David Brizel

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

Northwestern University

Grants:

Hyperthermia And Perfusion Effects In Cancer Therapy

Administered By
Radiation Oncology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Patient Reported Outcomes and Financial Toxicity in Head and Neck Cancer

Administered By
Radiation Oncology
Role
Principal Investigator
Start Date
End Date

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

Administered By
Radiation Oncology
Role
Principal Investigator
Start Date
End Date

Hyperglycemia and Oxygen Breathing in Head & Neck Cancer

Administered By
Radiation Oncology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Hyperthermia And Perfusion Effects In Cancer Therapy

Administered By
Radiation Oncology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Publications:

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, Oana, et al. “Dynamic contrast enhanced-MRI in head and neck cancer patients: variability of the precontrast longitudinal relaxation time (T10)..” Med Phys, vol. 37, no. 6, June 2010, pp. 2683–92. Pubmed, doi:10.1118/1.3427487.
URI
https://scholars.duke.edu/individual/pub1254812
PMID
28512937
Source
pubmed
Published In
Medical Physics
Volume
37
Published Date
Start Page
2683
End Page
2692
DOI
10.1118/1.3427487

TH‐E‐M100J‐02: Potential of Dynamic Contrast Enhanced‐Magnetic Resonance Imaging (DCE‐MRI) Extracted Parameters to Estimate Treatment Response in Locally Advanced Head and Neck (LAHN) Cancer Patients

Purpose: To evaluate the use of DCE‐MRI to measure changes in tumor physiology in LAHN cancer patients receiving TT and cisplatin based concurrent chemoradiation (ChemoRT). Material and Methods: Eligible patients with LAHN were enrolled on an IRB approved clinical trial to establish the safety and efficacy of adding TT (bevacizumab and erlotinib) to ChemoRT. To quantify this efficacy, DCE‐MR images were acquired on a 1.5T GE Signa Exite scanner before treatment started, at the end of the lead‐in phase (2 weeks of TT alone), at the end of week 1 of ChemoRT, and at the end of the ChemoRT (70 Gy). The images were analyzed using a full Time Point (fTP) pharmacokinetic analysis implemented by CAD Sciences® (White Plains, NY) that measures the vascular permeability (PERM) and extracellular volume fraction (EVF). The T10 for the primary and nodes was determined from series acquired with varying TRs. A dynamic 3D spoiled gradient echo sequence was used before and after bolus injection of Gd DTPA (Magnevist®). Regions of interest (ROIs) were defined over the entire extent of the tumor and LN, respectively. Enhancement curve analysis, PERM and EVF statistics and ROI volume comparisons were performed. Results: The T10 for tumor was 1500 msec, and 2000 msec for LN. All the fTP analyses used these values. Fifteen patients have been imaged to date. We found that coronal imaging allows better ROI selection without vascular averaging for this type of subjects. Detailed analyses of all time points have been completed on three patients, all with clinical complete response. Combined PERM and EVF analyses showed marked decreases with treatment (p<0.014). Conclusions: Preliminary results demonstrate the feasibility of using DCE‐MRI to measure treatment induced changes in tumor physiology. Correlations between these changes and treatment outcome will be determined as data from the remaining patients is analyzed. © 2007, American Association of Physicists in Medicine. All rights reserved.
Authors
Craciunescu, O; Muradyan, N; Barboriak, D; Macfall, J; Brizel, D
URI
https://scholars.duke.edu/individual/pub872577
Source
scopus
Published In
Medical Physics
Volume
34
Published Date
Start Page
2649
DOI
10.1118/1.2761755

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, Mark W., et al. “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, vol. 61, no. 2, Feb. 2005, pp. 480–91. Pubmed, doi:10.1016/j.ijrobp.2004.06.211.
URI
https://scholars.duke.edu/individual/pub714737
PMID
15667971
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
61
Published Date
Start Page
480
End Page
491
DOI
10.1016/j.ijrobp.2004.06.211

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, John P., et al. “A mathematical model of tumor oxygen and glucose mass transport and metabolism with complex reaction kinetics..” Radiat Res, vol. 159, no. 3, Mar. 2003, pp. 336–44. Pubmed, doi:10.1667/0033-7587(2003)159[0336:ammoto]2.0.co;2.
URI
https://scholars.duke.edu/individual/pub714778
PMID
12600236
Source
pubmed
Published In
Radiation Research
Volume
159
Published Date
Start Page
336
End Page
344
DOI
10.1667/0033-7587(2003)159[0336:ammoto]2.0.co;2

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., et al. “Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment..” Int J Radiat Oncol Biol Phys, vol. 46, no. 1, Jan. 2000, pp. 179–85. Pubmed, doi:10.1016/s0360-3016(99)00362-4.
URI
https://scholars.duke.edu/individual/pub686422
PMID
10656391
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
46
Published Date
Start Page
179
End Page
185
DOI
10.1016/s0360-3016(99)00362-4