12005544
Source
pubmed
Published In
Radiation Research
Volume
157
Issue
6
Publish Date
2002
Start Page
656
End Page
660

Tissue gradients of energy metabolites mirror oxygen tension gradients in a rat mammary carcinoma model.

PURPOSE: It has been shown that oxygen gradients exist in R3230AC tumors grown in window chambers. The fascial surface is better oxygenated than the tumor surface. The purpose of the present study was to determine whether gradients exist for energy metabolites and other end points related to oxygen transport. METHODS AND MATERIALS: Imaging bioluminescence was used to measure ATP, glucose, and lactate in cryosections of R3230AC tumors. Mean vessel density and hypoxic tissue fraction were assessed using immunohistochemistry. Tumor redox ratio was assessed by redox ratio scanning. RESULTS: Lactate content and hypoxic fraction increased, whereas ATP, glucose, redox ratio, and vessel density decreased from the fascial to the tumor surface. CONCLUSIONS: The data support a switch from aerobic to anaerobic metabolism concomitant with the PO2 gradient. The vascular hypoxia that exists in perfused vessels at the tumor surface leads to macroscopic tissue regions with restricted oxygen availability and altered metabolic status. Methods to reduce tumor hypoxia may have to take this into account if such gradients exist in human tumors. The results also have implications for hypoxia imaging, because macroscopic changes in PO2 (or related parameters) will be easier to see than PO2 gradients limited to the diffusion distance of oxygen.

Authors
Walenta, S; Snyder, S; Haroon, ZA; Braun, RD; Amin, K; Brizel, D; Mueller-Klieser, W; Chance, B; Dewhirst, MW
MLA Citation
Walenta, S, Snyder, S, Haroon, ZA, Braun, RD, Amin, K, Brizel, D, Mueller-Klieser, W, Chance, B, and Dewhirst, MW. "Tissue gradients of energy metabolites mirror oxygen tension gradients in a rat mammary carcinoma model." Int J Radiat Oncol Biol Phys 51.3 (November 1, 2001): 840-848.
PMID
11699496
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
51
Issue
3
Publish Date
2001
Start Page
840
End Page
848

Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer.

PURPOSE: Hypoxia shifts the balance of cellular energy production toward glycolysis with lactate generation as a by-product. Quantitative bioluminescence imaging allows for the quantitation of lactate concentrations in individual tumors. We assessed the relationship between pretreatment tumor lactate concentrations and subsequent development of metastatic disease in patients with newly diagnosed head-and-neck cancer. METHODS AND MATERIALS: At the time of biopsy of the primary site, a separate specimen was taken and flash-frozen for subsequent quantitation of lactate concentration using a luciferase bioluminescence technique. The two-dimensional spatial distribution of the bioluminescence intensity within the tissue section was registered directly using a microscope and an imaging photon counting system. Photon intensity was converted to distributions of volume-related tissue concentrations (micromol per gram wet weight). Treatment consisted of either surgery and postoperative radiotherapy or primary radiotherapy, based on presenting disease stage and institutional treatment policies. The subsequent development of metastatic disease constituted the primary clinical endpoint. RESULTS: Biopsies obtained from 40 patients were evaluable in 34. The larynx was the most frequent primary site (n = 25). Other sites included oropharynx (n = 5), hypopharynx (n = 3), and oral cavity (n = 1). Most patients (74%) presented with an advanced stage T3 or T4 primary tumor. Nodal involvement was present in 19 (54%) patients. The median tumor lactate concentration was 7.1 micromol/g. Tumors were classified as having either low or high lactate concentrations according to whether these values were below or above the median. The median follow-up time for surviving patients is 27 months. Two-year actuarial survival was 90% for patients with low-lactate-concentration tumor vs. 35% for patients with high-lactate-concentration primaries (<0.0001). Two-year metastasis-free survival was adversely influenced by high tumor lactate concentrations (90% vs. 25%, p < 0.0001). The median lactate concentration for tumors that subsequently metastasized was 12.9 micromol/g vs. 4.8 micromol/g for patients who remained continuously free of disease (p < 0.005). Lactate concentration was not correlated with presenting T stage or N stage. DISCUSSION: Elevated tumor lactate concentrations are associated with the subsequent development of nodal or distant metastases in head-and-neck cancer patients. This more aggressive malignant phenotype is probably associated with hypoxia-mediated radioresistance and the upregulation of metastasis-associated genes.

Authors
Brizel, DM; Schroeder, T; Scher, RL; Walenta, S; Clough, RW; Dewhirst, MW; Mueller-Klieser, W
MLA Citation
Brizel, DM, Schroeder, T, Scher, RL, Walenta, S, Clough, RW, Dewhirst, MW, and Mueller-Klieser, W. "Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer." Int J Radiat Oncol Biol Phys 51.2 (October 1, 2001): 349-353.
PMID
11567808
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
51
Issue
2
Publish Date
2001
Start Page
349
End Page
353

Simultaneous administration of glucose and hyperoxic gas achieves greater improvement in tumor oxygenation than hyperoxic gas alone.

PURPOSE: To test the feasibility of hyperglycemic reduction of oxygen consumption combined with oxygen breathing (O(2)), to improve tumor oxygenation. METHODS AND MATERIALS: Fischer-344 rats bearing 1 cm R3230Ac flank tumors were anesthetized with Nembutal. Mean arterial pressure, heart rate, tumor blood flow ([TBF], laser Doppler flowmetry), pH, and pO(2) were measured before, during, and after glucose (1 or 4 g/kg) and/or O(2). RESULTS: Mean arterial pressure and heart rate were unaffected by treatment. Glucose at 1 g/kg yielded maximum blood glucose of 400 mg/dL, no change in TBF, reduced tumor pH (0.17 unit), and 3 mm Hg pO(2) rise. Glucose at 4 g/kg yielded maximum blood glucose of 900 mg/dL, pH drop of 0.6 unit, no pO(2) change, and reduced TBF (31%). Oxygen tension increased by 5 mm Hg with O(2). Glucose (1 g/Kg) + O(2) yielded the largest change in pO(2) (27 mm Hg); this is highly significant relative to baseline or either treatment alone. The effect was positively correlated with baseline pO(2), but 6 of 7 experiments with baseline pO(2) < 10 mm Hg rose above 10 mm Hg after combined treatment. CONCLUSION: We demonstrated the feasibility of combining hyperglycemia with O(2) to improve tumor oxygenation. However, some cell lines are not susceptible to the Crabtree effect, and the magnitude is dependent on baseline pO(2). Additional or alternative manipulations may be necessary to achieve more uniform improvement in pO(2).

Authors
Snyder, SA; Lanzen, JL; Braun, RD; Rosner, G; Secomb, TW; Biaglow, J; Brizel, DM; Dewhirst, MW
MLA Citation
Snyder, SA, Lanzen, JL, Braun, RD, Rosner, G, Secomb, TW, Biaglow, J, Brizel, DM, and Dewhirst, MW. "Simultaneous administration of glucose and hyperoxic gas achieves greater improvement in tumor oxygenation than hyperoxic gas alone." Int J Radiat Oncol Biol Phys 51.2 (October 1, 2001): 494-506.
PMID
11567826
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
51
Issue
2
Publish Date
2001
Start Page
494
End Page
506

The role of amifostine as a radioprotector.

Effective radiotherapy for patients with cancer should include maximal tumor cell killing with minimal injury to normal tissue. Radiation doses that can be delivered, without causing severe damage to surrounding normal tissues, can be insufficient to eradicate a tumor. Agents have been developed to protect normal tissue from the toxicities of radiation. The aminothiol amifostine (Ethyol) is the subject of extensive research as a protector. Several studies have demonstrated that amifostine protects normal tissues from both acute and late radiation damage without protecting the tumor. This article reviews the physicochemical basis of radiation therapy on biologic tissues and the mechanisms responsible for the protective effects of amifostine. The increasing body of biochemical, preclinical, and clinical data can justify the use of protectors such as amifostine with radiotherapy to provide improved therapeutic efficacy and quality of life for the patient. This article will review the current understanding of the nature of toxicity resulting from radiation therapy and the benefits that can be derived from using protection to increase the tolerance of normal tissue to radiation damage.

Authors
Wasserman, TH; Brizel, DM
MLA Citation
Wasserman, TH, and Brizel, DM. "The role of amifostine as a radioprotector." Oncology (Williston Park) 15.10 (October 2001): 1349-1354. (Review)
PMID
11702962
Source
pubmed
Published In
Oncology
Volume
15
Issue
10
Publish Date
2001
Start Page
1349
End Page
1354

Has the outlook improved for amifostine as a clinical radioprotector.

Authors
Wasserman, TH; Brizel, DM
MLA Citation
Wasserman, TH, and Brizel, DM. "Has the outlook improved for amifostine as a clinical radioprotector." Radiother Oncol 60.3 (September 2001): 334-336. (Letter)
PMID
11570362
Source
pubmed
Published In
Radiotherapy & Oncology
Volume
60
Issue
3
Publish Date
2001
Start Page
334
End Page
336

A phase II trial testing the thermal dose parameter CEM43 degrees T90 as a predictor of response in soft tissue sarcomas treated with pre-operative thermoradiotherapy.

We prospectively evaluated whether delivering a thermal dose of > 10 cumulative equivalent minutes at 43 degrees C to >90% of the tumour sites monitored (CEM43 degrees T90) would produce a pathologic complete response (pCR) in > 75% of high-grade soft tissue sarcomas treated pre-operatively with thermoradiotherapy. The impact of thermal dose on local failure (LF), distant metastasis (DM), and toxicity was also assessed. Thirty-five patients > or = 18 years old with grade 2 or 3 soft tissue sarcomas accessible for invasive thermometry were enrolled on the protocol. All patients received megavoltage external beam radiotherapy (RT) in daily fractions of 1.8-2.0 Gy, five times a week, to a median total dose of 50 Gy and an initial hyperthermia treatment (HT) of I h duration utilizing the BSD 2000 with Sigma 60 or MAPA applicators at frequencies of 60-140 MHz. Further HT was given for patients with CEM43 degrees T90 > 0.5 after initial HT ('heatable' patients), twice a week to a maximum of 10 HT or CEM43 degrees T90 > 100. Of the 35 patients entered, 30 had heatable tumours, one of which was inevaluable for pCR or LF as the patient died of DM prior to surgery, leaving 29 evaluable patients. Of these 29 patients, 15 (52%) had a pCR (95% CI: 37-73%), significantly less than the projected rate of > or = 75% (p = 0.02). Of the 25 heatable tumours that achieved CEM43 degrees T90 > or = 10, 14 (56%) had a pCR (95% CI: 39-78%) significantly less than the projected rate (p = 0.06). Three of the 29 patients (10%) with heatable tumours had a LF, versus 1/5 unheatable tumours (p = 0.48). Fourteen of the 30 patients (47%) with heatable tumours developed DM, versus 2/5 unheatable tumours (p = 1.00). Ten of the 30 patients (33%) with heatable tumours developed treatment-induced toxicity. Thus, no correlation of thermal dose with histologic response was observed. Prospective control of CEM43 degrees T90 failed to achieve the projected pCR rate following pre-operative thermoradiotherapy for high-grade soft tissue sarcomas, despite excellent local control. Possible explanations for this outcome are discussed.

Authors
Maguire, PD; Samulski, TV; Prosnitz, LR; Jones, EL; Rosner, GL; Powers, B; Layfield, LW; Brizel, DM; Scully, SP; Harrelson, JM; Dewhirst, MW
MLA Citation
Maguire, PD, Samulski, TV, Prosnitz, LR, Jones, EL, Rosner, GL, Powers, B, Layfield, LW, Brizel, DM, Scully, SP, Harrelson, JM, and Dewhirst, MW. "A phase II trial testing the thermal dose parameter CEM43 degrees T90 as a predictor of response in soft tissue sarcomas treated with pre-operative thermoradiotherapy." Int J Hyperthermia 17.4 (July 2001): 283-290.
PMID
11471980
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
17
Issue
4
Publish Date
2001
Start Page
283
End Page
290

Phase III randomized trial of amifostine as a radioprotector in head and neck cancer [5] (multiple letters)

Authors
Vikram, B; Brizel, DM
MLA Citation
Vikram, B, and Brizel, DM. "Phase III randomized trial of amifostine as a radioprotector in head and neck cancer [5] (multiple letters)." Journal of Clinical Oncology 19.4 (2001): 1233-1234.
PMID
11181692
Source
scival
Published In
Journal of Clinical Oncology
Volume
19
Issue
4
Publish Date
2001
Start Page
1233
End Page
1234

Head and neck: Editorial

Authors
Weber, RS; Abemayor, E; Adams, GL; Adelstein, DJ; Alavi, A; Alford, E; Al-Sarraf, M; Alvi, A; Ambinder, R; Amdur, R; Amedee, RG; Anand, VK; Andersen, P; Anderson, T; Ang, K-K; Antonelli, PJ; Ariyan, S; Aviv, JE; Ayala, A; Jong, RJBD; Backous, D; Bailey, BJ; Baker, S; Baloch, ZW; Barnes, EL; Barrera, J; Bastian, R; Batsakis, JG; Bauman, N; Becker, D; Beenken, S; Beitler, JJ; Berke, G; Blacklock, JB; Blackwell, K; Blitzer, A; Blom, E; Bolger, WE; Bone, RC; Boyd, J; Boyd, D; Boyle, J; Braakhuis, B et al.
MLA Citation
Weber, RS, Abemayor, E, Adams, GL, Adelstein, DJ, Alavi, A, Alford, E, Al-Sarraf, M, Alvi, A, Ambinder, R, Amdur, R, Amedee, RG, Anand, VK, Andersen, P, Anderson, T, Ang, K-K, Antonelli, PJ, Ariyan, S, Aviv, JE, Ayala, A, Jong, RJBD, Backous, D, Bailey, BJ, Baker, S, Baloch, ZW, Barnes, EL, Barrera, J, Bastian, R, Batsakis, JG, Bauman, N, Becker, D, Beenken, S, Beitler, JJ, Berke, G, Blacklock, JB, Blackwell, K, Blitzer, A, Blom, E, Bolger, WE, Bone, RC, Boyd, J, Boyd, D, Boyle, J, and Braakhuis, B et al. "Head and neck: Editorial." Head and Neck 23.12 (2001): 1021-1023.
Source
scival
Published In
Head & Neck: Journal for the Sciences & Specialties of the Head and Neck
Volume
23
Issue
12
Publish Date
2001
Start Page
1021
End Page
1023
DOI
10.1002/hed.1148

Letter to the editor [2] (multiple letters)

Authors
Wasserman, TH; Brizel, DM
MLA Citation
Wasserman, TH, and Brizel, DM. "Letter to the editor [2] (multiple letters)." Radiotherapy and Oncology 60.3 (2001): 334-336.
Source
scival
Published In
Radiotherapy & Oncology
Volume
60
Issue
3
Publish Date
2001
Start Page
334
End Page
336
DOI
10.1016/S0167-8140(01)00402-9

Effect of amifostine on patient assessed clinical benefit in irradiated head and neck cancer.

PURPOSE: To determine if head and neck (H/N) cancer patients receiving daily amifostine during radiation therapy (RT) experienced clinical benefit (improvement in their ability to carry out normal functions with reduced discomfort) compared to nonamifostine treated patients. METHODS AND MATERIALS: This was an open-label, multi-institutional randomized trial in 303 H/N cancer patients treated with RT +amifostine. Clinical benefit was measured using an 8-item validated Patient Benefit Questionnaire (PBQ) during and up to 11 months after RT. RESULTS: 301 patients completed one or more PBQ assessments. Amifostine patients had significantly better PBQ scores (p < 0.05) than controls. The improvement in PBQ scores was most significant during chronic xerostomia. CONCLUSIONS: Amifostine use results in improved Patient Benefit Questionnaire (PBQ) scores, which is indicative of improved oral toxicity related outcomes and improved clinical benefit. Less oral toxicity should lead to preservation of late dental and oral health, and improvements in activities such as diet, nutrition, and sleep.

Authors
Wasserman, T; Mackowiak, JI; Brizel, DM; Oster, W; Zhang, J; Peeples, PJ; Sauer, R
MLA Citation
Wasserman, T, Mackowiak, JI, Brizel, DM, Oster, W, Zhang, J, Peeples, PJ, and Sauer, R. "Effect of amifostine on patient assessed clinical benefit in irradiated head and neck cancer." Int J Radiat Oncol Biol Phys 48.4 (November 1, 2000): 1035-1039.
PMID
11072160
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
48
Issue
4
Publish Date
2000
Start Page
1035
End Page
1039

Review of methods used to study oxygen transport at the microcirculatory level.

The existence of hypoxic regions in tumors has long been recognized as a key factor leading to radiation resistance. More recently, it has been found that low oxygen levels also affect drug resistance, angiogenesis, cytokine production, cell cycle control, apoptosis, and metastatic propensity of tumors. Until now, most approaches to eliminating hypoxia have been empirical. However, improved understanding of the underlying mechanisms may permit the development of more soundly based, effective approaches. As discussed in this review, critical evaluation of the factors governing oxygen transport in tumors requires a thorough understanding of the methods used to study this process. Many experimental methodologies can be used to address these issues. In this review, the emphasis is placed on techniques that measure parameters on the scale of the diffusion distance of oxygen. Studies at the microregional level provide the most detailed physiological information on such processes. Over the past few years, significant progress in technology has allowed us to measure tumor oxygenation, yet spatial and temporal heterogeneities continue to provide significant challenges to obtaining clear knowledge of oxygen transport.

Authors
Dewhirst, MW; Klitzman, B; Braun, RD; Brizel, DM; Haroon, ZA; Secomb, TW
MLA Citation
Dewhirst, MW, Klitzman, B, Braun, RD, Brizel, DM, Haroon, ZA, and Secomb, TW. "Review of methods used to study oxygen transport at the microcirculatory level." Int J Cancer 90.5 (October 20, 2000): 237-255. (Review)
PMID
11091348
Source
pubmed
Published In
International Journal of Cancer
Volume
90
Issue
5
Publish Date
2000
Start Page
237
End Page
255

Phase III randomized trial of amifostine as a radioprotector in head and neck cancer.

PURPOSE: Radiotherapy for head and neck cancer causes acute and chronic xerostomia and acute mucositis. Amifositine and its active metabolite, WR-1065, accumulate with high concentrations in the salivary glands. This randomized trial evaluated whether amifostine could ameliorate these side effects without compromising the effectiveness of radiotherapy in these patients. PATIENTS AND METHODS: Patients with previously untreated head and neck squamous cell carcinoma were eligible. Primary end points included the incidence of grade > or =2 acute xerostomia, grade > or =3 acute mucositis, and grade > or =2 late xerostomia and were based on the worst toxicity reported. Amifostine was administered (200 mg/m(2) intravenous) daily 15 to 30 minutes before irradiation. Radiotherapy was given once daily (1.8 to 2.0 Gy) to doses of 50 to 70 Gy. Whole saliva production was quantitated preradiotherapy and regularly during follow-up. Patients evaluated their symptoms through a questionnaire during and after treatment. Local-regional control was the primary antitumor efficacy end point. RESULTS: Nausea, vomiting, hypotension, and allergic reactions were the most common side effects. Fifty-three percent of the patients receiving amifostine had at least one episode of nausea and/or vomiting, but it only occurred with 233 (5%) of 4,314 doses. Amifostine reduced grade > or =2 acute xerostomia from 78% to 51% (P<.0001) and chronic xerostomia grade > or = 2 from 57% to 34% (P=.002). Median saliva production was greater with amifostine (0.26 g v 0.10 g, P=.04). Amifostine did not reduce mucositis. With and without amifostine, 2-year local-regional control, disease-free survival, and overall survival were 58% versus 63%, 53% versus 57%, and 71% versus 66%, respectively. CONCLUSION: Amifostine reduced acute and chronic xerostomia. Antitumor treatment efficacy was preserved.

Authors
Brizel, DM; Wasserman, TH; Henke, M; Strnad, V; Rudat, V; Monnier, A; Eschwege, F; Zhang, J; Russell, L; Oster, W; Sauer, R
MLA Citation
Brizel, DM, Wasserman, TH, Henke, M, Strnad, V, Rudat, V, Monnier, A, Eschwege, F, Zhang, J, Russell, L, Oster, W, and Sauer, R. "Phase III randomized trial of amifostine as a radioprotector in head and neck cancer." J Clin Oncol 18.19 (October 1, 2000): 3339-3345.
PMID
11013273
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
18
Issue
19
Publish Date
2000
Start Page
3339
End Page
3345
DOI
10.1200/JCO.2000.18.19.3339

Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment.

PURPOSE: The objectives of this study were to evaluate effects of hyperthermia on tumor oxygenation, extracellular pH (pHe), and blood flow in 13 dogs with spontaneous soft tissue sarcomas prior to and after local hyperthermia. METHODS AND MATERIALS: Tumor pO2 was measured using an Eppendorf polarographic device, pHe using interstitial electrodes, and blood flow using contrast-enhanced magnetic resonance imaging (MRI). RESULTS: There was an overall improvement in tumor oxygenation observed as an increase in median pO2 and decrease in hypoxic fraction (% of pO2 measurements <5 mm Hg) at 24-h post hyperthermia. These changes were most pronounced when the median temperature (T50) during hyperthermia treatment was less than 44 degrees C. Tumors with T50 > 44 degrees C were characterized by a decrease in median PO2 and an increase in hypoxic fraction. Similar thermal dose-related changes were observed in tumor perfusion. Perfusion was significantly higher after hyperthermia. Increases in perfusion were most evident in tumors with T50 < 44 degrees C. With T50 > 44 degrees C, there was no change in perfusion after hyperthermia. On average, pHe values declined in all animals after hyperthermia, with the greatest reduction seen for larger T50 values. CONCLUSION: This study suggests that hyperthermia has biphasic effects on tumor physiologic parameters. Lower temperatures tend to favor improved perfusion and oxygenation, whereas higher temperatures are more likely to cause vascular damage, thus leading to greater hypoxia. While it has long been recognized that such effects occur in rodent tumors, this is the first report to tie such changes to temperatures achieved during hyperthermia in the clinical setting. Furthermore, it suggests that the thermal threshold for vascular damage is higher in spontaneous tumors than in more rapidly growing rodent tumors.

Authors
Vujaskovic, Z; Poulson, JM; Gaskin, AA; Thrall, DE; Page, RL; Charles, HC; MacFall, JR; Brizel, DM; Meyer, RE; Prescott, DM; Samulski, TV; Dewhirst, MW
MLA Citation
Vujaskovic, Z, Poulson, JM, Gaskin, AA, Thrall, DE, Page, RL, Charles, HC, MacFall, JR, Brizel, DM, Meyer, RE, Prescott, DM, Samulski, TV, and Dewhirst, MW. "Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment." Int J Radiat Oncol Biol Phys 46.1 (January 1, 2000): 179-185.
PMID
10656391
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
46
Issue
1
Publish Date
2000
Start Page
179
End Page
185

Double blind randomized trial of sucralfate vs placebo during radical radiotherapy for head and neck cancers.

BACKGROUND: This study sought to determine whether sucralfate prophylaxis during a course of high dose radiation therapy (RT) for head and neck cancer decreases acute side effects. METHODS: Patients receiving curative intent RT for advanced head and neck cancers participated in a single institution double-blind randomized trial comparing sucralfate to placebo. Patients were stratified according to fractionation, use of concurrent chemotherapy, Karnofsky performance status (KPS), age, and pretreatment presence of a feeding gastrostomy. Patients were prospectively evaluated during weekly treatment checks, and analyzed with regard to time (measured in terms of dose) until development of the following: weight loss, mucositis, pain, nutritional intake, and need for a treatment break. After completion of RT, time until healing was similarly compared. RESULTS: Fifty-two patients received sucralfate and 50 received placebo. The mean (+/-SD) prescribed dose was 69 +/- 7 Gy. Sixty-nine patients received BID fractionation and 27 received concurrent chemotherapy. No difference was detected in any outcome measure in the direct comparison between the two groups. On multivariate analysis, weight loss >5% or >10% occurred more frequently in patients receiving chemotherapy (p < 0.01 and p = 0.05, respectively). Grade 3 mucositis was more common in patients receiving chemotherapy (p = 0.05) or BID fractionation (p = 0.04) or having a poor KPS (p = 0.02). Interval to healing was not associated with any of the pretreatment- or treatment-related factors. Sucralfate did not result in any additional toxicity. CONCLUSIONS: Prophylactic treatment with sucralfate during high-dose head and neck RT did not decrease acute treatment side effects. Other modalities should be investigated.

Authors
Carter, DL; Hebert, ME; Smink, K; Leopold, KA; Clough, RL; Brizel, DM
MLA Citation
Carter, DL, Hebert, ME, Smink, K, Leopold, KA, Clough, RL, and Brizel, DM. "Double blind randomized trial of sucralfate vs placebo during radical radiotherapy for head and neck cancers." Head Neck 21.8 (December 1999): 760-766.
PMID
10562690
Source
pubmed
Published In
Head & Neck: Journal for the Sciences & Specialties of the Head and Neck
Volume
21
Issue
8
Publish Date
1999
Start Page
760
End Page
766

The treatment of high-grade soft tissue sarcomas with preoperative thermoradiotherapy.

PURPOSE: To explore the use of a novel program of preoperative radiation and hyperthermia in the management of high-grade soft tissue sarcomas (STS). METHODS AND MATERIALS: Eligible patients were adults over 18 with Grade 2 or 3 STS, surgically resectable without a local excision prior to referral to Duke University Medical Center and without distant metastases. Patients were staged generally with CT and/or MR imaging. The diagnosis was established with fine needle aspiration or incisional biopsy. Patients were then treated with 5000 to 5040 cGy, 180-200 cGy per fraction. Chemotherapy was usually not employed. Generally two hyperthermia treatments per week were given with a planned thermal dose of 10-100 CEM 43 degrees T90. Invasive thermometry and thermal mapping were done in all patients. Surgical resection was planned 4-6 weeks after the completion of radiation and hyperthermia. RESULTS: Ninety-seven patients were treated on study between 1984 and 1996. Follow-up ranged from 12 to 155 months (median 32). All tumors were high-grade in nature, 44 greater than 10 cm in size (maximum tumor diameter), 43 5-10 cm in size, 10 less than 5 cm. Seventy-eight of the 97 tumors were located in an extremity. Of the 97 patients, 48 remain alive and continually free of disease following initial therapy. Of the remaining 49 patients, 44 have relapsed (34 dead, 10 living with disease), 3 have died secondary to complications of therapy, and 2 have died of unrelated causes. Ten-year actuarial overall survival, cause-specific survival, and relapse-free survival are 50, 47, and 47% respectively. The predominant pattern of failure has been distant metastases with only 2 patients developing local failure alone. Ten-year actuarial local control for extremity tumors is 94%, 63% for the 19 patients with tumors at sites other than the extremity. Of the 78 patients with extremity lesions, 63 have had limb preservation and remain locally controlled. Overall 38 patients experienced 57 major complications. There were 3 deaths, one due to adriamycin cardiomyopathy and two secondary to wound infections. Four patients required amputation secondary to postoperative wound healing problems. Complications directly attributable to hyperthermia occurred in 15 patients with 11 instances of second- or third-degree burns and two instances of subcutaneous fat necrosis. The hyperthermia complications were generally not severe and either healed readily or were excised at the time of surgical resection of the primary tumor. CONCLUSIONS: For these aggressive high-grade soft tissue sarcomas, this treatment program of preoperative thermoradiotherapy provided excellent local regional control for extremity lesions (95%) and satisfactory local regional control (63%) of nonextremity sarcomas, but did not appear to influence the rate of distant metastases or survival. Complications were frequent but apart from the direct thermal burns, not too different from those reported for preoperative radiotherapy alone. More effective adjuvant systemic therapy is necessary to impact favorably on survival.

Authors
Prosnitz, LR; Maguire, P; Anderson, JM; Scully, SP; Harrelson, JM; Jones, EL; Dewhirst, M; Samulski, TV; Powers, BE; Rosner, GL; Dodge, RK; Layfield, L; Clough, R; Brizel, DM
MLA Citation
Prosnitz, LR, Maguire, P, Anderson, JM, Scully, SP, Harrelson, JM, Jones, EL, Dewhirst, M, Samulski, TV, Powers, BE, Rosner, GL, Dodge, RK, Layfield, L, Clough, R, and Brizel, DM. "The treatment of high-grade soft tissue sarcomas with preoperative thermoradiotherapy." Int J Radiat Oncol Biol Phys 45.4 (November 1, 1999): 941-949.
PMID
10571201
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
45
Issue
4
Publish Date
1999
Start Page
941
End Page
949

Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome.

BACKGROUND AND PURPOSE: To evaluate the long term clinical significance of tumor oxygenation in a population of head and neck cancer patients receiving radiotherapy and to assess changes in tumor oxygenation during the course of treatment. METHODS AND MATERIALS: Patients with head and neck cancer receiving primary RT underwent pretreatment polarographic tumor oxygen measurement of the primary site or a metastatic neck lymph node. Treatment consisted of once daily (2 Gy/fraction to a total dose of 66-70 Gy) or twice daily irradiation (1.25 Gy/fraction to 70-75 Gy) to the primary site. Twenty-seven patients underwent a second series of measurements early in the course of irradiation. RESULTS: Sixty-three patients underwent pretreatment tumor oxygen assessment (primary site, n = 24; nodes, n = 39). The median pO2 for primary lesions was 4.8 mmHg, and it was 4.3 mmHg for cervical nodes. There was a weak association between anemia and more poorly oxygened tumors, but many non-anemic patients still had poorly oxygenated tumors. Repeat assessments of tumor oxygenation after 10-15 Gy were unchanged compared to pretreatment baselines. Poorly oxygenated nodes pretreatment were more likely to contain viable residual disease at post-radiation neck dissection. Median follow-up time for surviving patients was 20 months (range 3-50 months). Hypoxia (tumor median pO2 <10 mmHg) adversely affected 2 year local-regional control (30 vs. 73%, P = 0.01), disease-free survival (26 vs. 73%, P = 0.005), and survival (35 vs. 83%, P = 0.02). CONCLUSION: Tumor oxygenation affects the prognosis of head and neck cancer independently of other known prognostic variables. This parameter may be a useful tool for the selection of patients for investigational treatment strategies.

Authors
Brizel, DM; Dodge, RK; Clough, RW; Dewhirst, MW
MLA Citation
Brizel, DM, Dodge, RK, Clough, RW, and Dewhirst, MW. "Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome." Radiother Oncol 53.2 (November 1999): 113-117.
PMID
10665787
Source
pubmed
Published In
Radiotherapy & Oncology
Volume
53
Issue
2
Publish Date
1999
Start Page
113
End Page
117

Conformal radiation therapy treatment planning reduces the dose to the optic structures for patients with tumors of the paranasal sinuses.

PURPOSE: Compare dose distributions of traditional versus conformal beam orientations in paranasal sinus malignancies. MATERIALS AND METHODS: Maximum normal tissue doses, dose volume histograms (DVH), normal tissue complication probabilities (NTCP), and the percentage of each normal tissue receiving >80% of the average target dose (V80) were calculated. RESULTS/CONCLUSIONS: Conformal planning reduced the V80 to the optic nerves and chiasm as well as the normal tissue maximum doses to the ipsilateral and contralateral optic nerves and chiasm, and mean NTCPs.

Authors
Brizel, DM; Light, K; Zhou, SM; Marks, LB
MLA Citation
Brizel, DM, Light, K, Zhou, SM, and Marks, LB. "Conformal radiation therapy treatment planning reduces the dose to the optic structures for patients with tumors of the paranasal sinuses." Radiother Oncol 51.3 (June 1999): 215-218.
PMID
10435816
Source
pubmed
Published In
Radiotherapy & Oncology
Volume
51
Issue
3
Publish Date
1999
Start Page
215
End Page
218

Where there's smoke, is there fire?

Authors
Brizel, DM
MLA Citation
Brizel, DM. "Where there's smoke, is there fire?." Int J Hyperthermia 14.6 (November 1998): 589-591.
PMID
9886665
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
14
Issue
6
Publish Date
1998
Start Page
589
End Page
591

Radiotherapy and concurrent chemotherapy for the treatment of locally advanced head and neck squamous cell carcinoma.

Cure of locally advanced squamous cell carcinoma of the head and neck (SCCHN) is uncommon with radiotherapy alone. The desire for organ preservation in advanced resectable SCCHN and the need for better local therapy for unresectable disease have led to the development of treatment using radiotherapy and concurrent chemotherapy (RT/CCT). RT/CCT is an attractive strategy because the appropriate drug(s) may enhance radiation effects and independently contribute to local cytotoxicity. Concurrent treatment may combat tumor repopulation and provide the earliest possible treatment of distant micrometastases. RT/CCT may be integrated in synchronous or alternating schemes. Most randomized trials of RT/CCT versus radiation alone show superior local control, disease-free survival, and survival with combined modality treatment. Improved efficacy with RT/CCT is accompanied by increased acute toxicity, which necessitates compromises in the treatment design of most programs. Consequently the most effective RT/CCT regimen has not been defined. Chemical modifiers of toxicity are now under investigation in clinical trials and may allow for improved integration of RT/CCT.

Authors
Brizel, DM
MLA Citation
Brizel, DM. "Radiotherapy and concurrent chemotherapy for the treatment of locally advanced head and neck squamous cell carcinoma." Semin Radiat Oncol 8.4 (October 1998): 237-246.
PMID
9873101
Source
pubmed
Published In
Seminars in Radiation Oncology
Volume
8
Issue
4
Publish Date
1998
Start Page
237
End Page
246

Future directions in toxicity prevention.

The modern practice of radiation therapy has developed over several decades, taking into consideration the anatomic location of the tumor, technical aspects of radiation delivery, combined treatment modalities, and patient comorbidity. Improved understanding of tumor biology and kinetics has resulted in a more intensive application of multimodality therapy for many forms of cancer in the endeavor to increase treatment efficacy. However, increased treatment intensity carries a risk of increased toxicity. Conversely, reduction of toxicity by lessening treatment intensity incurs the risk of reduced efficacy. Preventing or minimizing toxicity while maintaining or increasing efficacy is necessary for overall improvement in the therapeutic ratio. New methods for reducing toxicity are currently being explored and include identification of risk factors associated with increased toxicity, the development of radioprotectants, and the use of growth factors to accelerate the replacement of damaged cells.

Authors
Brizel, DM
MLA Citation
Brizel, DM. "Future directions in toxicity prevention." Semin Radiat Oncol 8.4 Suppl 1 (October 1998): 17-20. (Review)
PMID
9794997
Source
pubmed
Published In
Seminars in Radiation Oncology
Volume
8
Issue
4 Suppl 1
Publish Date
1998
Start Page
17
End Page
20

Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer.

BACKGROUND: Radiotherapy is often the primary treatment for advanced head and neck cancer, but the rates of locoregional recurrence are high and survival is poor. We investigated whether hyperfractionated irradiation plus concurrent chemotherapy (combined treatment) is superior to hyperfractionated irradiation alone. METHODS: Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily, for a total of 7500 cGy. Patients in the combined-treatment group received 125 cGy twice daily, for a total of 7000 cGy, and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation. Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy. RESULTS: Of 122 patients who underwent randomization, 116 were included in the analysis. Most patients in both treatment groups had unresectable disease. The median follow-up was 41 months (range, 19 to 86). At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group (P=0.07). The relapse-free survival rate was higher in the combined-treatment group (61 percent vs. 41 percent, P=0.08). The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group (P=0.01). Confluent mucositis developed in 77 percent and 75 percent of the two groups, respectively. Severe complications occurred in three patients in the hyperfractionation group and five patients in the combined-treatment group. CONCLUSIONS: Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone.

Authors
Brizel, DM; Albers, ME; Fisher, SR; Scher, RL; Richtsmeier, WJ; Hars, V; George, SL; Huang, AT; Prosnitz, LR
MLA Citation
Brizel, DM, Albers, ME, Fisher, SR, Scher, RL, Richtsmeier, WJ, Hars, V, George, SL, Huang, AT, and Prosnitz, LR. "Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer." N Engl J Med 338.25 (June 18, 1998): 1798-1804.
PMID
9632446
Source
pubmed
Published In
The New England journal of medicine
Volume
338
Issue
25
Publish Date
1998
Start Page
1798
End Page
1804
DOI
10.1056/NEJM199806183382503

Artificial neural network model of survival in patients treated with irradiation with and without concurrent chemotherapy for advanced carcinoma of the head and neck.

PURPOSE: This study was performed to investigate the feasibility of predicting survival in squamous cell carcinoma of the head and neck (SCCHN) with an artificial neural network (ANN), and to compare ANN performance with conventional models. METHODS AND MATERIALS: Data were analyzed from a Phase III trial in which patients with locally advanced SCCHN received hyperfractionated irradiation with or without concurrent cisplatin and 5-fluorouracil. Of the 116 randomized patients, 95 who had 2-year follow-up and all required data were evaluated. ANN and logistic regression (LR) models were constructed to predict 2-year total survival using round-robin cross-validation. A modified staging model was also examined. RESULTS: The best LR model used tumor size, nodal stage, and race to predict survival. The best ANN used nodal stage, tumor size, stage, and resectability, and hemoglobin. Treatment type did not predict 2-year survival and was not included in either model. Using the respective best feature sets, the area under the receiver operating characteristic curve (Az) for the ANN was 0.78 +/- 0.05, showing more accurate overall performance than LR (Az = 0.67 +/- 0.05, p = 0.07). At 70% sensitivity, the ANN was 72% specific, while LR was 54% specific (p = 0.08). At 70% specificity, the ANN was 72% sensitive, while LR was 54% sensitive (p = 0.07). When both models used the five predictive variables best for an ANN, Az for LR decreased [Az = 0.61 +/- 0.06, p < 0.01 (ANN)]. The models performed equivalently when using the three variables best for LR. The best ANN also compared favorably with staging [Az = 0.60 +/- 0.07, p = 0.02 (ANN)]. CONCLUSIONS: An ANN modeled 2-year survival in this data set more accurately than LR or staging models and employed predictive variables that could not be used by LR. Further work is planned to confirm these results on larger patient samples, examining longer follow-up to incorporate treatment type into the model.

Authors
Bryce, TJ; Dewhirst, MW; Floyd, CE; Hars, V; Brizel, DM
MLA Citation
Bryce, TJ, Dewhirst, MW, Floyd, CE, Hars, V, and Brizel, DM. "Artificial neural network model of survival in patients treated with irradiation with and without concurrent chemotherapy for advanced carcinoma of the head and neck." Int J Radiat Oncol Biol Phys 41.2 (May 1, 1998): 339-345.
PMID
9607349
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
41
Issue
2
Publish Date
1998
Start Page
339
End Page
345

Treatment of head and neck cancer [3] (multiple letters)

Authors
Evans, RA; Rescigno, J; Heitjan, DF; Tobias, JS; Brizel, DM
MLA Citation
Evans, RA, Rescigno, J, Heitjan, DF, Tobias, JS, and Brizel, DM. "Treatment of head and neck cancer [3] (multiple letters)." New England Journal of Medicine 339.18 (1998): 1330-1331.
PMID
9841298
Source
scival
Published In
New England Journal of Medicine
Volume
339
Issue
18
Publish Date
1998
Start Page
1330
End Page
1331
DOI
10.1056/NEJM199810293391814

Future directions in toxicity prevention

The modern practice of radiation therapy has developed over several decades, taking into consideration the anatomic location of the tumor, technical aspects of radiation delivery, combined treatment modalities, and patient comorbidity. Improved understanding of tumor biology and kinetics has resulted in a more intensive application of multimodality therapy for many forms of cancer in the endeavor to increase treatment efficacy. However, increased treatment intensity carries a risk of increased toxicity. Conversely, reduction of toxicity by lessening treatment intensity incurs the risk of reduced efficacy. Preventing or minimizing toxicity while maintaining or increasing efficacy is necessary for overall improvement in the therapeutic ratio. New methods for reducing toxicity are currently being explored and include identification of risk factors associated with increased toxicity, the development of radioprotectants, and the use of growth factors to accelerate the replacement of damaged cells.

Authors
Brizel, DM
MLA Citation
Brizel, DM. "Future directions in toxicity prevention." Seminars in Radiation Oncology 8.4 SUPPL. 1 (1998): 17-20.
Source
scival
Published In
Seminars in Radiation Oncology
Volume
8
Issue
4 SUPPL. 1
Publish Date
1998
Start Page
17
End Page
20

Radiation techniques for the treatment of Hodgkin's disease with combined modality therapy or radiation alone.

This article reviews radiation techniques including field arrangements, anatomic borders, and doses for the treatment of Hodgkin's disease when radiotherapy is being used as the sole treatment and when it is part of a planned combined modality program with chemotherapy. We describe the techniques currently in use at Duke University Medical Center. Particular emphasis is placed on the evidence regarding the appropriate extent of the treatment field and the doses of radiation necessary to achieve local control. These issues assume increasing importance as we attempt to maintain high cure rates for Hodgkin's disease but lower the frequency of serious long-term complications.

Authors
Prosnitz, LR; Brizel, DM; Light, KL
MLA Citation
Prosnitz, LR, Brizel, DM, and Light, KL. "Radiation techniques for the treatment of Hodgkin's disease with combined modality therapy or radiation alone." Int J Radiat Oncol Biol Phys 39.4 (November 1, 1997): 885-895. (Review)
PMID
9369138
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
39
Issue
4
Publish Date
1997
Start Page
885
End Page
895

Interlaboratory variation in oxygen tension measurement by Eppendorf "Histograph" and comparison with hypoxic marker.

BACKGROUND AND OBJECTIVES: The median of pO2 values in tumor measured by Eppendorf "Histograph" with a needle-type electrode has been used as a prognostic indicator in cancer patients. However, it is not established that a pretreatment measured pO2 value can be used as a universal predictor of local control probability, because the variation in pO2 values, especially in hypoxic tissue, among institutes may not allow comparison of measured "absolute pO2 values." The purpose of this study was to examine the variation in oxygen tension measurement by Eppendorf "Histograph" among six laboratories using a single batch of mice and tumors and the same detailed protocol. These results were also compared to the immunohistochemical staining of 2-nitromidazole adducts. METHODS: C3H mice bearing FSaII murine fibrosarcoma subcutaneously were shipped to all laboratories, and the oxygen status in tumors and in normal subcutis was examined using Eppendorf "Histograph" and immunohistochemical hypoxic marker. RESULTS: All laboratories showed that the FSaII tumor was hypoxic with at least 77% of measured points under 10 mmHg in pO2 and with a median pO2 value less than that of normal subcutis. These results were further confirmed immunohistochemically. These findings are interpreted as evidence that the pO2 values measured by Eppendorf "Histograph" can be useful. However, the median values of tumor pO2 varied from 1.5 mmHg to 5.6 mmHg among the laboratories, and pO2 of normal subcutis also varied from 28 mmHg to 38 mmHg. There were also significant differences in hypoxic fraction, defined as the fraction under a given oxygen partial pressure (i.e., under 2.5, 5, or 10 mmHg), among institutes. CONCLUSIONS: Caution needs to be exercised in using the absolute, median, or distribution of pO2 values measured by the Eppendorf "Histograph" to compare the data between laboratories or to predict the radiation response in an individual subject.

Authors
Nozue, M; Lee, I; Yuan, F; Teicher, BA; Brizel, DM; Dewhirst, MW; Milross, CG; Milas, L; Song, CW; Thomas, CD; Guichard, M; Evans, SM; Koch, CJ; Lord, EM; Jain, RK; Suit, HD
MLA Citation
Nozue, M, Lee, I, Yuan, F, Teicher, BA, Brizel, DM, Dewhirst, MW, Milross, CG, Milas, L, Song, CW, Thomas, CD, Guichard, M, Evans, SM, Koch, CJ, Lord, EM, Jain, RK, and Suit, HD. "Interlaboratory variation in oxygen tension measurement by Eppendorf "Histograph" and comparison with hypoxic marker." J Surg Oncol 66.1 (September 1997): 30-38.
PMID
9290690
Source
pubmed
Published In
Journal of Surgical Oncology
Volume
66
Issue
1
Publish Date
1997
Start Page
30
End Page
38

Comparison of two head and neck immobilization systems.

PURPOSE: Accurate and reproducible patient positioning is fundamental to the success of fractionated radiotherapy. Concurrent with the introduction of three-dimensional treatment planning capabilities at our institution, a head and neck immobilization system consisting of a standard foam rubber head support and three casting strips was replaced by a customized mask-based device. This study was performed to analyze the impact of the customized immobilization system on the reproducibility of patient setup during irradiation of head and neck and brain tumors. METHODS AND MATERIALS: Patients treated from 1989-1991 were immobilized with the strip system while those treated from 1991-1995 were immobilized with the mask. All treatment fields were simulated and were treated on a 4 MV (where the strip, but not the mask, system was fixed to the treatment couch) or > or = 6 MV (where both the strip and the mask systems were fixed to the couch) accelerator. Port films were taken on the initial treatment day, routinely during treatment, and following shifts (requested). The number, magnitude, and direction of any isocenter shifts were retrospectively reviewed. A two-tailed chi square test was used to compare the differences in requested shifts in the strip and mask groups. RESULTS: The study population consisted of 69 brain tumor (35 strip, 34 mask) and 71 head and neck (37 strip, 34 mask) patients. A total of 1575 port films representing 1070 isocenter placements were analyzed. No differences between the immobilization systems was seen on the 4-MV accelerator (where the mask system was not fixed to the couch). On the > or = 6-MV units, the frequency of shifts was 16.1% versus 6.2% (p = 0.002) with the strips and mask, respectively. Almost all of the benefit was seen in the routine films, where the corresponding rates were 13.2% and 4.1% (p = 0.007). For the mask system, the rate of requested shifts on routine films was 4.1% (8/197) for the > or = 6-MV units and 14.5% (24/166) for the 4-MV unit (p = 0.001). CONCLUSION: Using the frequency of physician-requested isocenter shifts as an indicator of the accuracy of patient repositioning, the newer mask system appears to be an improvement over the previously used strip system, provided that the immobilization device is secured to the treatment couch. Increased accuracy of daily setup provides an opportunity to improve the therapeutic ratio both by increased likelihood of tumor control and decreased risk of normal tissue complications.

Authors
Bentel, GC; Marks, LB; Hendren, K; Brizel, DM
MLA Citation
Bentel, GC, Marks, LB, Hendren, K, and Brizel, DM. "Comparison of two head and neck immobilization systems." Int J Radiat Oncol Biol Phys 38.4 (July 1, 1997): 867-873.
PMID
9240656
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
38
Issue
4
Publish Date
1997
Start Page
867
End Page
873

Hyperbaric oxygen improves tumor radiation response significantly more than carbogen/nicotinamide.

This laboratory previously demonstrated that hyperbaric oxygen and hyperbaric carbogen improved oxygenation in the R3230Ac tumor, but normobaric 100% O2 and carbogen did not. The current study assessed tumor growth after exposure to radiation plus either hyperbaric oxygen, carbogen or carbogen/nicotinamide and the relationship between pretreatment tumor oxygenation and growth time. R3230Ac carcinomas were grown in the flanks of F344 rats. Animals were randomized to one of seven radiation treatment groups: sham irradiation or irradiation plus room air, hyperbaric oxygen (100% O2/3 atmospheres), nicotinamide (0.3 mg/g intraperitoneally 20 min before irradiation), carbogen, carbogen/nicotinamide or hyperbaric oxygen/nicotinamide. Tumors received 20 Gy in a single dose. Median growth times were 6, 18, 18, 20, 22, 28 and 27 days for controls and irradiation plus room air, carbogen, nicotinamide, carbogen/nicotinamide, hyperbaric oxygen and hyperbaric oxygen/nicotinamide, respectively. Irradiation with hyperbaric oxygen, hyperbaric oxygen/ nicotinamide and carbogen/nicotinamide increased growth time (P < 0.001, P < 0.001 and P = 0.003, respectively) relative to room air. Hyperbaric oxygen was significantly more effective than carbogen/nicotinamide (P = 0.001). Growth times for all tumors exposed to hyperbaric oxygen were longer than those of the most fully oxygenated tumors (no baseline pO2 values < 10 mm Hg) not exposed to hyperbaric oxygen (P < 0.001). These results suggest that hyperbaric oxygen may improve radiation response by additional mechanisms separate from overcoming the oxygen effect.

Authors
Brizel, DM; Hage, WD; Dodge, RK; Munley, MT; Piantadosi, CA; Dewhirst, MW
MLA Citation
Brizel, DM, Hage, WD, Dodge, RK, Munley, MT, Piantadosi, CA, and Dewhirst, MW. "Hyperbaric oxygen improves tumor radiation response significantly more than carbogen/nicotinamide." Radiat Res 147.6 (June 1997): 715-720.
PMID
9189170
Source
pubmed
Published In
Radiation Research
Volume
147
Issue
6
Publish Date
1997
Start Page
715
End Page
720

Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck.

PURPOSE: Tumor hypoxia adversely affects short term clinical radiation response of head and neck cancer lymph node metastases and long term disease-free survival (DFS) in cervix carcinoma. This study was performed to evaluate the relationship between tumor hypoxia and DFS in patients with squamous carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Pretreatment tumor pO2 was assessed polarographically in SCCHN patients. All patients were AJCC Stage IV and had pretreatment oxygen measurements taken from locally advanced primaries (T3 or T4) or neck nodes > or = 1.5 cm diameter. Treatment consisted of once daily (2 Gy/day to 66-70 Gy) or twice daily irradiation (1.25 Gy B.I.D. to 70-75 Gy) +/- planned neck dissection (for > or = N2A disease) according to institutional treatment protocols. RESULTS: Twenty-eight patients underwent tumor pO2 measurement. The average pre-treatment median pO2 was 11.2 mm Hg (range 0.4-60 mm Hg). The DFS at 12 months was 42%. The DFS was 78% for patients with median tumor pO2 > 10 mm Hg but only 22% for median pO2 < 10 mm Hg (p = 0.009). The average tumor median pO2 for relapsing patients was 4.1 mm Hg and 17.1 mm Hg in non-relapsing (NED) patients (p = 0.007). CONCLUSION: Tumor hypoxia adversely affected the prognosis of patients in this study. Understanding of the mechanistic relationship between hypoxia and treatment outcome will allow for the development of new and rational treatment programs in the future.

Authors
Brizel, DM; Sibley, GS; Prosnitz, LR; Scher, RL; Dewhirst, MW
MLA Citation
Brizel, DM, Sibley, GS, Prosnitz, LR, Scher, RL, and Dewhirst, MW. "Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck." Int J Radiat Oncol Biol Phys 38.2 (May 1, 1997): 285-289.
PMID
9226314
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
38
Issue
2
Publish Date
1997
Start Page
285
End Page
289

Is hyperbaric oxygen more effective than carbogen/nicotinamide in tumor radiation response? (multiple letters)

Authors
Hartmann, KA; Kleij, AJVD; Schneider, CJ; Sminia, P; Brizel, DM; Dewhirst, MW; Brown, JM; Wouters, BG
MLA Citation
Hartmann, KA, Kleij, AJVD, Schneider, CJ, Sminia, P, Brizel, DM, Dewhirst, MW, Brown, JM, and Wouters, BG. "Is hyperbaric oxygen more effective than carbogen/nicotinamide in tumor radiation response? (multiple letters)." Radiation Research 148.5 (1997): 523-527.
PMID
9355875
Source
scival
Published In
Radiation Research
Volume
148
Issue
5
Publish Date
1997
Start Page
523
End Page
527
DOI
10.2307/3579327

Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas.

The adverse prognostic impact of tumor hypoxia has been demonstrated in human malignancy. We report the effects of radiotherapy and hyperthermia (HT) on soft tissue sarcoma oxygenation and the relationship between treatment-induced changes in oxygenation and clinical treatment outcome. Patients receiving preoperative radiotherapy and HT underwent tumor oxygenation measurement pretreatment after the start of radiation/pre-HT and one day after the first HT treatment. The magnitude of improvement in tumor oxygenation after the first HT fraction relative to pretreatment baseline was positively correlated with the amount of necrosis seen in the resection specimen. Patients with <90% resection specimen necrosis experienced longer disease-free survival than those with > or = 90% necrosis. Increasing levels of tumor hypoxia were also correlated with diminished metabolic status as measured by P-31 magnetic resonance spectroscopy.

Authors
Brizel, DM; Scully, SP; Harrelson, JM; Layfield, LJ; Dodge, RK; Charles, HC; Samulski, TV; Prosnitz, LR; Dewhirst, MW
MLA Citation
Brizel, DM, Scully, SP, Harrelson, JM, Layfield, LJ, Dodge, RK, Charles, HC, Samulski, TV, Prosnitz, LR, and Dewhirst, MW. "Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas." Cancer Res 56.23 (December 1, 1996): 5347-5350.
PMID
8968082
Source
pubmed
Published In
Cancer Research
Volume
56
Issue
23
Publish Date
1996
Start Page
5347
End Page
5350

Monitoring of neoadjuvant therapy response of soft-tissue and musculoskeletal sarcoma using fluorine-18-FDG PET.

UNLABELLED: The purpose of this study was to investigate the potential role of FDG-PET in the monitoring of neoadjuvant therapy of soft-tissue and musculoskeletal sarcomas. METHODS: Nine patients were studied. Neoadjuvant therapy consisted of either chemotherapy or combined radiotherapy and hyperthermia. The FDG-PET studies were obtained, when possible, prior to therapy, 1-3 wk after commencement of therapy, and prior to surgery after completion of neoadjuvant therapy. In two patients, all three studies were completed. The remainder of patients underwent one or two studies at varying timepoints. RESULTS: In tumors treated with combined radiotherapy and hyperthermia, well-defined regions of absent uptake developed within responsive tumors, correlating pathologically with necrosis. Following treatment, a peripheral rim of FDG accumulation was found to correlate pathologically with the formation of a fibrous pseudocapsule. In tumors treated with chemotherapy, FDG accumulation decreased more homogeneously throughout the tumor, in responsive cases. Despite 100% tumor cell kill in some patients, persistent tumor FDG uptake was observed which correlated pathologically with uptake within benign therapy-related fibrous tissue. Significant FDG accumulation was also observed at the site of an uncontaminated incisional biopsy. CONCLUSION: These initial results demonstrate changes in tumor accumulation of FDG during and after neoadjuvant therapy; these changes are dependent on the type of neoadjuvant therapy administered. Prominent FDG accumulation was observed in benign tissues both within and adjacent to the treated tumor.

Authors
Jones, DN; McCowage, GB; Sostman, HD; Brizel, DM; Layfield, L; Charles, HC; Dewhirst, MW; Prescott, DM; Friedman, HS; Harrelson, JM; Scully, SP; Coleman, RE
MLA Citation
Jones, DN, McCowage, GB, Sostman, HD, Brizel, DM, Layfield, L, Charles, HC, Dewhirst, MW, Prescott, DM, Friedman, HS, Harrelson, JM, Scully, SP, and Coleman, RE. "Monitoring of neoadjuvant therapy response of soft-tissue and musculoskeletal sarcoma using fluorine-18-FDG PET." J Nucl Med 37.9 (September 1996): 1438-1444.
PMID
8790188
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
37
Issue
9
Publish Date
1996
Start Page
1438
End Page
1444

Arteriolar oxygenation in tumour and subcutaneous arterioles: effects of inspired air oxygen content.

Carbogen is thought to be more effective than normobaric oxygen in reducing tumour hypoxia because it may reduce hyperoxic vasoconstriction. In this study, tumour and normal arteriolar diameters were measured simultaneously with perivascular pO2 during air breathing followed by either carbogen or 100% oxygen to determine whether the action of carbogen is the result of alterations in feeding vessel diameter. Fischer-344 rats bearing dorsal flap window chambers, with or without implanted R3230AC tumours, were the experimental subjects. Arteriolar diameters were measured using optical techniques and perivascular pO2 was measured using recessed-tip electrodes (3-6 microns tip diameter). Baseline arteriolar pO2 averaged 30-50% of blood gas pO2 (mean = 97 mmHg). Both hyperoxic gases increased blood gas pO2 by 4-to 5-fold, but relative improvements in arteriolar pO2 were < or = 2.5 for all arterioles studied. This means that these normobaric high O2 gases are not very efficient in increasing O2 delivery to tumours. In addition, improvements in tumour arteriolar pO2 were transient for both hyperoxic gases. Oxygen and carbogen caused no change and mild vasodilatory responses in tumour arterioles, respectively. Normal arterioles on the other hand, tended toward vasoconstriction by carbogen breathing. Peri-arteriolar pO2 in tumours increased within the first 5 min of breathing either hyperoxic gas, followed by a decline back toward values seen with air-breathing. These results suggest that temporal changes in tumour oxygenation after exposure to carbogen or O2 may not be due to changes in perfusion. Other factors, such as changes in O2 consumption rate may be involved.

Authors
Dewhirst, MW; Ong, ET; Rosner, GL; Rehmus, SW; Shan, S; Braun, RD; Brizel, DM; Secomb, TW
MLA Citation
Dewhirst, MW, Ong, ET, Rosner, GL, Rehmus, SW, Shan, S, Braun, RD, Brizel, DM, and Secomb, TW. "Arteriolar oxygenation in tumour and subcutaneous arterioles: effects of inspired air oxygen content." Br J Cancer Suppl 27 (July 1996): S241-S246.
PMID
8763889
Source
pubmed
Published In
The British journal of cancer. Supplement
Volume
27
Publish Date
1996
Start Page
S241
End Page
S246

Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma.

This study was performed to explore the relationship between tumor oxygenation and treatment outcome in human soft tissue sarcoma. Twenty-two patients with nonmestastatic, high-grade, soft tissue sarcomas underwent preoperative irradiation and hyperthermia and pretreatment measurement of tumor oxygenation. The 18-month actuarial disease-free survival was 70% for patients with tumor median oxygen pressure (pO2) values of >10 mm Hg but only 35% for those with median pO2 values of <10 mm Hg (P=0.01). There were eight treatment failures; the first site of recurrence was lung in all patients. Median pO2 was 7.5 mm Hg for metastasizing tumors versus 20 mm Hg for nonmetastasizing tumors (P=0.03). Potential mechanisms and implications for clinical trial design are discussed.

Authors
Brizel, DM; Scully, SP; Harrelson, JM; Layfield, LJ; Bean, JM; Prosnitz, LR; Dewhirst, MW
MLA Citation
Brizel, DM, Scully, SP, Harrelson, JM, Layfield, LJ, Bean, JM, Prosnitz, LR, and Dewhirst, MW. "Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma." Cancer Res 56.5 (March 1, 1996): 941-943.
PMID
8640781
Source
pubmed
Published In
Cancer Research
Volume
56
Issue
5
Publish Date
1996
Start Page
941
End Page
943

Arteriolar oxygenation in tumour and subcutaneous arterioles: Effects of inspired air oxygen content

Carbogen is thought to be more effective than normobaric oxygen in reducing tumour hypoxia because it may reduce hyperoxic vasoconstriction. In this study, tumour and normal arteriolar diameters were measured simultaneously with perivascular pO2 during air breathing followed by either carbogen or 100% oxygen to determine whether the action of carbogen is the result of alterations in feeding vessel diameter. Fischer-344 rats bearing dorsal flap window chambers, with or without implanted R3230AC tumours, were the experimental subjects. Arteriolar diameters were measured using optical techniques and perivascular pO2 was measured using recessed-tip electrodes (3-6 μm tip diameter). Baseline arteriolar pO2 averaged 30-50% of blood gas pO2 (mean = 97 mmHg). Both hyperoxic gases increased blood gas pO2 by 4- to 5-fold, but relative improvements in arteriolar pO2 were ≤ 2.5 for all arterioles studied. This means that these normobaric high O2 gases are not very efficient in increasing O2 delivery to tumours. In addition, improvements in tumour arteriolar pO2 were transient for both hyperoxic gases. Oxygen and carbogen caused no change and mild vasodilatory responses in tumour arterioles, respectively. Normal arterioles on the other hand, tended toward vasoconstriction by carbogen breathing. Peri-arteriolar pO2 in tumours increased within the first 5 min of breathing either hyperoxic gas, followed by a decline back toward values seen with air breathing. These results suggest that temporal changes in tumour oxygenation after exposure to carbogen or O2 may not be due to changes in perfusion. Other factors, such as changes in O2 consumption rate may be involved.

Authors
Dewhirst, MW; Ong, ET; Rosner, GL; Rehmus, SW; Shan, S; Braun, RD; Brizel, DM; Secomb, TW
MLA Citation
Dewhirst, MW, Ong, ET, Rosner, GL, Rehmus, SW, Shan, S, Braun, RD, Brizel, DM, and Secomb, TW. "Arteriolar oxygenation in tumour and subcutaneous arterioles: Effects of inspired air oxygen content." British Journal of Cancer 74.SUPPL. XXVII (1996): S241-S246.
Source
scival
Published In
British Journal of Cancer
Volume
74
Issue
SUPPL. XXVII
Publish Date
1996
Start Page
S241
End Page
S246

The mechanisms by which hyperbaric oxygen and carbogen improve tumour oxygenation.

Hyperbaric oxygen (HBO) has been proposed to reduce tumour hypoxia by increasing the amount of dissolved oxygen in the plasma. That this actually occurs has not been verified experimentally. This study was performed to explore changes in tumour oxygenation induced by treatment with normobaric and hyperbaric oxygen and carbogen. R3230Ac mammary adenocarcinomas were implanted into Fisher 344 rats. Arterial blood gases, blood pressure and heart rate were monitored. Tumour oxygenation was measured polarographically in five sets of animals. They received either normobaric 100% oxygen, hyperbaric (3 atmospheres; atm) 100% oxygen, normobaric carbogen or hyperbaric (3 atm) carbogen (HBC) +/- bretylium. HBO reduced the mean level of low pO2 values (< 5 mmHg) from 0.49 to 0.07 (P = 0.0003) and increased the average median pO2 from 8 mmHg to 55 mmHg (P = 0.001). HBC reduced the level of low pO2 values from 0.82 to 0.51 (P = 0.002) an increased median pO2 from 2 mmHg to 6 mmHg (P = 0.05). Normobaric oxygen and carbogen did not change tumour oxygenation significantly. Sympathetic blockade with bretylium before HBC exposure improved oxygenation significantly more than HBC alone (low pO2 0.55-0.17, median pO2 4-17 mmHg). HBO and hyperbaric carbogen improved tumour oxygenation in this model, while normobaric oxygen or carbogen had no effect. Sympathetic-mediated vasoconstriction during hyperbaric carbogen caused it to be less effective than HBO. This mechanism also appeared to operate during normobaric carbogen breathing.

Authors
Brizel, DM; Lin, S; Johnson, JL; Brooks, J; Dewhirst, MW; Piantadosi, CA
MLA Citation
Brizel, DM, Lin, S, Johnson, JL, Brooks, J, Dewhirst, MW, and Piantadosi, CA. "The mechanisms by which hyperbaric oxygen and carbogen improve tumour oxygenation." Br J Cancer 72.5 (November 1995): 1120-1124.
PMID
7577456
Source
pubmed
Published In
British Journal of Cancer
Volume
72
Issue
5
Publish Date
1995
Start Page
1120
End Page
1124

Patterns and variability of tumor oxygenation in human soft tissue sarcomas, cervical carcinomas, and lymph node metastases.

PURPOSE: The validity of tumor pO2 measurement as a predictive outcome assay depends upon demonstrating that intrapatient pO2 variation is less than interpatient variation. No consensus exists regarding the appropriate distance between individual measurements. This distance could affect the calculation of the hypoxic fraction (% pO2s < 5 mm Hg) and the assessment of intra/interpatient heterogeneity. This study was performed to evaluate tumor oxygenation and to assess the effects of two different measurement intervals on pO2 heterogeneity in three different sets of patients. MATERIALS AND METHODS: Fifteen patients with soft tissue sarcoma, nine patients with cervical carcinoma, and eight patients with squamous carcinoma metastatic to lymph nodes underwent pretreatment polarographic pO2 measurements. Two grossly distinct sites were studied in each tumor, and 2-3 linear tracks were measured at each site. Track lengths varied from 20-36 mm. Distance between measured points was either 0.7-0.8 mm or 0.4 mm. Mean pO2, median pO2, and hypoxic fraction were calculated for each track. Data for each patient were also averaged across all tracks obtained for that patient. Track-specific data were used to evaluate intrapatient variation. The range of average values for each patient was used to assess interpatient heterogeneity. The ratio of these measures provided an assessment of within- vs. between-patient heterogeneity. RESULTS: The median number of pO2 measurements/patient was 200 (range: 88-356). The average length of hypoxic regions varied from 4.5-5.6 mm. Median tumor pO2s for the cervix, lymph node, and sarcoma patients were 4.5 mm Hg, 12.6 mm Hg, and 18.0 mm Hg, respectively (p = 0.07). Median hypoxic fractions were 0.61, 0.36, and 0.31, respectively (p = 0.07). Intrapatient heterogeneity was less than interpatient heterogeneity for all parameters in all patients, except for mean pO2 for the cervix patients measured at 0.7-mm increments (1.51). Assessment of oxygenation was not affected by the distance between samples. CONCLUSIONS: Heterogeneity of tumor oxygenation within tumors is less than that between tumors. Both 0.4 mm and 0.7-0.8 mm sampling increments provide similar data. Longer term follow-up of large numbers of uniformly treated patients is required to define the value of tumor oxygen measurement as a predictor of treatment outcome.

Authors
Brizel, DM; Rosner, GL; Prosnitz, LR; Dewhirst, MW
MLA Citation
Brizel, DM, Rosner, GL, Prosnitz, LR, and Dewhirst, MW. "Patterns and variability of tumor oxygenation in human soft tissue sarcomas, cervical carcinomas, and lymph node metastases." Int J Radiat Oncol Biol Phys 32.4 (July 15, 1995): 1121-1125.
PMID
7607933
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
32
Issue
4
Publish Date
1995
Start Page
1121
End Page
1125

The effect of the perflubron emulsion Oxygent on the calibration characteristics of polarographic oxygen electrodes.

The perfluorocarbon emulsion Oxygent improves normal tissue oxygenation. A clinical trial is planned to evaluate this effect in tumors. Polarographic oxygen electrodes were calibrated in solutions of saline +/- perflubron to assess whether Oxygent influenced probe behavior. Calibrations were linear under both conditions. There were no major differences in estimated oxygen tensions.

Authors
Brizel, DM; Dodge, R; Dewhirst, MW
MLA Citation
Brizel, DM, Dodge, R, and Dewhirst, MW. "The effect of the perflubron emulsion Oxygent on the calibration characteristics of polarographic oxygen electrodes." Radiother Oncol 33.3 (December 1994): 262-265.
PMID
7716267
Source
pubmed
Published In
Radiotherapy & Oncology
Volume
33
Issue
3
Publish Date
1994
Start Page
262
End Page
265

Pretreatment oxygenation profiles of human soft tissue sarcomas.

PURPOSE: Tumor oxygenation is thought to influence the radiocurability of many malignancies. Advances in polarographic electrode technology have facilitated the in situ measurement of human tumor pO2. The optimal method of defining a "hypoxic" tumor is not known. Characterization of intra-tumor and intertumor pO2 heterogeneity could help with this process. This study was performed to evaluate pretreatment tumor oxygenation status and pO2 heterogeneity in patients with soft tissue sarcoma. METHODS AND MATERIALS: Nine patients with soft tissue sarcomas underwent pretreatment pO2 measurements with the Eppendorf pO2 histograph. Two grossly distinct anatomic sites within each tumor were measured in all but one patient; these were localized under computerized tomography guidance to ensure that all measurements were obtained from tumor tissue. Multiple probe tracks were studied at each site. Measurements were performed in resting, awake patients. RESULTS: A total of 1588 pO2 readings was obtained (mean = 176/patient). Measurement path lengths ranged from 22-36 mm. The average hypoxic fraction (pO2 < 5 mm Hg) was 29% (range 0-76%). Arterial pO2 was positively correlated with mean and median tumor pO2. Tumor hypoxic fraction increased with increasing tumor volume. Linear pO2 profiles and frequency histograms provided similar estimates of the extent of hypoxia in individual tumors. Marked variation in oxygenation existed both within and between individual tumors. The intertumor variation was greater than the intratumor variation. CONCLUSION: Radiobiologic hypoxia exists in human soft tissue sarcomas. The pO2 variation within individual tumors is less than the variation between tumors. Further study is necessary to identify the best parameter for defining tumor hypoxia and to discern the relationship between tumor pO2 and treatment outcome.

Authors
Brizel, DM; Rosner, GL; Harrelson, J; Prosnitz, LR; Dewhirst, MW
MLA Citation
Brizel, DM, Rosner, GL, Harrelson, J, Prosnitz, LR, and Dewhirst, MW. "Pretreatment oxygenation profiles of human soft tissue sarcomas." Int J Radiat Oncol Biol Phys 30.3 (October 15, 1994): 635-642.
PMID
7928495
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
30
Issue
3
Publish Date
1994
Start Page
635
End Page
642

Cyclophosphamide, doxorubicin, vincristine, and prednisone for primary central nervous system lymphoma: short-duration response and multifocal intracerebral recurrence preceding radiotherapy.

The activity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the treatment of primary central nervous system lymphoma (PCNSL) prior to radiotherapy was studied in six patients. Primary lesions were reduced by 80% or more on contrast-enhancing cross-sectional area in four patients and to a lesser extent in two others after two cycles of chemotherapy. The primary lesion sites demonstrated no contrast enhancement in the three patients who completed four cycles of therapy. However, concurrent with response at the primary disease sites, multiple lesions occurred at distant, noncontiguous CNS parenchymal sites in five patients after two to four cycles of chemotherapy. Median survival was 8.5 months for the six enrolled patients and 16.5 months for the four patients completing craniospinal radiotherapy. PCNSL is highly responsive to standard systemic non-Hodgkin's lymphoma chemotherapy regimens, but the pattern and rapidity of relapse suggest mechanisms of failure including inherent or rapidly evolving antineoplastic drug resistance and perhaps limited drug delivery to occult sites of disease in the brain.

Authors
Lachance, DH; Brizel, DM; Gockerman, JP; Halperin, EC; Burger, PC; Boyko, OB; Brown, MT; Schold, SC
MLA Citation
Lachance, DH, Brizel, DM, Gockerman, JP, Halperin, EC, Burger, PC, Boyko, OB, Brown, MT, and Schold, SC. "Cyclophosphamide, doxorubicin, vincristine, and prednisone for primary central nervous system lymphoma: short-duration response and multifocal intracerebral recurrence preceding radiotherapy." Neurology 44.9 (September 1994): 1721-1727.
PMID
7936304
Source
pubmed
Published In
Neurology
Volume
44
Issue
9
Publish Date
1994
Start Page
1721
End Page
1727

A pilot study of etoposide, vinblastine, and doxorubicin plus involved field irradiation in advanced, previously untreated Hodgkin's disease.

BACKGROUND: Advanced stage Hodgkin's disease (HD) usually is treated with combination chemotherapy with or without supplemental irradiation. The risk of significant acute and long term toxicity when the chemotherapy regimen contains alkylating agents has provided the impetus for the development of systemic combinations that do not include alkylating agents. This trial was designed to assess the toxicity and efficacy of a regimen of etoposide, vinblastine, and doxorubicin (EVA) as part of a combined modality approach in patients with moderate to high risk HD. METHODS: This was a prospective pilot study that included 26 previously untreated patients. They received 6 cycles of EVA, and complete responders received low dose (1500-2500 cGy) involved field radiation. RESULTS: Four patients were hospitalized for sepsis during chemotherapy. Complete response was achieved in 54% of patients, and 46% patients experienced induction failures. Two year failure-free survival is 44%, while 2 year overall survival is 86%. Median follow-up is 27 months. CONCLUSIONS: The EVA regimen is no more efficacious than other programs already in use and may be less so. It also is potentially leukemogenic because of the presence of etoposide. New combinations that do not contain etoposide should be explored in therapy programs for advanced HD in the hopes of discovering an efficacious treatment program that has minimal long term side effects.

Authors
Brizel, DM; Gockerman, JP; Crawford, J; Hathorn, JW; Moore, JO; Osborne, B; Prosnitz, LR
MLA Citation
Brizel, DM, Gockerman, JP, Crawford, J, Hathorn, JW, Moore, JO, Osborne, B, and Prosnitz, LR. "A pilot study of etoposide, vinblastine, and doxorubicin plus involved field irradiation in advanced, previously untreated Hodgkin's disease." Cancer 74.1 (July 1, 1994): 159-163.
PMID
8004571
Source
pubmed
Published In
Cancer
Volume
74
Issue
1
Publish Date
1994
Start Page
159
End Page
163

Pilot study of positron emission tomography in patients with advanced head and neck cancer receiving radiotherapy and chemotherapy.

BACKGROUND: Positron emission tomography (PET) provides a noninvasive modality for evaluating the biochemical processes of normal and pathologic tissue. Preliminary reports of F-18 fluorodeoxyglucose (FDG) PET indicate its potential usefulness in evaluating head and neck tumors. The current study was performed to explore the relationship between changes in tumor FDG metabolism and local control in patients receiving hyperfractionated radiotherapy and concurrent chemotherapy. METHODS: The study group consisted of six patients with locally advanced, nonmetastatic squamous cell carcinoma of the head and neck. FDG studies were performed prior to, during, and 24 months post-therapy. Ratios of tumor to nontumor FDG uptake in regions of interest (ROI) were compared. RESULTS: All pretherapy studies demonstrated a focal hypermetabolic abnormality corresponding to the known tumor. The pretherapy tumor to nontumor FDG ratios declined significantly during therapy (p < 0.05) with a similar continued trend post-therapy (p < 0.07). CONCLUSION: The treatment-induced decrease in tumor hypermetabolism as seen on serial FDG PET parallels the clinical response in squamous carcinoma of the head and neck. Two-year follow-up scans also suggest that continued low tumor to nontumor ratios reflect eradication of local disease. Because of its high cost, a study of larger numbers of patients is necessary to better define the role of PET in the management of head and neck cancer.

Authors
Berlangieri, SU; Brizel, DM; Scher, RL; Schifter, T; Hawk, TC; Hamblen, S; Coleman, RE; Hoffman, JM
MLA Citation
Berlangieri, SU, Brizel, DM, Scher, RL, Schifter, T, Hawk, TC, Hamblen, S, Coleman, RE, and Hoffman, JM. "Pilot study of positron emission tomography in patients with advanced head and neck cancer receiving radiotherapy and chemotherapy." Head Neck 16.4 (July 1994): 340-346.
PMID
8056579
Source
pubmed
Published In
Head & Neck: Journal for the Sciences & Specialties of the Head and Neck
Volume
16
Issue
4
Publish Date
1994
Start Page
340
End Page
346

A phase I/II trial of twice daily irradiation and concurrent chemotherapy for locally advanced squamous cell carcinoma of the head and neck.

PURPOSE: This study was designed to test the toxicity and efficacy of a regimen of twice daily irradiation and concurrent multiagent chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: This was a prospective Phase I/II trial. Patients received 125 cGy b.i.d. to 7000 cGy with a 6 hr interfraction interval. Chemotherapy was given during weeks 1 and 6 of irradiation and consisted of a 5 day infusion of 5-fluorouracil at 600 mg/M2/day and 5 daily injections of cisplatin at 12 mg/M2/day. Two additional cycles of chemotherapy were given after the completion of radiotherapy. RESULTS: Forty-six patients were evaluable: 28 had technically unresectable disease and 18 had resectable tumors. All had Stage III or IV disease: 84% had T3 or T4 primaries while 53% had > or = N2 neck disease. The primary acute toxicity, confluent mucositis, was seen in 74% of patients. Late side effects occurred in four patients. Median follow-up is 36 months (range 25-44 months). Kaplan-Meier estimates of 2-year disease-free survival and overall survival are 65% and 73%, respectively, while 2-year local regional control and distant disease-free survival are 72% and 88%, respectively. Multivariate analysis revealed that resectability and receiving > 2 cycles of chemotherapy significantly influenced local regional control while age < 60 significantly influenced disease-free survival. CONCLUSION: This form of treatment can be delivered safely. The encouraging results have led to the initiation of a Phase III trial comparing this regimen with b.i.d. radiation alone.

Authors
Brizel, DM; Leopold, KA; Fisher, SR; Panella, TJ; Fine, RL; Bedrosian, CL; Kenan, PD; Huang, A; Womack, T; Bjurstrom, T
MLA Citation
Brizel, DM, Leopold, KA, Fisher, SR, Panella, TJ, Fine, RL, Bedrosian, CL, Kenan, PD, Huang, A, Womack, T, and Bjurstrom, T. "A phase I/II trial of twice daily irradiation and concurrent chemotherapy for locally advanced squamous cell carcinoma of the head and neck." Int J Radiat Oncol Biol Phys 28.1 (January 1, 1994): 213-220.
PMID
8270444
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
28
Issue
1
Publish Date
1994
Start Page
213
End Page
220

Radiation therapy for head and neck cancer in a patient with Takayasu's arteritis.

Authors
Kavanagh, BD; Brizel, DM; Leopold, KA; Acker, JC
MLA Citation
Kavanagh, BD, Brizel, DM, Leopold, KA, and Acker, JC. "Radiation therapy for head and neck cancer in a patient with Takayasu's arteritis." Acta Oncol 33.1 (1994): 73-74.
PMID
7908210
Source
pubmed
Published In
Acta Oncologica (Informa)
Volume
33
Issue
1
Publish Date
1994
Start Page
73
End Page
74

A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model.

This laboratory has previously used a window chamber model to measure red blood cell velocity in mammary tumors and normal granulation tissues of the F-344 rat. Because red cell flux and hematocrit more accurately reflect the oxygen carrying potential of blood, we used this model to measure these parameters. Red blood cells were labelled with fluorescein isothiocyanate, and 0.2 ml. packed cells were injected intravenously into rats bearing an 8 to 10 day old R-3230 mammary carcinoma. beta-phycoerythrin (0.15 mg.) was also injected and served as a plasma dye to outline the blood vessels. A sample of peripheral blood was then taken and analyzed by flow cytometry to determine the labeled fraction of red blood cells. Flowing tumor and normal tissue vessels were recorded onto a VCR, and these video images were used to determine vascular length and diameter, RBC flux and velocity, and hematocrit. Median vessel diameter and loge (red blood cell flux) were significantly greater in tumors than in normal tissues (p = 0.007 and p < 0.025, respectively). After controlling for these variables, the median tumor hematocrit of 19% was not significantly greater than the median normal tissue hematocrit of 15%. This technique provides a nontoxic and reproducible method that is now being used to assist in the in vivo definition of tumor oxygenation.

Authors
Brizel, DM; Klitzman, B; Cook, JM; Edwards, J; Rosner, G; Dewhirst, MW
MLA Citation
Brizel, DM, Klitzman, B, Cook, JM, Edwards, J, Rosner, G, and Dewhirst, MW. "A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model." Int J Radiat Oncol Biol Phys 25.2 (January 15, 1993): 269-276.
PMID
8420874
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
25
Issue
2
Publish Date
1993
Start Page
269
End Page
276

Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature.

Flunarizine is a diphenylpiperazine calcium entry blocker that has been shown previously to increase tumor blood flow and sensitivity to radiotherapy via reduction in the radiobiologically significant hypoxic fraction. Two mechanisms of action have been proposed previously (vasodilation, altered blood viscosity), but no studies have been performed to examine its mechanisms of action in vivo. Such information would be invaluable in determining the role of flunarizine in multimodality approaches to reduce tumor hypoxia. Fisher-344 rats bearing R3230Ac tumors transplanted into dorsal flap window chambers were used to examine microcirculatory changes after administration of flunarizine (1.0 mg/kg, iv). The drug increased the diameters of the microvasculature and red cell velocities specifically in central tumor regions (producing an average increase in vessel flow by a factor of 1.96), which was accompanied by an increase in perivascular pO2 of 12 mm Hg, on the average. The drug did not change the diameters of tumor "feeding" vessels, nor did it change vascular length densities. Thus the improvement in central tumor blood flow and oxygenation could not be attributed to dilation of feeding vessels. The oxygen-carrying capacity of the blood was not altered either since hemoglobin saturation (measured in vitro) and the hematocrits of the microvasculature were unchanged after drug administration. Therefore, by a process of elimination, the most likely explanation for the effect of the drug is modification of blood viscosity. Additional studies are under way in this laboratory to examine whether changes in viscosity occur after flunarizine administration.

Authors
Dewhirst, MW; Ong, ET; Madwed, D; Klitzman, B; Secomb, T; Brizel, D; Bonaventura, J; Rosner, G; Kavanagh, B; Edwards, J
MLA Citation
Dewhirst, MW, Ong, ET, Madwed, D, Klitzman, B, Secomb, T, Brizel, D, Bonaventura, J, Rosner, G, Kavanagh, B, and Edwards, J. "Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature." Radiat Res 132.1 (October 1992): 61-68.
PMID
1410275
Source
pubmed
Published In
Radiation Research
Volume
132
Issue
1
Publish Date
1992
Start Page
61
End Page
68

Perivascular oxygen tensions in a transplantable mammary tumor growing in a dorsal flap window chamber.

Fischer 344 rats with R3230 Ac mammary carcinomas implanted in dorsal flap window chambers served as a model to obtain measurements of perivascular and stromal oxygen tension in normal and tumor tissues using Whalen recessed-tip microelectrodes (3- to 6-microns tip). Perivascular measurements were made adjacent to vessels with continuous blood flow. Thus the measurements and models provided are reflective of conditions leading to chronic hypoxia. Perivascular oxygen tensions averaged 72 +/- 13 mmHg in normal tissue vessels adjacent to tumor, 26 +/- 5 mmHg in tumor periphery, and 12 +/- 3 mmHg in tumor central vessels. There was a significant trend toward lower perivascular oxygen tensions in the tumor center (Kruskal-Wallis test, P = 0.002). A similar tendency was seen with a limited number of stromal measurements. Krogh cylinder models, which incorporate these data for perivascular oxygen tension, along with morphometric data obtained from the same tumor model suggest that hypoxic regions will exist between tumor vessels in the tumor center unless O2 consumption rates are well below 0.6 ml/100 g/min. The low perivascular measurements observed near the tumor center combined with the theoretical considerations suggest, for this model at least, that tissue oxygenation may best be improved by increasing red cell velocity and input pO2 and reducing oxygen consumption. The low perivascular oxygen tensions observed near the center also suggest that conditions conducive to increased red cell rigidity exist, that drugs which can decrease red cell rigidity could improve tumor blood flow and oxygenation, and that the endothelium of those vessels may be susceptible to hypoxia-reoxygenation injury.

Authors
Dewhirst, MW; Ong, ET; Klitzman, B; Secomb, TW; Vinuya, RZ; Dodge, R; Brizel, D; Gross, JF
MLA Citation
Dewhirst, MW, Ong, ET, Klitzman, B, Secomb, TW, Vinuya, RZ, Dodge, R, Brizel, D, and Gross, JF. "Perivascular oxygen tensions in a transplantable mammary tumor growing in a dorsal flap window chamber." Radiat Res 130.2 (May 1992): 171-182.
PMID
1574573
Source
pubmed
Published In
Radiation Research
Volume
130
Issue
2
Publish Date
1992
Start Page
171
End Page
182

The radiation dose-response relationship in a human glioma xenograft and an evaluation of the influence of glutathione depletion by buthionine sulfoximine.

We have used an extensively characterized human glioma cell line in an athymic mouse model to evaluate new therapeutic approaches for human supratentorial high grade gliomas. The tumor, D-54MG, is a subline of a human anaplastic glioma. Eight days after homozygous nu/nu BALB/c athymic mice received intracranial (IC) injections of a tumor homogenate, the whole brain was irradiated with either single fractions of 4, 8, 9, and 12 Gy or twice daily fractions, separated by least 6 hr, of 2.28 Gy x 2 or 7.53 Gy x 2. To evaluate whether or not glutathione depletion influenced animal survival, animals at each dose level received either intraperitoneal (IP) buthionine sulfoximine (BSO) alone or I.P. BSO plus BSO in the drinking water. There was a stepwise prolongation of animal survival with increasing doses of external beam radiation. Mean survival in 9 of the 10 control groups (8-12 animals per group) ranged from 14.1 to 18.8 days. Mean survival ranged from 15.3 to 22.5 days at 4 Gy, 25 to 30 days at 8 Gy, 22.3 to 29.7 days at 9 Gy, and 32.9 to 33.6 days at 12 Gy single dose irradiation. At 2.28 Gy x 2 split dose irradiation mean survival was 29.3 days, for 7.53 Gy x 2 mean survival was over 47 days. The data for single fraction irradiation fit a linear regression line (r = 0.908) of mean animal survival = (1.22 [dose in Gy] + 16.7) days. Tumor GSH levels were decreased with all BSO dosing regimens tested. The most aggressive regimen (I.P. BSO+oral BSO for 5 days), reduced tumor GSH to 6.2% of control. Increased survival in irradiated glutathione depleted mice versus mice receiving radiation alone was not seen.

Authors
Halperin, EC; Brizel, DM; Honore, G; Sontag, MR; Griffith, OW; Bigner, DD; Friedman, HS
MLA Citation
Halperin, EC, Brizel, DM, Honore, G, Sontag, MR, Griffith, OW, Bigner, DD, and Friedman, HS. "The radiation dose-response relationship in a human glioma xenograft and an evaluation of the influence of glutathione depletion by buthionine sulfoximine." Int J Radiat Oncol Biol Phys 24.1 (1992): 103-109.
PMID
1512145
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
24
Issue
1
Publish Date
1992
Start Page
103
End Page
109

The radiation dose-response relationship in a human glioma xenograft and an evaluation of the influence of glutathione depletion by buthionine sulfoximine

We have used an extensively characterized human glioma cell line in an athymic mouse model to evaluate new therapeutic approaches for human supratentorial high grade gliomas. The tumor, D-54MG, is a subline of a human anaplastic glioma. Eight days after homozygous nu/nu BALB/c athymic mice received intracranial (IC) injections of a tumor homogenate, the whole brain was irradiated with either single fractions of 4, 8, 9, and 12 Gy or twice daily fractions, separated by least 6 hr, of 2.28 Gy × 2 or 7.53 Gy × 2. To evaluate whether or not glutathione depletion influenced animal survival, animals at each dose level received either intraperitoneal (IP) buthionine sulfoximine (BSO) alone or I.P. BSO plus BSO in the drinking water. There was a stepwise prolongation of animal survival with increasing doses of external beam radiation. Mean survival in 9 of the 10 control groups (8-12 animals per group) ranged from 14.1 to 18.8 days. Mean survival ranged from 15.3 to 22.5 days at 4 Gy, 25 to 30 days at 8 Gy, 22.3 to 29.7 days at 9 Gy, and 32.9 to 33.6 days at 12 Gy single dose irradiation. At 2.28 Gy × 2 split dose irradiation mean survival was 29.3 days, for 7.53 Gy × 2 mean survival was over 47 days. The data for single fraction irradiation fit a linear regression line (r = 0.908) of mean animal survival = (1.22 [dose in Gy] + 16.7) days. Tumor GSH levels were decreased with all BSO dosing regimens tested. The most aggressive regimen (I.P. BSO + oral BSO for 5 days), reduced tumor GSH to 6.2% of control. Increased survival in irradiated glutathione depleted mice versus mice receiving radiation alone was not seen. © 1992.

Authors
Halperin, EC; Brizel, DM; Honore, G; Sontag, MR; Griffith, OW; Bigner, DD; Friedman, HS
MLA Citation
Halperin, EC, Brizel, DM, Honore, G, Sontag, MR, Griffith, OW, Bigner, DD, and Friedman, HS. "The radiation dose-response relationship in a human glioma xenograft and an evaluation of the influence of glutathione depletion by buthionine sulfoximine." International Journal of Radiation Oncology, Biology, Physics 24.1 (1992): 103-109.
Source
scival
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
24
Issue
1
Publish Date
1992
Start Page
103
End Page
109

Improved survival in advanced Hodgkin's disease with the use of combined modality therapy.

To compare the effectiveness of combined modality therapy and chemotherapy alone for the treatment of advanced Hodgkin's disease (Stages IIB-IV), records of 154 patients who achieved a complete or partial response to induction combination chemotherapy were analyzed. Sixty-seven patients received consolidation radiotherapy and 87 patients received no further treatment. Thirty of 154 patients participated in a prospective randomized trial of the Southeastern Cancer Study Group (SEG). Ten-year actuarial survival (Hodgkin's disease deaths only) was 93% for the combined modality therapy patients compared with 59% for the chemotherapy alone patients (p less than 0.0005). Combined modality therapy patients had an 87% 10-year actuarial freedom from relapse as opposed to 56% for the chemotherapy alone patients (p less than 0.0005). Relapse occurred in 33 of the chemotherapy alone patients, 28 (85%) being in sites involved at initial diagnosis. Seven combined modality therapy patients recurred with only two true in-field failures. Multi-variate analysis demonstrated treatment (combined modality) as the only variable affecting outcome. Patients prospectively treated with combined modality therapy in the Southeastern Cancer Study Group trial also showed a statistically significant improvement in both survival and freedom from relapse compared with patients receiving chemotherapy only. There was no apparent increase in toxicity from using combined modality therapy compared with chemotherapy. Three chemotherapy patients and one combined modality therapy patients developed acute leukemia.

Authors
Brizel, DM; Winer, EP; Prosnitz, LR; Scott, J; Crawford, J; Moore, JO; Gockerman, JP
MLA Citation
Brizel, DM, Winer, EP, Prosnitz, LR, Scott, J, Crawford, J, Moore, JO, and Gockerman, JP. "Improved survival in advanced Hodgkin's disease with the use of combined modality therapy." Int J Radiat Oncol Biol Phys 19.3 (September 1990): 535-542.
PMID
2211201
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
19
Issue
3
Publish Date
1990
Start Page
535
End Page
542

Failure patterns and survival in pediatric soft tissue sarcoma.

We retrospectively analyzed 44 patients with localized soft tissue sarcomas who were seen and treated at the JCRT, DFCI, and TCH between 1970-1984. Patients with rhabdomyosarcoma were excluded. Primary tumors were located in the following sites: extremities 19 (43%), head and neck 9 (20%), and trunk 16 (37%). Median follow-up for survivors was 7.7 years (range 24 mo-16 years). Surgery was the initial aspect of treatment for all patients. All patients also received post-operative irradiation, 43 at presentation and one at local relapse, and 26 received adjuvant chemotherapy. Radiation was delivered to a dose of 4000 cGy (median) followed by a boost to a median dose of 5760 cGy (range 4500-7000 cGy). Actuarial 5- and 10-year disease-free survivals (DFS) were 70% and 59% while the actuarial 5- and 10-year overall survivals (OS) were both 75%. All parameters were assessed for significance by univariate analysis. OS was significantly affected by presenting stage when analyzed according to both the Intergroup Rhabdomyosarcoma Staging System (IRS) and the American Joint Committee on Cancer system (AJCC). For the IRS, OS at 10 years was 100% for Stage I, 72% for Stage II, and 54% for Stage III (p = 0.04). For the AJCC, OS at 10 years was 100% for Stage I and 65% for Stage II and III (p = 0.05). Primary site, histology, and use of adjuvant chemotherapy did not influence OS or DFS. Fourteen patients failed: 8 local, 1 distant, and 5 combined local and distant. There was no LF among the 9 pts. with primary lesions less than 5 cm compared to 11/29 (39%) whose tumor was greater than 5 cm (p = 0.04). Pts. with gross residual disease had a local DFS of 42%, but those with no residual or microscopic residual had a local DFS of 71% (p = 0.02). In conclusion, childhood STS has an excellent OS (75% at 10 years). Tumor size and residual tumor after surgery strongly predicted for local failure. Of interest, the pattern of failure is predominantly local in our series. This suggests that more aggressive local treatment is indicated in management of children with STS. Higher doses of irradiation as used for adult STS are probably indicated for patients with gross residual disease.

Authors
Brizel, DM; Weinstein, H; Hunt, M; Tarbell, NJ
MLA Citation
Brizel, DM, Weinstein, H, Hunt, M, and Tarbell, NJ. "Failure patterns and survival in pediatric soft tissue sarcoma." Int J Radiat Oncol Biol Phys 15.1 (July 1988): 37-41.
PMID
3391826
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
15
Issue
1
Publish Date
1988
Start Page
37
End Page
41
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