Quynh-Thu Le, MD

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Radiation Oncology

Trabajo y Educación

Formación Profesional

University of California at San Francisco School of Medicine, San Francisco, CA, 1993


Alameda County Medical Center UCSF East Bay Surgical Residency, Oakland, CA, 1994


UCSF Medical Center, San Francisco, CA, 1997

Certificaciones Médicas

Radiation Oncology, American Board of Radiology

Todo Publicaciones

The impact of developing a speech and swallow rehab program: Improving patient satisfaction and multidisciplinary care. Laryngoscope Starmer, H. M., Ayoub, N., Byward, C., Kizner, J., Le, Q., Hara, W., Holsinger, F. C. 2017


The objective of this study was to evaluate the impact of developing an integrated head and neck cancer speech and swallowing rehabilitation program on physician/team focus on functional outcomes.Prospective cross-sectional design.Surveys regarding physician behavior and patient satisfaction with speech and swallowing were administered in an academic oncology practice prior to and 1 year following establishment of a dedicated head and neck speech and swallowing rehabilitation program. Participants included new and established head and neck cancer patients recruited consecutively. The primary outcome was physician behavior regarding speech and swallowing outcomes (as measured by discussion of function, providing suggestions regarding function, and referral to speech-language pathology services).A total of 199 surveys were returned at the first time point and 271 at the second. Demographic variables were comparable between the two groups. The later cohort was more likely to report team discussion and suggestions regarding speech and swallowing function than the former (P<.001, 95% confidence interval [CI]: -0.775 to -0.265; P<.001, 95% CI: -0.928 to -0.035, respectively). Although there was no significant difference between the groups in regard to satisfaction with speech (P=.07), more favorable satisfaction with swallowing was reported by the later cohort (P=.028, 95% CI: -0.531 to -0.029).Integration of speech and swallowing rehabilitation into head and neck cancer programs is associated with increased physician focus on functional outcomes and greater patient satisfaction in regard to swallowing function. We advocate for standard integration of such services into the multidisciplinary head and neck cancer care team.4. Laryngoscope, 2017.

View details for DOI 10.1002/lary.26695

View details for PubMedID 28561453

Very high-energy electron (VHEE) beams in radiation therapy; Treatment plan comparison between VHEE, VMAT, and PPBS. Medical physics Schler, E., Eriksson, K., Hynning, E., Hancock, S. L., Hiniker, S. M., Bazalova-Carter, M., Wong, T., Le, Q., Loo, B. W., Maxim, P. G. 2017


The aim of this study was to evaluate the performance of very high-energy electron beams (VHEE) in comparison to clinically derived treatment plans generated with volumetric modulated arc therapy (VMAT) and proton pencil beam scanning (PPBS) technology. We developed a custom optimization script that could be applied automatically across modalities to eliminate operator bias during IMRT optimization.Four clinical cases were selected (prostate cancer, lung cancer, pediatric brain tumor, and head and neck cancer (HNC)). The VHEE beams were calculated in the EGSnrc/DOSXYZnrc Monte Carlo code for 100 and 200MeV beams. Treatment plans with VHEE, VMAT, and PPBS were optimized in a research version of RayStation using an in-house developed script to minimize operator bias between the different techniques.The in-house developed script generated similar or superior plans to the clinically used plans. In the comparisons between the modalities, the integral dose was lowest for the PPBS-generated plans in all cases. For the prostate case, the 200MeV VHEE plan showed reduced integral dose and reduced organ at risk (OAR) dose compared to the VMAT plan. For all other cases, both the 100 and the 200MeV VHEE plans were superior to the VMAT plans, and the VHEE plans showed better conformity and lower spinal cord dose in the pediatric brain case and lower brain stem dose in the HNC case when compared to the PPBS plan.The automated optimization developed in this study generated similar or superior plans as compared to the clinically used plan and represents an unbiased approach to compare treatment plans generated for different modalities. In the present study, we also show that VHEE plans are similar or superior to VMAT plans with reduced mean OAR dose and increased target conformity for a variety of clinical cases, and VHEE plans can even achieve reductions in OAR doses compared to PPBS plans for shallow targets. With increased VHEE energy, better conformity and even higher reductions in mean OAR doses are achieved. On the whole, VHEE was intermediate between photon VMAT and PPBS for OAR sparing.

View details for DOI 10.1002/mp.12233

View details for PubMedID 28339108

Robust Estimation of Electron Density From Anatomic Magnetic Resonance Imaging of the Brain Using a Unifying Multi-Atlas Approach. International journal of radiation oncology, biology, physics Ren, S., Hara, W., Wang, L., Buyyounouski, M. K., Le, Q., Xing, L., Li, R. 2017; 97 (4): 849-857


Todevelop a reliable method to estimate electron density based on anatomic magnetic resonance imaging (MRI) of the brain.We proposed a unifying multi-atlas approach for electron density estimation based on standard T1- and T2-weighted MRI. First, a composite atlas was constructed through a voxelwise matching process using multiple atlases, with the goal of mitigating effects of inherent anatomic variations between patients. Next we computed for each voxel 2 kinds of conditional probabilities: (1) electron density given its image intensity on T1- and T2-weighted MR images; and (2) electron density given its spatial location in a reference anatomy, obtained by deformable image registration. These were combined into a unifying posterior probability density function using the Bayesian formalism, which provided the optimal estimates for electron density. We evaluated the method on 10 patients using leave-one-patient-out cross-validation. Receiver operating characteristic analysesfor detecting different tissue types were performed.The proposed method significantly reduced the errors in electron density estimation, with a mean absolute Hounsfield unit error of 119, compared with 140 and 144 (P<.0001) using conventional T1-weighted intensity and geometry-based approaches, respectively. For detection of bony anatomy, the proposed method achieved an 89% area under the curve, 86% sensitivity, 88% specificity, and 90% accuracy, which improved upon intensity and geometry-based approaches (area under the curve: 79% and 80%, respectively).The proposed multi-atlas approach provides robust electron density estimation and bone detection based on anatomic MRI. If validated on a larger population, our work could enable the use of MRI as a primary modality for radiation treatment planning.

View details for DOI 10.1016/j.ijrobp.2016.11.053

View details for PubMedID 28244422

The role of postoperative chemoradiation for oropharynx carcinoma: A critical appraisal revisited. Cancer Cooper, J. S., Fortpied, C., Gregoire, V., Le, Q., Pajak, T. F., Zhang, Q. E., Bernier, J. 2017; 123 (1): 12-16

View details for DOI 10.1002/cncr.30266

View details for PubMedID 27727449

Immunotherapy of head and neck cancer: Emerging clinical trials from a National Cancer Institute Head and Neck Cancer Steering Committee Planning Meeting. Cancer Bauman, J. E., Cohen, E., Ferris, R. L., Adelstein, D. J., Brizel, D. M., Ridge, J. A., O'Sullivan, B., Burtness, B. A., Butterfield, L. H., Carson, W. E., Disis, M. L., Fox, B. A., Gajewski, T. F., Gillison, M. L., Hodge, J. W., Le, Q., Raben, D., Strome, S. E., Lynn, J., Malik, S. 2016


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 2017;123:1259-1271. 2016 American Cancer Society.

View details for DOI 10.1002/cncr.30449

View details for PubMedID 27906454

Prognostic value of midtreatment FDG-PET in oropharyngeal cancer. Head & neck Pollom, E. L., Song, J., Durkee, B. Y., Aggarwal, S., Bui, T., von Eyben, R., Li, R., Brizel, D. M., Loo, B. W., Le, Q., Hara, W. Y. 2016; 38 (10): 1472-1478


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, 2016.

View details for DOI 10.1002/hed.24454

View details for PubMedID 27043927

Prognostic Value of p16 Status on the Development of a Complete Response in Involved Oropharynx Cancer Neck Nodes After Cisplatin-Based Chemoradiation: A Secondary Analysis of NRG Oncology RTOG 0129. International journal of radiation oncology, biology, physics Galloway, T. J., Zhang, Q. E., Nguyen-Tan, P. F., Rosenthal, D. I., Soulieres, D., Fortin, A., Silverman, C. L., Daly, M. E., Ridge, J. A., Hammond, J. A., Le, Q. 2016; 96 (2): 362-371


To determine the relationship between p16 status and the regional response of patients with node-positive oropharynx cancer treated on NRG Oncology RTOG 0129.Patients with N1-N3 oropharynx cancer and known p16 status who underwent treatment on RTOG 0129 were analyzed. Pathologic complete response (pCR) rates in patients treated with a postchemoradiation neck dissection (with p16-positive or p16-negative cancer) were compared by Fisher exact test. Patients managed expectantly were compared with those treated with a neck dissection.Ninety-nine (34%) of 292 patients with node-positive oropharynx cancer and known p16 status underwent a posttreatment neck dissection (p16-positive: n=69; p16-negative: n=30). The remaining 193 patients with malignant lymphadenopathy at diagnosis were observed. Neck dissection was performed a median of 70 (range, 17-169) days after completion of chemoradiation. Neither the pretreatment nodal stage (P=.71) nor the postradiation, pre-neck dissection clinical/radiographic neck assessment (P=.42) differed by p16 status. A pCR was more common among p16-positive patients (78%) than p16-negative patients (53%, P=.02) and was associated with a reduced incidence of local-regional failure (hazard ratio 0.33, P=.003). On multivariate analysis of local-regional failure, a test for interaction between pCR and p16 status was not significant (P=.37). One-hundred ninety-three (66%) of 292 of initially node-positive patients were managed without a posttreatment neck dissection. Development of a clinical (cCR) was not significantly influenced by p16-status (P=.42). Observed patients with a clinical nodal CR had disease control outcomes similar to those in patients with a pCR neck dissection.Patients with p16-positive tumors had significantly higher pCR and locoregional control rates than those with p16-negative tumors.

View details for DOI 10.1016/j.ijrobp.2016.05.026

View details for PubMedID 27478170

Design and rationale of a prospective, multi-institutional registry for patients with sinonasal malignancy. Laryngoscope Beswick, D. M., Holsinger, F. C., Kaplan, M. J., Fischbein, N. J., Hara, W., Colevas, A. D., Le, Q., Berry, G. J., Hwang, P. H. 2016; 126 (9): 1977-1980


Assessment of patients with sinonasal malignancy is challenging due to the low disease incidence and diverse histopathology. The current literature is composed mainly of retrospective studies with heterogeneous cohorts, and the rarity of cases limits our understanding of disease characteristics and treatment outcomes. We describe the development of a prospective, multi-institutional registry that utilizes cloud-based computing to evaluate treatment outcomes in patients with sinonasal cancer.A web-based, secure database was built to prospectively capture longitudinal outcomes and quality-of-life (QoL) data in patients diagnosed with sinonasal malignancy. Demographics, tumor staging, and treatment outcomes data are being collected. The Sinonasal Outcome Test-22 and University of Washington Quality of Life Questionnaire are administered at presentation and at recurring intervals. To date, seven institutions are participating nationally.This prospective, multi-institutional registry will provide novel oncological and QoL outcomes on patients with sinonasal malignancy to inform management decisions and disease prognostication. The application of cloud-based computing facilitates secure multi-institutional collaboration and may serve as a model for future registry development for the study of rare diseases in otolaryngology.2C. Laryngoscope, 2016.

View details for DOI 10.1002/lary.25996

View details for PubMedID 27283472

Acridine Derivatives as Inhibitors of the IRE1a-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma. Molecular cancer therapeutics Jiang, D., Tam, A. B., Alagappan, M., Hay, M. P., Gupta, A., Kozak, M. M., Solow-Cordero, D. E., Lum, P. Y., Denko, N. C., Giaccia, A. J., Le, Q., Niwa, M., Koong, A. C. 2016; 15 (9): 2055-2065


Using a luciferase reporter-based high throughput chemical library screen and topological data analysis (TDA), we identified N-acridine-9-yl-N',N'-dimethylpropane-1,3-diamine (DAPA) as a inhibitor of the IRE1-XBP1 pathway of the unfolded protein response (UPR). We designed a collection of analogues based on the structure of DAPA to explore structure-activity relationships (SAR) and identified N9-(3-(dimethylamino)propyl)-N3,N3,N6,N6-tetramethylacridine-3,6,9-triamine (3,6-DMAD), with 3,6-dimethylamino substitution on the chromophore, as a potent inhibitor. 3,6-DMAD inhibited both IRE1 oligomerization and in vitro endoribonuclease (RNase) activity, while the other analogues only blocked IRE1 oligomerization. Consistent with the inhibition of IRE1-mediated XBP1 splicing, which is critical for multiple myeloma (MM) cell survival, these analogues were cytotoxic to MM cell lines. Furthermore, 3,6-DMAD inhibited XBP1 splicing and the growth of MM tumor xenografts. Our study not only confirmed the utilization of topological data analysis in drug discovery but also identified a class of compounds with a unique mechanism of action as potent IRE1-XBP1 inhibitors in the treatment of MM.

View details for DOI 10.1158/1535-7163.MCT-15-1023

View details for PubMedID 27307600

Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis. Proceedings of the National Academy of Sciences of the United States of America Bhat, R., Belardi, B., Mori, H., Kuo, P., Tam, A., Hines, W. C., Le, Q., Bertozzi, C. R., Bissell, M. J. 2016; 113 (33): E4820-7


Branching morphogenesis in the mammary gland is achieved by the migration of epithelial cells through a microenvironment consisting of stromal cells and extracellular matrix (ECM). Here we show that galectin-1 (Gal-1), an endogenous lectin that recognizes glycans bearing N-acetyllactosamine (LacNAc) epitopes, induces branching migration of mammary epithelia in vivo, ex vivo, and in 3D organotypic cultures. Surprisingly, Gal-1's effects on mammary patterning were independent of its glycan-binding ability and instead required localization within the nuclei of mammary epithelia. Nuclear translocation of Gal-1, in turn, was regulated by discrete cell-surface glycans restricted to the front of the mammary end buds. Specifically, 2,6-sialylation of terminal LacNAc residues in the end buds masked Gal-1 ligands, thereby liberating the protein for nuclear translocation. Within mammary epithelia, Gal-1 localized within nuclear Gemini bodies and drove epithelial invasiveness. Conversely, unsialylated LacNAc glycans, enriched in the epithelial ducts, sequestered Gal-1 in the extracellular environment, ultimately attenuating invasive potential. We also found that malignant breast cells possess higher levels of nuclear Gal-1 and 2,6-SA and lower levels of LacNAc than nonmalignant cells in culture and in vivo and that nuclear localization of Gal-1 promotes a transformed phenotype. Our findings suggest that differential glycosylation at the level of tissue microanatomy regulates the nuclear function of Gal-1 in the context of mammary gland morphogenesis and in cancer progression.

View details for DOI 10.1073/pnas.1609135113

View details for PubMedID 27496330

Quality of Life and Performance Status From a Substudy Conducted Within a Prospective Phase 3 Randomized Trial of Concurrent Accelerated Radiation Plus Cisplatin With or Without Cetuximab for Locally Advanced Head and Neck Carcinoma: NRG Oncology Radiation Therapy Oncology Group 0522. International journal of radiation oncology, biology, physics Truong, M. T., Zhang, Q., Rosenthal, D. I., List, M., Axelrod, R., Sherman, E., Weber, R., Nguyen-Tn, P. F., El-Naggar, A., Konski, A., Galvin, J., Schwartz, D., Trotti, A., Silverman, C., Singh, A., Godette, K., Bonner, J. A., Jones, C. U., Garden, A. S., Shenouda, G., Matthiesen, C., Le, Q., Bruner, D. 2016


To analyze the quality of life (QOL) and performance status (PS) (secondary outcome) in patients with stage III to IV head and neck cancer (HNC) enrolled on a prospective randomized phase 3 trial comparing radiation-cisplatin without cetuximab (CIS) or with cetuximab (CET/CIS). The QOL hypothesis proposed a between-arm difference in Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN) total score of 10% of the instrument range from baseline to 1year.Patients who gave consent to the QOL/PS study completed the FACT-HN, Performance Status Scale for HNC (PSS-HN), and EuroQol (EQ-5D) at baseline through to 5years. The pretreatment QOL/PS scores were correlated with outcome and p16 status in patients with oropharyngeal cancer (OPC).Of 818 analyzable patients, the 1-year change from baseline score for FACT-HN total was -0.41 (CIS arm) and -5.11 (CET/CIS arm) (P=.016), representing a 3.2% between-arm change of the FACT-HN total score. The mean EQ-5D index and PSS-HN scores were not significantly different between arms. The p16-positive OPC patients had significantly higher baseline and 1-year scores for PSS-HN, FACT-HN total, physical and functional subscales, and 2-yearsfor the EQ-5D index compared with p16-negative OPC patients. Higher pretreatment PSS-HN diet, PSS-HN eating, FACT-HN, and EQ-5D index scores were associated with better overall survival (OS) and progression-free (PFS) survival on multivariate analysis. Higher baseline FACT-HN total, functional, physical subscale, and EQ-5D index scores were associated with improved OS and PFS in p16-positive OPC patients but not in p16-negative and non-OPC patients.There was no clinically meaningful difference in QOL/PS between arms. The p16-positive OPC patients had significantly higher QOL/PS than did p16-negative patients. Pretreatment QOL/PS is a significant independent predictor of outcome in locally advanced HNC.

View details for DOI 10.1016/j.ijrobp.2016.08.003

View details for PubMedID 27727066

Correlation Between the Severity of Cetuximab-Induced Skin Rash and Clinical Outcome for Head and Neck Cancer Patients: TheRTOG Experience. International journal of radiation oncology, biology, physics Bar-Ad, V., Zhang, Q. E., Harari, P. M., Axelrod, R., Rosenthal, D. I., Trotti, A., Jones, C. U., Garden, A. S., Song, G., Foote, R. L., Raben, D., Shenouda, G., Spencer, S. A., Harris, J., Le, Q. 2016; 95 (5): 1346-1354


To evaluate the severity of cetuximab-induced skin rash and its correlation with clinical outcome and late skin toxicity in patients with head and neck squamous cell carcinoma treated with chemoradiation therapy and cetuximab.Analysis included patients who received loading doseand1 cetuximab dose concurrent with definitive chemoradiation therapy (70Gy+cisplatin) or postoperative chemoradiation therapy (60-66Gy+docetaxel or cisplatin).Six hundred two patients were analyzed; 383 (63.6%) developed grade 2 to 4 cetuximab rash. Patients manifesting grade 2 to 4 rash had younger age (P<.001), fewer pack-years smoking history (P<.001), were more likely to be males (P=.04), and had p16-negative (P=.04) oropharyngeal tumors (P=.003). In univariate analysis, grade 2 to 4 rash was associated with better overall survival (hazard ratio [HR] 0.58, P<.001) and progression-free survival (HR 0.75, P=.02), and reduced distant metastasis rate (HR 0.61, P=.03), but not local-regional failure (HR 0.79, P=.16) relative to grade 0 to 1 rash. In multivariable analysis, HRs for overall survival, progression-free survival, distant metastasis, and local-regional failure were, respectively, 0.68 (P=.008), 0.85 (P=.21), 0.64 (P=.06), and 0.89 (P=.48). Grade 2 rash was associated with improved survival in p16-negative patients (HR 0.28 [95% confidence interval 0.11-0.74]) but not in p16-positive patients (HR 1.10 [0.42-2.89]) (P=.05 for interaction). Twenty-five percent of patients with grade 2 to 4 acute in-field radiation dermatitis experienced grade 2 to 4 late skin fibrosis, versus 14% of patients with grade 0 to 1 acute in-field radiation dermatitis (P=.002).Grade 2 to 4 cetuximab rash was associated with better survival, possibly due to reduction of distant metastasis. This observation was noted mainly in p16-negative patients. Grade 2 to 4 acute in-field radiation dermatitis was associated with higher rate of late grade 2 to 4 skin fibrosis.

View details for DOI 10.1016/j.ijrobp.2016.03.011

View details for PubMedID 27212198

Quality of Life and Performance Status From a Substudy Conducted Within a Prospective Phase 3 Randomized Trial of Concurrent Standard Radiation Versus Accelerated Radiation Plus Cisplatin for Locally Advanced Head and Neck Carcinoma: NRG Oncology RTOG 0129. International journal of radiation oncology, biology, physics Xiao, C., Zhang, Q., Nguyen-Tn, P. F., List, M., Weber, R. S., Ang, K. K., Rosenthal, D., Filion, E. J., Kim, H., Silverman, C., Raben, A., Galloway, T., Fortin, A., Gore, E., Winquist, E., Jones, C. U., Robinson, W., Raben, D., Le, Q., Bruner, D. 2016


To analyze quality of life (QOL) and performance status (PS) for head and neck cancer (HNC) patients treated on NRG Oncology RTOG 0129 by treatment (secondary outcome) and p16 status, and to examine the association between QOL/PS and survival.Eligible patients were randomized into either an accelerated-fractionation arm or a standard-fractionation arm, and completed the Performance Status Scale for the Head and Neck (PSS-HN), the Head and Neck Radiotherapy Questionnaire (HNRQ), and the Spitzer Quality of Life Index (SQLI) at 8 time points from before treatment to 5years after treatment.The results from the analysis of area under the curve showed that QOL/PS was not significantly different between the 2 arms from baseline to year after treatment (P ranged from .39 to .98). The results from general linear mixed models further supported the nonsignificant treatment effects until 5years after treatment (P=.95, .90, and .84 for PSS-HN Diet, Eating, and Speech, respectively). Before treatment and after 1year after treatment, p16-positive oropharyngeal cancer (OPC) patients had better QOL than did p16-negative patients (P ranged from .0283 to <.0001 for all questionnaires). However, QOL/PS decreased more significantly from pretreatment to the last 2weeks of treatment in the p16-positive group than in the p16-negative group (P ranged from .0002 to <.0001). Pretreatment QOL/PS was a significant independent predictor of overall survival, progression-free survival, and local-regional failure but not of distant metastasis (P ranged from .0063 to <.0001).The results indicated that patients in both arms may have experienced similar QOL/PS. p16-positive patients had better QOL/PS at baseline and after 1year of follow-up. Patients presenting with better baseline QOL/PS scores had better survival.

View details for DOI 10.1016/j.ijrobp.2016.07.020

View details for PubMedID 27727063

Establishing quality indicators for neck dissection: Correlating the number of lymph nodes with oncologic outcomes (NRG Oncology RTOG 9501 and RTOG 0234). Cancer Divi, V., Harris, J., Harari, P. M., Cooper, J. S., McHugh, J., Bell, D., Sturgis, E. M., Cmelak, A. J., Suntharalingam, M., Raben, D., Kim, H., Spencer, S. A., Laramore, G. E., Trotti, A., Foote, R. L., Schultz, C., Thorstad, W. L., Zhang, Q. E., Le, Q. T., Holsinger, F. C. 2016


Prospective quality metrics for neck dissection have not been established for patients with head and neck squamous cell carcinoma. The purpose of this study was to investigate the association between lymph node counts from neck dissection, local-regional recurrence, and overall survival.The number of lymph nodes counted from neck dissection in patients treated in 2 NRG Oncology trials (Radiation Therapy Oncology Group [RTOG] 9501 and RTOG 0234) was evaluated for its prognostic impact on overall survival with a multivariate Cox model adjusted for demographic, tumor, and lymph node data and stratified by the postoperative treatment group.Five hundred seventy-two patients were analyzed at a median follow-up of 8 years. Ninety-eight percent of the patients were pathologically N+. The median numbers of lymph nodes recorded on the left and right sides were 24 and 25, respectively. The identification of fewer than 18 nodes was associated with worse overall survival in comparison with 18 or more nodes (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.09-1.74; P=.007). The difference appeared to be driven by local-regional failure (HR, 1.46; 95% CI, 1.02-2.08; P=.04) but not by distant metastases (HR, 1.08; 95% CI, 0.77-1.53; P=.65). When the analysis was limited to NRG Oncology RTOG 0234 patients, adding the p16 status to the model did not affect the HR for dissected nodes, and the effect of nodes did not differ with the p16 status.The removal and identification of 18 or more lymph nodes was associated with improved overall survival and lower rates of local-regional failure, and this should be further evaluated as a measure of quality in neck dissections for mucosal squamous cell carcinoma. Cancer 2016. 2016 American Cancer Society.

View details for DOI 10.1002/cncr.30204

View details for PubMedID 27419843

Pre-treatment non-target lung FDG-PET uptake predicts symptomatic radiation pneumonitis following Stereotactic Ablative Radiotherapy (SABR). Radiotherapy and oncology Chaudhuri, A. A., Binkley, M. S., Rigdon, J., Carter, J. N., Aggarwal, S., Dudley, S. A., Qian, Y., Kumar, K. A., Hara, W. Y., Gensheimer, M., Nair, V. S., Maxim, P. G., Shultz, D. B., Bush, K., Trakul, N., Le, Q., Diehn, M., Loo, B. W., Guo, H. H. 2016; 119 (3): 454-460


To determine if pre-treatment non-target lung FDG-PET uptake predicts for symptomatic radiation pneumonitis (RP) following lung stereotactic ablative radiotherapy (SABR).We reviewed a 258 patient database from our institution to identify 28 patients who experienced symptomatic (grade2) RP after SABR, and compared them to 57 controls who did not develop symptomatic RP. We compared clinical, dosimetric and functional imaging characteristics between the 2 cohorts including pre-treatment non-target lung FDG-PET uptake.Median follow-up time was 26.9months. Patients who experienced symptomatic RP had significantly higher non-target lung FDG-PET uptake as measured by mean SUV (p<0.0001) than controls. ROC analysis for symptomatic RP revealed area under the curve (AUC) of 0.74, with sensitivity 82.1% and specificity 57.9% with cutoff mean non-target lung SUV>0.56. Predictive value increased (AUC of 0.82) when mean non-target lung SUV was combined with mean lung dose (MLD). We developed a 0-2 point model using these 2 variables, 1 point each for SUV>0.56 or MLD>5.88Gy equivalent dose in 2Gy per fraction (EQD2), predictive for symptomatic RP in our cohort with hazard ratio 10.01 for score 2 versus 0 (p<0.001).Patients with elevated pre-SABR non-target lung FDG-PET uptake are at increased risk of symptomatic RP after lung SABR. Our predictive model suggests patients with mean non-target lung SUV>0.56 and MLD>5.88Gy EQD2 are at highest risk. Our predictive model should be validated in an external cohort before clinical implementation.

View details for DOI 10.1016/j.radonc.2016.05.007

View details for PubMedID 27267049

Quantitative and qualitative analysis of [(18)F]FDG and [(18)F]FAZA positron emission tomography of head and neck cancers and associations with HPV status and treatment outcome. European journal of nuclear medicine and molecular imaging Graves, E. E., Hicks, R. J., Binns, D., Bressel, M., Le, Q., Peters, L., Young, R. J., Rischin, D. 2016; 43 (4): 617-625


While methods for imaging tumor hypoxia with positron emission tomography (PET) have been developed, optimal methods for interpreting and utilizing these datasets in the clinic remain unclear. In this study, we analyzed hypoxia PET images of head and neck cancer patients and compared imaging metrics with human papilloma virus (HPV) status and clinical outcome.Forty-one patients treated as part of a phase III trial of the hypoxic cytotoxin tirapazamine (TROG 02.02) were imaged with PET using fluorodeoxyglucose (FDG) and fluoroazomycin arabinoside (FAZA). FDG and FAZA PET images were interpreted qualitatively and quantitatively, and compared with tumor T stage, HPV status, and treatment outcome using multivariate statistics.PET signals in the tumor and lymph nodes exhibited significant intra- and inter-patient variability. The FAZA hypoxic volume demonstrated a significant correlation with tumor T stage. PET-hypoxic tumors treated with cisplatin exhibited significantly worse treatment outcomes relative to PET-oxic tumors or PET-hypoxic tumors treated with tirapazamine.Quantitative analysis of FAZA PET yielded metrics that correlated with clinical T stage and were capable of stratifying patient outcome. These results encourage further development of this technology, with particular emphasis on establishment of robust quantitative methods.

View details for DOI 10.1007/s00259-015-3247-7

View details for PubMedID 26577940

Botulinum Toxin Confers Radioprotection in Murine Salivary Glands. International journal of radiation oncology, biology, physics Zeidan, Y. H., Xiao, N., Cao, H., Kong, C., Le, Q., Sirjani, D. 2016; 94 (5): 1190-1197


Xerostomia is a common radiation sequela, which has a negative impact on the quality of life of patients with head and neck cancer. Current treatment strategies offer only partial relief. Botulinum toxins (BTX) have been successfully used in treating a variety of radiation sequelae such as cystitis, proctitis, fibrosis, and facial pain. The purpose of this study was to evaluate the effect of BTX on radiation-induced salivary gland damage.We used a previously established model for murine salivary gland irradiation (IR). The submandibular glands (SMGs) of C5BL/6 mice (n=6/group) were injected with saline or BTX 72hours before receiving 15Gy of focal irradiation. Saliva flow was measured 3, 7, and 28days after treatment. The SMGs were collected for immunohistochemistry, confocal microscopy, and Western blotting. A cytokine array consisting of 40 different mouse cytokines was used to evaluate cytokine profiles after radiation treatment.Irradiated mice showed a 50% reduction in saliva flow after 3days, whereas mice preinjected with BTX had 25% reduction in saliva flow (P<.05). Cell death detected by TUNEL staining was similar in SMG sections of both groups. However, neutrophil infiltrate, detected by myeloperoxidase staining, was 3-fold lower for the BTX treated mice. A cytokine array showed a 2-fold upregulation of LPS-induced chemokine (LIX/CXCL5) 3days after IR. BTX pretreatment reduced LIX levels by 40%. At 4weeks after IR, the saline (control) group showed a 40% reduction in basal SMG weight, compared with 20% in the BTX group. Histologically, BTX-pretreated glands showed relative preservation of acinar structures after radiation.These data suggest that BTX pretreatment ameliorates radiation-induced saliva dysfunction. Moreover, we demonstrate a novel role for CXCL5 in the acute phase of salivary gland damage after radiation. These results carry important clinical implications for the treatment of xerostomia in patients with head and neck cancer.

View details for DOI 10.1016/j.ijrobp.2015.12.371

View details for PubMedID 26907915

Neurotrophic Factors and Their Potential Applications in Tissue Regeneration. Archivum immunologiae et therapiae experimentalis Xiao, N., Le, Q. 2016; 64 (2): 89-99


Neurotrophic factors are growth factors that can nourish neurons and promote neuron survival and regeneration. They have been studied as potential drug candidates for treating neurodegenerative diseases. Since their identification, there are more and more evidences to indicate that neurotrophic factors are also expressed in non-neuronal tissues and regulate the survival, anti-inflammation, proliferation and differentiation in these tissues. This mini review summarizes the characteristics of the neurotrophic factors and their potential clinical applications in the regeneration of neuronal and non-neuronal tissues.

View details for DOI 10.1007/s00005-015-0376-4

View details for PubMedID 26611762

Botulinum Toxin Confers Radioprotection in Murine Salivary Glands INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Zeidan, Y. H., Xiao, N., Cao, H., Kong, C., Le, Q., Sirjani, D. 2016; 94 (5): 1190-1197
Importance of Radiation Oncologist Experience Among Patients With Head-and-Neck Cancer Treated With Intensity-Modulated Radiation Therapy. Journal of clinical oncology Boero, I. J., Paravati, A. J., Xu, B., Cohen, E. E., Mell, L. K., Le, Q., Murphy, J. D. 2016; 34 (7): 684-690


Over the past decade, intensity-modulated radiation therapy (IMRT) has replaced conventional radiation techniques in the management of head-and-neck cancers (HNCs). We conducted this population-based study to evaluate the influence of radiation oncologist experience on outcomes in patients with HNC treated with IMRT compared with patients with HNC treated with conventional radiation therapy.We identified radiation providers from Medicare claims of 6,212 Medicare beneficiaries with HNC treated between 2000 and 2009. We analyzed the impact of provider volume on all-cause mortality, HNC mortality, and toxicity end points after treatment with either conventional radiation therapy or IMRT. All analyses were performed by using either multivariable Cox proportional hazards or Fine-Gray regression models controlling for potential confounding variables.Among patients treated with conventional radiation, we found no significant relationship between provider volume and patient survival or any toxicity end point. Among patients receiving IMRT, those treated by higher-volume radiation oncologists had improved survival compared with those treated by low-volume providers. The risk of all-cause mortality decreased by 21% for every additional five patients treated per provider per year (hazard ratio [HR], 0.79; 95% CI, 0.67 to 0.94). Patients treated with IMRT by higher-volume providers had decreased HNC-specific mortality (subdistribution HR, 0.68; 95% CI, 0.50 to 0.91) and decreased risk of aspiration pneumonia (subdistribution HR, 0.72; 95% CI, 0.52 to 0.99).Patients receiving IMRT for HNC had improved outcomes when treated by higher-volume providers. These findings will better inform patients and providers when making decisions about treatment, and emphasize the critical importance of high-quality radiation therapy for optimal treatment of HNC.

View details for DOI 10.1200/JCO.2015.63.9898

View details for PubMedID 26729432

Hypoxic repression of pyruvate dehydrogenase activity is necessary for metabolic reprogramming and growth of model tumours. Scientific reports Golias, T., Papandreou, I., Sun, R., Kumar, B., Brown, N. V., Swanson, B. J., Pai, R., Jaitin, D., Le, Q., Teknos, T. N., Denko, N. C. 2016; 6: 31146-?


Tumour cells fulfil the bioenergetic and biosynthetic needs of proliferation using the available environmental metabolites. Metabolic adaptation to hypoxia causes decreased mitochondrial function and increased lactate production. This work examines the biological importance of the hypoxia-inducible inhibitory phosphorylations on the pyruvate dehydrogenase E1 subunit. Pancreatic cancer cell lines were genetically manipulated to alter the net phosphorylation of PDH E1 through reduced kinase expression or enhanced phosphatase expression. The modified cells were tested for hypoxic changes in phosphorylated E1, mitochondrial metabolism and growth as xenografted tumours. Even though there are four PDHK genes, PDHK1 is essential for inhibitory PDH phosphorylation of E1 at serine 232, is partially responsible for modification of serines 293 and 300, and these phosphorylations are necessary for model tumour growth. In order to determine the clinical relevance, a cohort of head and neck cancer patient biopsies was examined for phosphorylated E1 and expression of PDHK1. Patients with detectable 232 phosphorylation or expression of PDHK1 tend to have worse clinical outcome. These data show that PDHK1 activity is unique and non-redundant in the family of PHDK enzymes and a PDHK1 specific inhibitor would therefore have anti-cancer activity with reduced chance of side effects from inhibition of other PDHKs.

View details for DOI 10.1038/srep31146

View details for PubMedID 27498883

Identification of Doxorubicin as an Inhibitor of the IRE1a-XBP1 Axis of the Unfolded Protein Response. Scientific reports Jiang, D., Lynch, C., Medeiros, B. C., Liedtke, M., Bam, R., Tam, A. B., Yang, Z., Alagappan, M., Abidi, P., Le, Q., Giaccia, A. J., Denko, N. C., Niwa, M., Koong, A. C. 2016; 6: 33353-?


Activation of the IRE1-XBP1 branch of the unfolded protein response (UPR) has been implicated in multiple types of human cancers, including multiple myeloma (MM). Through an in silico drug discovery approach based on protein-compound virtual docking, we identified the anthracycline antibiotic doxorubicin as an in vitro and in vivo inhibitor of XBP1 activation, a previously unknown activity for this widely utilized cancer chemotherapeutic drug. Through a series of mechanistic and phenotypic studies, we showed that this novel activity of doxorubicin was not due to inhibition of topoisomerase II (Topo II). Consistent with its inhibitory activity on the IRE1-XBP1 branch of the UPR, doxorubicin displayed more potent cytotoxicity against MM cell lines than other cancer cell lines that have lower basal IRE1-XBP1 activity. In addition, doxorubicin significantly inhibited XBP1 activation in CD138(+) tumor cells isolated from MM patients. Our findings suggest that the UPR-modulating activity of doxorubicin may be utilized clinically to target IRE1-XBP1-dependent tumors such as MM.

View details for DOI 10.1038/srep33353

View details for PubMedID 27634301

A prospective study of electronic quality of life assessment using tablet devices during and after treatment of head and neck cancers. Oral oncology Pollom, E. L., Wang, E., Bui, T. T., Ognibene, G., von Eyben, R., Divi, V., Sunwoo, J., Kaplan, M., Dimitri Colevas, A., Le, Q., Hara, W. Y. 2015; 51 (12): 1132-1137


Electronic data collection is increasingly used for quality of life (QOL) assessments in the field of oncology. It is important to assess the feasibility of these new data capture technologies.Patients at our institution who were 18years or older with a pathological diagnosis of head and neck cancer were prospectively enrolled. Each patient completed two questionnaires [EORTC-QLQ-C30 and EORTC-QLQ-H&N35] administered on a touch-screen tablet device (iPad) at initial consult, during treatment, at the completion of treatment and at each subsequent follow up visit for one year after treatment.A total of 50 patients were included in this study. Although all patients completed the surveys at the initial consult, 86% of initially enrolled patients completed surveys at the end of radiation treatment, and 48% of initially enrolled patients completed surveys by the fourth follow-up visit. Average time to complete the survey for all patients over all time points was 9.8min (standard deviation 6.1). Age as a continuous variable was significantly associated with time for survey completion (p<0.001), with older age associated with longer survey completion times.QOL assessment using tablet devices in head and neck cancer patients is feasible, but may be more challenging in elderly patients. Patients 70years old may benefit from more assistance with electronic forms and should be allotted more time for completing tablet-based QOL surveys.

View details for DOI 10.1016/j.oraloncology.2015.10.003

View details for PubMedID 26475062

-Radioluminescence Imaging: A Comparative Evaluation with Cerenkov Luminescence Imaging. Journal of nuclear medicine : official publication, Society of Nuclear Medicine King, M. T., Carpenter, C. M., Sun, C., Ma, X., Le, Q., Sunwoo, J. B., Cheng, Z., Pratx, G., Xing, L. 2015; 56 (9): 1458-1464


Cerenkov luminescence imaging (CLI) can provide high-resolution images of (18)F-FDG-avid tumors but requires prolonged acquisition times because of low photon sensitivity. In this study, we proposed a new modality, termed -radioluminescence imaging (-RLI), which incorporates a scintillator with a -rejection strategy for imaging particles. We performed a comparative evaluation of -RLI with CLI in both in vitro and in vivo systems.Using in vitro phantoms, we characterized the photon sensitivity and resolution of CLI and -RLI. We also conducted a series of in vivo experiments with xenograft mouse models using both amelanotic (A375, UMSCC1-Luc) and melanotic (B16F10-Luc) cell lines. The B16F10 and UMSCC1 cell lines were transfected with the luciferase gene (Luc). CLI was acquired over 300 s, and -RLI was acquired using two 10-s acquisitions. We correlated (18)F -: FDG activities, as assessed by PET, with tumor radiances for both -RLI and CLI. We also compared tumor signal-to-background ratios (SBRs) between these modalities for amelanotic and melanotic tumors.For in vitro experiments, the photon sensitivity for -RLI was 560-fold greater than that for CLI. However, the spatial resolution for -RLI (4.4 mm) was inferior to that of CLI (1.0 mm). For in vivo experiments, correlations between (18)F-FDG activity and tumor radiance were 0.52 (P < 0.01) for -RLI, 0.81 (P = 0.01) for amelanotic lesions with CLI, and -0.08 (negative contrast; P = 0.80) for melanotic lesions with CLI. Nine of 13 melanotic lesions had an SBR less than 1 for CLI, despite an SBR greater than 1 among all lesions for -RLI.-RLI can produce functional images of both amelanotic and melanotic tumors in a shorter time frame than CLI. Further engineering developments are needed to realize the full clinical potential of this modality.

View details for DOI 10.2967/jnumed.115.158337

View details for PubMedID 26205301

Colorectal Histology Is Associated With an Increased Risk of Local Failure in Lung Metastases Treated With Stereotactic Ablative Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Binkley, M. S., Trakul, N., Jacobs, L. R., von Eyben, R., Quynh-Thu Le, Q. T., Maxim, P. G., Loo, B. W., Shultz, D. B., Diehn, M. 2015; 92 (5): 1044-1052


Stereotactic ablative radiation therapy (SABR) is increasingly used to treat lung oligometastases. We set out to determine the safety and efficacy of this approach and to identify factors associated with outcomes.We conducted a retrospective study of patients treated with SABR for metastatic lung tumors at our institution from 2003 to 2014. We assessed the association between various patient and treatment factors with local failure (LF), progression, subsequent treatment, systemic treatment, and overall survival (OS), using univariate and multivariate analyses.We identified 122 tumors in 77 patients meeting inclusion criteria for this study. Median follow-up was 22months. The 12- and 24-month cumulative incidence rates of LF were 8.7% and 16.2%, respectively; the 24-month cumulative incidence rates of progression, subsequent treatment, and subsequent systemic treatment were 75.2%, 64.5%, and 35.1%, respectively. Twenty-four-month OS was 74.6%, and median OS was 36months. Colorectal metastases had a significantly higher cumulative incidence of LF at 12 and 24months (25.5% and 42.2%, respectively), than all other histologies (4.4% and 9.9%, respectively; P<.0004). The 24-month cumulative incidences of LF for colorectal metastases treated with a biologically effective dose at /=10 (BED10) of <100Gy versus BED10 of 100Gy were 62.5% and 16.7%, respectively (P=.08). Toxicity was minimal, with only a single grade 3 or higher event observed.SABR for metastatic lung tumors appears to be safe and effective with excellent local control, treatment-free intervals, and OS. An exception is metastases from colorectal cancer, which have a high LF rate consistent with a radioresistant phenotype, suggesting a potential role for dose escalation.

View details for DOI 10.1016/j.ijrobp.2015.04.004

View details for Web of Science ID 000357900600024

View details for PubMedID 26025776

Emerging Treatment Paradigms in Radiation Oncology. Clinical cancer research Le, Q., Shirato, H., Giaccia, A. J., Koong, A. C. 2015; 21 (15): 3393-3401


Rapid advancements in radiotherapy and molecularly targeted therapies have resulted in the development of potential paradigm-shifting use of radiotherapy in the treatment of cancer. In this review, we discuss some of the most promising therapeutic approaches in the field of radiation oncology. These strategies include the use of highly targeted stereotactic radiotherapy and particle therapy as well as combining radiotherapy with agents that modulate the DNA damage response, augment the immune response, or protect normal tissues. Clin Cancer Res; 21(15); 3393-401. 2015 AACR.

View details for DOI 10.1158/1078-0432.CCR-14-1191

View details for PubMedID 25991820

Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy. International journal of radiation oncology, biology, physics Pollom, E. L., Deng, L., Pai, R. K., Brown, J. M., Giaccia, A., Loo, B. W., Shultz, D. B., Le, Q. T., Koong, A. C., Chang, D. T. 2015; 92 (3): 568-576


Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.

View details for DOI 10.1016/j.ijrobp.2015.02.016

View details for PubMedID 26068491

TU-AB-BRA-10: Prognostic Value of Intra-Radiation Treatment FDG-PET and CT Imaging Features in Locally Advanced Head and Neck Cancer. Medical physics Song, J., Cui, Y., Pollom, E., Durkee, B., Aggarwal, S., Bui, T., Le, Q., Loo, B., Hara, W., Li, R. 2015; 42 (6): 3588-?


To predict response to radiation treatment using computational FDG-PET and CT images in locally advanced head and neck cancer (HNC).68 patients with State III-IVB HNC treated with chemoradiation were included in this retrospective study. For each patient, we analyzed primary tumor and lymph nodes on PET and CT scans acquired both prior to and during radiation treatment, which led to 8 combinations of image datasets. From each image set, we extracted high-throughput, radiomic features of the following types: statistical, morphological, textural, histogram, and wavelet, resulting in a total of 437 features. We then performed unsupervised redundancy removal and stability test on these features. To avoid over-fitting, we trained a logistic regression model with simultaneous feature selection based on least absolute shrinkage and selection operator (LASSO). To objectively evaluate the prediction ability, we performed 5-fold cross validation (CV) with 50 random repeats of stratified bootstrapping. Feature selection and model training was solely conducted on the training set and independently validated on the holdout test set. Receiver operating characteristic (ROC) curve of the pooled Result and the area under the ROC curve (AUC) was calculated as figure of merit.For predicting local-regional recurrence, our model built on pre-treatment PET of lymph nodes achieved the best performance (AUC=0.762) on 5-fold CV, which compared favorably with node volume and SUVmax (AUC=0.704 and 0.449, p<0.001). Wavelet coefficients turned out to be the most predictive features. Prediction of distant recurrence showed a similar trend, in which pre-treatment PET features of lymph nodes had the highest AUC of 0.705.The radiomics approach identified novel imaging features that are predictive to radiation treatment response. If prospectively validated in larger cohorts, they could aid in risk-adaptive treatment of HNC.

View details for DOI 10.1118/1.4925515

View details for PubMedID 26128812

Reply to B. O'Sullivan et Al. Journal of clinical oncology Fakhry, C., Zhang, Q., Nguyen-Tan, P. F., Rosenthal, D., El-Naggar, A. K., Garden, A. S., Soulieres, D., Trotti, A., Avizonis, V. N., Ridge, J. A., Harris, J., Le, Q., Gillison, M. 2015; 33 (15): 1708-1709

View details for DOI 10.1200/JCO.2014.60.3555

View details for PubMedID 25823732

Survival benefit for adjuvant radiation therapy in minor salivary gland cancers. Oral oncology Zeidan, Y. H., Pekelis, L., An, Y., Holsinger, F. C., Kong, C. S., Chang, D. T., Le, Q. 2015; 51 (5): 438-445


The goal of the current study is to investigate the role of adjuvant radiation therapy (adjuvant RT) in minor salivary gland tumors (mSGT) using an established national database.The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients treated with or without adjuvant RT for mSGT from 1988 to 2008. Regression analyses were performed to identify factors associated with improved overall survival (OS).Most tumors were located within the oral cavity (75%) followed by nasal cavity/paranasal sinuses (15%). Multivariate Cox analysis showed that adjuvant RT was associated with better OS compared to surgery alone. Using logistic regression analysis, we provide a novel web based tool for predicting survival impact of adjuvant RT in patients with mSGT.Adjuvant RT is associated with improved survival in patients with mSGT and adverse clinicopathologic factors such as advanced T/N category, adenoid cystic histology, high grade, and nasopharynx location.

View details for DOI 10.1016/j.oraloncology.2015.02.096

View details for PubMedID 25771077

Aspiration pneumonia after concurrent chemoradiotherapy for head and neck cancer. Cancer Xu, B., Boero, I. J., Hwang, L., Le, Q., Moiseenko, V., Sanghvi, P. R., Cohen, E. E., Mell, L. K., Murphy, J. D. 2015; 121 (8): 1303-1311


Aspiration pneumonia represents an under-reported complication of chemoradiotherapy in patient with head and neck cancer. The objective of the current study was to evaluate the incidence, risk factors, and mortality of aspiration pneumonia in a large cohort of patients with head and neck cancer who received concurrent chemoradiotherapy.Patients who had head and neck cancer diagnosed between 2000 and 2009 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Aspiration pneumonia was identified from Medicare billing claims. The cumulative incidence, risk factors, and survival after aspiration pneumonia were estimated and compared with a noncancer population.Of 3513 patients with head and neck cancer, 801 developed aspiration pneumonia at a median of 5 months after initiating treatment. The 1-year and 5-year cumulative incidence of aspiration pneumonia was 15.8% and 23.8%, respectively, for patients with head and neck cancer and 3.6% and 8.7%, respectively, for noncancer controls. Among the patients with cancer, multivariate analysis identified independent risk factors (P <.05) for aspiration pneumonia, including hypopharyngeal and nasopharyngeal tumors, male gender, older age, increased comorbidity, no surgery before radiation, and care received at a teaching hospital. Among the patients with cancer who experienced aspiration pneumonia, 674 (84%) were hospitalized; and, of these, 301 (45%) were admitted to an intensive care unit. The 30-day mortality rate after hospitalization for aspiration pneumonia was 32.5%. Aspiration pneumonia was associated with a 42% increased risk of death (hazard ratio, 1.42; P <.001) after controlling for confounders.The current results indicated that nearly 25% of elderly patients will develop aspiration pneumonia within 5 years after receiving chemoradiotherapy for head and neck cancer. A better understanding of mitigating factors will help identify patients who are at risk for this potentially lethal complication.

View details for DOI 10.1002/cncr.29207

View details for PubMedID 25537836

Long-term results of radiation therapy oncology group 9903: a randomized phase 3 trial to assess the effect of erythropoietin on local-regional control in anemic patients treated with radiation therapy for squamous cell carcinoma of the head and neck. International journal of radiation oncology, biology, physics Shenouda, G., Zhang, Q., Ang, K. K., Machtay, M., Parliament, M. B., Hershock, D., Suntharalingam, M., Lin, A., Rotman, M., Nabid, A., Hong, S., Shehata, S., Cmelak, A. J., Sultanem, K., Le, Q. 2015; 91 (5): 907-915


This paper reports long-term results of RTOG 9903,to determine whether the addition of erythropoietin (EPO) would improve the outcomes of radiation therapy (RT) in mildly to moderately anemic patients with head and neck squamous cell carcinoma (HNSCCa).The trial included HNSCCa patients treated with definitive RT. Patients with stage III or IV disease received concomitant chemoradiation therapy or accelerated fractionation. Pretreatment hemoglobin levels were required to be between 9.0 and 13.5g/dL (12.5g/dL for females). EPO, 40,000 U, was administered weekly starting 7 to 10days before RT was initiated in the RT+EPO arm.A total of 141 of 148 enrolled patients were evaluable. The baseline median hemoglobin level was 12.1g/dL. In the RT+EPO arm, the mean hemoglobin level at 4weeks increased by 1.66g/dL, whereas it decreased by 0.24g/dL in the RT arm. With a median follow-up of 7.95years (range: 1.66-10.08years) for surviving patients and 3.33years for all patients (range: 0.03-10.08years), the 5-year estimate of local-regional failure was 46.2% versus 39.4% (P=.42), local-regional progression-free survival was 31.5% versus 37.6% (P=.20), and overall survival was 36.9% versus 38.2% (P=.54) for the RT+EPO and RT arms, respectively. Late toxicity was not different between the 2 arms.This long-term analysis confirmed that despite the ability of EPO to raise hemoglobin levels in anemic patients with HNSCCa, it did not improve outcomes when added to RT. The possibility of a detrimental effect of EPO could not be ruled out.

View details for DOI 10.1016/j.ijrobp.2014.12.018

View details for PubMedID 25670542

Metabolic tumor volume as a prognostic imaging-based biomarker for head-and-neck cancer: pilot results from Radiation Therapy Oncology Group protocol 0522. International journal of radiation oncology, biology, physics Schwartz, D. L., Harris, J., Yao, M., Rosenthal, D. I., Opanowski, A., Levering, A., Ang, K. K., Trotti, A. M., Garden, A. S., Jones, C. U., Harari, P., Foote, R., Holland, J., Zhang, Q., Le, Q. 2015; 91 (4): 721-729


To evaluate candidate fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging biomarkers for head-and-neck chemoradiotherapy outcomes in the cooperative group trial setting.Radiation Therapy Oncology Group (RTOG) protocol 0522 patients consenting to a secondary FDG-PET/CT substudy were serially imaged at baseline and 8 weeks after radiation. Maximum standardized uptake value (SUVmax), SUV peak (mean SUV within a 1-cm sphere centered on SUVmax), and metabolic tumor volume (MTV) using 40% of SUVmax as threshold were obtained from primary tumor and involved nodes.Of 940 patients entered onto RTOG 0522, 74 were analyzable for this substudy. Neither high baseline SUVmax nor SUVpeak from primary or nodal disease were associated with poor treatment outcomes. However, primary tumor MTV above the cohort median was associated with worse local-regional control (hazard ratio 4.01, 95% confidence interval 1.28-12.52, P=.02) and progression-free survival (hazard ratio 2.34, 95% confidence interval 1.02-5.37, P=.05). Although MTV and T stage seemed to correlate (mean MTV 6.4, 13.2, and 26.8 for T2, T3, and T4 tumors, respectively), MTV remained a strong independent prognostic factor for progression-free survival in bivariate analysis that included T stage. Primary MTV remained prognostic in p16-associated oropharyngeal cancer cases, although sample size was limited.High baseline primary tumor MTV was associated with worse treatment outcomes in this limited patient subset of RTOG 0522. Additional confirmatory work will be required to validate primary tumor MTV as a prognostic imaging biomarker for patient stratification in future trials.

View details for DOI 10.1016/j.ijrobp.2014.12.023

View details for PubMedID 25752384

Concurrent cetuximab versus platinum-based chemoradiation for the definitive treatment of locoregionally advanced head and neck cancer. Head & neck Tang, C., Chan, C., Jiang, W., Murphy, J. D., von Eyben, R., Colevas, A. D., Pinto, H., Lee-Enriquez, N., Kong, C., Le, Q. 2015; 37 (3): 386-392


The purpose of this study was to present our experience utilizing cetuximab and platinum-based concurrent chemoradiotherapy for the definitive treatment of head and neck squamous cell carcinoma (HNSCC).Patients (n = 177) who received definitive concurrent chemoradiotherapy for HNSCC were stratified into 3 groups: receiving cetuximab monotherapy (n = 24), cetuximab and chemotherapy combination (n = 33), or platinum-based chemotherapy without cetuximab (n = 120). Primary endpoints were freedom from relapse, event-free survival, and overall survival (OS).Patients receiving cetuximab monotherapy were older with lower Karnofsky performance status (KPS) and higher Charlson comorbidity scores compared with those treated with combination cetuximab and chemotherapy or platinum-based concurrent chemoradiotherapy. Patients treated with platinum-based concurrent chemoradiotherapy exhibited significantly better freedom from relapse, event-free survival, and OS compared with those receiving cetuximab monotherapy or cetuximab and chemotherapy combination therapies (all p < .05). Differences between patients receiving cetuximab monotherapy and platinum-based concurrent chemoradiotherapy held on multivariate Cox regression.This study suggests that platinum-based concurrent chemoradiotherapy is superior to cetuximab-based monotherapy for the definitive treatment of HNSCC. 2014 Wiley Periodicals, Inc. Head Neck 37: 386-392, 2015.

View details for DOI 10.1002/hed.23609

View details for PubMedID 24431011

Prognostic model for distant metastasis in locally advanced nasopharyngeal carcinoma after concurrent chemoradiotherapy HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Chen, C., Chen, S., Le, Q., Chen, J., Chen, Z., Li, D., Zhou, M., Li, D. 2015; 37 (2): 209-214


A prognostic model should be established for distant metastasis in locally advanced nasopharyngeal carcinoma (NPC) after concurrent chemoradiotherapy (CCRT).Patients with locally advanced NPC who received CCRT were divided into a construction set (230 patients) and a validating set (115 patients). The constructed index was derived on the former and then tested on the latter.The prognostic score was defined as the number of adverse prognostic factors: age >45, N3 category, hemoglobin <11.0 g/dL and lactate dehydrogenase 240 U/L. The score predicted the 5-year distant metastasis-free survival as follows: 0, 91%; 1, 74%; 2, 51%; and 3, 12%. In the validating set, the observed 5-year distant metastasis-free survival of these 4 groups with scores of 0, 1, 2, 3, or higher were 81%, 68%, 47%, and 15%, respectively.The established model might be useful for predicting the risk of distant metastasis in patients with locally advanced NPC who underwent CCRT and may identify the patients' need for intensified adjuvant chemotherapy.

View details for DOI 10.1002/hed.23583

View details for Web of Science ID 000348548700015

View details for PubMedID 24375647

Institutional clinical trial accrual volume and survival of patients with head and neck cancer. Journal of clinical oncology Wuthrick, E. J., Zhang, Q., Machtay, M., Rosenthal, D. I., Nguyen-Tan, P. F., Fortin, A., Silverman, C. L., Raben, A., Kim, H. E., Horwitz, E. M., Read, N. E., Harris, J., Wu, Q., Le, Q., Gillison, M. L. 2015; 33 (2): 156-164


National Comprehensive Cancer Network guidelines recommend patients with head and neck cancer (HNC) receive treatment at centers with expertise, but whether provider experience affects survival is unknown.The effect of institutional experience on overall survival (OS) in patients with stage III or IV HNC was investigated within a randomized trial of the Radiation Therapy Oncology Group (RTOG 0129), which compared cisplatin concurrent with standard versus accelerated fractionation radiotherapy. As a surrogate for experience, institutions were classified as historically low- (HLACs) or high-accruing centers (HHACs) based on accrual to 21 RTOG HNC trials (1997 to 2002). The effect of accrual volume on OS was estimated by Cox proportional hazards models.Median RTOG accrual (1997 to 2002) at HLACs was four versus 65 patients at HHACs. Analysis included 471 patients in RTOG 0129 (2002 to 2005) with known human papillomavirus and smoking status. Patients at HLACs versus HHACs had better performance status (0: 62% v 52%; P = .04) and lower T stage (T4: 26.5% v 35.3%; P = .002) but were otherwise similar. Radiotherapy protocol deviations were higher at HLACs versus HHACs (18% v 6%; P < .001). When compared with HHACs, patients at HLACs had worse OS (5 years: 51.0% v 69.1%; P = .002). Treatment at HLACs was associated with increased death risk of 91% (hazard ratio [HR], 1.91; 95% CI, 1.37 to 2.65) after adjustment for prognostic factors and 72% (HR, 1.72; 95% CI, 1.23 to 2.40) after radiotherapy compliance adjustment.OS is worse for patients with HNC treated at HLACs versus HHACs to cooperative group trials after accounting for radiotherapy protocol deviations. Institutional experience substantially influences survival in locally advanced HNC.

View details for DOI 10.1200/JCO.2014.56.5218

View details for PubMedID 25488965

View details for PubMedCentralID PMC4279235

p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. Journal of clinical oncology Chung, C. H., Zhang, Q., Kong, C. S., Harris, J., Fertig, E. J., Harari, P. M., Wang, D., Redmond, K. P., Shenouda, G., Trotti, A., Raben, D., Gillison, M. L., Jordan, R. C., Le, Q. 2014; 32 (35): 3930-3938


Although p16 protein expression, a surrogate marker of oncogenic human papillomavirus (HPV) infection, is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC), its prevalence and significance have not been well established in cancer of the oral cavity, hypopharynx, or larynx, collectively referred as non-OPSCC, where HPV infection is less common than in the oropharynx.p16 expression and high-risk HPV status in non-OPSCCs from RTOG 0129, 0234, and 0522 studies were determined by immunohistochemistry (IHC) and in situ hybridization (ISH). Hazard ratios from Cox models were expressed as positive or negative, stratified by trial, and adjusted for clinical characteristics.p16 expression was positive in 14.1% (12 of 85), 24.2% (23 of 95), and 19.0% (27 of 142) and HPV ISH was positive in 6.5% (six of 93), 14.6% (15 of 103), and 6.9% (seven of 101) of non-OPSCCs from RTOG 0129, 0234, and 0522 studies, respectively. Hazard ratios for p16 expression were 0.63 (95% CI, 0.42 to 0.95; P = .03) and 0.56 (95% CI, 0.35 to 0.89; P = .01) for progression-free (PFS) and overall survival (OS), respectively. Comparing OPSCC and non-OPSCC, patients with p16-positive OPSCC have better PFS and OS than patients with p16-positive non-OPSCC, but patients with p16-negative OPSCC and non-OPSCC have similar outcomes.Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement of HPV detection methods are warranted before broad application in the clinical setting.

View details for DOI 10.1200/JCO.2013.54.5228

View details for PubMedID 25267748

Palliative Radiation Before Hospice: The Long and the Short of It JOURNAL OF PAIN AND SYMPTOM MANAGEMENT Yeung, H. N., Mitchell, W. M., Roeland, E. J., Xu, B., Mell, L. K., Quynh-Thu Le, Q. T., Murphy, J. D. 2014; 48 (6): 1070-1079


Randomized data support shorter radiotherapy courses for management of cancer-related symptoms in the palliative setting.The purpose of this study was to evaluate the length of palliative radiotherapy before hospice enrollment among the elderly U.S. population, with a further focus on factors that influence the duration of radiation and the length of survival on hospice, including whether the duration of radiation was associated with length of survival on hospice.A total of 6982 patients with breast, prostate, lung, or colorectal cancer who received a course of radiotherapy within 30days before hospice enrollment were identified within the Surveillance, Epidemiology, and End Results-Medicare linked database. The primary end points included the duration of palliative radiotherapy and the time from hospice enrollment through death (hospice duration). Multivariate linear regression and multivariate Cox models evaluated factors associated with the length of radiotherapy course and hospice duration.The median length of palliative radiotherapy was 14days, and the median hospice duration was 13days. The course of palliative radiotherapy was longer than hospice duration in 48% of the patients. Breast and lung cancer were associated with longer courses of radiotherapy and shorter stays on hospice. Patients treated in freestanding radiation centers had longer courses of radiotherapy. For these groups, a longer radiotherapy course was not associated with longer hospice duration.This study found relatively long courses of radiotherapy before short lengths of survival on hospice. Future research is needed to identify barriers to shorter radiotherapy courses.

View details for DOI 10.1016/j.jpainsymman.2014.04.004

View details for Web of Science ID 000346742300006

View details for PubMedID 24819083

A unifying probabilistic Bayesian approach to derive electron density from MRI for radiation therapy treatment planning PHYSICS IN MEDICINE AND BIOLOGY Gudur, M. S., Hara, W., Le, Q., Wang, L., Xing, L., Li, R. 2014; 59 (21): 6595-6606
A unifying probabilistic Bayesian approach to derive electron density from MRI for radiation therapy treatment planning. Physics in medicine and biology Gudur, M. S., Hara, W., Le, Q., Wang, L., Xing, L., Li, R. 2014; 59 (21): 6595-6606


MRI significantly improves the accuracy and reliability of target delineation in radiation therapy for certain tumors due to its superior soft tissue contrast compared to CT. A treatment planning process with MRI as the sole imaging modality will eliminate systematic CT/MRI co-registration errors, reduce cost and radiation exposure, and simplify clinical workflow. However, MRI lacks the key electron density information necessary for accurate dose calculation and generating reference images for patient setup. The purpose of this work is to develop a unifying method to derive electron density from standard T1-weighted MRI. We propose to combine both intensity and geometry information into a unifying probabilistic Bayesian framework for electron density mapping. For each voxel, we compute two conditional probability density functions (PDFs) of electron density given its: (1) T1-weighted MRI intensity, and (2) geometry in a reference anatomy, obtained by deformable image registration between the MRI of the atlas and test patient. The two conditional PDFs containing intensity and geometry information are combined into a unifying posterior PDF, whose mean value corresponds to the optimal electron density value under the mean-square error criterion. We evaluated the algorithm's accuracy of electron density mapping and its ability to detect bone in the head for eight patients, using an additional patient as the atlas or template. Mean absolute HU error between the estimated and true CT, as well as receiver operating characteristics for bone detection (HU>200) were calculated. The performance was compared with a global intensity approach based on T1 and no density correction (set whole head to water). The proposed technique significantly reduced the errors in electron density estimation, with a mean absolute HU error of 126, compared with 139 for deformable registration (p = 210(-4)), 283 for the intensity approach (p = 210(-6)) and 282 without density correction (p = 510(-6)). For 90% sensitivity in bone detection, the proposed method achieved a specificity of 86%, compared with 80, 11 and 10% using deformable registration, intensity and without density correction, respectively. Notably, the Bayesian approach was more robust against anatomical differences between patients, with a specificity of 62% in the worst case (patient), compared to 30% specificity in registration-based approach. In conclusion, the proposed unifying Bayesian method provides accurate electron density estimation and bone detection from MRI of the head with highly heterogeneous anatomy.

View details for DOI 10.1088/0031-9155/59/21/6595

View details for PubMedID 25321341

Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response. Clinical cancer research Kuo, P., Bratman, S. V., Shultz, D. B., von Eyben, R., Chan, C., Wang, Z., Say, C., Gupta, A., Loo, B. W., Giaccia, A. J., Koong, A. C., Diehn, M., Le, Q. 2014; 20 (21): 5558-5569


Radiotherapy can result in lymphopenia, which has been linked to poorer survival. Here, we test the hypothesis that radiotherapy-induced lymphopenia is mediated by a tumor-secreted factor, Galectin-1 (Gal-1), which possesses T-cell proapoptotic activities.Matched Gal-1 wild-type (WT) or null mice were implanted with Lewis lung carcinoma (LLC-1) that either expressed Gal-1 or had Gal-1 stably downregulated. Tumors were irradiated locally and circulating Gal-1 and T cells were measured. Tumor growth, lung metastasis, intratumoral T-cell apoptosis, and microvessel density count were quantified. Thiodigalactoside (TDG), a Gal-1 inhibitor, was used to inhibit Gal-1 function in another group of mice to validate the observations noted with Gal-1 downregulation. Lymphocyte counts, survival, and plasma Gal-1 were analyzed in cohorts of radiotherapy-treated lung [non-small cell lung cancer (NSCLC)] and head and neck cancer patients.LLC irradiation increased Gal-1 secretion and decreased circulating T cells in mice, regardless of host Gal-1 expression. Inhibition of tumor Gal-1 with either shRNA or thiodigalactoside ablated radiotherapy-induced lymphopenia. Irradiated shGal-1 tumors showed significantly less intratumoral CD8(+) T-cell apoptosis and microvessel density, which led to marked tumor growth delay and reduced lung metastasis compared with controls. Similar observations were made after thiodigalactoside treatment. Radiotherapy-induced lymphopenia was associated with poorer overall survival in patients with NSCLC treated with hypofractionated radiotherapy. Plasma Gal-1 increased whereas T-cell decreased after radiation in another group of patients.Radiotherapy-related systemic lymphopenia appeared to be mediated by radiotherapy-induced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis. Clin Cancer Res; 20(21); 5558-69. 2014 AACR.

View details for DOI 10.1158/1078-0432.CCR-14-1138

View details for PubMedID 25189484

Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. Journal of clinical oncology Fakhry, C., Zhang, Q., Nguyen-Tan, P. F., Rosenthal, D., El-Naggar, A., Garden, A. S., Soulieres, D., Trotti, A., Avizonis, V., Ridge, J. A., Harris, J., Le, Q., Gillison, M. 2014; 32 (30): 3365-3373


Risk of cancer progression is reduced for patients with human papillomavirus (HPV) -positive oropharynx cancer (OPC) relative to HPV-negative OPC, but it is unknown whether risk of death after progression is similarly reduced.Patients with stage III-IV OPC enrolled onto Radiation Therapy Oncology Group trials 0129 or RTOG 0522 who had known tumor p16 status plus local, regional, and/or distant progression after receiving platinum-based chemoradiotherapy were eligible for a retrospective analysis of the association between tumor p16 status and overall survival (OS) after disease progression. Rates were estimated by Kaplan-Meier method and compared by log-rank; hazard ratios (HRs) were estimated by Cox models. Tests and models were stratified by treatment protocol.A total of 181 patients with p16-positive (n = 105) or p16-negative (n = 76) OPC were included in the analysis. Patterns of failure and median time to progression (8.2 v 7.3 months; P = .67) were similar for patients with p16-positive and p16-negative tumors. After a median follow-up period of 4.0 years after disease progression, patients with p16-positive OPC had significantly improved survival rates compared with p16-negative patients (2-year OS, 54.6% v 27.6%; median, 2.6 v 0.8 years; P < .001). p16-positive tumor status (HR, 0.48; 95% CI, 0.31 to 0.74) and receipt of salvage surgery (HR, 0.48; 95% CI; 0.27 to 0.84) reduced risk of death after disease progression whereas distant versus locoregional progression (HR, 1.99; 95% CI, 1.28 to 3.09) increased risk, after adjustment for tumor stage and cigarette pack-years at enrollment.Tumor HPV status is a strong and independent predictor of OS after disease progression and should be a stratification factor for clinical trials for patients with recurrent or metastatic OPC.

View details for DOI 10.1200/JCO.2014.55.1937

View details for PubMedID 24958820

View details for PubMedCentralID PMC4195851

Galectin-1 links tumor hypoxia and radiotherapy. Glycobiology Kuo, P., Le, Q. 2014; 24 (10): 921-925


Radiation therapy is a main stay in treating solid tumors and plays a significant role in definitive and adjuvant therapy. Unfortunately, local control remains a challenge, in which the success of radiotherapy is largely dictated by tumor hypoxia, DNA damage repair and the antitumor immune response. Extensive efforts have therefore been devoted to targeting the factors that attenuate tumor radiosensitivity, although with limited success. Mounting evidence suggests that tumor and endothelial cells may utilize galectin-1 (Gal-1) for protection against radiation through several mechanisms. Targeting Gal-1 in combination with radiotherapy provides an exciting approach to address several radiation-prohibitive mechanisms.

View details for DOI 10.1093/glycob/cwu062

View details for PubMedID 24973253

Galectin-1 links tumor hypoxia and radiotherapy GLYCOBIOLOGY Kuo, P., Quynh-Thu Le, Q. T. 2014; 24 (10): 921-925
Commutability of the Epstein-Barr virus WHO international standard across two quantitative PCR methods. Journal of clinical microbiology Abeynayake, J., Johnson, R., Libiran, P., Sahoo, M. K., Cao, H., Bowen, R., Chan, K. C., Le, Q., Pinsky, B. A. 2014; 52 (10): 3802-3804


The commutability of international reference standards is critical for ensuring quantitative agreement across different viral load assays. Here, we demonstrate the commutability of the Epstein-Barr virus (EBV) WHO international standard for the BamHI-W and artus EBV assays.

View details for DOI 10.1128/JCM.01676-14

View details for PubMedID 25078918

Age disparity in palliative radiation therapy among patients with advanced cancer. International journal of radiation oncology, biology, physics Wong, J., Xu, B., Yeung, H. N., Roeland, E. J., Martinez, M. E., Le, Q., Mell, L. K., Murphy, J. D. 2014; 90 (1): 224-230


Palliative radiation therapy represents an important treatment option among patients with advanced cancer, although research shows decreased use among older patients. This study evaluated age-related patterns of palliative radiation use among an elderly Medicare population.We identified 63,221 patients with metastatic lung, breast, prostate, or colorectal cancer diagnosed between 2000 and 2007 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Receipt of palliative radiation therapy was extracted from Medicare claims. Multivariate Poisson regression analysis determined residual age-related disparity in the receipt of palliative radiation therapy after controlling for confounding covariates including age-related differences in patient and demographic covariates, length of life, and patient preferences for aggressive cancer therapy.The use of radiation decreased steadily with increasing patient age. Forty-two percent of patients aged 66 to 69 received palliative radiation therapy. Rates of palliative radiation decreased to 38%, 32%, 24%, and 14% among patients aged 70 to 74, 75 to 79, 80 to 84, and over 85, respectively. Multivariate analysis found that confounding covariates attenuated these findings, although the decreased relative rate of palliative radiation therapy among the elderly remained clinically and statistically significant. On multivariate analysis, compared to patients 66 to 69 years old, those aged 70 to 74, 75 to 79, 80 to 84, and over 85 had a 7%, 15%, 25%, and 44% decreased rate of receiving palliative radiation, respectively (all P<.0001).Age disparity with palliative radiation therapy exists among older cancer patients. Further research should strive to identify barriers to palliative radiation among the elderly, and extra effort should be made to give older patients the opportunity to receive this quality of life-enhancing treatment at the end of life.

View details for DOI 10.1016/j.ijrobp.2014.03.050

View details for PubMedID 25195994

CD271 is a functional and targetable marker of tumor-initiating cells in head and neck squamous cell carcinoma. Oncotarget Murillo-Sauca, O., Chung, M. K., Shin, J. H., Karamboulas, C., Kwok, S., Jung, Y. H., Oakley, R., Tysome, J. R., Farnebo, L. O., Kaplan, M. J., Sirjani, D., Divi, V., Holsinger, F. C., Tomeh, C., Nichols, A., Le, Q. T., Colevas, A. D., Kong, C. S., Uppaluri, R., Lewis, J. S., Ailles, L. E., Sunwoo, J. B. 2014; 5 (16): 6854-6866


Tumor-initiating cells (TICs) in squamous cell carcinoma of the head and neck (SCCHN) are best characterized by their surface expression of CD44. Although there is great interest in identifying strategies to target this population, no marker of these cells has been found to be functionally active. Here, we examined the expression of the purported marker of normal human oral epithelial stem cells, CD271. We show that CD271 expression is restricted to a subset of the CD44+ cells. Using xenograft assays, we show that the CD44+CD271+ subpopulation contains the most tumorigenic cells. Loss of CD271 function results in a block in the G2-M phase of the cell cycle and a profound negative impact on the capacity of these cells to initiate tumor formation in vivo. Incubation with recombinant NGF results in enhanced phosphorylation of Erk, providing additional evidence that CD271 is functionally active. Finally, incubation of SCCHN cells with antibody to CD271 results in decreased Erk phosphorylation and decreased tumor formation in vivo. Thus, our data are the first to demonstrate that CD271 more specifically identifies the TIC subpopulation within the CD44+ compartment in SCCHN and that this receptor is a functionally active and targetable molecule.

View details for PubMedID 25149537

Salvage Treatment for Locally Recurrent Nasopharyngeal Carcinoma (NPC). American journal of clinical oncology Chen, C., Fee, W., Chen, J., Chan, C., Khong, B., Hara, W., Goffinet, D., Li, D., Le, Q. 2014; 37 (4): 327-331


It is important to determine the outcomes of retreatment in patients with locally recurrent nasopharyngeal carcinoma.We reviewed the records of patients treated for local recurrence at Stanford and Shantou Universities. The end points were local relapse-free survival (LRFS) and overall survival after retreatment.Fifty-six patients from Stanford and 98 from Shantou qualified. For the Stanford patients, 33 had surgery alone (S group), 12 had surgery plus radiotherapychemotherapy (CMT group), and 22 had radiotherapychemotherapy (RT Stanford group). All Shantou patients received radiotherapychemotherapy (RT Shantou group). The 5-year LRFS rates were: 57% for S group, 25% for CMT group, 53% for RT Stanford group, and 41% for RT Shantou group (P>0.05) for rT1-2 tumors; they were 29% for S group, 25% for CMT group, 39% for RT Stanford group, and 9% for RT Shantou group for rT3-4 tumors (P>0.05). For RT patients, 5-year overall survival rates were 49% for Stanford and 25% for Shantou patients (P=0.026).Similar and durable LRFS rates were attained for both S and RT groups when stratified by rT-stage.

View details for DOI 10.1097/COC.0b013e318277d804

View details for PubMedID 23275273

Neurotrophic factor GDNF promotes survival of salivary stem cells. journal of clinical investigation Xiao, N., Lin, Y., Cao, H., Sirjani, D., Giaccia, A. J., Koong, A. C., Kong, C. S., Diehn, M., Le, Q. 2014; 124 (8): 3364-3377


Stem cell-based regenerative therapy is a promising treatment for head and neck cancer patients that suffer from chronic dry mouth (xerostomia) due to salivary gland injury from radiation therapy. Current xerostomia therapies only provide temporary symptom relief, while permanent restoration of salivary function is not currently feasible. Here, we identified and characterized a stem cell population from adult murine submandibular glands. Of the different cells isolated from the submandibular gland, this specific population, Lin-CD24+c-Kit+Sca1+, possessed the highest capacity for proliferation, self renewal, and differentiation during serial passage in vitro. Serial transplantations of this stem cell population into the submandibular gland of irradiated mice successfully restored saliva secretion and increased the number of functional acini. Gene-expression analysis revealed that glial cell line-derived neurotrophic factor (Gdnf) is highly expressed in Lin-CD24+c-Kit+Sca1+ stem cells. Furthermore, GDNF expression was upregulated upon radiation therapy in submandibular glands of both mice and humans. Administration of GDNF improved saliva production and enriched the number of functional acini in submandibular glands of irradiated animals and enhanced salisphere formation in cultured salivary stem cells, but did not accelerate growth of head and neck cancer cells. These data indicate that modulation of the GDNF pathway may have potential therapeutic benefit for management of radiation-induced xerostomia.

View details for DOI 10.1172/JCI74096

View details for PubMedID 25036711

View details for PubMedCentralID PMC4109543

Imaging features associated with disease progression after stereotactic ablative radiotherapy for stage I non-small-cell lung cancer. Clinical lung cancer Shultz, D. B., Trakul, N., Abelson, J. A., Murphy, J. D., Maxim, P. G., Le, Q., Loo, B. W., Diehn, M. 2014; 15 (4): 294-301 e3


The aim of this study was to identify imaging-based predictors of progression in patients treated with SABR for stage I NSCLC.Between March 2003 and December 2012, 117 patients with stage I NSCLC meeting our study criteria were treated with SABR at Stanford University. Median follow-up was 17 months (range, 3-74 months) for all patients and 19 months for living patients (range, 3-74 months). Tumors were classified according to whether or not they contacted the pleura adjacent to the chest wall or mediastinum (MP), according to their maximum dimension based on computed tomography scans, and, for 102 patients who had archived pretreatment fluorine-18 fluorodeoxyglucose positron-emission tomography scans, according to SUVmax.Ten patients (9%) developed local progression, 17 (15%) developed regional progression, and 19 (16%) developed distant metastasis. Two-year freedom from local progression, freedom from regional progression, and freedom from distant metastasis (FFDM) were 88%, 83%, and 83%, respectively. Overall survival was 70% at 2 years. FFDM was significantly associated with MP contact, maximum tumor dimension, and SUVmax, and these variables could be combined into an exploratory prognostic index that identified patients at highest risk for developing metastases.In our cohort, noninvasive, imaging-based features were associated with distant progression after SABR for early stage NSCLC. If validated, our prognostic index could allow identification of patients who might benefit from systemic therapy after SABR.

View details for DOI 10.1016/j.cllc.2013.12.011

View details for PubMedID 24594400

Human papillomavirus 16 detected in nasopharyngeal carcinomas in white Americans but not in endemic Southern Chinese patients. Head & neck Lin, Z., Khong, B., Kwok, S., Cao, H., West, R. B., Le, Q., Kong, C. S. 2014; 36 (5): 709-714


BACKGROUND: We evaluated the relationship of HPV and EBV with race in endemic and non-endemic cohorts of patients with nasopharyngeal carcinoma (NPC), and with smoking status in the non-endemic cohort. METHODS: Tissue microarrays (TMA) were constructed using samples from 86 patients treated in southern China and 108 patients from Stanford. TMAs were stained with p16, HPV ISH, and EBV ISH. PCR was used to confirm EBV(-) cases and HPV status in p16(+) cases. Survival data was available for the Stanford cohort only. RESULTS: No HPV(+) cases were detected in the Chinese cohort. In the Stanford cohort, 5/11 EBV(-) cases harbored HPV16, 10/10 occurred in Caucasians, and 8/11 were smokers. Patients with EBV(-) NPC also showed a trend towards worse survival. CONCLUSIONS: EBV(-) NPC shows an association with the presence of HPV, Caucasian race, and smoking. In contrast, EBV(-) NPC shows no association with HPV in the endemic cohort. Head Neck, 2013.

View details for DOI 10.1002/hed.23362

View details for PubMedID 23616441

Risk Factors for Clinician-Reported Symptom Clusters in Patients With Advanced Head and Neck Cancer in a Phase 3 Randomized Clinical Trial: RTOG 0129 CANCER Xiao, C., Hanlon, A., Zhang, Q., Movsas, B., Ang, K., Rosenthal, D. I., Nguyen-Tan, P. F., Kim, H., Le, Q., Bruner, D. W. 2014; 120 (6): 848-854


Chemoradiotherapy has become the standard of care for head and neck squamous cell carcinoma; however, those patients often experience multiple treatment-related symptoms or symptom clusters. Two symptom clusters have been identified for this population. Little is known about the risk factors of these symptom clusters.Subjects comprised 684 patients who were treated with concurrent chemoradiotherapy in a phase 3 randomized clinical trial. This trial compared standard fractionation radiotherapy to accelerated fractionation radiotherapy. Symptom clusters were evaluated at the end of the first and the second cycle of chemotherapy, and 3 months after the start of radiotherapy. Mixed-effect modeling was used to observe risk factors for symptom clusters.Race and education were independent predictors for the head and neck cluster, whereas sex and history of tobacco use were independent predictors for the gastrointestinal cluster. Primary cancer site was only significant for the head and neck cluster when other factors were not controlled: patients with oropharyngeal cancer had more severe symptoms in the head and neck clusters than did patients with laryngeal cancer. In addition, patients receiving accelerated fractionation radiotherapy experienced more symptoms of radiomucositis, pain, and nausea at 3 months after the start of radiotherapy than those receiving standard fractionation radiotherapy.Demographic characteristics were more predictive to symptom clusters, whereas clinical characteristics, such as cancer site and treatment arms, were more significant for individual symptoms. Knowing the risk factors will enhance the capability of clinicians to evaluate patients' risk of severe symptom clusters and to personalize management strategies.

View details for DOI 10.1002/cncr.28500

View details for Web of Science ID 000332140100013

View details for PubMedID 24338990

A Population-Based Comparative Effectiveness Study of Radiation Therapy Techniques in Stage III Non-Small Cell Lung Cancer. International journal of radiation oncology, biology, physics Harris, J. P., Murphy, J. D., Hanlon, A. L., Le, Q., Loo, B. W., Diehn, M. 2014; 88 (4): 872-884


Concerns have been raised about the potential for worse treatment outcomes because of dosimetric inaccuracies related to tumor motion and increased toxicity caused by the spread of low-dose radiation to normal tissues in patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity modulated radiation therapy (IMRT). We therefore performed a population-based comparative effectiveness analysis of IMRT, conventional 3-dimensional conformal radiation therapy (3D-CRT), and 2-dimensional radiation therapy (2D-RT) in stage III NSCLC.We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify a cohort of patients diagnosed with stage III NSCLC from 2002 to 2009 treated with IMRT, 3D-CRT, or 2D-RT. Using Cox regression and propensity score matching, we compared survival and toxicities of these treatments.The proportion of patients treated with IMRT increased from 2% in 2002 to 25% in2009, and the use of 2D-RT decreased from 32% to 3%. In univariate analysis, IMRT wasassociated with improved overall survival (OS) (hazard ratio [HR] 0.90, P=.02) and cancer-specific survival (CSS) (HR 0.89, P=.02). After controlling for confounders, IMRT was associated with similar OS (HR 0.94, P=.23) and CSS (HR 0.94, P=.28) compared with 3D-CRT. Both techniques had superior OS compared with 2D-RT. IMRT was associated with similar toxicity risks on multivariate analysis compared with 3D-CRT. Propensity score matched model results were similar to those from adjusted models.In this population-based analysis, IMRT for stage III NSCLC was associated with similar OS and CSS and maintained similar toxicity risks compared with 3D-CRT.

View details for DOI 10.1016/j.ijrobp.2013.12.010

View details for PubMedID 24495591

Discovery of recurrent structural variants in nasopharyngeal carcinoma. Genome research Valouev, A., Weng, Z., Sweeney, R. T., Varma, S., Le, Q., Kong, C., Sidow, A., West, R. B. 2014; 24 (2): 300-309


We present the discovery of genes recurrently involved in structural variation in nasopharyngeal carcinoma (NPC) and the identification of a novel type of somatic structural variant. We identified the variants with high complexity mate-pair libraries and a novel computational algorithm specifically designed for tumor-normal comparisons, SMASH. SMASH combines signals from split reads and mate-pair discordance to detect somatic structural variants. We demonstrate a >90% validation rate and a breakpoint reconstruction accuracy of 3 bp by Sanger sequencing. Our approach identified three in-frame gene fusions (YAP1-MAML2, PTPLB-RSRC1, and SP3-PTK2) that had strong levels of expression in corresponding NPC tissues. We found two cases of a novel type of structural variant, which we call "coupled inversion," one of which produced the YAP1-MAML2 fusion. To investigate whether the identified fusion genes are recurrent, we performed fluorescent in situ hybridization (FISH) to screen 196 independent NPC cases. We observed recurrent rearrangements of MAML2 (three cases), PTK2 (six cases), and SP3 (two cases), corresponding to a combined rate of structural variation recurrence of 6% among tested NPC tissues.

View details for DOI 10.1101/gr.156224.113

View details for PubMedID 24214394

Racial Disparity in Consultation, Treatment, and the Impact on Survival in Metastatic Colorectal Cancer JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Simpson, D. R., Martinez, M. E., Gupta, S., Hattangadi-Gluth, J., Mell, L. K., Heestand, G., Fanta, P., Ramamoorthy, S., Le, Q., Murphy, J. D. 2013; 105 (23): 1814-1820


Black patients with metastatic colorectal cancer have inferior survival compared to white patients. The purpose of this study was to examine disparity in specialist consultation and multimodality treatment and the impact that treatment inequality has on survival.We identified 9935 non-Hispanic white and 1281 black patients with stage IV colorectal cancer aged 66 years and older from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Logistic regression models identified race-based differences in consultation rates and subsequent treatment with surgery, chemotherapy, or radiation. Multivariable Cox regression models identified potential factors that explain race-based survival differences. All statistical tests were two-sided.Black patients had lower rates of consultation with surgery, medical oncology, and radiation oncology. Among patients seen in consultation, black patients received less surgery directed at the primary tumor, liver- or lung-directed surgery, chemotherapy, and radiotherapy. Unadjusted survival analysis found a 15% higher chance of dying for black patients compared with white patients (hazard ratio [HR] = 1.15; 95% confidence interval (CI) = 1.08 to 1.22; P < .001). Adjustment for patient, tumor, and demographic variables marginally reduced the risk of death (HR = 1.08; 95% CI = 1.01 to 1.15; P = .03). After adjustment for differences in treatment, the increased risk of death for black patients disappeared.Our study shows racial disparity in specialist consultation as well as subsequent treatment with multimodality therapy for metastatic colorectal cancer, and it suggests that inferior survival for black patients may stem from this treatment disparity. Further research into the underlying causes of this inequality will improve access to treatment and survival in metastatic colorectal cancer.

View details for DOI 10.1093/jnci/djt318

View details for Web of Science ID 000328370000011

View details for PubMedID 24231453

Long-Term Outcomes of Surgery Followed by Radiation Therapy for Minor Salivary Gland Carcinomas LARYNGOSCOPE Zeidan, Y. H., Shultz, D. B., Murphy, J. D., Chan, C., Kaplan, M. J., Colevas, A. D., Kong, C., Chang, D. T., Le, Q. 2013; 123 (11): 2675-2680


Postoperative radiation therapy is often used in patients with high-risk salivary gland carcinomas. In this study we evaluated the outcomes and prognostic factors in patients with minor salivary gland cancers treated with adjuvant radiation therapy.Retrospective cohort study.We performed a retrospective analysis of 90 patients treated with curative intent. Median follow-up was 71 months. Fifty-eight patients (64%) had adenoid cystic carcinomas, 22 (24%) had adenocarcinomas, and 10 (11%) had mucoepidermoid cancers. Primary disease site included 39 (43%) sinonasal, 35 (39%) oral cavity, 10 (11%) oropharynx, and six (7%) others. Twenty-seven patients (30%) were treated with intensity-modulated radiation therapy.Eight local, four neck, and 24 distant relapses were detected. Local control rates at 5 and 10 years were 90% and 88%, respectively. Advanced T stage was associated with worse local control. Distant metastasis rates were 24% and 28% at 5 and 10 years, respectively. Tumor stage, histology, perineural invasion, and lymphovascular space invasion were significant predictors of distant metastasis on univariate analysis. However, on multivariate analysis only the American Joint Committee on Cancer stage was significant. Overall survival rates were 76% and 63% at 5 and 10 years, respectively. More advanced T stage and N stage correlated with worse overall survival.Tumor stage remains the best predictor for locoregional and distant disease control of minor salivary gland cancers. Postoperative radiation therapy for high-risk patients results in excellent long-term locoregional disease control. Further work is needed to improve systemic control.

View details for DOI 10.1002/lary.24081

View details for Web of Science ID 000326231200029

View details for PubMedID 23553253

Radio logic assessment of retropharyngeal node involvement in oropharyngeal carcinomas stratified by HPV status RADIOTHERAPY AND ONCOLOGY Tang, C., Komakula, S., Chan, C., Murphy, J. D., Jiang, W., Kong, C., Lee-Enriquez, N., Jensen, K. C., Fischbein, N. J., Quynh-Thu Le, Q. T. 2013; 109 (2): 293-296
Radiologic assessment of retropharyngeal node involvement in oropharyngeal carcinomas stratified by HPV status. Radiotherapy and oncology Tang, C., Komakula, S., Chan, C., Murphy, J. D., Jiang, W., Kong, C., Lee-Enriquez, N., Jensen, K. C., Fischbein, N. J., Le, Q. 2013; 109 (2): 293-296


Radiation of retropharyngeal nodes (RPN) results in increased toxicities. This study assessed characteristics associated with RPN involvement in 165 oropharynx cancer patients. Factors associated with involvement were stage N2c-3 disease and stage N2b disease with either advanced T-stage, 3 involved cervical LN, and 1 involved contralateral LN, or lateral/posterior subsites.

View details for DOI 10.1016/j.radonc.2013.09.001

View details for PubMedID 24103114

Clinical impact of dose overestimation by effective path length calculation in stereotactic ablative radiation therapy of lung tumors. Practical radiation oncology Liu, M. B., Eclov, N. C., Trakul, N., Murphy, J., Diehn, M., Le, Q., Dieterich, S., Maxim, P. G., Loo, B. W. 2013; 3 (4): 294-300


To determine the clinical impact of calculated dose differences between effective path length (EPL) and Monte Carlo (MC) algorithms in stereotactic ablative radiation therapy (SABR) of lung tumors.We retrospectively analyzed the treatment plans and clinical outcomes of 77 consecutive patients treated with SABR for 82 lung tumors between 2003 and 2009 at our institution. Sixty treatments were originally planned using EPL, and 22 using MC. All plans were recalculated for the same beam specifications using MC and EPL, respectively. The doses covering 95%, 50%, and 5% (D95, D50, D5, respectively) of the target volumes were compared between EPL and MC (assumed to be the actual delivered dose), both as physical dose and biologically effective dose. Time to local recurrence was correlated with dose by Cox regression analysis. The relationship between tumor control probability (TCP) and biologically effective dose was determined via logistic regression and used to estimate the TCP decrements due to prescribing by EPL calculations.EPL overestimated dose compared with MC in all tumor dose-volume histogram parameters in all plans. The difference was >10% of the MC D95 to the planning target volume and gross tumor volume in 60 of 82 (73%) and 52 of 82 plans (63%), respectively. Local recurrence occurred in 13 of 82 tumors. Controlling for gross tumor volume, higher physical and biologically effective planning target volume D95 correlated significantly with local control (P = .007 and P = .045, respectively). Compared with MC, prescribing based on EPL translated to a median TCP decrement of 4.3% (range, 1.2%-37%) and a >5% decrement in 46% of tumors.Clinical follow-up for local lung tumor control in a sizable cohort of patients treated with SABR demonstrates that EPL overestimates dose by amounts that substantially decrease TCP in a large proportion. EPL algorithms should be avoided for lung tumor SABR.

View details for DOI 10.1016/j.prro.2012.09.003

View details for PubMedID 24674401

Radiotherapy for nonadenoid cystic carcinomas of major salivary glands. American journal of otolaryngology Chung, M. P., Tang, C., Chan, C., Hara, W. Y., Loo, B. W., Kaplan, M. J., Fischbein, N., Le, Q., Chang, D. T. 2013; 34 (5): 425-430


To report outcomes in patients treated with postoperative radiotherapy for nonadenoid cystic carcinomas of the major salivary glands.From 1998-2011, 37 patients with nonadenoid cystic carcinomas of the major salivary gland underwent postoperative radiotherapy. The median radiation dose was 60 Gy (range, 45-70 Gy). TNM distribution included T1-2 (n=16, 44%), T3-T4 (n=21, 56%), N0 (n=19, 51%), and N+ (n=18, 49%). Histologies included adenocarcinoma (n=13, 35%), squamous cell carcinoma (n=8, 22%), mucoepidermoid carcinoma (n=8, 22%), and other (n=8, 21%). Median follow-up was 4.7 years for all patients (range, 0.3-14.1 years) and 5.0 years for living patients (range, 1.2-12.2 years).Five-year local-regional control, overall survival (OS), and cancer-specific survival (CSS) were 97%, 76%, and 84%. On univariate analysis, OS was significantly worse for patients 65 years old (p=0.04). CSS was significantly worse for positive perineural invasion (p=0.02), extraparenchymal extension (p=0.04), and in patients who received no chemotherapy (p=0.02). Doses >60 Gy was significantly worse for OS (p=0.003) and CSS (p=0.003), although these patients had higher TNM (>T2, p=0.01) and trended towards a higher rate of extraparenchymal extension (p=0.08). Four patients (11%) developed grade 2 toxicities; 3 patients developed early toxicities and one patient developed late toxicities.Radiotherapy for salivary gland tumors provides excellent local-regional control when combined with surgery. Distant metastasis is the predominant pattern of failure, although chemotherapy seemed to improve cancer-specific survival.

View details for DOI 10.1016/j.amjoto.2013.03.007

View details for PubMedID 23583094

Patterns of care in palliative radiotherapy: a population-based study. Journal of oncology practice / American Society of Clinical Oncology Murphy, J. D., Nelson, L. M., Chang, D. T., Mell, L. K., Le, Q. 2013; 9 (5): e220-7


Approximately one half of the radiotherapy (RT) prescribed in the United States is delivered with palliative intent. The purpose of this study was to investigate the patterns of delivery of palliative RT across the United States.Using the Surveillance, Epidemiology, and End Results-Medicare linked database, 51,610 patients were identified with incident stage IV breast, prostate, lung, or colorectal cancer diagnosed between 2000 and 2007 and observed through 2009. Multivariate logistic regression determined predictors of palliative RT.Forty-one percent of the study population received palliative RT, including 53% of patients with lung cancer, followed by those with breast (42%), prostate (40%), and colorectal cancers (12%). Multivariate analysis revealed that older patients (P<.001) and those with higher Charlson comorbidity scores (P<.001) were less likely to receive palliative RT. Black patients with prostate cancer were 20% less likely (P<.001), and black patients with colorectal cancer were 28% less likely (P<.001), than white patients to receive palliative RT. Among those treated with RT, 23% of patients with lung cancer died within 2 weeks of completing treatment, followed by those with colorectal (12%), breast (11%), and prostate cancers (8%). In addition to tumor site, significant predictors (P<.05) of death within 2 weeks of receiving RT included increased age, increased comorbidity, and male sex.Inequality in the receipt of palliative RT exists among the elderly and patients with comorbid conditions and varies with race. In addition, a significant number of patients die shortly after receiving RT. Understanding these patterns of care, along with further research into the underlying causes, will improve access and quality of palliative RT.

View details for DOI 10.1200/JOP.2012.000835

View details for PubMedID 23943892

A Novel Aldehyde Dehydrogenase-3 Activator (Alda-89) Protects Submandibular Gland Function from Irradiation without Accelerating Tumor Growth. Clinical cancer research Xiao, N., Cao, H., Chen, C., Kong, C. S., Ali, R., Chan, C., Sirjani, D., Graves, E., Koong, A., Giaccia, A., Mochly-Rosen, D., Le, Q. 2013; 19 (16): 4455-4464


To determine the effect of Alda-89 (an ALDH3 activitor) on (i) the function of irradiated (radiotherapy) submandibular gland (SMG) in mice, (ii) its toxicity profile, and (iii) its effect on the growth of head and neck cancer (HNC) in vitro and in vivo.Adult mice were infused with Alda-89 or vehicle before, during, and after radiotherapy. Saliva secretion was monitored weekly. Hematology, metabolic profile, and postmortem evaluation for toxicity were examined at the time of sacrifice. Alda-89 or vehicle was applied to HNC cell lines in vitro, and severe combined immunodeficient (SCID) mice transplanted with HNC in vivo with or without radiation; HNC growth was monitored. The ALDH3A1 and ALDH3A2 protein expression was evaluated in 89 patients with HNC and correlated to freedom from relapse (FFR) and overall survival (OS).Alda-89 infusion significantly resulted in more whole saliva production and a higher percentage of preserved acini after radiotherapy compared with vehicle control. There was no difference in the complete blood count, metabolic profile, and major organ morphology between the Alda-89 and vehicle groups. Compared with vehicle control, Alda-89 treatment neither accelerated HNC cell proliferation in vitro, nor did it affect tumor growth in vivo with or without radiotherapy. Higher expression of ALDH3A1 or ALDH3A2 was not significantly associated with worse FFR or OS in either human papillomavirus (HPV)-positive or HPV-negative group.Alda-89 preserves salivary function after radiotherapy without affecting HNC growth or causing measurable toxicity in mice. It is a promising candidate to mitigate radiotherapy-related xerostomia.

View details for DOI 10.1158/1078-0432.CCR-13-0127

View details for PubMedID 23812668

View details for PubMedCentralID PMC3745542

Low-dose radiation therapy (2 Gy 2) in the treatment of orbital lymphoma. International journal of radiation oncology, biology, physics Fasola, C. E., Jones, J. C., Huang, D. D., Le, Q., Hoppe, R. T., Donaldson, S. S. 2013; 86 (5): 930-935


Low-dose radiation has become increasingly used in the management of indolent non-Hodgkin lymphoma (NHL), but has not been studied specifically for cases of ocular adnexal involvement. The objective of this study is to investigate the effectiveness of low-dose radiation in the treatment of NHL of the ocular adnexa.We reviewed the records of 20 NHL patients with 27 sites of ocular adnexal involvement treated with low-dose radiation consisting of 2 successive fractions of 2 Gy at our institution between 2005 and 2011. The primary endpoint of this study is freedom from local relapse (FFLR).At a median follow-up time of 26 months (range 7-92), the overall response rate for the 27 treated sites was 96%, with a complete response (CR) rate of 85% (n=23) and a partial response rate of 11% (n=3). Among all treated sites with CR, the 2-year FFLR was 100%, with no in-treatment field relapses. The 2-year freedom from regional relapse rate was 96% with 1 case of relapse within the ipsilateral orbit (outside of the treatment field). This patient underwent additional treatment with low-dose radiation of 4 Gy to the area of relapse achieving a CR and no evidence of disease at an additional 42 months of follow-up. Orbital radiation was well tolerated with only mild acute side effects (dry eye, conjunctivitis, transient periorbital edema) in 30% of treated sites without any reports of long-term toxicity.Low-dose radiation with 2 Gy 2 is effective and well tolerated in the treatment of indolent NHL of the ocular adnexa with high response rates and durable local control with the option of reirradiation in the case of locoregional relapse.

View details for DOI 10.1016/j.ijrobp.2013.04.035

View details for PubMedID 23726002

Cost-effectiveness landscape analysis of treatments addressing xerostomia in patients receiving head and neck radiation therapy. Oral surgery, oral medicine, oral pathology and oral radiology Sasportas, L. S., Hosford, D. N., Sodini, M. A., Waters, D. J., Zambricki, E. A., Barral, J. K., Graves, E. E., Brinton, T. J., Yock, P. G., Le, Q., Sirjani, D. 2013; 116 (1): e37-51


Head and neck (H&N) radiation therapy (RT) can induce irreversible damage to the salivary glands thereby causing long-term xerostomia or dry mouth in 68%-85% of the patients. Not only does xerostomia significantly impair patients' quality-of-life (QOL) but it also has important medical sequelae, incurring high medical and dental costs. In this article, we review various measures to assess xerostomia and evaluate current and emerging solutions to address this condition in H&N cancer patients. These solutions typically seek to accomplish 1 of the 4 objectives: (1) to protect the salivary glands during RT, (2) to stimulate the remaining gland function, (3) to treat the symptoms of xerostomia, or (4) to regenerate the salivary glands. For each treatment, we assess its mechanisms of action, efficacy, safety, clinical utilization, and cost. We conclude that intensity-modulated radiation therapy is both the most widely used prevention approach and the most cost-effective existing solution and we highlight novel and promising techniques on the cost-effectiveness landscape.

View details for DOI 10.1016/j.oooo.2013.02.017

View details for PubMedID 23643579

Stereotactic radiosurgery for retreatment of gross perineural invasion in recurrent cutaneous squamous cell carcinoma of the head and neck. American journal of clinical oncology Tang, C., Fischbein, N. J., Murphy, J. D., Chu, K. P., Bavan, B., Dieterich, S., Hara, W., Kaplan, M. J., Colevas, A. D., Le, Q. 2013; 36 (3): 293-298


: To report outcomes, failure patterns, and toxicity after stereotactic radiosurgery (SRS) for recurrent head and neck cutaneous squamous cell carcinoma with gross perineural invasion (GPNI).: Ten patients who received SRS as part of retreatment for recurrent head and neck cutaneous squamous cell carcinoma with GPNI were included. All patients exhibited clinical and radiologic evidence of GPNI before SRS. Previous treatments included surgery alone in 3 patients and surgery with adjuvant external beam radiotherapy (EBRT) in 7 patients. Retreatment included SRS alone in 2 and EBRT boosted with SRS in 8 patients. Magnetic resonance images were obtained every 3 to 6 months after SRS to track failure patterns.: At a median 22-month follow-up, the 2-year progression-free and overall survival rates were 20% and 50%, respectively. Seven patients exhibited local failures, all of which occurred outside both SRS and EBRT fields. Five local failures occurred in previously clinically uninvolved cranial nerves (CNs). CN disease spreads through 3 distinct patterns: among different branches of CN V; between CNs V and VII; and between V1 and CNs III, IV, and/or VI. Five patients experienced side effects potentially attributable to radiation.: Although there is excellent in-field control with this approach, the rate of out-of-field failures remains unacceptably high. We found that the majority of failures occurred in previously clinically uninvolved CNs often just outside treatment fields. Novel treatment strategies targeting this mode of perineural spread are needed.

View details for DOI 10.1097/COC.0b013e3182468019

View details for PubMedID 22547009

Opportunities and challenges in the era of molecularly targeted agents and radiation therapy. Journal of the National Cancer Institute Lin, S. H., George, T. J., Ben-Josef, E., Bradley, J., Choe, K. S., Edelman, M. J., Guha, C., Krishnan, S., Lawrence, T. S., Le, Q., Lu, B., Mehta, M., Peereboom, D., Sarkaria, J., Seong, J., Wang, D., Welliver, M. X., Coleman, C. N., Vikram, B., Yoo, S., Chung, C. H. 2013; 105 (10): 686-693


The first annual workshop for preclinical and clinical development of radiosensitizers took place at the National Cancer Institute on August 8-9, 2012. Radiotherapy is one of the most commonly applied and effective oncologic treatments for solid tumors. It is well recognized that improved clinical efficacy of radiotherapy would make a substantive impact in clinical practice and patient outcomes. Advances in genomic technologies and high-throughput drug discovery platforms have brought a revolution in cancer treatment by providing molecularly targeted agents for various cancers. Development of predictive biomarkers directed toward specific subsets of cancers has ushered in a new era of personalized therapeutics. The field of radiation oncology stands to gain substantial benefit from these advances given the concerted effort to integrate this progress into radiation therapy. This workshop brought together expert clinicians and scientists working in various disease sites to identify the exciting opportunities and expected challenges in the development of molecularly targeted agents in combination with radiation therapy.

View details for DOI 10.1093/jnci/djt055

View details for PubMedID 23503600

An international collaboration to harmonize the quantitative plasma Epstein-Barr virus DNA assay for future biomarker-guided trials in nasopharyngeal carcinoma. Clinical cancer research Le, Q., Zhang, Q., Cao, H., Cheng, A., Pinsky, B. A., Hong, R., Chang, J. T., Wang, C., Tsao, K., Lo, Y. D., Lee, N., Ang, K. K., Chan, A. T., Chan, K. C. 2013; 19 (8): 2208-2215


Persistently elevated posttreatment plasma EBV DNA is a robust predictor of relapse in nasopharyngeal carcinoma (NPC). However, assay standardization is necessary for use in biomarker-driven trials. We conducted a study to harmonize the method between four centers with expertise in EBV DNA quantitation.Plasma samples of 40 patients with NPC were distributed to four centers. DNA was extracted and EBV DNA copy number was determined by real-time quantitative PCR (BamHI-W primer/probe). Centers used the same protocol but generated their own calibrators. A harmonization study was then conducted using the same calibrators and PCR master mix and validated with ten pooled samples.The initial intraclass correlations (ICC) for the first 40 samples between each center and the index center were 0.62 [95% confidence interval (CI): 0.39-0.78], 0.70 (0.50-0.83), and 0.59 (0.35-0.76). The largest variability was the use of different PCR master mixes and calibrators. Standardization improved ICC to 0.83 (0.5-0.95), 0.95 (0.83-0.99) and 0.96 (0.86-0.99), respectively, for ten archival frozen samples. For fresh plasma with spiked-in EBV DNA, correlations were more than 0.99 between the centers. At 5 EBV DNA copies per reaction or above, the coefficient of variance (CV) was less than 10% for the cycle threshold (Ct) among all centers, suggesting this concentration can be reliably used as a cutoff for defining the presence of detectable EBV DNA.Quantitative PCR assays, even when conducted in experienced clinical labs, can yield large variability in plasma EBV DNA copy numbers without harmonization. The use of common calibrators and PCR master mix can help to reduce variability.

View details for DOI 10.1158/1078-0432.CCR-12-3702

View details for PubMedID 23459720

View details for PubMedCentralID PMC3630245

Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence. Cancer Ho, A. S., Tsao, G. J., Chen, F. W., Shen, T., Kaplan, M. J., Colevas, A. D., Fischbein, N. J., Quon, A., Le, Q., Pinto, H. A., Fee, W. E., Sunwoo, J. B., Sirjani, D., Hara, W., Yao, M. 2013; 119 (7): 1349-1356


In head and neck cancer (HNC), 3-month post-treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post-treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months.A 10-year retrospective analysis of HNC patients was carried out with long-term serial imaging. Imaging at 3 months included either PET/CT or magnetic resonance imaging, with all subsequent imaging comprised of PET/CT. PET/CT scans at 12 and 24 months were evaluated only if preceding interval scans were negative. Of 1114 identified patients, 284 had 3-month scans, 175 had 3- and 12-month scans, and 77 had 3-, 12-, and 24-month scans.PET/CT detection rates in clinically occult patients were 9% (15 of 175) at 12 months, and 4% (3 of 77) at 24 months. No difference in outcomes was identified between PET/CT-detected and clinically detected recurrences, with similar 3-year disease-free survival (41% vs 46%, P = .91) and 3-year overall survival (60% vs 54%, P = .70) rates. Compared with 3-month PET/CT, 12-month PET/CT demonstrated fewer equivocal reads (26% vs 10%, P < .001). Of scans deemed equivocal, 6% (5 of 89) were ultimately found to be positive.HNC patients with negative 3-month imaging appear to derive limited benefit from subsequent PET/CT surveillance. No survival differences were observed between PET/CT-detected and clinically detected recurrences, although larger prospective studies are needed for further investigation.

View details for DOI 10.1002/cncr.27892

View details for PubMedID 23225544

Results of a phase 2 study examining the effects of omitting elective neck irradiation to nodal levels IV and Vb in patients with N(0-1) nasopharyngeal carcinoma. International journal of radiation oncology, biology, physics Chen, J., Le, Q., Han, F., Lu, L., Huang, S., Lin, C., Deng, X., Cui, N., Zhao, C. 2013; 85 (4): 929-934


To evaluate the patterns of nodal failure and toxicity in clinically negative necks of N0-1 nasopharyngeal carcinoma (NPC) patients who were treated with intensity modulated radiation therapy (IMRT) but did not receive elective neck irradiation (ENI) to level IV and Vb nodes.We conducted a phase 2 prospective study in N0-1 NPC patients treated with IMRT. ENI included the retropharyngeal nodes and levels II to Va but omitted levels IV and Vb in clinically negative necks. Patterns of nodal failure, regional control (RC), and late toxicity were evaluated.Between 2001 and 2008, a total of 212 patients (128 N0 and 84 N1) were enrolled in the study. Seven patients (4 in-field and 3 out-of-field) developed nodal failure. One patient (0.5%) developed nodal failure at level Vb, but no patients developed nodal failure at level IV. The 5-year RC rates of the entire group, N0 patients and N1 patients were 95.6%, 98.2%, and 91.3%, respectively. Fifteen patients (7.1%) developed distant metastases. The 5-year distant failure-free survival (DFFS) and overall survival (OS) rates were 91.4% and 89.8%, respectively. The rates of grade 2 or greater skin dystrophy, subcutaneous fibrosis and xerostomia were 6.2%, 16.6%, and 17.9%, respectively.The rate of out-of-field nodal failure when omitting ENI to levels IV and Vb in clinically negative necks of patients with N0-1 NPC was extremely low; therefore, a further phase 3 study is warranted.

View details for DOI 10.1016/j.ijrobp.2012.07.2356

View details for PubMedID 22975606

Volumetric-modulated arc radiotherapy for skull-base and non-skull-base head and neck cancer: a treatment planning comparison with fixed Beam IMRT. Technology in cancer research & treatment Chen, J., Mok, E., Wang, L., Chen, C., Le, Q. 2013; 12 (1): 11-18


The purpose of this study is to compare the dose distribution, monitor units (MUs) and radiation delivery time between volumetric-modulated arc (VMAT) and fix-beam intensity modulated radiotherapy (FB-IMRT) in skull-base and non-skull-base head and neck cancer (HNC). CT datasets of 8 skull-base and 7 non-skull-base HNC were identified. IMRT and VMAT plans were generated. The prescription dose ranged 45-70Gy (1.8-2.2Gy/fraction). The VMAT delivery time was measured when these plans were delivered to the patients. The FB-IMRT delivery time was generated on a phantom. Comparison of dose-volume histogram data, MUs, and delivery times was performed using T-test. Our results show that both plans yield similar target volume coverage, homogeneity, and conformity. In skull-base cases, compared to FB-IMRT, VMAT generated significantly smaller hot-spot inside PTV (2.0% vs. 4.5%, p =0.031), lower maximum chiasm dose (32 11Gy vs. 41 15Gy, p =0.026), lower ipsilateral temporal-mandibular joint dose (D33: 41.4Gy vs. 46.1Gy, p =0.016), lower mean ipsilateral middle ear dose (43 9Gy vs. 38 10Gy, p =0.020) and a trend for lower optic nerve, temporal lobe, parotid, and oral cavity dose. In non-skull-base cases, doses to normal tissues were similar between the two plans. There was a reduction of 70% in MUs (486 95 vs. 1614 493, p <0.001) and 73% in delivery times (3.0 0.6 vs. 11.0 3.3 min, p <0.001) favoring VMAT. We conclude that VMAT appears to spare more normal tissues from high radiation dose for the tested skull-base tumors. Dosimetrically, both approaches were equivalent for non-skull-base tumor with VMAT using fewer MUs and shorter delivery time.

View details for PubMedID 22905805

Migration of implanted markers for image-guided lung tumor stereotactic ablative radiotherapy. Journal of applied clinical medical physics Hong, J. C., Eclov, N. C., Yu, Y., Rao, A. K., Dieterich, S., Le, Q., Diehn, M., Sze, D. Y., Loo, B. W., Kothary, N., Maxim, P. G. 2013; 14 (2): 4046-?


The purpose of this study was to quantify postimplantation migration of percutaneously implanted cylindrical gold seeds ("seeds") and platinum endovascular embolization coils ("coils") for tumor tracking in pulmonary stereotactic ablative radiotherapy (SABR). We retrospectively analyzed the migration of markers in 32 consecutive patients with computed tomography scans postimplantation and at simulation. We implanted 147 markers (59 seeds, 88 coils) in or around 34 pulmonary tumors over 32 procedures, with one lesion implanted twice. Marker coordinates were rigidly aligned by minimizing fiducial registration error (FRE), the root mean square of the differences in marker locations for each tumor between scans. To also evaluate whether single markers were responsible for most migration, we aligned with and without the outlier causing the largest FRE increase per tumor. We applied the resultant transformation to all markers. We evaluated migration of individual markers and FRE of each group. Median scan interval was 8 days. Median individual marker migration was 1.28 mm (interquartile range [IQR] 0.78-2.63 mm). Median lesion FRE was 1.56 mm (IQR 0.92-2.95 mm). Outlier identification yielded 1.03 mm median migration (IQR 0.52-2.21 mm) and 1.97 mm median FRE (IQR 1.44-4.32 mm). Outliers caused a mean and median shift in the centroid of 1.22 and 0.80 mm (95th percentile 2.52 mm). Seeds and coils had no statistically significant difference. Univariate analysis suggested no correlation of migration with the number of markers, contact with the chest wall, or time elapsed. Marker migration between implantation and simulation is limited and unlikely to cause geometric miss during tracking.

View details for DOI 10.1120/jacmp.v14i2.4046

View details for PubMedID 23470933

Loss of the p53/p63 target PERP is an early event in oral carcinogenesis and correlates with higher rate of local relapse. Oral surgery, oral medicine, oral pathology and oral radiology Kong, C. S., Cao, H., Kwok, S., Nguyen, C. M., Jordan, R. C., Beaudry, V. G., Attardi, L. D., Le, Q. 2013; 115 (1): 95-103


PERP is a p53/p63-regulated gene encoding a desmosomal protein that plays a critical role in cell-cell adhesion and tumor suppression.We evaluated PERP expression in different grades of oral dysplasia (34 cases) and at different stages of invasive squamous cell carcinoma (SCC), and correlated the latter with clinical outcome. A tissue microarray consisting of nondysplastic mucosa, carcinoma in situ, SCC, and nodal metastases from 33 patients with human papilloma virus-negative SCC was stained for PERP and E-cadherin.Complete loss of PERP expression was associated with worse local control in patients with SCC. The 5-year local control rate was 91% for patients with partial PERP loss versus 31% for those with complete loss (P = .01).This is the first study to show that loss of PERP expression correlates with the transition to SCC and with increased local relapse in patients with oral cavity SCC.

View details for DOI 10.1016/j.oooo.2012.10.017

View details for PubMedID 23217540

Metabolic imaging metrics correlate with survival in early stage lung cancer treated with stereotactic ablative radiotherapy. Lung cancer Abelson, J. A., Murphy, J. D., Trakul, N., Bazan, J. G., Maxim, P. G., Graves, E. E., Quon, A., Le, Q., Diehn, M., Loo, B. W. 2012; 78 (3): 219-224


To test whether (18)F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) imaging metrics correlate with outcomes in patients with stage I non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR).Fifty-four patients with stage I NSCLC underwent pre-SABR PET at simulation and/or post-SABR PET within 6 months. We analyzed maximum standardized uptake value (SUV(max)) and metabolic tumor volume defined using several thresholds (MTV50%, or MTV2, 4, 7, and 10). Endpoints included primary tumor control (PTC), progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS). We performed Kaplan-Meier, competing risk, and Cox proportional hazards survival analyses.Patients received 25-60 Gy in 1 to 5 fractions. Median follow-up time was 13.2 months. The 1-year estimated PTC, PFS, OS and CSS were 100, 83, 87 and 94%, respectively. Pre-treatment SUV(max) (p=0.014), MTV(7) (p=0.0077), and MTV(10) (p=0.0039) correlated significantly with OS. In the low-MTV(7)vs. high-MTV(7) sub-groups, 1-year estimated OS was 100 vs. 78% (p=0.0077) and CSS was 100 vs. 88% (p=0.082).In this hypothesis-generating study we identified multiple pre-treatment PET-CT metrics as potential predictors of OS and CSS in patients with NSCLC treated with SABR. These could aid risk-stratification and treatment individualization if validated prospectively.

View details for DOI 10.1016/j.lungcan.2012.08.016

View details for PubMedID 23009727

CD44+cells have cancer stem cell-like properties in nasopharyngeal carcinoma INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY Janisiewicz, A. M., Shin, J. H., Murillo-Sauca, O., Kwok, S., Quynh-Thu Le, Q. T., Kong, C., Kaplan, M. J., Sunwoo, J. B. 2012; 2 (6): 465-470


A subpopulation of cells within a tumor appears to have the exclusive ability to initiate tumors, self-renew, and differentiate. These "cancer stem cells" (CSCs) are CD44(+) in several epithelial malignancies. We examined the potential of CD44 to identify the CSC population in nasopharyngeal carcinoma (NPC).C666, an Epstein-Barr virus-positive (EBV(+) ) human NPC cell line, was stained for CD44 and sorted by fluorescence-activated cell sorting (FACS). CD44(+) and CD44(-) subpopulations were evaluated for (1) proliferative potential, (2) ability to differentiate, (3) expression of markers of epithelial-to-mesenchymal transition (EMT) and EBV genes, and (4) the ability to initiate tumors in vivo. Immunocompromised mice were injected with CD44(+) and CD44(-) populations to assess the tumor-initiating capacity. Immunohistochemistry for CD44 was performed on an 87-patient tissue microarray (TMA), and clinical correlations were examined.Heterogeneous expression of CD44 was seen among C666 cells. CD44(+) cells differentiated into CD44(-) cells, indicating a hierarchical relationship. Further, CD44(+) cells exhibited a more robust tumor-initiating capacity in the xenograft model. However, no differences were seen in proliferation rates in vitro, EBV gene expression, or expression of EMT markers between CD44(+) and CD44(-) subsets. Patient tumors were heterogeneous for CD44 staining, and a trend toward an association between CD44 expression and clinical outcome was observed.NPC contains a CD44(+) subpopulation with features consistent with CSCs. There was a trend toward an association between CD44 expression within NPC tumors and decreased time to local failure/relapse in patients.

View details for DOI 10.1002/alr.21068

View details for Web of Science ID 000312142200006

View details for PubMedID 22887934

Feasibility of Pulmonary Interstitial Lymphography-guided Targeting in Stereotactic Ablative Radiation Therapy of Lung Tumors 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Abelson, J. A., Kothary, N., Fleischmann, D., Hofmann, L., Kielar, K., Maxim, P., Le, Q., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2012: S173S173
Radiologic Assessment of Lymph Node Involvement in HPV/p16+Oropharyngeal Cancers 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Tang, C., Komakula, S., Chan, C., Murphy, J., Kong, C., Jensen, K., Le, Q. ELSEVIER SCIENCE INC. 2012: S473S473
Feasibility of Optimizing IMRT Plans Based on Measured Mucosal Dose to Adjacent Metallic Dental Fillings for Head-and-Neck Cancer Patients 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Wang, L., Mok, E., Xing, L., Khong, B., Hara, W., Le, Q. ELSEVIER SCIENCE INC. 2012: S462S463
The Application of FDG-PET as Prognostic Indicators in Head and Neck Squamous Cell Carcinoma. PET clinics Siddiqui, F., Faulhaber, P. F., Yao, M., Le, Q. 2012; 7 (4): 381-394


This article discusses the role of FDG-PETederived parameters as prognostic indicators in patients with squamous cell carcinoma of the head and neck. The basic underlying biology of FDG-PET scans and the quantitative information that can be derived are discussed. A review of the literature is performed. Potential applications in the management of head and neck cancer and future directions in clinical trials are discussed.

View details for DOI 10.1016/j.cpet.2012.06.003

View details for PubMedID 27157645

Esophageal tolerance to high-dose stereotactic ablative radiotherapy DISEASES OF THE ESOPHAGUS Abelson, J. A., Murphy, J. D., Loo, B. W., Chang, D. T., Daly, M. E., Wiegner, E. A., Hancock, S., Chang, S. D., Le, Q., Soltys, S. G., Gibbs, I. C. 2012; 25 (7): 623-629


Dose-volume parameters are needed to guide the safe administration of stereotactic ablative radiotherapy (SABR). We report on esophageal tolerance to high-dose hypofractionated radiation in patients treated with SABR. Thirty-one patients with spine or lung tumors received single- or multiple-fraction SABR to targets less than 1 cm from the esophagus. End points evaluated include D(5cc) (minimum dose in Gy to 5 cm(3) of the esophagus receiving the highest dose), D(2cc) , D(1cc) , and D(max) (maximum dose to 0.01 cm(3) ). Multiple-fraction treatments were correlated using the linear quadratic and linear quadratic-linear/universal survival models. Three esophageal toxicity events occurred, including esophagitis (grade 2), tracheoesophageal fistula (grade 4-5), and esophageal perforation (grade 4-5). Chemotherapy was a cofactor in the high-grade events. The median time to development of esophageal toxicity was 4.1 months (range 0.6-6.1 months). Two of the three events occurred below a published D(5cc) threshold, all three were below a D(2cc) threshold, and one was below a D(max) threshold. We report a dosimetric analysis of incidental dose to the esophagus from SABR. High-dose hypofractionated radiotherapy led to a number of high-grade esophageal adverse events, suggesting that conservative parameters to protect the esophagus are necessary when SABR is used, especially in the setting of chemotherapy or prior radiotherapy.

View details for DOI 10.1111/j.1442-2050.2011.01295.x

View details for Web of Science ID 000308712300008

View details for PubMedID 22168251

Stereotactic Ablative Radiotherapy for Reirradiation of Locally Recurrent Lung Tumors JOURNAL OF THORACIC ONCOLOGY Trakul, N., Harris, J. P., Le, Q., Hara, W. Y., Maxim, P. G., Loo, B. W., Diehn, M. 2012; 7 (9): 1462-1465


Patients with thoracic tumors that recur after irradiation currently have limited therapeutic options. Retreatment using stereotactic ablative radiotherapy (SABR) is appealing for these patients because of its high conformity but has not been studied extensively. Here we report our experience with SABR for lung tumors in previously irradiated regions.We conducted a retrospective study of patients with primary lung cancer or metastatic lung tumors treated with SABR. We identified 17 such tumors in 15 patients and compared their outcomes with those of a cohort of 135 previously unirradiated lung tumors treated with SABR during the same time period.Twelve-month local control (LC) for retreated tumors was 65.5%, compared with 92.1% for tumors receiving SABR as initial treatment. Twelve-month LC was significantly worse for reirradiated tumors in which the time interval between treatments was 16 months or less (46.7%), compared with those with longer intertreatment intervals (87.5%). SABR reirradiation did not lead to significant increases in treatment-related toxicity.SABR for locally recurrent lung tumors arising in previously irradiated fields seems to be feasible and safe for appropriately selected patients. LC of retreated lesions was significantly lower, likely owing to the lower doses used for retreatment. Shorter time to retreatment was associated with increased risk of local failure, suggesting that these tumors may be particularly radioresistant. Our findings suggest that dose escalation may improve LC while maintaining acceptable levels of toxicity for these patients.

View details for DOI 10.1097/JTO.0b013e31825f22ce

View details for Web of Science ID 000308073300024

View details for PubMedID 22895143

Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Trakul, N., Chang, C. N., Harris, J., Chapman, C., Rao, A., Shen, J., Quinlan-Davidson, S., Filion, E. J., Wakelee, H. A., Colevas, A. D., Whyte, R. I., Dieterich, S., Maxim, P. G., Hristov, D., Tran, P., Quynh-Thu Le, Q. T., Loo, B. W., Diehn, M. 2012; 84 (1): 231-237


Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy.We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume 12 mL) received multifraction regimens with BED 100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2).The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02).A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

View details for DOI 10.1016/j.ijrobp.2011.10.071

View details for Web of Science ID 000308061900060

View details for PubMedID 22381907

Intrafraction Verification of Gated RapidArc by Using Beam-Level Kilovoltage X-Ray Images INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Li, R., Mok, E., Chang, D. T., Daly, M., Loo, B. W., Diehn, M., Quynh-Thu Le, Q. T., Koong, A., Xing, L. 2012; 83 (5): E709-E715


To verify the geometric accuracy of gated RapidArc treatment using kV images acquired during dose delivery.Twenty patients were treated using the gated RapidArc technique with a Varian TrueBeam STx linear accelerator. One to 7 metallic fiducial markers were implanted inside or near the tumor target before treatment simulation. For patient setup and treatment verification purposes, the internal target volume (ITV) was created, corresponding to each implanted marker. The gating signal was generated from the Real-time Position Management (RPM) system. At the beginning of each fraction, individualized respiratory gating amplitude thresholds were set based on fluoroscopic image guidance. During the treatment, we acquired kV images immediately before MV beam-on at every breathing cycle, using the on-board imaging system. After the treatment, all implanted markers were detected, and their 3-dimensional (3D) positions in the patient were estimated using software developed in-house. The distance from the marker to the corresponding ITV was calculated for each patient by averaging over all markers and all fractions.The average 3D distance between the markers and their ITVs was 0.8 0.5 mm (range, 0-1.7 mm) and was 2.1 1.2 mm at the 95th percentile (range, 0-3.8 mm). On average, a left-right margin of 0.6 mm, an anterior-posterior margin of 0.8 mm, and a superior-inferior margin of 1.5 mm is required to account for 95% of the intrafraction uncertainty in RPM-based RapidArc gating.To our knowledge, this is the first clinical report of intrafraction verification of respiration-gated RapidArc treatment in stereotactic ablative radiation therapy. For some patients, the markers deviated significantly from the ITV by more than 2 mm at the beginning of the MV beam-on. This emphasizes the need for gating techniques with beam-on/-off controlled directly by the actual position of the tumor target instead of external surrogates such as RPM.

View details for DOI 10.1016/j.ijrobp.2012.03.006

View details for Web of Science ID 000306128100022

View details for PubMedID 22554582

View details for PubMedCentralID PMC4476315

Evaluation of ProExC as a Prognostic Marker in Oropharyngeal Squamous Cell Carcinomas AMERICAN JOURNAL OF SURGICAL PATHOLOGY Mills, A. M., Beck, A. H., Pourmand, N., Quynh Thu Le, Q. T., Kong, C. S. 2012; 36 (8): 1158-1164


ProExC expression has been shown to perform similarly to p16 as an aid in the diagnosis of cervical dysplasia but has not been well characterized in head and neck squamous cell carcinomas (SCC). The purpose of this study is to determine whether ProExC performs similarly to p16 as a prognostic marker in oropharyngeal SCC and to evaluate the threshold of ProExC and p16 staining that correlates with survival. ProExC, p16, and human papillomavirus DNA in situ hybridization were performed on tissue microarray (TMA) cores and whole sections from 62 patients with oropharyngeal SCC. Sensitivity and specificity for high-risk HPV and correlation with overall survival (OS), cancer-specific survival (CSS), and time to distant metastasis (TDM) were calculated for ProExC and p16 at different thresholds. ProExC did not prove to be a robust marker. It showed strong correlation with OS at a 66% threshold on TMA cores, but correlation with OS was lost on whole sections. It also exhibited low sensitivity (53.7%) on TMA cores and low specificity on whole sections (65%). ProExC at a 33% threshold exhibited unacceptably low specificity and did not correlate with OS, CSS, or TDM. Sensitivity and specificity of p16 varied predictably with threshold: higher sensitivity and lower specificity with lower thresholds and vice versa for higher thresholds. p16 at a 50% threshold offers a balance between sensitivity and specificity, and correlates with OS, CSS, and TDM on whole sections; correlation with TDM is lost on TMA cores. These findings indicate that ProExC does not perform well enough to be used as a prognostic marker in oropharyngeal SCC. p16 should be used and scored as positive when at least half the tumor is strongly stained.

View details for DOI 10.1097/PAS.0b013e3182600eaa

View details for Web of Science ID 000306656500006

View details for PubMedID 22790856

Validation that metabolic tumor volume predicts outcome in head-and-neck cancer. International journal of radiation oncology, biology, physics Tang, C., Murphy, J. D., Khong, B., La, T. H., Kong, C., Fischbein, N. J., Colevas, A. D., Iagaru, A. H., Graves, E. E., Loo, B. W., Le, Q. 2012; 83 (5): 1514-1520


We have previously reported that metabolic tumor volume (MTV) obtained from pretreatment (18)F-fluorodeoxydeglucose positron emission tomography (FDG PET)/ computed tomography (CT) predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study was to validate these results on an independent dataset, determine whether the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16(INK4a) status as a surrogate marker for human papillomavirus (HPV).The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan before receiving definitive radiotherapy. MTV and maximum standardized uptake value (SUV(max)) were calculated for the primary tumor, the involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor vs. nodal MTV.Similarly to our prior findings, an increase in total MTV of 17 cm(3) (difference between the 75th and 25th percentiles) was associated with a 2.1-fold increase in the risk of disease progression (p = 0.0002) and a 2.0-fold increase in the risk of death (p = 0.0048). SUV(max) was not associated with either outcome. Primary tumor MTV predicted progression-free (hazard ratio [HR] = 1.94; p < 0.0001) and overall (HR = 1.57; p < 0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR = 4.23; p < 0.0001) and overall (HR = 3.21; p = 0.0029) survival in patients with p16(INK4a)-positive oropharyngeal cancer.This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk-stratifying biomarker in future studies of HNC.

View details for DOI 10.1016/j.ijrobp.2011.10.023

View details for PubMedID 22270174

Prognostic Value of Metabolic Tumor Volume and Velocity in Predicting Head-and-Neck Cancer Outcomes INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chu, K. P., Murphy, J. D., La, T. H., Krakow, T. E., Iagaru, A., Graves, E. E., Hsu, A., Maxim, P. G., Loo, B., Chang, D. T., Quynh-Thu Le, Q. T. 2012; 83 (5): 1521-1527


We previously showed that metabolic tumor volume (MTV) on positron emission tomography-computed tomography (PET-CT) predicts for disease recurrence and death in head-and-neck cancer (HNC). We hypothesized that increases in MTV over time would correlate with tumor growth and biology, and would predict outcome. We sought to examine tumor growth over time in serial pretreatment PET-CT scans.From 2006 to 2009, 51 patients had two PET-CT scans before receiving HNC treatment. MTV was defined as the tumor volume 50% of maximum SUV (SUV(max)). MTV was calculated for the primary tumor, nodal disease, and composite (primary tumor + nodes). MTV and SUV velocity were defined as the change in MTV or SUV(max) over time, respectively. Cox regression analyses were used to examine correlations between SUV, MTV velocity, and outcome (disease progression and overall survival).The median follow-up time was 17.5 months. The median time between PET-CT scans was 3 weeks. Unexpectedly, 51% of cases demonstrated a decrease in SUV(max) (average, -0.1 cc/week) and MTV (average, -0.3 cc/week) over time. Despite the variability in MTV, primary tumor MTV velocity predicted disease progression (hazard ratio 2.94; p = 0.01) and overall survival (hazard ratio 1.85; p = 0.03).Primary tumor MTV velocity appears to be a better prognostic indicator of disease progression and survival in comparison to nodal MTV velocity. However, substantial variability was found in PET-CT biomarkers between serial scans. Caution should be used when PET-CT biomarkers are integrated into clinical protocols for HNC.

View details for DOI 10.1016/j.ijrobp.2011.10.022

View details for Web of Science ID 000306128100047

View details for PubMedID 22270168

Molecular profiling to optimize treatment in non-small cell lung cancer: a review of potential molecular targets for radiation therapy by the translational research program of the radiation therapy oncology group. International journal of radiation oncology, biology, physics Ausborn, N. L., Le, Q. T., Bradley, J. D., Choy, H., Dicker, A. P., Saha, D., Simko, J., Story, M. D., Torossian, A., Lu, B. 2012; 83 (4): e453-64


Therapeutic decisions in non-small cell lung cancer (NSCLC) have been mainly based on disease stage, performance status, and co-morbidities, and rarely on histological or molecular classification. Rather than applying broad treatments to unselected patients that may result in survival increase of only weeks to months, research efforts should be, and are being, focused on identifying predictive markers for molecularly targeted therapy and determining genomic signatures that predict survival and response to specific therapies. The availability of such targeted biologics requires their use to be matched to tumors of corresponding molecular vulnerability for maximum efficacy. Molecular markers such as epidermal growth factor receptor (EGFR), K-ras, vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and anaplastic lymphoma kinase (ALK) represent potential parameters guide treatment decisions. Ultimately, identifying patients who will respond to specific therapies will allow optimal efficacy with minimal toxicity, which will result in more judicious and effective application of expensive targeted therapy as the new paradigm of personalized medicine develops.

View details for DOI 10.1016/j.ijrobp.2012.01.056

View details for PubMedID 22520478

A Planned Neck Dissection Is Not Necessary in All Patients With N2-3 Head-and-Neck Cancer After Sequential Chemoradiotherapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Soltys, S. G., Choi, C. Y., Fee, W. E., Pinto, H. A., Le, Q. 2012; 83 (3): 994-999


To assess the role of a planned neck dissection (PND) after sequential chemoradiotherapy for patients with head-and-neck cancer with N2-N3 nodal disease.We reviewed 90 patients with N2-N3 head-and-neck squamous cell carcinoma treated between 1991 and 2001 on two sequential chemoradiotherapy protocols. All patients received induction and concurrent chemotherapy with cisplatin and 5-fluorocuracil, with or without tirapazamine. Patients with less than a clinical complete response (cCR) in the neck proceeded to a PND after chemoradiation. The primary endpoint was nodal response. Clinical outcomes and patterns of failure were analyzed.The median follow-up durations for living and all patients were 8.3 years (range, 1.5-16.3 year) and 5.4 years (range, 0.6-16.3 years), respectively. Of the 48 patients with nodal cCR whose necks were observed, 5 patients had neck failures as a component of their recurrence [neck and primary (n = 2); neck, primary, and distant (n = 1); neck only (n = 1); neck and distant (n = 1)]. Therefore, PND may have benefited only 2 patients (4%) [neck only failure (n = 1); neck and distant failure (n = 1)]. The pathologic complete response (pCR) rate for those with a clinical partial response (cPR) undergoing PND (n = 30) was 53%. The 5-year neck control rates after cCR, cPRpCR, and cPRpPR were 90%, 93%, and 78%, respectively (p = 0.36). The 5-year disease-free survival rates for the cCR, cPRpCR, and cPRpPR groups were 53%, 75%, and 42%, respectively (p = 0.04).In our series, patients with N2-N3 neck disease achieving a cCR in the neck, PND would have benefited only 4% and, therefore, is not recommended. Patients with a cPR should be treated with PND. Residual tumor in the PND specimens was associated with poor outcomes; therefore, aggressive therapy is recommended. Studies using novel imaging modalities are needed to better assess treatment response.

View details for DOI 10.1016/j.ijrobp.2011.07.042

View details for Web of Science ID 000305256000055

View details for PubMedID 22137026

Intensity-Modulated Radiotherapy for Tumors of the Nasal Cavity and Paranasal Sinuses: Clinical Outcomes and Patterns of Failure 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Wiegner, E. A., Daly, M. E., Murphy, J. D., Abelson, J., Chapman, C. H., Chung, M., Yu, Y., Colevas, A. D., Kaplan, M. J., Fischbein, N., Quynh-Thu Le, Q. T., Chang, D. T. ELSEVIER SCIENCE INC. 2012: 24351


To report outcomes in patients treated with intensity-modulated radiotherapy (IMRT) for tumors of the paranasal sinuses and nasal cavity (PNS/NC).Between June 2000 and December 2009, 52 patients with tumors of the PNS/NC underwent postoperative or definitive radiation with IMRT. Twenty-eight (54%) patients had squamous cell carcinoma (SCC). Twenty-nine patients (56%) received chemotherapy. The median follow-up was 26.6 months (range, 2.9-118.4) for all patients and 30.9 months for living patients.Eighteen patients (35%) developed local-regional failure (LRF) at median time of 7.2 months. Thirteen local failures (25%) were observed, 12 in-field and 1 marginal. Six regional failures were observed, two in-field and four out-of-field. No patients treated with elective nodal radiation had nodal regional failure. Two-year local-regional control (LRC), in-field LRC, freedom from distant metastasis (FFDM), and overall survival (OS) were 64%, 74%, 71%, and 66% among all patients, respectively, and 43%, 61%, 61%, and 53% among patients with SCC, respectively. On multivariate analysis, SCC and >1 subsite involved had worse LRC (p = 0.0004 and p = 0.046, respectively) and OS (p = 0.003 and p = 0.046, respectively). Cribriform plate invasion (p = 0.005) and residual disease (p = 0.047) also had worse LRC. Acute toxicities included Grade 3 mucositis in 19 patients (37%), and Grade 3 dermatitis in 8patients (15%). Six patients had Grade 3 late toxicity including one optic toxicity.IMRT for patients with PNS/NC tumors has good outcomes compared with historical series and is well tolerated. Patients with SCC have worse LRC and OS. LRF is the predominant pattern of failure.

View details for DOI 10.1016/j.ijrobp.2011.05.044

View details for Web of Science ID 000302993900057

View details for PubMedID 22019239

Prognostic and Predictive Significance of Plasma HGF and IL-8 in a Phase III Trial of Chemoradiation with or without Tirapazamine in Locoregionally Advanced Head and Neck Cancer CLINICAL CANCER RESEARCH Quynh-Thu Le, Q. T., Fisher, R., Oliner, K. S., Young, R. J., Cao, H., Kong, C., Graves, E., Hicks, R. J., McArthur, G. A., Peters, L., O'Sullivan, B., Giaccia, A., Rischin, D. 2012; 18 (6): 1798-1807


Hepatocyte growth factor (HGF) is a hypoxia-induced secreted protein that binds to cMet and regulates interleukin (IL)-8 expression. We evaluated the role of circulating HGF and IL-8 as prognostic and predictive factors for efficacy of tirapazamine (TPZ), a hypoxic cell cytotoxin.Patients with stages III to IV head and neck cancer were randomized to receive radiotherapy with cisplatin (CIS) or CIS plus TPZ (TPZ/CIS). Eligibility for the substudy included plasma sample availability for HGF and IL-8 assay by ELISA and no major radiation deviations (N = 498). Analyses included adjustment for major prognostic factors. p16(INK4A) staining (human papillomavirus surrogate) was carried out on available tumors. Thirty-nine patients had hypoxia imaging with (18)F-fluoroazomycin arabinoside ((18)FAZA)-positron emission tomography.Elevated IL-8 level was associated with worse overall survival (OS) irrespective of treatment. There was an interaction between HGF and treatment arm (P = 0.053); elevated HGF was associated with worse OS in the control but not in the TPZ/CIS arm. Similar trends were observed in analyses restricted to p16(INK4A)-negative patients. Four subgroups defined by high and low HGF/IL-8 levels were examined for TPZ effect; the test for interaction with arm was P = 0.099. TPZ/CIS seemed to be beneficial for patients with high HGF and IL-8 but adverse for low HGF and high IL-8. Only HGF correlated with (18)FAZA tumor standard uptake value.IL-8 is an independent prognostic factor irrespective of treatment. There is an interaction between HGF and treatment arm. Certain subgroups based on IL-8/HGF levels seemed to do better with TPZ/CIS while others did worse, highlighting the complexity of hypoxia targeting in unselected patients.

View details for DOI 10.1158/1078-0432.CCR-11-2094

View details for Web of Science ID 000301672400037

View details for PubMedID 22383739

Quantitation of Human Papillomavirus DNA in Plasma of Oropharyngeal Carcinoma Patients INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Cao, H., Banh, A., Kwok, S., Shi, X., Wu, S., Krakow, T., Khong, B., Bavan, B., Bala, R., Pinsky, B. A., Colevas, D., Pourmand, N., Koong, A. C., Kong, C. S., Quynh-Thu Le, Q. T. 2012; 82 (3): E351-E358


To determine whether human papillomavirus (HPV) DNA can be detected in the plasma of patients with HPV-positive oropharyngeal carcinoma (OPC) and to monitor its temporal change during radiotherapy.We used polymerase chain reaction to detect HPV DNA in the culture media of HPV-positive SCC90 and VU147T cells and the plasma of SCC90 and HeLa tumor-bearing mice, non-tumor-bearing controls, and those with HPV-negative tumors. We used real-time quantitative polymerase chain reaction to quantify the plasma HPV DNA in 40 HPV-positive OPC, 24 HPV-negative head-and-neck cancer patients and 10 non-cancer volunteers. The tumor HPV status was confirmed by p16(INK4a) staining and HPV16/18 polymerase chain reaction or HPV in situ hybridization. A total of 14 patients had serial plasma samples for HPV DNA quantification during radiotherapy.HPV DNA was detectable in the plasma samples of SCC90- and HeLa-bearing mice but not in the controls. It was detected in 65% of the pretreatment plasma samples from HPV-positive OPC patients using E6/7 quantitative polymerase chain reaction. None of the HPV-negative head-and-neck cancer patients or non-cancer controls had detectable HPV DNA. The pretreatment plasma HPV DNA copy number correlated significantly with the nodal metabolic tumor volume (assessed using (18)F-deoxyglucose positron emission tomography). The serial measurements in 14 patients showed a rapid decline in HPV DNA that had become undetectable at radiotherapy completion. In 3 patients, the HPV DNA level had increased to a discernable level at metastasis.Xenograft studies indicated that plasma HPV DNA is released from HPV-positive tumors. Circulating HPV DNA was detectable in most HPV-positive OPC patients. Thus, plasma HPV DNA might be a valuable tool for identifying relapse.

View details for DOI 10.1016/j.ijrobp.2011.05.061

View details for Web of Science ID 000300423500003

View details for PubMedID 21985946

View details for PubMedCentralID PMC3257411

Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial LANCET ONCOLOGY Lee, N. Y., Zhang, Q., Pfister, D. G., Kim, J., Garden, A. S., Mechalakos, J., Hu, K., Le, Q. T., Colevas, A. D., Glisson, B. S., Chan, A. T., Ang, K. K. 2012; 13 (2): 172-180


We aimed to improve the outcomes for locoregionally advanced nasopharyngeal carcinoma by testing the feasibility and safety of the addition of bevacizumab to chemoradiotherapy.We enrolled patients older than 18 years with stage IIB-IVB nasopharyngeal carcinoma from 19 centres in North America and Hong Kong. Treatment consisted of three cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m(2)) both given on days 1, 22, and 43 of radiation (70 Gy) with intensity-modulated radiation therapy delivered over 33 days on a daily basis, Monday through Friday. Patients then received three cycles of bevacizumab (15 mg/kg) and cisplatin (80 mg/m(2)), both given on days 64, 85, and 106 after radiation, and three cycles of fluorouracil (1000 mg/m(2) per day), given on days 64-67, 85-88, and 106-109 after radiation. The primary endpoint was the occurrence of treatment-related grade 4 haemorrhage or any grade 5 adverse event in the first year. Analyses were done with all eligible patients who started protocol treatment. The trial is registered at, number NCT00408694.From Dec 13, 2006, to Feb 5, 2009, we enrolled 46 patients, of whom 44 were eligible for analysis. We recorded no grade 3-4 haemorrhages or grade 5 adverse events; nine patients (20%) had a treatment-related grade 1-2 haemorrhage. Nine patients had one or more grade 4 blood or bone marrow-related complication (grade 4 leucopenia was noted in six patients, grade 4 lymphopenia in five, grade 4 neutrophils in five, and grade 4 anaemia in one). One patient had two grade 4 infections with grade 3-4 neutrophils. One patient reported grade 4 tinnitus, one patient reported grade 4 thrombosis, one reported grade 4 radiation mucositis, and two reported grade 4 pharyngolaryngeal pain. With a median follow-up of 25 years (IQR 21-29), the estimated 2 year locoregional progression-free interval was 837% (95% CI 726-949), the 2 year distant metastasis-free interval was 908% (822-995), the 2 year progression-free survival was 747% (618-876), and 2 year overall survival was 909% (823-994).The addition of bevacizumab to standard chemoradiation treatment for patients with nasopharyngeal carcinoma is feasible, and might delay the progression of subclinical distant disease.National Cancer Institute, USA.

View details for DOI 10.1016/S1470-2045(11)70303-5

View details for Web of Science ID 000300197400042

View details for PubMedID 22178121

View details for PubMedCentralID PMC4985181

Identification of Pathogens in Archival Tissues Using a High-Throughput Sequencing Approach, 3SEQ 101st Annual Meeting of United-States-and-Canadian-Academy-of-Pathology (USCAP) SWEENEY, R. T., Brunner, A. L., Montgomery, K. D., Zhu, S. X., Kong, C., Le, Q., West, R. B. NATURE PUBLISHING GROUP. 2012: 467A467A
Identification of Pathogens in Archival Tissues Using a High-Throughput Sequencing Approach, 35EQ 101st Annual Meeting of United-States-and-Canadian-Academy-of-Pathology (USCAP) SWEENEY, R. T., Brunner, A. L., Montgomery, K. D., Zhu, S. X., Kong, C., Le, Q., West, R. B. NATURE PUBLISHING GROUP. 2012: 467A467A
Metabolic Tumor Volume is an Independent Prognostic Factor in Patients Treated Definitively for Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Lee, P., Bazan, J. G., Lavori, P. W., Weerasuriya, D. K., Quon, A., Quynh-Thu Le, Q. T., Wakelee, H. A., Graves, E. E., Loo, B. W. 2012; 13 (1): 52-58


Fluorine-18 flurodeoxyglucose positron emission tomography (FDG-PET) imaging has rapidly become the standard of care for staging patients with lung cancer. We evaluated the prognostic value of metabolic tumor volume (MTV), a measure of tumor burden on FDG-PET imaging, in patients with non-small-cell lung cancer (NSCLC) treated definitively.A retrospective review identified 61 patients with NSCLC who underwent FDG-PET imaging for pretreatment staging. Metabolically active tumor regions were segmented on the PET scans semiautomatically to calculate the total body MTV. We determined the relationship of overall survival (OS) and progression-free survival (PFS) with MTV in the entire cohort, and in the subgroup treated definitively.The estimated median PFS and OS for the entire cohort were 11.1 months and 18.9 months. Higher MTV was significantly associated with worse OS (P = 0.00075) and PFS (P = 0.00077). For definitively treated patients, when MTV was analyzed as a binary value above or below the median value, 2-year PFS was 60% versus 39.7% (median PFS 34.9 vs. 11.9 months) and 2-year OS was 79.7% versus 33.3% (median OS 41.9 vs. 18.9 months), respectively (log-rank P = 0.12 for PFS and P = 0.066 for OS). When MTV was analyzed as a continuous variable, multivariate Cox proportional hazards analysis demonstrated a trend to worse PFS (hazard ratio [HR] = 1.31; P = 0.12) and significantly worse OS (HR = 1.53; P = 0.018) with increasing MTV after controlling for known prognostic variables.Tumor burden as assessed by MTV yields prognostic information on survival beyond that of established prognostic factors in patients with NSCLC treated definitively.

View details for DOI 10.1016/j.cllc.2011.05.001

View details for Web of Science ID 000299270900008

View details for PubMedID 21703935

Evaluation of a metal artifact reduction technique in tonsillar cancer delineation. Practical radiation oncology Abelson, J. A., Murphy, J. D., Wiegner, E. A., Abelson, D., Sandman, D. N., Boas, F. E., Hristov, D., Fleischmann, D., Daly, M. E., Chang, D. T., Loo, B. W., Hara, W., Le, Q. 2012; 2 (1): 27-34


Metal artifacts can degrade computed tomographic (CT) simulation imaging and impair accurate delineation of tumors for radiation treatment planning purposes. We investigated a Digital Imaging and Communications in Medicine-based metal artifact reduction technique in tonsillar cancer delineation.Eight patients with significant artifact and tonsil cancer were evaluated. Each patient had a positron emission tomography (PET)-CT and a contrast-enhanced CT obtained at the same setting during radiotherapy simulation. The CTs were corrected for artifact using the metal deletion technique (MDT). Two radiation oncologists independently delineated primary gross tumor volumes (GTVs) for each patient on native (CTnonMDT), metal corrected (CTMDT), and reference standard (CTPET/nonMDT) imaging, 1 week apart. Mixed effects models were used to determine if differences among GTVs were statistically significant. Two diagnostic radiologists and 2 radiation oncologists independently qualitatively evaluated CTs for each patient. Ratings were on an ordinal scale from -3 to +3, denoting that CTMDT was markedly, moderately, or slightly worse or better than CTnonMDT. Scores were compared with a Wilcoxon signed-rank test.The GTVPET/nonMDT were significantly smaller than GTVnonMDT (P = .004) and trended to be smaller than GTVMDT (P = .084). The GTVnonMDT and GTVMDT were not significantly different (P = .93). There was no significant difference in the extent to which GTVnonMDT or GTVMDT encompassed GTVPET/nonMDT (P = .33). In the subjective assessment of image quality, CTMDT did not significantly outperform CTnonMDT. In the majority of cases, the observer rated the CTMDT equivalent to (53%) or slightly superior (41%) to the corresponding CTnonMDT.The MTD modified images did not produce GTVMDT that more closely reproduced GTVPET/nonMDT than did GTVnonMDT. Moreover, the MTD modified images were not judged to be significantly superior when compared to the uncorrected images in terms of subjective ability to visualize the tonsilar tumors. This study failed to demonstrate value of the adjunctive use of a CT corrected for artifacts in the tumor delineation process. Artifacts do make tumor delineation challenging, and further investigation of other body sites is warranted.

View details for DOI 10.1016/j.prro.2011.06.004

View details for PubMedID 24674033

Prognostic Significance of Plasma Osteopontin in Patients with Locoregionally Advanced Head and Neck Squamous Cell Carcinoma Treated on TROG 02.02 Phase III Trial CLINICAL CANCER RESEARCH Lim, A. M., Rischin, D., Fisher, R., Cao, H., Kwok, K., Truong, D., McArthur, G. A., Young, R. J., Giaccia, A., Peters, L., Le, Q. 2012; 18 (1): 301-307


High plasma osteopontin (OPN) levels have been reported to be an adverse prognostic factor in head and neck squamous cell carcinomas (HNSCC), correlate with tumor hypoxia, and be predictive of benefit from hypoxia-targeted therapy. We sought to confirm the prognostic and predictive significance of OPN in patients treated on a large international trial.Patients with stage III/IV HNSCC were randomized to receive definitive radiotherapy concurrently with cisplatin or cisplatin plus the hypoxic cell cytotoxin, tirapazamine (TPZ). Eligibility criteria for this prospective substudy included plasma sample availability for OPN assay by ELISA and absence of major radiation therapy deviations (N = 578). OPN concentrations were analyzed for overall survival (OS) and time to locoregional failure (TTLRF), adjusting for known prognostic factors. Additional analysis was carried out in patients with available tumor p16(INK4A) staining status.The median OPN level was 544 ng/mL (range: 7-2,640). High OPN levels were not associated with worse OS (relative HR, 1.03 for highest tertile) or TTLRF (relative HR 0.91 for highest tertile). There was no interaction between OPN and treatment arm for OS or TTLRF (P = 0.93 for OS; P = 0.87 for TTLRF). For the highest tertile the 2-year OS was 66% on control arm and 67% on TPZ arm (HR = 1.11, P = 0.67). Similarly for p16(INK4A) negative patients in the highest tertile, the 2-year OS was 61% on control arm and 63% on TPZ arm (HR = 1.05, P = 0.86).We found no evidence that high plasma OPN levels were associated with an adverse prognosis in HNSCC, or were predictive of benefit with hypoxia targeting therapy.

View details for DOI 10.1158/1078-0432.CCR-11-2295

View details for Web of Science ID 000298758900032

View details for PubMedID 22096023

A Novel Aldehyde Dehydrogenase-3 Activator Leads to Adult Salivary Stem Cell Enrichment In Vivo CLINICAL CANCER RESEARCH Banh, A., Xiao, N., Cao, H., Chen, C., Kuo, P., Krakow, T., Bavan, B., Khong, B., Yao, M., Ha, C., Kaplan, M. J., Sirjani, D., Jensen, K., Kong, C. S., Mochly-Rosen, D., Koong, A. C., Quynh-Thu Le, Q. T. 2011; 17 (23): 7265-7272


To assess aldehyde dehydrogenase (ALDH) expression in adult human and murine submandibular gland (SMG) stem cells and to determine the effect of ALDH3 activation in SMG stem cell enrichment.Adult human and murine SMG stem cells were selected by cell surface markers (CD34 for human and c-Kit for mouse) and characterized for various other stem cell surface markers by flow cytometry and ALDH isozymes expression by quantitative reverse transcriptase PCR. Sphere formation and bromodeoxyuridine (BrdUrd) incorporation assays were used on selected cells to confirm their renewal capacity and three-dimensional (3D) collagen matrix culture was applied to observe differentiation. To determine whether ALDH3 activation would increase stem cell yield, adult mice were infused with a novel ALDH3 activator (Alda-89) or with vehicle followed by quantification of c-Kit(+)/CD90(+) SMG stem cells and BrdUrd(+) salispheres.More than 99% of CD34(+) huSMG stem cells stained positive for c-Kit, CD90 and 70% colocalized with CD44, Nestin. Similarly, 73.8% c-Kit(+) mSMG stem cells colocalized with Sca-1, whereas 80.7% with CD90. Functionally, these cells formed BrdUrd(+) salispheres, which differentiated into acinar- and ductal-like structures when cultured in 3D collagen. Both adult human and murine SMG stem cells showed higher expression of ALDH3 than in their non-stem cells and 84% of these cells have measurable ALDH1 activity. Alda-89 infusion in adult mice significantly increased c-Kit(+)/CD90(+) SMG population and BrdUrd(+) sphere formation compared with control.This is the first study to characterize expression of different ALDH isozymes in SMG stem cells. In vivo activation of ALDH3 can increase SMG stem cell yield, thus providing a novel means for SMG stem cell enrichment for future stem cell therapy.

View details for DOI 10.1158/1078-0432.CCR-11-0179

View details for Web of Science ID 000298133600009

View details for PubMedID 21998334

View details for PubMedCentralID PMC3544360

Correlation between metabolic tumor volume and pathologic tumor volume in squamous cell carcinoma of the oral cavity RADIOTHERAPY AND ONCOLOGY Murphy, J. D., Chisholm, K. M., Daly, M. E., Wiegner, E. A., Truong, D., Iagaru, A., Maxim, P. G., Loo, B. W., Graves, E. E., Kaplan, M. J., Kong, C., Le, Q. 2011; 101 (3): 356-361


To explore the relationship between pathologic tumor volume and volume estimated from different tumor segmentation techniques on (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in oral cavity cancer.Twenty-three patients with squamous cell carcinoma of the oral tongue had PET-CT scans before definitive surgery. Pathologic tumor volume was estimated from surgical specimens. Metabolic tumor volume (MTV) was defined from PET-CT scans as the volume of tumor above a given SUV threshold. Multiple SUV thresholds were explored including absolute SUV thresholds, relative SUV thresholds, and gradient-based techniques.Multiple MTV's were associated with pathologic tumor volume; however the correlation was poor (R(2) range 0.29-0.58). The ideal SUV threshold, defined as the SUV that generates an MTV equal to pathologic tumor volume, was independently associated with maximum SUV (p=0.0005) and tumor grade (p=0.024). MTV defined as a function of maximum SUV and tumor grade improved the prediction of pathologic tumor volume (R(2)=0.63).Common SUV thresholds fail to predict pathologic tumor volume in head and neck cancer. The optimal technique that allows for integration of PET-CT with radiation treatment planning remains to be defined. Future investigation should incorporate biomarkers such as tumor grade into definitions of MTV.

View details for DOI 10.1016/j.radonc.2011.05.040

View details for Web of Science ID 000298894700003

View details for PubMedID 21665308

View details for PubMedCentralID PMC3178721



To evaluate the positioning accuracy of an optical positioning system for stereotactic radiosurgery in a pilot experience of optically guided, conventionally fractionated, radiotherapy for paranasal sinus and skull base tumors.Before each daily radiotherapy session, the positioning of 28 patients was set up using an optical positioning system. After this initial setup, the patients underwent standard on-board imaging that included daily orthogonal kilovoltage images and weekly cone beam computed tomography scans. Daily translational shifts were made after comparing the on-board images with the treatment planning computed tomography scans. These daily translational shifts represented the daily positional error in the optical tracking system and were recorded during the treatment course. For 13 patients treated with smaller fields, a three-degree of freedom (3DOF) head positioner was used for more accurate setup.The mean positional error for the optically guided system in patients with and without the 3DOF head positioner was 1.4 1.1 mm and 3.9 1.6 mm, respectively (p <.0001). The mean positional error drifted 0.11 mm/wk upward during the treatment course for patients using the 3DOF head positioner (p = .057). No positional drift was observed in the patients without the 3DOF head positioner.Our initial clinical experience with optically guided head-and-neck fractionated radiotherapy was promising and demonstrated clinical feasibility. The optically guided setup was especially useful when used in conjunction with the 3DOF head positioner and when it was recalibrated to the shifts using the weekly portal images.

View details for DOI 10.1016/j.ijrobp.2010.08.049

View details for Web of Science ID 000296823600035

View details for PubMedID 21543166



To compare the retention rates of two types of implanted fiducial markers for stereotactic ablative radiotherapy (SABR) of pulmonary tumors, smooth cylindrical gold "seed" markers ("seeds") and platinum endovascular embolization coils ("coils"), and to compare the complication rates associated with the respective implantation procedures.We retrospectively analyzed the retention of percutaneously implanted markers in 54 consecutive patients between January 2004 and June 2009. A total of 270 markers (129 seeds, 141 coils) were implanted in or around 60 pulmonary tumors over 59 procedures. Markers were implanted using a percutaneous approach under computed tomography (CT) guidance. Postimplantation and follow-up imaging studies were analyzed to score marker retention relative to the number of markers implanted. Markers remaining near the tumor were scored as retained. Markers in a distant location (e.g., pleural space) were scored as lost. CT imaging artifacts near markers were quantified on radiation therapy planning scans.Immediately after implantation, 140 of 141 coils (99.3%) were retained, compared to 110 of 129 seeds (85.3%); the difference was highly significant (p<0.0001). Of the total number of lost markers, 45% were reported lost during implantation, but 55% were lost immediately afterwards. No additional markers were lost on longer-term follow-up. Implanted lesions were peripherally located for both seeds (mean distance, 0.33 cm from pleural surface) and coils (0.34 cm) (p=0.96). Incidences of all pneumothorax (including asymptomatic) and pneumothorax requiring chest tube placement were lower in implantation of coils (23% and 3%, respectively) vs. seeds (54% and 29%, respectively; p=0.02 and 0.01). The degree of CT artifact was similar between marker types.Retention of CT-guided percutaneously implanted coils is significantly better than that of seed markers. Furthermore, implanting coils is at least as safe as implanting seeds. Using coils should permit implantation of fewer markers and require fewer repeat implantation procedures owing to lost markers.

View details for DOI 10.1016/j.ijrobp.2010.04.037

View details for Web of Science ID 000294093300012

View details for PubMedID 20675070

New translational possibilities for microenvironmental modulation of radiosensitivity. Radiation research Glazer, P. M., Le, Q., Bristow, R., Helleday, T., Pelroy, R., Bernhard, E. J. 2011; 176 (3): 412-414

View details for PubMedID 21867431

Radiation Resistance in Cancer Therapy: meeting summary and research opportunities. Report of an NCI Workshop held September 1-3, 2010. Radiation research Glazer, P. M., Grandis, J., Powell, S. N., Brown, J. M., Helleday, T., Bristow, R., Powis, G., Hill, R. P., Le, Q., Pelroy, R., Mohla, S., Bernhard, E. J. 2011; 176 (3): e0016-21

View details for PubMedID 21867428

Targeting Galectin-1, a Hypoxia Induced Protein, in Non-Small Cell Lung Cancers European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care Banh, A., Zhang, J., Cao, H., Bouley, D., Kwok, S., Kong, C., Giaccia, A., Koong, A., Le, Q. ELSEVIER SCI LTD. 2011: S60S60
Results from a Single Institution Phase II Trial of Concurrent Docetaxel/Carboplatin/Radiotherapy Followed by Surgical Resection and Consolidation Docetaxel/Carboplatin in Stage III Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Das, M., Donington, J. S., Murphy, J., Kozak, M., Eclov, N., Whyte, R. I., Hoang, C. D., Zhou, L., Le, Q., Loo, B. W., Wakelee, H. 2011; 12 (5): 280-285


The optimal treatment of locally advanced non-small-cell lung cancer (NSCLC) remains controversial. We hypothesized that using a trimodality approach in selected patients with stage IIIA/IIIB disease would be both feasible and efficacious with reasonable toxicity.We enrolled 13 patients with resectable stage III NSCLC on a prospective phase II trial of trimodality therapy. Induction treatment consisted of weekly docetaxel 20 mg/m(2) and weekly carboplatin at an area under curve (AUC) of 2 concurrent with 45 Gy thoracic radiotherapy. Resection was performed unless felt to be unsafe or if patients had progressive disease. Postoperative consolidation consisted of docetaxel 75 mg/m(2) and carboplatin at an AUC of 6 every 3 weeks for 3 cycles with growth factor support.All patients responded to induction chemoradiotherapy as measured by total gross tumor volume reductions of 43% on average (range, 27%-64%). Twelve patients underwent resection of the tumor and involved nodes, yielding a resectability rate of 92%. The primary endpoint of 2-year overall survival (OS) was 72% (95% confidence interval [CI], 36%-90%), and 2-year progression-free survival (PFS) was 36% (95% CI, 9%-64%). The maximal toxicity observed per patient was grade II in 5 patients (38%); grade III in 7 patients (54%); grade IV in 1 patient (8%); and grade V in none.This trimodality approach resulted in promising outcomes with reasonable toxicity in carefully selected patients with stage III NSCLC at a single institution.

View details for DOI 10.1016/j.cllc.2011.06.003

View details for Web of Science ID 000294600800003

View details for PubMedID 21752720



Few studies have evaluated the use of intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma (SCC) of the oral cavity (OC). We report clinical outcomes and failure patterns for these patients.Between October 2002 and June 2009, 37 patients with newly diagnosed SCC of the OC underwent postoperative (30) or definitive (7) IMRT. Twenty-five patients (66%) received systemic therapy. The median follow-up was 38 months (range, 10-87 months). The median interval from surgery to RT was 5.9 weeks (range, 2.1-10.7 weeks).Thirteen patients experienced local-regional failure at a median of 8.1 months (range, 2.4-31.9 months), and 2 additional patients experienced local recurrence between surgery and RT. Seven local failures occurred in-field (one with simultaneous nodal and distant disease) and two at the margin. Four regional failures occurred, two in-field and two out-of-field, one with synchronous metastases. Six patients experienced distant failure. The 3-year actuarial estimates of local control, local-regional control, freedom from distant metastasis, and overall survival were 67%, 53%, 81%, and 60% among postoperative patients, respectively, and 60%, 60%, 71%, and 57% among definitive patients. Four patients developed Grade 2 chronic toxicity. Increased surgery to RT interval predicted for decreased LRC (p = 0.04).Local-regional control for SCC of the OC treated with IMRT with or without surgery remains unsatisfactory. Definitive and postoperative IMRT have favorable toxicity profiles. A surgery-to-RT interval of < 6 weeks improves local-regional control. The predominant failure pattern was local, suggesting that both improvements in target delineation and radiosensitization and/or dose escalation are needed.

View details for DOI 10.1016/j.ijrobp.2010.04.031

View details for Web of Science ID 000293207600020

View details for PubMedID 20675073

Palifermin Reduces Severe Mucositis in Definitive Chemoradiotherapy of Locally Advanced Head and Neck Cancer: A Randomized, Placebo-Controlled Study JOURNAL OF CLINICAL ONCOLOGY Le, Q., Kim, H. E., Schneider, C. J., Murakozy, G., Skladowski, K., Reinisch, S., Chen, Y., Hickey, M., Mo, M., Chen, M., Berger, D., Lizambri, R., Henke, M. 2011; 29 (20): 2808-2814


Oral mucositis (OM) is a debilitating toxicity of chemoradiotherapy for head and neck cancer (HNC). This randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of palifermin to reduce OM associated with definitive chemoradiotherapy for locally advanced HNC.Patients receiving conventionally fractionated radiotherapy (2.0 Gy/d, 5 days/wk to 70 Gy) with cisplatin (100 mg/m(2) on days 1, 22, and 43) received palifermin (180 g/kg) or placebo before starting chemoradiotherapy and then once weekly for 7 weeks. The primary end point was the incidence of severe, observable, and functional OM (WHO grade 3 to 4).The palifermin (n = 94) and placebo (n = 94) arms were well balanced. The incidence of severe OM was significantly lower for palifermin than for placebo (54% v 69%; P = .041). In the palifermin arm, median time to severe OM was delayed (47 v 35 days), median duration of severe OM was shortened (5 v 26 days), and the incidence of xerostomia grade 2 was lower (67% v 80%), favoring palifermin; however, the differences were not significant after multiplicity adjustment. Opioid analgesic use, average mouth and throat soreness scores, and chemoradiotherapy compliance were not significantly different between treatment arms. Adverse events were similar between arms (98%, palifermin; 93%, placebo). The most common study drug-related adverse events were rash, flushing, and dysgeusia. After median follow-up of 25.8 months, overall survival and progression-free survival were similar between treatment arms.Although palifermin reduced severe functional OM, its role in the management of locally advanced HNC during chemoradiotherapy remains to be elucidated.

View details for DOI 10.1200/JCO.2010.32.4095

View details for Web of Science ID 000292508500022

View details for PubMedID 21670453

Radiation Resistance in Cancer Therapy: Meeting Summary and Research Opportunities: Report of an NCI Workshop held September 1-3, 2010. Radiation research Glazer, P. M., Grandis, J., Powell, S. N., Brown, J. M., Helleday, T., Bristow, R., Powis, G., Hill, R. P., Le, Q., Pelroy, R., Mohla, S., Bernhard, E. J. 2011: -?

View details for PubMedID 21740251

Tumor Galectin-1 Mediates Tumor Growth and Metastasis through Regulation of T-Cell Apoptosis CANCER RESEARCH Banh, A., Zhang, J., Cao, H., Bouley, D. M., Kwok, S., Kong, C., Giaccia, A. J., Koong, A. C., Le, Q. 2011; 71 (13): 4423-4431


Galectin-1 (Gal-1), a carbohydrate-binding protein whose secretion is enhanced by hypoxia, promotes tumor aggressiveness by promoting angiogenesis and T-cell apoptosis. However, the importance of tumor versus host Gal-1 in tumor progression is undefined. Here we offer evidence that implicates tumor Gal-1 and its modulation of T-cell immunity in progression. Comparing Gal-1-deficient mice as hosts for Lewis lung carcinoma cells where Gal-1 levels were preserved or knocked down, we found that tumor Gal-1 was more critical than host Gal-1 in promoting tumor growth and spontaneous metastasis. Enhanced growth and metastasis associated with Gal-1 related to its immunomodulatory function, insofar as the benefits of Gal-1 expression to Lewis lung carcinoma growth were abolished in immunodeficient mice. In contrast, angiogenesis, as assessed by microvessel density count, was similar between tumors with divergent Gal-1 levels when examined at a comparable size. Our findings establish that tumor rather than host Gal-1 is responsible for mediating tumor progression through intratumoral immunomodulation, with broad implications in developing novel targeting strategies for Gal-1 in cancer.

View details for DOI 10.1158/0008-5472.CAN-10-4157

View details for Web of Science ID 000292287300013

View details for PubMedID 21546572



To explore the prognostic value of metabolic tumor volume measured on postradiation (18)F-fluorodeoxyglucose positron emission tomography (PET) imaging in patients with head-and-neck cancer.Forty-seven patients with head-and-neck cancer who received pretreatment and posttreatment PET/computed tomography (CT) imaging along with definitive chemoradiotherapy were included in this study. The PET/CT parameters evaluated include the maximum standardized uptake value, metabolic tumor volume (MTV(2.0)-MTV(4.0); where MTV(2.0) refers to the volume above a standardized uptake value threshold of 2.0), and integrated tumor volume. Kaplan-Meier and Cox regression models were used to test for association between PET endpoints and disease-free survival and overall survival.Multiple postradiation PET endpoints correlated significantly with outcome; however, the most robust predictor of disease progression and death was MTV(2.0). An increase in MTV(2.0) of 21 cm(3) (difference between 75th and 25th percentiles) was associated with an increased risk of disease progression (hazard ratio [HR] = 2.5, p = 0.0001) and death (HR = 2.0, p = 0.003). In patients with nonnasopharyngeal carcinoma histology (n = 34), MTV(2.0) <18 cm(3) and MTV(2.0) 18 cm(3) yielded 2-year disease-free survival rates of 100% and 63%, respectively (p = 0.006) and 2-year overall survival rates of 100% and 81%, respectively (p = 0.009). There was no correlation between MTV(2.0) and disease-free survival or overall survival with nasopharyngeal carcinoma histology (n = 13). On multivariate analysis, only postradiation MTV(2.0) was predictive of disease-free survival (HR = 2.47, p = 0.0001) and overall survival (HR = 1.98, p = 0.003).Postradiation metabolic tumor volume is an adverse prognostic factor in head-and-neck cancer. Biomarkers such as MTV are important for risk stratification and will be valuable in the future with risk-adapted therapies.

View details for DOI 10.1016/j.ijrobp.2010.01.057

View details for Web of Science ID 000290837100028

View details for PubMedID 20646870

Head and Neck Cancer-Specific Survival Based on Socioeconomic Status in Asians and Pacific Islanders CANCER Chu, K. P., Shema, S., Wu, S., Gomez, S. L., Chang, E. T., Quynh-Thu Le, Q. T. 2011; 117 (9): 1935-1945


Lower socioeconomic status (SES) has been linked to higher incidence of head and neck cancer (HNC) and lower survival. However, little is known about the effect of SES on HNC survival in Asians and Pacific Islanders (APIs). This study's purpose was to examine the effect of SES on disease-specific survival (DSS) and overall survival (OS) in APIs with HNC using population-based data.A total of 53,544 HNC patients (4,711 = APIs) were identified from the California Cancer Registry from 1988 to 2007. Neighborhood (block-group-level) SES, based on composite Census 1990 and 2000 data, was calculated for each patient based on address at diagnosis, categorized into statewide quintiles, and collapsed into 2 groups for comparison (low SES = quintiles 1-3; high SES = quintiles 4-5). DSS and OS were computed by the Kaplan-Meier method. Adjusted hazards ratios (HR) were estimated using Cox proportional hazards regression models.Among APIs, lower neighborhood SES was significantly associated with poorer DSS (HR range for oral cavity, oropharynx, or larynx/hypopharynx cancer, 1.07-1.34) and OS (HR, 1.13-1.37) after adjusting for patient and tumor characteristics. Lower SES was significantly associated with poorer survival in API with all HNC sites combined: DSS HR: 1.26 (95% confidence interval [CI], 1.08-1.48) and OS HR, 1.30 (95% CI, 1.16-1.45).Neighborhood SES was associated with longer DSS and OS in API with HNC. The effect of SES on HNC survival should be considered in future studies, and particular attention should be paid to clinical care of lower-SES HNC patients.

View details for DOI 10.1002/cncr.25723

View details for Web of Science ID 000289833100020

View details for PubMedID 21509771

Tumor Volume as a Potential Imaging-Based Risk-Stratification Factor in Trimodality Therapy for Locally Advanced Non-small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Kozak, M. M., Murphy, J. D., Schipper, M. L., Donington, J. S., Zhou, L., Whyte, R. I., Shrager, J. B., Hoang, C. D., Bazan, J., Maxim, P. G., Graves, E. E., Diehn, M., Hara, W. Y., Quon, A., Quynh-Thu Le, Q. T., Wakelee, H. A., Loo, B. W. 2011; 6 (5): 920-926


The role of trimodality therapy for locally advanced non-small cell lung cancer (NSCLC) continues to be defined. We hypothesized that imaging parameters on pre- and postradiation positron emission tomography (PET)-computed tomography (CT) imaging are prognostic for outcome after preoperative chemoradiotherapy (CRT)/resection/consolidation chemotherapy and could help risk-stratify patients in clinical trials.We enrolled 13 patients on a prospective clinical trial of trimodality therapy for resectable locally advanced NSCLC. PET-CT was acquired for radiation planning and after 45 Gy. Gross tumor volume (GTV) and standardized uptake value were measured at pre- and post-CRT time points and correlated with nodal pathologic complete response, loco-regional and/or distant progression, and overall survival. In addition, we evaluated the performance of automatic deformable image registration (ADIR) software for volumetric response assessment.All patients responded with average total GTV reductions after 45 Gy of 43% (range: 27-64%). Pre- and post-CRT GTVs were highly correlated (R = 0.9), and their respective median values divided the patients into the same two groups. ADIR measurements agreed closely with manually segmented post-CRT GTVs. Patients with GTV median (137 ml pre-CRT and 67 ml post-CRT) had 3-year progression-free survival (PFS) of 14% versus 75% for GTV less than median, a significant difference (p = 0.049). Pre- and post-CRT PET-standardized uptake value did not correlate significantly with pathologic complete response, PFS, or overall survival.Preoperative CRT with carboplatin/docetaxel/45 Gy resulted in excellent response rates. In this exploratory analysis, pre- and post-CRT GTV predicted PFS in trimodality therapy, consistent with our earlier studies in a broader cohort of NSCLC. ADIR seems robust enough for volumetric response assessment in clinical trials.

View details for DOI 10.1097/JTO.0b013e31821517db

View details for Web of Science ID 000289554100012

View details for PubMedID 21774104

Glioma-Associated Oncogene Family Zinc Finger 1 Expression and Metastasis in Patients With Head and Neck Squamous Cell Carcinoma Treated With Radiation Therapy (RTOG 9003) JOURNAL OF CLINICAL ONCOLOGY Chung, C. H., Dignam, J. J., Hammond, M. E., Klimowicz, A. C., Petrillo, S. K., Magliocco, A., Jordan, R., Trotti, A., Spencer, S., Cooper, J. S., Le, Q., Ang, K. K. 2011; 29 (10): 1326-1333


Glioma-associated oncogene family zinc finger 1 (GLI1) expression was assessed to determine a potential role of hedgehog (Hh) signaling in head and neck squamous cell carcinoma (HNSCC). Additional proteins known to be modulated by Hh signaling, including beta-catenin (CTNNB1) and epidermal growth factor receptor (EGFR), were also assessed to determine the correlation among these distinct signaling pathways.Nuclear GLI1 and CTNNB1 expression levels were determined in tumors from patients enrolled on Radiation Therapy Oncology Group (RTOG) 9003, a radiation fractionation trial. The results were also correlated with previously determined EGFR expression. The expression levels were evaluated in relation to three end points: time to metastasis (TTM), time to disease progression (TDP), and overall survival (OS).Among 1,068 eligible patients, data on GLI1, CTNNB1, and EGFR were available in 339, 164, and 300 patients, respectively. Although CTNNB1 expression did not differentiate prognosis, GLI1 was associated with poorer outcomes, adjusted for age, TNM stages, and Karnofsky performance score, and the significant influence persisted in a multivariable analysis (quartile 4 [Q4] v Q1 to Q3: TTM hazard ratio [HR], 2.7; 95% CI, 1.5 to 4.9; TDP HR, 1.6; 95% CI, 1.1 to 2.5; OS HR, 1.9; 95% CI, 1.4 to 2.7). The significance of GLI1 persisted in a multivariable analysis that included EGFR expression levels.These data suggest that Hh signaling may play an important role in metastasis and that GLI1 could serve as a marker in HNSCC, but the regulatory mechanisms and oncogenic significance need further investigation. Risk classification based on this analysis needs a validation in independent cohorts.

View details for DOI 10.1200/JCO.2010.32.3295

View details for Web of Science ID 000288990100030

View details for PubMedID 21357786

MYB Expression and Translocation in Adenoid Cystic Carcinomas and Other Salivary Gland Tumors With Clinicopathologic Correlation AMERICAN JOURNAL OF SURGICAL PATHOLOGY West, R. B., Kong, C., Clarke, N., Gilks, T., Lipsick, J. S., Cao, H., Kwok, S., Montgomery, K. D., Varma, S., Le, Q. 2011; 35 (1): 92-99


Adenoid cystic carcinoma is a locally aggressive salivary gland neoplasm, which has a poor long-term prognosis. A chromosomal translocation involving the genes encoding the transcription factors, MYB and NFIB, has been recently discovered in these tumors.MYB translocation and protein expression were studied in 37 adenoid cystic carcinomas, 112 other salivary gland neoplasms, and 409 nonsalivary gland neoplasms by fluorescence in situ hybridization and immunohistochemistry. MYB translocation and expression status in adenoid cystic carcinoma was correlated with clinicopathologic features including outcome, with a median follow-up of 77.1 months (range, 23.2 to 217.5 mo) for living patients.A balanced translocation between MYB and NFIB is present in 49% of adenoid cystic carcinomas but is not identified in other salivary gland tumors or nonsalivary gland neoplasms. There is no apparent translocation of MYB in 35% of the cases. Strong Myb immunostaining is very specific for adenoid cystic carcinomas but is only present in 65% of all cases. It is interesting to note that Myb immunostaining is confined to the basal cell component although the translocation is present in all the cells. Neoplasms with MYB translocation show a trend toward higher local relapse rates, but the results are not statistically significant with the current number of cases.MYB translocation and expression are useful diagnostic markers for a subset of adenoid cystic carcinomas. The presence of the translocation may be indicative of local aggressive behavior, but a larger cohort may be required to show statistical significance.

View details for DOI 10.1097/PAS.0b013e3182002777

View details for Web of Science ID 000285409900011

View details for PubMedID 21164292

Stereotactic Ablative Radiotherapy for Previously Irradiated Lung Tumors Trakul, N., Harris, J. P., Le, Q., Hara, W. Y., Maxim, P. G., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2011: S605S605
Volume Doubling Times and Outcomes in Stereotactic Ablative Radiotherapy of Early-stage Non-small Cell Lung Cancer Chung, M. P., Trakul, N., Le, Q., Hara, W. Y., Dieterich, S., Maxim, P. G., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2011: S592S592
Targeting Lung Tumors in Image-Guided Stereotactic Ablative Radiotherapy using Pulmonary Interstitial Lymphography Abelson, J. A., Kothary, N., Fleischmann, D., Hofmann, L., Kielar, K. N., Maxim, P. G., Le, Q., Hara, W. Y., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2011: S601S601
Radiotherapy For Adenoid Cystic Carcinomas Of The Head and Neck: Clinical Outcomes And Patterns Of Failure Shultz, D. B., Murphy, J. D., Daly, M. E., Hara, W., Le, Q. T., Chang, D. T. ELSEVIER SCIENCE INC. 2011: S528S528
Changes in FDG-PET/CT Parameters on Serial Pre-radiotherapy Scans Predict Disease Progression and Survival in Patients with Non-small Cell Lung Cancer Bazan, J. G., Chung, M. P., Eastham, D. V., Wakelee, H., Hara, W. Y., Maxim, P. G., Graves, E., Le, Q. T., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2011: S579S580
Analysis of Migration of Implanted Markers for Image-Guided Lung Tumor Stereotactic Ablative Radiotherapy Hong, J. C., Eclov, N. C., Yu, Y., Rao, A. K., Dieterich, S., Maxim, P. G., Le, Q., Diehn, M., Kothary, N., Loo, B. W. ELSEVIER SCIENCE INC. 2011: S580S581


Limited data evaluate intensity-modulated radiotherapy (IMRT) for cancers of the hypopharynx and larynx. We report clinical outcomes and failure patterns for these patients.Between September 2001 and December 2007, 42 patients with squamous cell carcinoma (SCC) of the hypopharynx (n = 23) and larynx (n = 19) underwent IMRT, 11 postoperatively and 31 definitively. Thirty-six received systemic therapy. Median follow-up was 30 months among surviving patients.Three local failures occurred within the high-dose region and 3 occurred in regional nodes. Seven patients developed distant metastasis as the initial failure. Three-year actuarial estimates of locoregional control, freedom from distant metastasis, and overall survival rates were, respectively, 80%, 72%, and 46%.IMRT provides good locoregional control for SCC of the hypopharynx and larynx compared with historical controls. Locoregional relapses occurred in the high-dose volumes, suggesting adequate target volume delineation. Hypopharyngeal tumors, which fare worse than laryngeal tumors, warrant investigation of more aggressive treatment.

View details for DOI 10.1002/hed.21406

View details for Web of Science ID 000286290400017

View details for PubMedID 20848427

Intensity-Modulated and Image-Guided Radiation Therapy for Head and Neck Cancers IMRT IGRT SBRT- ADVANCES IN THE TREATMENT PLANNING AND DELIVERY OF RADIOTHERAPY Chu, K. P., Le, Q. 2011; 43: 217-254


Radiation therapy is a key component of the multidisciplinary treatment of head and neck cancers (HNC), which are ideal tumors for intensity-modulated radiation therapy (IMRT) because of their location and intimate relationship to the surrounding critical structures. Several institutional studies have suggested that IMRT is superior to conventional radiation therapy in salivary preservation and holds promises for improved locoregional control of these tumors. Small randomized studies have supported the role of IMRT in reducing xerostomia and possibly improving quality of life. Target delineation for IMRT in these tumors is complex and requires detailed knowledge of head and neck anatomy and pathways of tumor spread. The advent of image-guided radiation therapy offers a new innovation that can refine IMRT delivery even further. This article focuses on the issues surrounding IMRT target delineation for typical HNC presentations and a discussion on the role of FDG-PET imaging in HNC treatment planning.

View details for Web of Science ID 000292117400011

View details for PubMedID 21625156

Thymic Malignancies JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Ettinger, D. S., Akerley, W., Bepler, G., Blum, M. G., Chang, A., Cheney, R. T., Chineac, L. R., Amico, T. A., Demmy, T. L., Govindan, R., Grannis, F. W., Jahan, T., Johnson, D. H., Kessinger, A., Komaki, R., Kong, F., Kris, M. G., Krug, L. M., Le, Q. T., Lennes, I. T., Martins, R., Malley, J. O., Osarogiagbon, R. U., Otterson, G. A., Patel, J. D., Pisters, K. M., Reckamp, K., Riely, G. J., Rohren, E., Swanson, S. J., Wood, D. E., Yang, S. C. 2010; 8 (11): 1302-1315

View details for Web of Science ID 000284302300005

View details for PubMedID 21081786



Our aim was to determine the incidence rates of head and neck cancer in Vietnamese Californians compared with other Asian and non-Asian Californians.Age-adjusted incidence rates of head and neck cancer between 1988 and 2004 were computed for Vietnamese Californians compared with other racial/ethnic groups by time period, ethnicity, neighborhood-level socioeconomic status (SES), and sex using data from the population-based California Cancer Registry (CCR). Data by smoking and alcohol status were tabulated from the California Health Interview Survey.Vietnamese men had a higher incidence rate of head and neck cancer than other Asian men. Specifically, the laryngeal cancer rate was significantly higher for Vietnamese men (6.5/100,000; 95% confidence interval [CI], 5.0-8.2) than all other Asian men (range, 2.6-3.8/100,000), except Korean men (5.1/100,000; 95% CI, 3.9-6.4). Both Vietnamese and Korean men had the highest percentage of current smokers. Neighborhood SES was inversely related to head and neck cancer rates among Vietnamese men and women.The higher incidence rate of head and neck cancer in Vietnamese men may correspond to the higher smoking prevalence in this group. Individual-level data are needed to establish the link of tobacco, alcohol, and other risk factors with head and neck cancer in these patients.

View details for DOI 10.1002/hed.21330

View details for Web of Science ID 000282707500008

View details for PubMedID 20091688

View details for PubMedCentralID PMC4349526

Hypoxia in Models of Lung Cancer: Implications for Targeted Therapeutics CLINICAL CANCER RESEARCH Graves, E. E., Vilalta, M., Cecic, I. K., Erler, J. T., Tran, P. T., Felsher, D., Sayles, L., Sweet-Cordero, A., Le, Q., Giaccia, A. J. 2010; 16 (19): 4843-4852


To efficiently translate experimental methods from bench to bedside, it is imperative that laboratory models of cancer mimic human disease as closely as possible. In this study, we sought to compare patterns of hypoxia in several standard and emerging mouse models of lung cancer to establish the appropriateness of each for evaluating the role of oxygen in lung cancer progression and therapeutic response.Subcutaneous and orthotopic human A549 lung carcinomas growing in nude mice as well as spontaneous K-ras or Myc-induced lung tumors grown in situ or subcutaneously were studied using fluorodeoxyglucose and fluoroazomycin arabinoside positron emission tomography, and postmortem by immunohistochemical observation of the hypoxia marker pimonidazole. The response of these models to the hypoxia-activated cytotoxin PR-104 was also quantified by the formation of H2AX foci in vitro and in vivo. Finally, our findings were compared with oxygen electrode measurements of human lung cancers.Minimal fluoroazomycin arabinoside and pimonidazole accumulation was seen in tumors growing within the lungs, whereas subcutaneous tumors showed substantial trapping of both hypoxia probes. These observations correlated with the response of these tumors to PR-104, and with the reduced incidence of hypoxia in human lung cancers relative to other solid tumor types.These findings suggest that in situ models of lung cancer in mice may be more reflective of the human disease, and encourage judicious selection of preclinical tumor models for the study of hypoxia imaging and antihypoxic cell therapies.

View details for DOI 10.1158/1078-0432.CCR-10-1206

View details for Web of Science ID 000282647900017

View details for PubMedID 20858837

Prognostic Significance of p16(INK4A) and Human Papillomavirus in Patients With Oropharyngeal Cancer Treated on TROG 02.02 Phase III Trial 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Rischin, D., Young, R. J., Fisher, R., Fox, S. B., Le, Q., Peters, L. J., Solomon, B., Choi, J., O'Sullivan, B., Kenny, L. M., McArthur, G. A. AMER SOC CLINICAL ONCOLOGY. 2010: 414248


To determine the prognostic importance of p16 and human papillomavirus (HPV) in patients with oropharyngeal cancer treated on a phase III concurrent chemoradiotherapy trial.Patients with stage III or IV head and neck squamous cell cancer were randomly assigned to concurrent radiotherapy and cisplatin with or without tirapazamine. In this substudy, analyses were restricted to patients with oropharyngeal cancer. p16 was detected by immunohistochemistry, and HPV was detected by in situ hybridization and polymerase chain reaction.Slides were available for p16 assay in 206 of 465 patients, of which 185 were eligible, and p16 and HPV were evaluable in 172 patients. One hundred six (57%) of 185 were p16-positive, and in patients evaluable for both p16 and HPV, 88 (86%) of 102 p16-positive patients were also HPV-positive. Patients who were p16-positive had lower T and higher N categories and better Eastern Cooperative Oncology Group (ECOG) performance status. p16-positive tumors compared with p16-negative tumors were associated with better 2-year overall survival (91% v 74%; hazard ratio [HR], 0.36; 95% CI, 0.17 to 0.74; P = .004) and failure-free survival (87% v 72%; HR, 0.39; 95% CI, 0.20 to 0.74; P = .003). p16 was a significant prognostic factor on multivariable analysis (HR, 0.45; 95% CI, 0.21 to 0.96; P = .04). p16-positive patients had lower rates of locoregional failure and deaths due to other causes. There was a trend favoring the tirapazamine arm for improved locoregional control in p16-negative patients (HR, 0.33; 95% CI, 0.09 to 1.24; P = .13).HPV-associated oropharyngeal cancer is a distinct entity with a favorable prognosis compared with HPV-negative oropharyngeal cancer when treated with cisplatin-based chemoradiotherapy.

View details for DOI 10.1200/JCO.2010.29.2904

View details for Web of Science ID 000281909700009

View details for PubMedID 20697079

Dose reconstruction for volumetric modulated arc therapy (VMAT) using cone-beam CT and dynamic log files PHYSICS IN MEDICINE AND BIOLOGY Qian, J., Lee, L., Liu, W., Chu, K., Mok, E., Luxton, G., Le, Q., Xing, L. 2010; 55 (13): 3597-3610


Volumetric modulated arc therapy (VMAT) has recently emerged as a new clinical modality for conformal radiation therapy. The aim of this work is to establish a methodology and procedure for retrospectively reconstructing the actual dose delivered in VMAT based on the pre-treatment cone-beam computed tomography (CBCT) and dynamic log files. CBCT was performed before the dose delivery and the system's log files were retrieved after the delivery. Actual delivery at a control point including MLC leaf positions, gantry angles and cumulative monitor units (MUs) was recorded in the log files and the information was extracted using in-house developed software. The extracted information was then embedded into the original treatment DICOM-radiation therapy (RT) file to replace the original control point parameters. This reconstituted DICOM-RT file was imported into the Eclipse treatment planning system (TPS) and dose was computed on the corresponding CBCT. A series of phantom experiments was performed to show the feasibility of dose reconstruction, validate the procedure and demonstrate the efficacy of this methodology. The resultant dose distributions and dose-volume histograms (DVHs) were compared with those of the original treatment plan. The studies indicated that CBCT-based VMAT dose reconstruction is readily achievable and provides a valuable tool for monitoring the dose actually delivered to the tumor target as well as the sensitive structures. In the absence of setup errors, the reconstructed dose shows no significant difference from the original pCT-based plan. It is also elucidated that the proposed method is capable of revealing the dosimetric changes in the presence of setup errors. The method reported here affords an objective means for dosimetric evaluation of VMAT delivery and is useful for adaptive VMAT in future.

View details for DOI 10.1088/0031-9155/55/13/002

View details for Web of Science ID 000279004300002

View details for PubMedID 20526034

The Tumor Microenvironment in Non-Small-Cell Lung Cancer SEMINARS IN RADIATION ONCOLOGY Graves, E. E., Maity, A., Le, Q. 2010; 20 (3): 156-163


The tumor microenvironment (TME) of NSCLC is heterogeneous with variable blood flow through leaky immature vessels resulting in regions of acidosis and hypoxia. Hypoxia has been documented in NSCLC directly by polarographic needle electrodes and indirectly by assessing tissue and plasma hypoxia markers. In general, elevated expression of these markers portends poorer outcomes in NSCLC. Impaired vascularity and hypoxia can lead to increased metastasis and treatment resistance. Compounds that directly target hypoxic cells such as tirapazamine have been tested in clinical trials for NSCLC with mixed results. Preclinical data, however, suggest other ways of exploiting the abnormal TME in NSCLC for therapeutic gain. The inhibition of hypoxia-inducible factor-1alpha or vascular endothelial growth factor may increase local control after radiation. Inhibitors of the epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/Akt pathway, such as erlotinib or PI-103, may "normalize" tumor vessels, allowing for increased chemotherapy delivery or improved oxygenation and radiation response. To select patients who may respond to these therapies and to evaluate the effects of these agents, a noninvasive means of imaging the TME is critical. Presently, there are several promising modalities to image hypoxia and the tumor vasculature; these include dynamic perfusion imaging and positron emission tomography scanning with radiolabled nitroimidazoles.

View details for DOI 10.1016/j.semradonc.2010.01.003

View details for Web of Science ID 000279360800003

View details for PubMedID 20685578

Image-based modeling of tumor shrinkage in head and neck radiation therapy 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Chao, M., Xie, Y., Moros, E. G., Le, Q., Xing, L. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2010: 235158


Understanding the kinetics of tumor growth/shrinkage represents a critical step in quantitative assessment of therapeutics and realization of adaptive radiation therapy. This article presents a novel framework for image-based modeling of tumor change and demonstrates its performance with synthetic images and clinical cases.Due to significant tumor tissue content changes, similarity-based models are not suitable for describing the process of tumor volume changes. Under the hypothesis that tissue features in a tumor volume or at the boundary region are partially preserved, the kinetic change was modeled in two steps: (1) Autodetection of homologous tissue features shared by two input images using the scale invariance feature transformation (SIFT) method; and (2) establishment of a voxel-to-voxel correspondence between the images for the remaining spatial points by interpolation. The correctness of the tissue feature correspondence was assured by a bidirectional association procedure, where SIFT features were mapped from template to target images and reversely. A series of digital phantom experiments and five head and neck clinical cases were used to assess the performance of the proposed technique.The proposed technique can faithfully identify the known changes introduced when constructing the digital phantoms. The subsequent feature-guided thin plate spline calculation reproduced the "ground truth" with accuracy better than 1.5 mm. For the clinical cases, the new algorithm worked reliably for a volume change as large as 30%.An image-based tumor kinetic algorithm was developed to model the tumor response to radiation therapy. The technique provides a practical framework for future application in adaptive radiation therapy.

View details for DOI 10.1118/1.3399872

View details for Web of Science ID 000277242800043

View details for PubMedID 20527569

View details for PubMedCentralID PMC2874043

MiR-210-micromanager of the hypoxia pathway TRENDS IN MOLECULAR MEDICINE Huang, X., Le, Q., Giaccia, A. J. 2010; 16 (5): 230-237


Hypoxia inducible factors (HIFs) regulate a variety of genes to prepare cells to adapt and survive under a hypoxic environment. Recently, microRNAs (miRNAs) have emerged as a new class of genes regulated by HIFs in response to hypoxia, of which miR-210 is the most consistently and predominantly upregulated miRNA. Functional studies have demonstrated that miR-210 is a versatile gene that regulates many aspects of hypoxia pathways, both in physiological and malignant conditions. Here, we summarize recent findings on the mechanism of hypoxia regulation of miR-210 expression and its multifaceted biological functions in normal physiological and malignant conditions, and discuss the challenges we face in elucidating the biological functions of miR-210 and exploring its potential use for therapeutics.

View details for DOI 10.1016/j.molmed.2010.03.004

View details for Web of Science ID 000278669500004

View details for PubMedID 20434954

Circulating miR-210 as a Novel Hypoxia Marker in Pancreatic Cancer TRANSLATIONAL ONCOLOGY Ho, A. S., Huang, X., Cao, H., Christman-Skieller, C., Bennewith, K., Le, Q., Koong, A. C. 2010; 3 (2): 109-113


MicroRNA are small noncoding transcripts involved in many cellular mechanisms, including tumorigenesis. miR-210, in particular, is induced by hypoxia and correlates with adverse outcomes in certain cancers. Because pancreatic adenocarcinomas exhibit extremely hypoxic signatures, we hypothesized that miR-210 may serve as a diagnostic marker for screening or surveillance for pancreatic cancer. Plasma samples were obtained from newly diagnosed pancreatic cancer patients and age-matched noncancer controls. miRNA was extracted directly from plasma and reverse-transcribed to complementary DNA. A known quantity of synthetic Caenorhabditis elegans miR-54 (celmiR-54) was added for normalization. miR-210 and cel-miR-54 were then measured using quantitative reverse transcription polymerase chain reaction. An initial cohort of 11 pancreatic cancer patients and 14 age-matched controls was used as the test set and a second cohort of 11 pancreatic cancer patients and 11 controls was used as the validating set in this study. miR-210 was reliably detected and quantified, with a statistically significant four-fold increase in expression in pancreatic cancer patients compared with normal controls (P < .00004) in the test set. This difference was confirmed in the validation group (P < .018). In summary, circulating miR-210 levels are elevated in pancreatic cancer patients and may potentially serve as a useful biomarker for pancreatic cancer diagnosis.

View details for DOI 10.1593/tlo.09256

View details for Web of Science ID 000278912800005

View details for PubMedID 20360935

Cetuximab-Based Immunotherapy and Radioimmunotherapy of Head and Neck Squamous Cell Carcinoma CLINICAL CANCER RESEARCH Niu, G., Sun, X., Cao, Q., Courter, D., Koong, A., Le, Q., Gambhir, S. S., Chen, X. 2010; 16 (7): 2095-2105


To show the relationship between antibody delivery and therapeutic efficacy in head and neck cancers, in this study we evaluated the pharmacokinetics and pharmacodynamics of epidermal growth factor receptor (EGFR)-targeted immunotherapy and radioimmunotherapy by quantitative positron emission tomography (PET) imaging.EGFR expression on UM-SCC-22B and SCC1 human head and neck squamous cell cancer (HNSCC) cells were determined by flow cytometry and immunostaining. Tumor delivery and distribution of cetuximab in tumor-bearing nude mice were evaluated with small animal PET using (64)Cu-DOTA-cetuximab. The in vitro toxicity of cetuximab to HNSCC cells was evaluated by MTT assay. The tumor-bearing mice were then treated with four doses of cetuximab at 10 mg/kg per dose, and tumor growth was evaluated by caliper measurement. FDG PET was done after the third dose of antibody administration to evaluate tumor response. Apoptosis and tumor cell proliferation after cetuximab treatment were analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Ki-67 staining. Radioimmunotherapy was done with (90)Y-DOTA-cetuximab.EGFR expression on UM-SCC-22B cells is lower than that on SCC1 cells. However, the UM-SCC-22B tumors showed much higher (64)Cu-DOTA-cetuximab accumulation than the SCC1 tumors. Cetuximab-induced apoptosis in SCC1 tumors and tumor growth was significantly inhibited, whereas an agonistic effect of cetuximab on UM-SCC-22B tumor growth was observed. After cetuximab treatment, the SCC1 tumors showed decreased FDG uptake, and the UM-SCC-22B tumors had increased FDG uptake. UM-SCC-22B tumors are more responsive to (90)Y-DOTA-cetuximab treatment than SCC1 tumors, partially due to the high tumor accumulation of the injected antibody.Cetuximab has an agonistic effect on the growth of UM-SCC-22B tumors, indicating that tumor response to cetuximab treatment is not necessarily related to EGFR expression and antibody delivery efficiency, as determined by PET imaging. Although PET imaging with antibodies as tracers has limited function in patient screening, it can provide guidance for targeted therapy using antibodies as delivery vehicles.

View details for DOI 10.1158/1078-0432.CCR-09-2495

View details for Web of Science ID 000278595800013

View details for PubMedID 20215534



To report outcomes, failures, and toxicities in patients treated with intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma of the oropharynx.Between Aug 2001 and Oct 2007, 107 patients were treated with IMRT with curative intent at Stanford University. Twenty-two patients were treated postoperatively, and 85 were treated definitively. Concurrent platinum-based chemotherapy was administered to 86 patients (80%) and cetuximab to 8 patients (7%). The prescribed dose was 66 Gy at 2.2 Gy/fraction for definitively treated cases and 60 Gy at 2 Gy/fraction for postoperative cases. Median follow-up was 29 months among surviving patients (range, 4-105 months).Eight patients had persistent disease or local-regional failure at a median of 6.5 months (range, 0-9.9 months). Six local failures occurred entirely within the high-risk clinical target volume (CTV) (one with simultaneous distant metastasis). One patient relapsed within the high- and intermediate-risk CTV. One patient had a recurrence at the junction between the IMRT and low-neck fields. Seven patients developed distant metastasis as the first site of failure. The 3-year local-regional control (LRC), freedom from distant metastasis, overall survival, and disease-free survival rates were 92%, 92%, 83%, and 81%, respectively. T stage (T4 vs. T1-T3) was predictive of poorer LRC (p = 0.001), overall survival (p = 0.001), and disease-free survival (p < 0.001) rates. Acute toxicity consisted of 58% grade 3 mucosal and 5% grade 3 skin reactions. Six patients (6%) developed grade >or=3 late complications.IMRT provides excellent LRC for oropharyngeal squamous cell carcinoma. Distant metastases are a major failure pattern. No marginal failures were observed.

View details for DOI 10.1016/j.ijrobp.2009.04.006

View details for Web of Science ID 000276675300012

View details for PubMedID 19540068

The RGD Domain of Human Osteopontin Promotes Tumor Growth and Metastasis through Activation of Survival Pathways PLOS ONE Courter, D., Cao, H., Kwok, S., Kong, C., Banh, A., Kuo, P., Bouley, D. M., Vice, C., Brustugun, O. T., Denko, N. C., Koong, A. C., Giaccia, A., Le, Q. 2010; 5 (3)


Human osteopontin (OPN), a known tumor associated protein, exists in different isoforms, whose function is unclear. It also possesses a RGD domain, which has been implicated in diverse function. Here, we use genetic approaches to systematically investigate the function of the RGD domain in different OPN isoforms on tumor progression and metastasis for 2 different solid tumor models.Using isoform-specific qRT-PCR, we found that OPN-A and B were the main isoforms overexpressed in evaluated human tumors, which included 4 soft tissue sarcomas, 24 lung and 30 head and neck carcinomas. Overexpression of either OPN-A or B in two different cell types promoted local tumor growth and lung metastasis in SCID mouse xenografts. However, expression of either isoform with the RGD domain either mutated or deleted decreased tumor growth and metastasis, and resulted in increased apoptosis by TUNEL staining. In vitro, whereas mutation of the RGD domain did not affect cell-cell adhesion, soft agar growth or cell migration, it increased apoptosis under hypoxia and serum starvation. This effect could be mitigated when the RGD mutant cells were treated with condition media containing WT OPN. Mechanistically, the RGD region of OPN inhibited apoptosis by inducing NF-kappaB activation and FAK phosphorylation. Inhibition of NF-kappaB (by siRNA to the p65 subunit) or FAK activation (by a inhibitor) significantly increased apoptosis under hypoxia in WT OPN cells, but not in RGD mutant cells.Unlike prior reports, our data suggest that the RGD domain of both OPN-A and B promote tumor growth and metastasis mainly by protecting cells against apoptosis under stressed conditions and not via migration or invasion. Future inhibitors directed against OPN should target multiple isoforms and should inhibit cell survival mechanisms that involve the RGD domain, FAK phosphorylation and NF-kappaB activation.

View details for DOI 10.1371/journal.pone.0009633

View details for Web of Science ID 000275328800027

View details for PubMedID 20224789

Imaging the Unfolded Protein Response in Primary Tumors Reveals Microenvironments with Metabolic Variations that Predict Tumor Growth CANCER RESEARCH Spiotto, M. T., Banh, A., Papandreou, I., Cao, H., Galvez, M. G., Gurtner, G. C., Denko, N. C., Le, Q. T., Koong, A. C. 2010; 70 (1): 78-88


Cancer cells exist in harsh microenvironments that are governed by various factors, including hypoxia and nutrient deprivation. These microenvironmental stressors activate signaling pathways that affect cancer cell survival. While others have previously measured microenvironmental stressors in tumors, it remains difficult to detect the real-time activation of these downstream signaling pathways in primary tumors. In this study, we developed transgenic mice expressing an X-box binding protein 1 (XBP1)-luciferase construct that served as a reporter for endoplasmic reticulum (ER) stress and as a downstream response for the tumor microenvironment. Primary mammary tumors arising in these mice exhibited luciferase activity in vivo. Multiple tumors arising in the same mouse had distinct XBP1-luciferase signatures, reflecting either higher or lower levels of ER stress. Furthermore, variations in ER stress reflected metabolic and hypoxic differences between tumors. Finally, XBP1-luciferase activity correlated with tumor growth rates. Visualizing distinct signaling pathways in primary tumors reveals unique tumor microenvironments with distinct metabolic signatures that can predict for tumor growth.

View details for DOI 10.1158/0008-5472.CAN-09-2747

View details for Web of Science ID 000278404300011

View details for PubMedID 20028872

Definitive Radiotherapy for New Primary Tumors in the Lung: The Benefit of the Doubt 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Jones, J. C., Trakul, N., Hara, W., Abelson, J. A., Maxim, P., Dieterich, S., Le, Q., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2010: S500S500
Volume Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Trakul, N., Harris, J., Dieterich, S., Maxim, P., Le, Q., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2010: S179S179
High Retention and Safety of Percutaneously Implanted Endovascular Embolization Coils as Fiducial Markers for Image-guided Stereotactic Ablative Radiotherapy of Pulmonary Tumors 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Hong, J. C., Yu, Y., Rao, A. K., Dieterich, S., Maxim, P. G., Le, Q. T., Diehn, M., Sze, D. Y., Kothary, N., Loo, B. W. ELSEVIER SCIENCE INC. 2010: S518S519
Prognostic Value of Metabolic Tumor Volume and Velocity in Predicting Head and Neck Cancer Outcomes 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Chu, K. P., Murphy, J., La, T. H., Loo, B. W., Krakow, T. E., Hsu, A., Maxim, P. G., Graves, E., Chang, D., Le, Q. ELSEVIER SCIENCE INC. 2010: S460S460
Clinical Management of Patients with Temporal Lobe Necrosis 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Krakow, T. E., Hara, W., Yun, S., Soltys, S., Chang, S., Fischbein, N., Loo, B., Le, Q. ELSEVIER SCIENCE INC. 2010: S455S455
Can Temporal Lobe Necrosis be Prevented in Patients with Nasopharyngeal/Skull Base Tumors Undergoing a Stereotactic Radiosurgery Boost? A Dose Volume Analysis 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Hara, W., Yun, S., Hsu, A., Soltys, S., Adler, J., Le, Q., Loo, B. W. ELSEVIER SCIENCE INC. 2010: S431S431
Identification of a biomarker panel using a multiplex proximity ligation assay improves accuracy of pancreatic cancer diagnosis JOURNAL OF TRANSLATIONAL MEDICINE Chang, S. T., Zahn, J. M., Horecka, J., Kunz, P. L., Ford, J. M., Fisher, G. A., Le, Q. T., Chang, D. T., Ji, H., Koong, A. C. 2009; 7


Pancreatic cancer continues to prove difficult to clinically diagnose. Multiple simultaneous measurements of plasma biomarkers can increase sensitivity and selectivity of diagnosis. Proximity ligation assay (PLA) is a highly sensitive technique for multiplex detection of biomarkers in plasma with little or no interfering background signal.We examined the plasma levels of 21 biomarkers in a clinically defined cohort of 52 locally advanced (Stage II/III) pancreatic ductal adenocarcinoma cases and 43 age-matched controls using a multiplex proximity ligation assay. The optimal biomarker panel for diagnosis was computed using a combination of the PAM algorithm and logistic regression modeling. Biomarkers that were significantly prognostic for survival in combination were determined using univariate and multivariate Cox survival models.Three markers, CA19-9, OPN and CHI3L1, measured in multiplex were found to have superior sensitivity for pancreatic cancer vs. CA19-9 alone (93% vs. 80%). In addition, we identified two markers, CEA and CA125, that when measured simultaneously have prognostic significance for survival for this clinical stage of pancreatic cancer (p < 0.003).A multiplex panel assaying CA19-9, OPN and CHI3L1 in plasma improves accuracy of pancreatic cancer diagnosis. A panel assaying CEA and CA125 in plasma can predict survival for this clinical cohort of pancreatic cancer patients.

View details for DOI 10.1186/1479-5876-7-105

View details for Web of Science ID 000272889900001

View details for PubMedID 20003342

View details for PubMedCentralID PMC2796647



Nasopharyngeal carcinoma (NPC) has a bimodal age distribution. In contrast to the adult variant, little is known about the juvenile form. This study examined the treatment results between adult (aNPC) and juvenile NPC (jNPC) patients for future treatment considerations in jNPC.The jNPC population included 53 patients treated at two institutions between 1972 and 2004. The aNPC population included 84 patients treated at one institution. The patients had received a median dose of 66 Gy of external beam radiotherapy and 72% underwent chemotherapy. The mean follow-up for surviving patients was 12.6 years for jNPC and 6.6 years for aNPC.The jNPC patients presented with more advance stages than did the aNPC patients (92% vs. 67% Stage III-IV, p = .006). However, jNPC patients had significantly better overall survival (OS) than did aNPC patients. The 5-year OS rate was 71% for jNPC and 58% for aNPC (p = .03). The jNPC group also demonstrated a trend for greater relapse-free survival than the aNPC group (5-year relapse-free survival rate, 69% vs. 49%; p = .056). The pattern of failure analysis revealed that the jNPC patients had greater locoregional control and freedom from metastasis but the differences were not statistically significant. Univariate analysis for OS revealed that age group, nodal classification, and chemotherapy use were significant prognostic factors. Age group remained significant for OS on multivariate analysis, after adjusting for N classification and treatment.Despite more advance stage at presentation, jNPC patients had better survival than did aNPC patients. Future treatment strategies should take into consideration the long-term complications in these young patients.

View details for DOI 10.1016/j.ijrobp.2008.12.030

View details for Web of Science ID 000271489600017

View details for PubMedID 19327901

Mucositis-Related Morbidity and Resource Utilization in Head and Neck Cancer Patients Receiving Radiation Therapy With or Without Chemotherapy JOURNAL OF PAIN AND SYMPTOM MANAGEMENT Murphy, B. A., Beaumont, J. L., Isitt, J., Garden, A. S., Gwede, C. K., Trotti, A. M., Meredith, R. F., Epstein, J. B., Le, Q., Brizel, D. M., Bellm, L. A., Wells, N., Cella, D. 2009; 38 (4): 522-532


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.

View details for DOI 10.1016/j.jpainsymman.2008.12.004

View details for Web of Science ID 000271297000005

View details for PubMedID 19608377

Hypoxia-Inducible mir-210 Regulates Normoxic Gene Expression Involved in Tumor Initiation MOLECULAR CELL Huang, X., Ding, L., Bennewith, K. L., Tong, R. T., Welford, S. M., Ang, K. K., Story, M., Le, Q., Giaccia, A. J. 2009; 35 (6): 856-867


Previous studies have suggested that the HIF transcription factors can both activate and inhibit gene expression. Here we show that HIF1 regulates the expression of mir-210 in a variety of tumor types through a hypoxia-responsive element. Expression analysis in primary head and neck tumor samples indicates that mir-210 may serve as an in vivo marker for tumor hypoxia. By Argonaute protein immunoprecipitation, we identified 50 potential mir-210 targets and validated randomly selected ones. The majority of these 50 genes are not classical hypoxia-inducible genes, suggesting mir-210 represses genes expressed under normoxia that are no longer necessary to adapt and survive in a hypoxic environment. When human head and neck or pancreatic tumor cells ectopically expressing mir-210 were implanted into immunodeficient mice, mir-210 repressed initiation of tumor growth. Taken together, these data implicate an important role for mir-210 in regulating the hypoxic response of tumor cells and tumor growth.

View details for DOI 10.1016/j.molcel.2009.09.006

View details for Web of Science ID 000270559100018

View details for PubMedID 19782034

View details for PubMedCentralID PMC2782615

Validation of Lysyl Oxidase As a Prognostic Marker for Metastasis and Survival in Head and Neck Squamous Cell Carcinoma: Radiation Therapy Oncology Group Trial 90-03 JOURNAL OF CLINICAL ONCOLOGY Le, Q., Harris, J., Magliocco, A. M., Kong, C. S., Diaz, R., Shin, B., Cao, H., Trotti, A., Erler, J. T., Chung, C. H., Dicker, A., Pajak, T. F., Giaccia, A. J., Ang, K. K. 2009; 27 (26): 4281-4286


To validate lysyl oxidase (LOX), a hypoxia-related protein, as a marker for metastasis in an independent head and neck cancer (HNC) patient group enrolled onto a prospective trial.We performed traditional immunohistochemical (IHC) staining and automated quantitative analysis (AQUA) for LOX expression in 66 HNC patients from one institution. We also performed AQUA staining for LOX in 306 of 1,113 patients treated on a phase III trial comparing four radiation fractionation schedules in locally advanced HNC (RTOG 90-03). Pretreatment characteristics and outcome were similar between patients with and without LOX assessment. We correlated AQUA LOX expression with time to metastasis (TTM), time to progression (TTP), and overall survival (OS).LOX expression from both staining methods predicted for TTM in the first 66 patients. Multivariate analysis, controlling for significant parameters including nodal stage and performance status, revealed tumor LOX expression, as a continuous variable, was an independent predictor for TTM (hazard ratio [HR], 1.21; 95% CI, 1.10 to 1.33; P = .0001), TTP (HR, 1.06; 95% CI, 1.02 to 1.10; P = .0069), and OS (HR, 1.04; 95% CI, 1.00 to 1.07; P = .0311) in RTOG 90-03 patients. This translates into a 259% increase in metastatic risk for a patient at the 75th percentile of LOX compared with one at the 25th percentile.AQUA LOX expression was strongly associated with increased metastasis, progression, and death in RTOG 90-03 patients. This study validates that LOX is a marker for metastasis and survival in HNC.

View details for DOI 10.1200/JCO.2008.20.6003

View details for Web of Science ID 000269652200010

View details for PubMedID 19667273

Quantification of pre-treatment metabolic tumor growth rate in lung cancer Eastham, D., Chapman, C. H., Rao, A. K., Balasubramanian, N., Quon, A., Vasanawala, M. S., Wakelee, H., Le, Q., Colevas, D. A., Maxim, P. A., Graves, E., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S733S733
Mid-treatment PET predicts progression in hypofractionated accelerated radiation therapy for lung tumors Chang, C. N., Fillion, E., Chapman, C., Rao, A., Wakelee, H., Ganjoo, K., Le, Q., Maxim, P., Quon, A., Graves, E. E., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S939S939
Excellent early local control with tumor volume adapted dosing of stereotactic body radiation therapy for pulmonary tumors Chang, C. N., Zhou, L. Y., MacFarlane, G., Tran, P., Rao, A., Chapman, C., Le, Q., Wakelee, H., Colevas, A. D., Whyte, R., Hristov, D., Dieterich, S., Maxim, P., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S938S939
METABOLIC TUMOR VOLUME PREDICTS FOR RECURRENCE AND DEATH IN HEAD-AND-NECK CANCER 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) La, T. H., Filion, E. J., Turnbull, B. B., Chu, J. N., Lee, P., Nguyen, K., Maxim, P., Quon, A., Graves, E. E., Loo, B. W., Le, Q. ELSEVIER SCIENCE INC. 2009: 133541


To evaluate the prognostic value of metabolic tumor volume measured on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and other clinical factors in patients treated for locally advanced head-and-neck cancer (HNC) at a single institution.Between March 2003 and August 2007, 85 patients received positron emission tomography (PET)/computed tomography-guided chemoradiotherapy for HNC. Metabolically active tumor regions were delineated on pretreatment PET scans semiautomatically using custom software. We evaluated the relationship of (18)F-fluorodeoxyglucose-PET maximum standardized uptake value (SUV) and total metabolic tumor volume (MTV) with disease-free survival (DFS) and overall survival (OS).Mean follow-up for surviving patients was 20.4 months. The estimated 2-year locoregional control, DFS, and OS for the group were 88.0%, 69.5%, and 78.4%, respectively. The median time to first failure was 9.8 months among the 16 patients with relapse. An increase in MTV of 17.4 mL (difference between the 75th and 25th percentiles) was significantly associated with an increased hazard of first event (recurrence or death) (1.9-fold, p < 0.001), even after controlling for Karnofsky performance status (KPS) (1.8-fold, p = 0.001), and of death (2.1-fold, p < 0.001). We did not find a significant relationship of maximum SUV, stage, or other clinical factors with DFS or OS.Metabolic tumor volume is an adverse prognostic factor for disease recurrence and death in HNC. MTV retained significance after controlling for KPS, the only other significant adverse prognostic factor found in this cohort. MTV is a direct measure of tumor burden and is a potentially valuable tool for risk stratification and guiding treatment in future studies.

View details for DOI 10.1016/j.ijrobp.2008.10.060

View details for Web of Science ID 000268346100006

View details for PubMedID 19289263

PET of EGFR Antibody Distribution in Head and Neck Squamous Cell Carcinoma Models JOURNAL OF NUCLEAR MEDICINE Niu, G., Li, Z., Xie, J., Le, Q., Chen, X. 2009; 50 (7): 1116-1123


Epidermal growth factor receptor (EGFR) is a well-characterized protooncogene that has been shown to promote tumor progression in solid cancers. Clinical results for EGFR targeting with specific monoclonal antibodies (mAbs) such as cetuximab and panitumumab are promising; however, most studies indicate that only a subgroup of patients receiving the mAbs benefit from the immunotherapy, independent of EGFR expression level. To understand the in vivo kinetics of antibody delivery and localization, we performed small-animal PET studies with (64)Cu-labeled panitumumab in xenografts derived from 3 cell lines of human head and neck squamous cell carcinoma (HNSCC).Nude mice bearing HNSCC tumors with different levels of EGFR expression were imaged with small-animal PET using (64)Cu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-panitumumab. Antibody distribution in the tumors was confirmed by ex vivo immunostaining using panitumumab and fluorescein 5(6)-isothiocyanate (FITC) panitumumab. CD31 immunostaining and Evans blue assay were also performed to assess the tumor vascular density and permeability.Among these 3 tumor models, UM-SCC-22B tumors with the lowest EGFR protein expression showed the highest (64)Cu-DOTA-panitumumab accumulation, whereas SQB20 tumors with the highest EGFR expression showed the lowest (64)Cu-DOTA-panitumumab accumulation. Ex vivo staining demonstrated that SQB20 cells still had extremely high EGFR expression after forming tumors in nude mice, indicating that the low uptake of (64)Cu-DOTA-panitumumab in SQB20 tumors was not due to the loss of EGFR expression. The results from CD31 immunostaining and Evans blue permeability assay suggest that the low vessel density, poor vascular permeability, and binding site barrier are likely responsible for the overall low tumor uptake of the highly EGFR-expressing SQB20 tumors.The results from this study provide a possible explanation for the lack of an observed correlation between therapeutic efficacy of cetuximab and panitumumab and EGFR expression level as determined by immunohistochemistry or fluorescent in situ hybridization and may shed new light on the complications of anti-EGFR mAb therapy for HNSCC and other malignancies.

View details for DOI 10.2967/jnumed.109.061820

View details for Web of Science ID 000272547100023

View details for PubMedID 19525473



To evaluate the relationship between human papillomavirus (HPV) status and known prognostic makers for head and neck cancers including tumor hypoxia, epidermal growth factor receptor (EGFR) expression and intratumoral T-cell levels and to determine the prognostic impact of these markers by HPV status.HPV status in 82 evaluable head and neck squamous cell carcinomas patients was determined by pyrosequencing and related to p16(INK4a) staining and treatment outcomes. It was correlated with tumor hypoxia (tumor pO(2) and carbonic anhydrase [CAIX] staining), EGFR status, and intratumoral lymphocyte expression (CD3 staining).Forty-four percent of evaluable tumors had strong HPV signal by pyrosequencing. There was a significant relationship between strong HPV signal and p16(INK4a) staining as well as oropharynx location. The strong HPV signal group fared significantly better than others, both in time to progression (TTP, p = 0.008) and overall survival (OS, p = 0.004) for all patients and for the oropharyngeal subset. Positive p16(INK4a) staining was associated with better TTP (p = 0.014) and OS (p = 0.00002). There was no relationship between HPV status and tumor pO(2) or CAIX staining. However, HPV status correlated inversely with EGFR reactivity (p = 0.0006) and directly with CD3(+) T-lymphocyte level (p = 0.03). Whereas CAIX and EGFR overexpression were negative prognostic factors regardless of HPV status, CD3(+) T-cell levels was prognostic only in HPV(-) tumors.HPV status was a prognostic factor for progression and survival. It correlated inversely with EGFR expression and directly with T-cell infiltration. The prognostic effect of CAIX and EGFR expression was not influenced by HPV status, whereas intratumoral T-cell levels was significant only for HPV(-) tumors.

View details for DOI 10.1016/j.ijrobp.2009.02.015

View details for Web of Science ID 000266057900035

View details for PubMedID 19427557

Detection of circulating hypoxia-regulated miR-210 in pancreatic adenocarcinoma patients 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Ho, A. S., Huang, X., Cao, H., Koong, A. C., Le, Q. T. AMER SOC CLINICAL ONCOLOGY. 2009
Prognostic significance of HPV and p16 status in patients with oropharyngeal cancer treated on a large international phase III trial 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Rischin, D., Young, R., Fisher, R., Fox, S., Le, Q., Peters, L., Choi, J., O'Sullivan, B., Giralt, J., McArthur, G. AMER SOC CLINICAL ONCOLOGY. 2009
Towards adaptive radiation therapy: Image-based tumor shrinkage modeling in head and neck cancer 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Chao, M., Xie, Y., Le, Q., Xing, L. AMER SOC CLINICAL ONCOLOGY. 2009
X box-binding protein 1 regulates angiogenesis in human pancreatic adenocarcinomas. Translational oncology Romero-Ramirez, L., Cao, H., Regalado, M. P., Kambham, N., Siemann, D., Kim, J. J., Le, Q. T., Koong, A. C. 2009; 2 (1): 31-38


Tumors encounter endoplasmic reticulum stress during tumor growth and activate an adaptive pathway known as the unfolded protein response (UPR). Because this pathway is induced by the tumor microenvironment, it is a promising target for cancer therapy. We have previously demonstrated that X-box binding protein 1 (XBP-1), a key regulator of the UPR, was required for survival under hypoxia and critical for tumor growth in tumor xenografts. In this study, we investigated the role of XBP-1 in regulating tumor angiogenesis.We used an intradermal angiogenesis model to quantify the effect of XBP-1 on angiogenesis. We also used a human tumor xenograft model to assay for tumor growth delay. We determined vascular endothelial growth factor (VEGF) expression by quantitative polymerase chain reaction and ELISA. Finally, we stained human pancreatic adenocarcinoma specimens for XBP-1 expression and correlated the expression pattern of XBP-1 with CD31 (endothelial cell marker) expression.We demonstrated that XBP-1 is essential for angiogenesis during early tumor growth. Inhibiting XBP-1 expression by short-hairpin RNA sequence specific for XBP-1 reduced blood vessel formation in tumors from mouse embryonic fibroblast cells and human fibrosarcoma tumor cells (HT1080). Expressing a dominant-negative form of IRE1alpha also reduced blood vessel formation in tumors. Moreover, expression of spliced XBP-1 (XBP-1s) restored angiogenesis in IRE1alpha dominant-negative expressing cells. We further demonstrated that XBP-1-mediated angiogenesis does not depend on VEGF.We propose that the IRE1alpha-XBP-1 branch of the UPR modulates a complex proangiogenic, VEGF-independent response that depends on signals received from the tumor microenvironment.

View details for PubMedID 19252749

XBP-1 regulates angiogenesis in human pancreatic adenocarcinomas TRANSLATIONAL ONCOLOGY Romero-Ramirez, L., Cao, H., Regalado, M. P., Kambham, N., Siemann, D., Kim, J. J., Le, Q. T., Koong, A. C. 2009; 2 (1): 31-U42

View details for DOI 10.1593/tlo.08211

View details for Web of Science ID 000272550900004

Hypoxia-Induced Lysyl Oxidase Is a Critical Mediator of Bone Marrow Cell Recruitment to Form the Premetastatic Niche CANCER CELL Erler, J. T., Bennewith, K. L., Cox, T. R., Lang, G., Bird, D., Koong, A., Le, Q., Giaccia, A. J. 2009; 15 (1): 35-44


Tumor cell metastasis is facilitated by "premetastatic niches" formed in destination organs by invading bone marrow-derived cells (BMDCs). Lysyl oxidase (LOX) is critical for premetastatic niche formation. LOX secreted by hypoxic breast tumor cells accumulates at premetastatic sites, crosslinks collagen IV in the basement membrane, and is essential for CD11b+ myeloid cell recruitment. CD11b+ cells adhere to crosslinked collagen IV and produce matrix metalloproteinase-2, which cleaves collagen, enhancing the invasion and recruitment of BMDCs and metastasizing tumor cells. LOX inhibition prevents CD11b+ cell recruitment and metastatic growth. CD11b+ cells and LOX also colocalize in biopsies of human metastases. Our findings demonstrate a critical role for LOX in premetastatic niche formation and support targeting LOX for the treatment and prevention of metastatic disease.

View details for DOI 10.1016/j.ccr.2008.11.012

View details for Web of Science ID 000262334800007

View details for PubMedID 19111879

Integrating Biologically Targeted Therapy in Head and Neck Squamous Cell Carcinomas SEMINARS IN RADIATION ONCOLOGY Le, Q., Rabent, D. 2009; 19 (1): 53-62


The integration of targeted therapies such as cetuximab to radiation therapy has revolutionized the management of head and neck cancers in the last decade. However, the use of targeted therapies raised several clinically relevant questions that have yet to be answered. These questions include the optimal patient and tumor profile for biologically targeted therapy, the optimal radiation fractionation to use with targeted therapies, how to integrate them into standard or new chemoradiation regimens, their schedule and duration of administration, their toxicity, and which direction to consider for novel targeted treatment. In this review, we highlight several of these important issues, discuss the clinical trials that are designed to address these issues, and introduce some novel targeted therapies that may contribute to the improvement of the therapeutic ratio for head and neck cancer therapy.

View details for DOI 10.1016/j.semradonc.2008.09.010

View details for Web of Science ID 000261524800009

View details for PubMedID 19028346

The Unique Microenvironments of Spontaneous Tumors Differentially Sensitize Them to Radiation 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Spiotto, M. T., Bahn, A., Cao, H., Le, Q., Koong, A. C. ELSEVIER SCIENCE INC. 2009: S171S171
Does Pre-treatment Metabolic Tumor Growth Rate (MTGR) Predict Progression in Lung Cancer? 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Eastham, D. V., Chapman, C. H., Rao, A. K., Narasimhan, B., Quon, A., Vasanawala, M. S., Wakelee, H., Le, Q., Colevas, A. D., Loo, B. W. ELSEVIER SCIENCE INC. 2009: S446S446
Lower osteopontin plasma levels are associated with superior outcomes in advanced non-small-cell lung cancer patients receiving platinum-based chemotherapy: SWOG study S0003 JOURNAL OF CLINICAL ONCOLOGY Mack, P. C., Redman, M. W., Chansky, K., Williamson, S. K., Farneth, N. C., Lara, P. N., Franklin, W. A., Le, Q., Crowley, J. J., Gandara, D. R. 2008; 26 (29): 4771-4776


S0003 was a phase III trial of carboplatin/paclitaxel with or without the hypoxic cytotoxin tirapazamine in patients with advanced or metastatic non-small-cell lung cancer (NSCLC). We investigated the relationship between clinical outcomes and plasma levels of the hypoxia-associated protein osteopontin (OPN) in patients on this protocol.Baseline plasma was obtained from 172 patients. In 56 patients, sequential plasma was obtained after one or two cycles. Concentrations of OPN, as well as plasminogen activator inhibitor-1 (PAI-1) and vascular endothelial growth factor (VEGF), were measured using enzyme-linked immunosorbent assay. Tumor expression of OPN was assessed by immunohistochemistry in 61 matched archival specimens.Patients with lower OPN levels (below the median) had a significantly superior overall survival compared with patients with higher levels, regardless of treatment arm (hazard ratio [HR] = 0.60, P = .002). A similar correlation was observed for progression-free survival (HR = 0.69, P = .02). When examined as a continuous variable, OPN maintained its significant association with both progression-free (HR = 1.05, P = .01) and overall survival (HR = 1.09, P < .0001). Patients with lower plasma OPN levels were significantly more likely to have tumor response (P = .03). No differences were observed between treatment arms. Tumor OPN levels did not correlate with patient outcomes or with plasma levels. No associations were observed between patient outcomes and VEGF or PAI-1 levels; however, plasma concentrations of these markers were significantly interrelated (P < .0001) and significantly decreased after treatment (P = .0002 and P = .03, respectively).Pretreatment plasma levels of OPN are significantly associated with patient response, progression-free survival, and overall survival in chemotherapy-treated patients with advanced NSCLC.

View details for DOI 10.1200/JCO.2008.17.0662

View details for Web of Science ID 000259902800014

View details for PubMedID 18779603

Clinical biomarkers for hypoxia targeting CANCER AND METASTASIS REVIEWS Le, Q., Courter, D. 2008; 27 (3): 351-362


Tumor hypoxia or a reduction of the tissue oxygen tension is a key microenvironmental factor for tumor progression and treatment resistance in solid tumors. Because hypoxic tumor cells have been demonstrated to be more resistant to ionizing radiation, hypoxia has been a focus of laboratory and clinical research in radiation therapy for many decades. It is believed that proper detection of hypoxic regions would guide treatment options and ultimately improve tumor response. To date, most clinical efforts in targeting tumor hypoxia have yielded equivocal results due to the lack of appropriate patient selection. However, with improved understanding of the molecular pathways regulated by hypoxia and the discovery of novel hypoxia markers, the prospect of targeting hypoxia has become more tangible. This chapter will focus on the development of clinical biomarkers for hypoxia targeting.

View details for DOI 10.1007/s10555-008-9144-9

View details for Web of Science ID 000258592700004

View details for PubMedID 18483785

In vivo H-1 magnetic resonance spectroscopy of lactate in patients with Stage IV head and neck squamous cell carcinoma 49th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Le, Q., Koong, A., Lieskovsky, Y. Y., Narasimhan, B., Graves, E., Pinto, H., Brown, J. M., Spielman, D. ELSEVIER SCIENCE INC. 2008: 115157


To investigate in vivo(1)H magnetic resonance spectroscopy imaging of lactate for assessing tumor hypoxia in head and neck cancers and to determine its utility in predicting the response and outcomes.Volume-localized lactate-edited (1)H magnetic resonance spectroscopy at 1.5 T was performed in vivo on involved neck nodes and control subcutaneous tissues in 36 patients with Stage IV head and neck cancer. The signal intensities (SIs) of lactate, choline, and creatine and the choline/creatine ratio were measured. The tumor partial pressure of oxygen (pO(2)) was obtained in the same lymph node before MRS. Patients were treated with either two cycles of induction chemotherapy (tirapazamine, cisplatin, 5-fluorouracil) followed by simultaneous chemoradiotherapy or the same regimen without tirapazamine. The lactate SI and the choline/creatine ratio correlated with the tumor pO(2), nodal response, and locoregional control.The lactate SI was greater for the involved nodes (median, 0.25) than for the subcutaneous tissue (median, 0.04; p = 0.07). No significant correlation was found between the lactate SI and tumor pO(2) (mean, 0.46 +/- 0.10 for hypoxic nodes [pO(2) < or =10 mm Hg, n = 15] vs. 0.36 +/- 0.07 for nonhypoxic nodes [pO(2) >10 mm Hg, n = 21], p = 0.44). A significant correlation was found between the choline/creatine ratios and tumor pO(2) (mean, 2.74 +/- 0.34 for hypoxic nodes vs. 1.78 +/- 0.31 for nonhypoxic nodes, p = 0.02). No correlation was found between the lactate SI and the complete nodal response (p = 0.52) or locoregional control rates.The lactate SI did not correlate with tumor pO(2), treatment response, or locoregional control. Additional research is needed to refine this technique.

View details for DOI 10.1016/j.ijrobp.2007.11.030

View details for Web of Science ID 000257299200025

View details for PubMedID 18258377

Excellent local control with stereotactic radiotherapy boost after external beam radiotherapy in patients with nasopharyngeal carcinoma 87th Annual Meeting of the American-Radium-Society Hara, W., Loo, B. W., Goffinet, D. R., Chang, S. D., Adler, J. R., Pinto, H. A., Fee, W. E., Kaplan, M. J., Fischbein, N. J., Le, Q. ELSEVIER SCIENCE INC. 2008: 393400


To determine long-term outcomes in patients receiving stereotactic radiotherapy (SRT) as a boost after external beam radiotherapy (EBRT) for locally advanced nasopharyngeal carcinoma (NPC).Eight-two patients received an SRT boost after EBRT between September 1992 and July 2006. Nine patients had T1, 30 had T2, 12 had T3, and 31 had T4 tumors. Sixteen patients had Stage II, 19 had Stage III, and 47 had Stage IV disease. Patients received 66 Gy of EBRT followed by a single-fraction SRT boost of 7-15 Gy, delivered 2-6 weeks after EBRT. Seventy patients also received cisplatin-based chemotherapy delivered concurrently with and adjuvant to radiotherapy.At a median follow-up of 40.7 months (range, 6.5-144.2 months) for living patients, there was only 1 local failure in a patient with a T4 tumor. At 5 years, the freedom from local relapse rate was 98%, freedom from nodal relapse 83%, freedom from distant metastasis 68%, freedom from any relapse 67%, and overall survival 69%. Late toxicity included radiation-related retinopathy in 3, carotid aneurysm in 1, and radiographic temporal lobe necrosis in 10 patients, of whom 2 patients were symptomatic with seizures. Of 10 patients with temporal lobe necrosis, 9 had T4 tumors.Stereotactic radiotherapy boost after EBRT provides excellent local control for patients with NPC. Improved target delineation and dose homogeneity of radiation delivery for both EBRT and SRT is important to avoid long-term complications. Better systemic therapies for distant control are needed.

View details for DOI 10.1016/j.ijrobp.2007.10.027

View details for Web of Science ID 000255971100013

View details for PubMedID 18164839

New developments in radiation therapy for head and neck cancer: Intensity-modulated radiation therapy and hypoxia targeting SEMINARS IN ONCOLOGY Lee, N. Y., Le, Q. 2008; 35 (3): 236-250


Intensity-modulated radiation therapy (IMRT) has revolutionized radiation treatment for head and neck cancers (HNCs). When compared to the traditional techniques, IMRT has the unique ability to minimize the dose delivered to normal tissues without compromising tumor coverage. As a result, side effects from high-dose radiation have decreased and patient quality of life has improved. In addition to toxicity reduction, excellent clinical outcomes have been reported for IMRT. The first part of this review will focus on clinical results of IMRT for HNC. Tumor hypoxia, or the condition of low oxygen, is a key factor for tumor progression and treatment resistance. Hypoxia develops in solid tumors due to aberrant blood vessel formation, fluctuation in blood flow, and increasing oxygen demands for tumor growth. Because hypoxic tumor cells are more resistant to ionizing radiation, hypoxia has been a focus of clinical research in radiation therapy for half a decade. Interest for targeting tumor hypoxia has waxed and waned as promising treatments emerged from the laboratory, only to fail in the clinics. However, with the development of new technologies, the prospect of targeting tumor hypoxia is more tangible. The second half of the review will focus on approaches for assessing tumor hypoxia and on the strategies for targeting this important microenvironmental factor in HNC.

View details for DOI 10.1053/j.seminoncol.2008.03.003

View details for Web of Science ID 000257150400007

View details for PubMedID 18544439

Molecular Imaging of Hypoxia-Inducible Factor 1 alpha and von Hippel-Lindau Interaction in Mice MOLECULAR IMAGING Choi, C. Y., Chau, D. A., Paulmurugan, R., Sutphin, P. D., Le, Q., Koong, A. C., Zundel, W., Gambhir, S. S., Giaccia, A. J. 2008; 7 (3): 139-146


Tumor hypoxia plays a crucial role in tumorigenesis. Under hypoxia, hypoxia-inducible factor 1 alpha (HIF-1 alpha) regulates activation of genes promoting malignant progression. Under normoxia, HIF-1 alpha is hydroxylated on prolines 402 and 564 and is targeted for ubiquitin-mediated degradation by interacting with the von Hippel-Lindau protein complex (pVHL). We have developed a novel method of studying the interaction between HIF-1 alpha and pVHL using the split firefly luciferase complementation-based bioluminescence system in which HIF-1 alpha and pVHL are fused to amino-terminal and carboxy-terminal fragments of the luciferase, respectively. We demonstrate that hydroxylation-dependent interaction between the HIF-1 alpha and pVHL leads to complementation of the two luciferase fragments, resulting in bioluminescence in vitro and in vivo. Complementation-based bioluminescence is diminished when mutant pVHLs with decreased affinity for binding HIF-1 alpha are used. This method represents a new approach for studying interaction of proteins involved in the regulation of protein degradation.

View details for DOI 10.2310/7290.2008.00017

View details for Web of Science ID 000260954700004

View details for PubMedID 19123984

LINAC-based on-board imaging feasibility and the dosimetric consequences of head roll in head-and-neck IMRT plans MEDICAL DOSIMETRY Kim, G., Pawlicki, T., Le, Q., Luxton, G. 2008; 33 (1): 93-99


Kilovoltage imaging systems on linear accelerators are used for patient localization in many clinics. The purpose of this work is to assess on-board imaging (OBI) detection of systematic setup errors and in particular, the dosimetric consequences of undetected head roll in head-and-neck intensity modulated radiation therapy (IMRT) plans when using these systems. The system used in this study was the Trilogy linear accelerator and associated software (Varian Medical Systems, Palo Alto, CA). Accuracy of OBI localization was evaluated using an anthropomorphic head phantom. The head phantom is rigidly attached to a specially designed positioning device with 5 degrees of freedom, 3 translational and 2 rotational in the axial and coronal planes. Simulated setup errors were 3 degrees and 5 degrees rotations in the axial plane and displacements of 5 mm in the left-right, anterior-posterior, and superior-inferior directions. The coordinates set by the positioning device were compared with the coordinates obtained as measured by using the image matching tools of paired 2-dimensional (2D) orthogonal image matching, and 3D cone-beam computed tomography (CT) volume matching. In addition, 6 physician-approved IMRT plans of nasopharynx and tonsil carcinoma were recalculated to evaluate the impact of undetected 3 degrees and 5 degrees head roll. Application of cone-beam CT (CBCT) for patient localization was superior to 2D matching techniques for detecting rotational setup errors. The use of CBCT allowed the determination of translational errors to within 0.5 mm, whereas kV planar was within 1 to 2 mm. Head roll in the axial plane was not easily detected with orthogonal image sets. Compared to the IMRT plans with no head roll, dose-volume histogram analysis demonstrated an average increase in the maximal spinal cord dose of 3.1% and 6.4% for 3 degrees and 5 degrees angles of rotation, respectively. Dose to the contralateral parotid was unchanged with 3 degrees roll and increased by 2.7% with 5 degrees roll. The results of this study show that volumetric setup verification using CBCT can improve bony anatomy setup detection to millimeter accuracy, and is a reliable method to detect head roll. However, the magnitude of possible dose errors due to undetected head roll suggests that CBCT does not need to be performed on a daily basis but rather weekly or bi-weekly to ensure fidelity of the head position with the immobilization system.

View details for DOI 10.1016/j.meddos.2007.05.004

View details for Web of Science ID 000253610200015

View details for PubMedID 18262130

Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose NEW ENGLAND JOURNAL OF MEDICINE Chung, C. H., Mirakhur, B., Chan, E., Le, Q., Berlin, J., Morse, M., Murphy, B. A., Satinover, S. M., Hosen, J., Mauro, D., Slebos, R. J., Zhou, Q., Gold, D., Hatley, T., Hicklin, D. J., Platts-Mills, T. A. 2008; 358 (11): 1109-1117


Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, is approved for use in colorectal cancer and squamous-cell carcinoma of the head and neck. A high prevalence of hypersensitivity reactions to cetuximab has been reported in some areas of the United States.We analyzed serum samples from four groups of subjects for IgE antibodies against cetuximab: pretreatment samples from 76 case subjects who had been treated with cetuximab at multiple centers, predominantly in Tennessee, Arkansas, and North Carolina; samples from 72 control subjects in Tennessee; samples from 49 control subjects with cancer in northern California; and samples from 341 female control subjects in Boston.Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction to the drug. IgE antibodies against cetuximab were found in pretreatment samples from 17 of these subjects; only 1 of 51 subjects who did not have a hypersensitivity reaction had such antibodies (P<0.001). IgE antibodies against cetuximab were found in 15 of 72 samples (20.8%) from control subjects in Tennessee, in 3 of 49 samples (6.1%) from northern California, and in 2 of 341 samples (0.6%) from Boston. The IgE antibodies were shown to be specific for an oligosaccharide, galactose-alpha-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain.In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose-alpha-1,3-galactose.

View details for Web of Science ID 000253877200004

View details for PubMedID 18337601

Retrospective IMRT dose reconstruction based on cone-beam CT and MLC log-file INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Lee, L., Le, Q., Xing, L. 2008; 70 (2): 634-644


Head-and-neck (HN) cone-beam computed tomography (CBCT) can be exploited to probe the IMRT dose delivered to a patient taking into account the interfraction anatomic variation and any potential inaccuracy in the IMRT delivery. The aim of this work is to reconstruct the intensity-modulated radiation therapy dose delivered to an HN patient using the CBCT and multileaf collimator (MLC) log-files.A cylindrical CT phantom was used for calibrating the electron density and validating the procedures of the dose reconstruction. Five HN patients were chosen, and for each patient, CBCTs were performed on three separate fractions spaced every 2 weeks starting from the first fraction. The respective MLC log-files were retrieved and converted into fluence maps. The dose was then reconstructed on the corresponding CBCT with the regenerated fluence maps. The reconstructed dose distribution, dosimetric endpoints, and DVHs were compared with that of the treatment plan.Phantom study showed that HN CBCT can be directly used for dose reconstruction. For most treatment sessions, the CBCT-based dose reconstructions yielded DVHs of the targets close (within 3%) to that of the original treatment plans. However, dosimetric changes (within 10%) due to anatomic variations caused by setup inaccuracy, organ deformation, tumour shrinkage, or weight loss (or a combination of these) were observed for the critical organs.The methodology we established affords an objective dosimetric basis for the clinical decision on whether a replanning is necessary during the course of treatment and provides a valuable platform for adaptive therapy in future.

View details for DOI 10.1016/j.ijrobp.2007.09.054

View details for Web of Science ID 000252521700042

View details for PubMedID 18207036

Metabolic tumor volume predicts for recurrence and death in head and neck cancer 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) La, T. H., Filion, E. J., Turnbull, B. B., CHU, J. N., Lee, P., Nguyen, K., Maxim, P., Loo, B. W., Graves, E. E., Le, Q. ELSEVIER SCIENCE INC. 2008: S159S160
Radiographic assessment of the sinuses in patients treated for nasopharyngeal carcinoma AMERICAN JOURNAL OF RHINOLOGY Raviv, J., Downing, L., Le, Q., Hwang, P. 2008; 22 (1): 64-67


Patients undergoing therapy for nasopharyngeal carcinoma (NPC) often experience dysfunction of the sinonasal mucosa as a side effect of radiotherapy and chemotherapy. Sinonasal mucosal changes may vary throughout the treatment and posttreatment periods, but little objective data exist characterizing such changes. We evaluated serial radiologic changes of the paranasal sinus mucosa in patients with NPC undergoing treatment.Medical and radiographic records were reviewed for all patients treated for NPC between 2004 and 2006 at Stanford University Medical Center. Pretreatment computed tomography (CT) images served as the baseline images for comparison, and posttreatment CT and magnetic resonance imaging (MRI) images were categorized temporally into 3-month intervals, up to 25 months after initiation of treatment. Images were scored in a blinded fashion using the Lund-Mackay (LM) staging system.Thirty-five patients received treatment for NPC during the study period, of whom 27 had adequate data for analysis and inclusion in the study. The mean pretreatment LM score was 1.41, and a statistically significant increase in LM score was observed at 3, 6, 9, 12, 15, and 18, 22, and 28 months. There was continued progression of radiologic sinus opacification over the first 30 months after treatment.The treatment of NPC with radiotherapy and chemotherapy is associated with radiologic evidence of sinus mucosal thickening. The extent of mucosal thickening can be expected to progress after treatment for up to 30 months. Patients undergoing treatment for NPC should be monitored carefully throughout the posttreatment period for clinical manifestations of dysfunctional sinonasal mucosa.

View details for DOI 10.2500/ajr.2007.21.3091

View details for Web of Science ID 000253232100012

View details for PubMedID 17958946

Relationship between human papillomavirus (HPV) status, epidermal growth factor receptor (EGFR) and Phospho-EGFR (pEGFR) expression in head and neck squamous cell carcinoma (HNSCC) 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Filion, E. J., Kong, C. S., Narasimhan, B., Cao, H., Erickson, J. P., Andersson, A., Koong, A., Pourmand, N., Fredriksson, S., Le, Q. ELSEVIER SCIENCE INC. 2008: S23S23
Tumor size is a critical determinant of local control in single fraction stereotactic radiotherapy of pulmonary tumors 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Loo, B. W., Shen, J., Quinlan-Davidson, S., Filion, E., Dieterich, S., Maxim, P. G., Wakelee, H. A., Whyte, R. I., Le, Q. ELSEVIER SCIENCE INC. 2008: S467S468
Quantification of motion of different thoracic locations using four-dimensional computed tomography: Implications for radiotherapy planning 48th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Maxim, P. G., Loo, B. W., Shirazi, H., Thorndyke, B., Luxton, G., Le, Q. ELSEVIER SCIENCE INC. 2007: 13951401


To assess the respiratory motion of different thoracic nodal locations and its dependence on the presence of enlarged nodes; to assess the respiratory motion of different parenchymal tumor locations; and to determine the appropriate margins to cover the respiratory motion of targets at these locations.We reviewed the four-dimensional computed tomography scans of 20 patients with thoracic tumors treated at our institution. The motion of four central thoracic locations (aortic arch, carina, and bilateral hila), parenchymal tumor locations (upper vs. lower, and anterior vs. middle vs. posterior thorax), and bilateral diaphragmatic domes was measured.For the central thoracic locations, the largest motion was in the superoinferior (SI) dimension (>5 mm for bilateral hila and carina, but <4 mm for aortic arch). No significant difference was found in the motion of these locations in the absence or presence of enlarged nodes. For parenchymal tumors, upper tumors exhibited smaller SI motion than did lower tumors (3.7 vs. 10.4 mm, p = 0.029). Similarly, anterior tumors exhibited smaller motion than did posterior tumors in both the SI (4.0 vs. 8.0 mm, p = 0.013) and lateral (2.8 vs. 4.6 mm, p = 0.045) directions. The margins that would be needed to encompass the respiratory motion of each of the evaluated locations in 95% of patients were tabulated and range from 3.4 to 37.2 mm, depending on the location and direction.The results of our study have provided data for appropriate site-specific internal target volume expansion that could be useful in the absence of four-dimensional computed tomography-based treatment planning. However, generalizing the results from a small patient population requires discretion.

View details for Web of Science ID 000251561100008

View details for PubMedID 17869025

Metabolic tumor burden predicts for disease progression and death in lung cancer 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Lee, P., Weerasuriya, D. K., Lavori, P. W., Quon, A., Hara, W., Maxim, P. G., Le, Q., Wakelee, H. A., Donington, J. S., Graves, E. E., Loo, B. W. ELSEVIER SCIENCE INC. 2007: 32833


In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging.We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV).The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS.In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively.

View details for DOI 10.1016/j.ijrobp.2007.04.036

View details for Web of Science ID 000249796100002

View details for PubMedID 17869659

Expression and prognostic significance of a panel of tissue hypoxia markers in head-and-neck squamous cell carcinomas 48th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Le, Q., Kong, C., Lavori, P. W., O'Byrne, K., Erler, J. T., Huang, X., Chen, Y., Cao, H., Tibshiran, R., Denko, N., Giaccia, A. J., Koong, A. C. ELSEVIER SCIENCE INC. 2007: 16775


To investigate the expression pattern of hypoxia-induced proteins identified as being involved in malignant progression of head-and-neck squamous cell carcinoma (HNSCC) and to determine their relationship to tumor pO(2) and prognosis.We performed immunohistochemical staining of hypoxia-induced proteins (carbonic anhydrase IX [CA IX], BNIP3L, connective tissue growth factor, osteopontin, ephrin A1, hypoxia inducible gene-2, dihydrofolate reductase, galectin-1, IkappaB kinase beta, and lysyl oxidase) on tumor tissue arrays of 101 HNSCC patients with pretreatment pO(2) measurements. Analysis of variance and Fisher's exact tests were used to evaluate the relationship between marker expression, tumor pO(2), and CA IX staining. Cox proportional hazard model and log-rank tests were used to determine the relationship between markers and prognosis.Osteopontin expression correlated with tumor pO(2) (Eppendorf measurements) (p = 0.04). However, there was a strong correlation between lysyl oxidase, ephrin A1, and galectin-1 and CA IX staining. These markers also predicted for cancer-specific survival and overall survival on univariate analysis. A hypoxia score of 0-5 was assigned to each patient, on the basis of the presence of strong staining for these markers, whereby a higher score signifies increased marker expression. On multivariate analysis, increasing hypoxia score was an independent prognostic factor for cancer-specific survival (p = 0.015) and was borderline significant for overall survival (p = 0.057) when adjusted for other independent predictors of outcomes (hemoglobin and age).We identified a panel of hypoxia-related tissue markers that correlates with treatment outcomes in HNSCC. Validation of these markers will be needed to determine their utility in identifying patients for hypoxia-targeted therapy.

View details for DOI 10.1016/j.ijrobp.2007.01.071

View details for Web of Science ID 000248978300024

View details for PubMedID 17707270

Retrospective IMRT dose reconstruction based on cone-beam computed tomography (CBCT) and the MLC positional log-file recorded during treatment 49th Annual Meeting of the American-Association-of-Physicists-in-Medicine Lee, K., Le, Q., Xing, L. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2007: 26002600
Longitudinal evaluation of the oral mucositis weekly questionnaire-head and neck cancer, a patient-reported outcomes questionnaire CANCER Epstein, J. B., Beaumont, J. L., Gwede, C. K., Murphy, B., Garden, A. S., Meredith, R., Le, Q., Brizel, D., Isitt, J., Cella, D. 2007; 109 (9): 1914-1922


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.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.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.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.

View details for DOI 10.1002/cncr.22620

View details for Web of Science ID 000245937000030

View details for PubMedID 17377917

Evaluation of patterns of failure and subjective salivary function in patients treated with intensity modulated radiotherapy for head and neck squamous cell carcinoma 45th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Daly, M. E., Lieskovsky, Y., Pawlicki, T., Yau, J., Pinto, H., Kaplan, M., Fee, W. E., Koong, A., Goffinet, D. R., Xing, L., Le, Q. JOHN WILEY & SONS INC. 2007: 21120


Our aim was to correlate patterns of failure with target volume delineations in patients with head and neck squamous cell carcinoma (HNSCC) treated with intensity-modulated radiation therapy (IMRT) and to report subjective xerostomia outcomes after IMRT as compared with conventional radiation therapy (CRT).Between January 2000 and April 2005, 69 patients with newly diagnosed nonmetastatic HNSCC underwent curative parotid-sparing IMRT at Stanford University. Sites included were oropharynx (n = 39), oral cavity (n = 8), larynx (n = 8), hypopharynx (n = 8), and unknown primary (n = 6). Forty-six patients received definitive IMRT (66 Gy, 2.2 Gy/fraction), and 23 patients received postoperative IMRT (60.2 Gy, 2.15 Gy/fraction). Fifty-one patients also received concomitant chemotherapy. Posttreatment salivary gland function was evaluated by a validated xerostomia questionnaire in 29 IMRT and 75 matched CRT patients >6 months after completing radiation treatment.At a median follow-up of 25 months for living patients (range, 10-60), 7 locoregional failures were observed, 5 in the gross target or high-risk postoperative volume, 1 in the clinical target volume, and 1 at the junction of the IMRT and supraclavicular fields. The 2-year Kaplan-Meier estimates for locoregional control and overall survival were 92% and 74% for definitive IMRT and 87% and 87% for postoperative IMRT patients, respectively. The mean total xerostomia questionnaire score was significantly better for IMRT than for CRT patients (p = .006).The predominant pattern of failure in IMRT-treated patients is in the gross tumor volume. Parotid sparing with IMRT resulted in less subjective xerostomia and may improve quality of life in irradiated HNSCC patients.

View details for DOI 10.1002/hed.20505

View details for Web of Science ID 000244459100002

View details for PubMedID 17111429

A differentiation based immunohistochemical classifier that is prognostic for head and neck tumor patients 96th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Ross, D. T., Ring, B. Z., Seitz, R. S., Beck, R. A., DeFoe, S., Robert, F., Schreeder, M. T., Chung, C. H., Kong, C. S., Le, Q. T. NATURE PUBLISHING GROUP. 2007: 228A228A
Identifying and targeting hypoxia in head and neck cancer: A brief overview of current approaches 1st Multidisciplinary Head and Neck Cancer Symposium Le, Q. ELSEVIER SCIENCE INC. 2007: S56S58

View details for DOI 10.1016/j.ijrobp.2007.04.081

View details for Web of Science ID 000249999000018

View details for PubMedID 17848296

Nasopharyngeal and oropharyngeal carcinomas: Target delineation, therapy delivery and stereotactic boost procedures with intensity-modulated/image-guided radiation therapy 38th San Francisco Radiation Oncology Conference Le, Q. KARGER. 2007: 208231


Radiation therapy is a key component of the multidisciplinary treatment of nasopharyngeal and oropharyngeal carcinomas, which are ideal tumors for intensity-modulated radiation therapy (IMRT) because of their location and intimate relationship to the surrounding critical structures. Several studies have suggested that IMRT is superior to conventional radiation therapy in salivary preservation and holds promise for improved locoregional control of these tumors. Target delineation for IMRT in these tumors is complex and requires detailed knowledge of head and neck anatomy and pathways of tumor spread. This article focuses on target delineation for IMRT for oropharyngeal and nasopharyngeal carcinomas. In addition, we also present data on the use of stereotactic radiotherapy as a boost to improve local control of nasopharyngeal carcinomas.

View details for Web of Science ID 000248596600013

View details for PubMedID 17641511

Clinical role of F-18-FDG PET/CT in the management of squamous cell carcinoma of the head and neck and thyroid carcinoma JOURNAL OF NUCLEAR MEDICINE Quon, A., Fischbein, N. J., McDougall, I. R., Le, Q., Loo, B. W., Pinto, H., Kaplan, M. J. 2007; 48: 58S-67S


18F-FDG PET/CT has rapidly become a widely used imaging modality for evaluating a variety of malignancies, including squamous cell carcinoma of the head and neck and thyroid cancer. Using both published data and the multidisciplinary experience at our institution, we provide a practical set of guidelines and algorithms for the use of 18F-FDG PET/CT in the evaluation and management of head and neck cancer and thyroid cancer.

View details for Web of Science ID 000243420900008

View details for PubMedID 17204721

Plasma osteopontin is an independent prognostic marker for head and neck cancers 41st Annual Meeting of the American-Society-of-Clinical-Oncology Petrik, D., Lavori, P. W., Cao, H., Zhu, Y., Wong, P., Christofferson, E., Kaplan, M. J., Pinto, H. A., Sutphin, P., Koong, A. C., Giaccia, A. J., Le, Q. AMER SOC CLINICAL ONCOLOGY. 2006: 529197


To confirm the relationship between plasma osteopontin (OPN) levels and treatment outcomes in head and neck squamous cell carcinoma (HNSCC) patients in an expanded study.One hundred forty patients with newly diagnosed HNSCC were enrolled onto this study, 54 previously reported and 86 new patients. Pretreatment plasma OPN levels were assessed in all patients by an enzyme-linked immunosorbent assay method. OPN levels were correlated to treatment outcomes in the new group of patients. Detailed analyses were also performed on the relationship between OPN and tumor control rate, event-free survival (EFS), and postrelapse survival for the entire group.Using a previously defined cut off point of 450 ng/mL, there was a significant correlation between OPN and freedom-from-relapse (P = .047), overall survival (P = .019), and EFS (P = .023) in the new, independent patient cohort (n = 86). Sequence of event analyses using the entire group (N = 140) revealed that OPN was an independent prognostic factor for initial tumor control, EFS in those who have achieved tumor control, and postrelapse survival.In this expanded study, we were able to replicate the prognostic significance of OPN using a predefined cut off point in an independent patient group and demonstrated that plasma OPN is an independent prognostic marker for HNSCC.

View details for DOI 10.1200/JCO.2006.06.8627

View details for Web of Science ID 000242342800017

View details for PubMedID 17114663

Results of a phase I dose-escalation study using single-fraction stereotactic radiotherapy for lung tumors 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q., Loo, B. W., Ho, A., Cotrutz, C., Koong, A. C., Wakelee, H., Kee, S. T., Constantinescu, D., Whyte, R. I., Donington, J. LIPPINCOTT WILLIAMS & WILKINS. 2006: 8029


The purpose of this study was to report initial results of a phase I study using single-fraction stereotactic radiotherapy (RT) in patients with inoperable lung tumors.Eligible patients included those with inoperable T1-2N0 non-small cell lung cancer (NSCLC) or solitary lung metastases. Treatments were delivered by means of the CyberKnife. All patients underwent computed tomography-guided metallic fiducial placement in the tumor for image-guided targeting. Nine to 20 patients were treated per dose cohort starting at 15 Gy/fraction followed by dose escalation of 5 to 10 Gy to a maximal dose of 30 Gy/fraction. A minimal 3-month period was required between each dose level to monitor toxicity.Thirty-two patients (21 NSCLC and 11 metastatic tumors) were enrolled. At 25 Gy, pulmonary toxicity was noted in patients with prior pulmonary RT and treatment volumes greater than 50 cc; therefore, dose escalation to 30 Gy was applied only to unirradiated patients and treatment volume less than 50 cc. Ten patients received doses less than 20 Gy, 20 received 25 Gy, and two received 30 Gy. RT-related complications were noted for doses greater than 25 Gy and included four cases of grade 2 to 3 pneumonitis, one pleural effusion, and three possible treatment-related deaths. The 1-year freedom from local progression was 91% for dose greater than 20 Gy and 54% for dose less than 20 Gy in NSCLC (p = 0.03). NSCLC patients had significantly better freedom from relapse (p = 0.003) and borderline higher survival than those with metastatic tumors (p = 0.07).Single-fraction stereotactic RT is feasible for selected patients with lung tumors. For those with prior thoracic RT, 25 Gy may be too toxic. Higher dose was associated with improved local control. Longer follow-up is necessary to determine the treatment efficacy and toxicity.

View details for Web of Science ID 000241649300008

View details for PubMedID 17409963

Indirect MR lymphangiography of the head and neck using conventional gadolinium contrast: A pilot study in humans 45th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Loo, B. W., Draney, M. T., Sivanandan, R., Ruehm, S. G., Pawlicki, T., Xing, L., Herfkens, R. J., Le, Q. ELSEVIER SCIENCE INC. 2006: 46268


To evaluate indirect magnetic resonance lymphangiography (MR-LAG) using interstitial injection of conventional gadolinium contrast (gadoteridol and gadopentetate dimeglumine) for delineating the primary lymphatic drainage of head-and-neck sites.We performed head-and-neck MR-LAG in 5 healthy volunteers, with injection of dermal and mucosal sites. We evaluated the safety of the procedure, the patterns of enhancement categorized by injection site and nodal level, the time course of enhancement, the optimal concentration and volume of contrast, and the optimal imaging sequence.The worst side effects of interstitial contrast injection were brief, mild pain and swelling at the injected sites that were self-limited. MR-LAG resulted in consistent visualization of the primary lymphatic drainage pattern specific to each injected site, which was reproducible on repeated examinations. The best enhancement was obtained with injection of small volumes (0.3-0.5 mL) of either agent diluted, imaging within 5-15 min of injection, and a three-dimensional fast spoiled gradient echo sequence with magnetization transfer.We found head-and-neck MR-LAG to be a safe, convenient imaging method that provides functional information about the lymphatic drainage of injected sites. Applied to head-and-neck cancer, it has the potential to identify sites at highest risk of occult metastatic spread for radiotherapy or surgical planning, and possibly to visualize micrometastases.

View details for DOI 10.1016/j.ijrobp.2006.05.045

View details for Web of Science ID 000240699500024

View details for PubMedID 16965993

A multidisciplinary approach to management in a patient with bilateral superior sulcus non-small-cell lung carcinoma CLINICAL LUNG CANCER Roy, M. S., Le, Q., Donington, J. S., Wakelee, H. A. 2006; 8 (2): 146-148


Superior sulcus tumors comprise a rare subset of non-small-cell lung carcinomas that are particularly challenging to treat because of their location and extent of nerve and vessel involvement. In this report, we present a case illustrating the uncommon situation of a patient presenting with bilateral superior sulcus tumors, and we review the latest combined therapeutic approach developed to aggressively treat the more common unilateral presentation of these tumors.

View details for Web of Science ID 000242173600010

View details for PubMedID 17026817

Advanced-staged tonsillar squamous carcinoma: Organ preservation versus surgical management of the primary site 90th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America Shirazi, H. A., Sivanandan, R., Goode, R., Fee, W. E., Kaplan, M. J., Pinto, H. A., Goffinet, D. R., Le, Q. JOHN WILEY & SONS INC. 2006: 58794


Our aim was to review our experience in the management of advanced tonsillar squamous cell carcinoma (SCC) and to compare treatment outcomes between patients treated with and without surgery to the primary site.The records of 74 patients with advanced-stage tonsillar SCC were reviewed. The median age at diagnosis was 58 years. Thirty-eight patients received definitive surgery to the primary site, and 36 were treated with an organ-preservation approach (OP) using radiotherapy +/- chemotherapy.No significant difference in overall survival (OS) or freedom from relapse (FFR) by treatment was found. T classification and N status were significant independent predictors on multivariate analysis for OS and FFR. Major late toxicity was noted in 10 patients in the surgical group and nine in the OP group.Patients treated with OP and primary surgery had comparable OS and FFR. T classification and N status were significant independent predictors for tumor relapse and survival. On the basis of these results, we favor organ-preservation therapy for patients with advanced-stage tonsillar SCC.

View details for DOI 10.1002/hed.20372

View details for Web of Science ID 000238690100003

View details for PubMedID 16475199

Lung cancer in women: Exploring sex differences in susceptibility, biology, and therapeutic response CLINICAL LUNG CANCER Donington, J. S., Le, Q., Wakelee, H. A. 2006; 8 (1): 22-29


Src tyrosine kinases regulate a large number of important mechanisms in normal and cancerous cells, are overexpressed in a broad range of tumors including lung cancer, and thus represent a potential target for cancer therapy. Preclinical experiments indicate that small-molecule inhibitors of Src block tumor growth, metastasis, and angiogenesis. Phase I data from healthy volunteers also suggest that inhibitors of Src prevent bone resorption. Several phase II trials with small-molecule inhibitors of Src are under way or have been initiated in lung cancer and in other malignancies, as discussed herein.

View details for Web of Science ID 000242173500003

View details for PubMedID 16870042

Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis CANCER RESEARCH Dornhoefer, N., Spong, S., Bennewith, K., Salim, A., Klaus, S., Kambham, N., Wong, C., Kaper, F., Sutphin, P., Nacalumi, R., Hoeckel, M., Le, Q., Longaker, M., Yang, G., Koong, A., Giaccia, A. 2006; 66 (11): 5816-5827


Pancreatic cancer is highly aggressive and refractory to most existing therapies. Past studies have shown that connective tissue growth factor (CTGF) expression is elevated in human pancreatic adenocarcinomas and some pancreatic cancer cell lines. To address whether and how CTGF influences tumor growth, we generated pancreatic tumor cell lines that overexpress different levels of human CTGF. The effect of CTGF overexpression on cell proliferation was measured in vitro in monolayer culture, suspension culture, or soft agar, and in vivo in tumor xenografts. Although there was no effect of CTGF expression on proliferation in two-dimensional cultures, anchorage-independent growth (AIG) was enhanced. The capacity of CTGF to enhance AIG in vitro was linked to enhanced pancreatic tumor growth in vivo when these cells were implanted s.c. in nude mice. Administration of a neutralizing CTGF-specific monoclonal antibody, FG-3019, had no effect on monolayer cell proliferation, but blocked AIG in soft agar. Consistent with this observation, anti-CTGF treatment of mice bearing established CTGF-expressing tumors abrogated CTGF-dependent tumor growth and inhibited lymph node metastases without any toxicity observed in normal tissue. Together, these studies implicate CTGF as a new target in pancreatic cancer and suggest that inhibition of CTGF with a human monoclonal antibody may control primary and metastatic tumor growth.

View details for DOI 10.1158/0008-5472.CAN-06-0081

View details for Web of Science ID 000238003100038

View details for PubMedID 16740721

Mature results from a randomized phase II trial of cisplatin plus 5-fluorouracil and radiotherapy with or without tirapazamine in patients with resectable stage IV head and neck squamous cell carcinomas CANCER Le, Q. T., Taira, A. I., Budenz, S., Dorie, M. J., Goffinet, D. R., Fee, W. E., Goode, R., Bloch, D., Koong, A., Brown, J. M., Pinto, H. A. 2006; 106 (9): 1940-1949


The objective of this article was to report the results from a randomized trial that evaluated the efficacy and toxicity of adding tirapazamine (TPZ) to chemoradiotherapy in the treatment of patients with head and neck squamous cell carcinomas (HNSCC).Sixty-two patients with lymph node-positive, resectable, TNM Stage IV HNSCC were randomized to receive either 2 cycles of induction chemotherapy (TPZ, cisplatin, and 5-fluorouracil [5-FU]) followed by simultaneous chemoradiotherapy (TPZ, cisplatin, and 5-FU) or to receive the same regimen without TPZ. Patients who did not achieve a complete response at 50 Grays underwent surgical treatment. Stratification factors for randomization included tumor site, TNM stage, and median tumor oxygen tension. The primary endpoint was complete lymph node response.The addition of TPZ resulted in increased hematologic toxicity. There was 1 treatment-related death from induction chemotherapy. The complete clinical and pathologic response rate in the lymph nodes was 90% and 74% for the standard treatment arm and the TPZ arm, respectively (P = .08) and 89% and 90% at the primary site in the respective treatment arms (P = .71). The 5-year overall survival rate was 59%, the cause-specific survival rate was 68%, the rate of freedom from recurrence was 69%, and the locoregional control rate was 77% for the entire group. There was no difference with regard to any of the outcome parameters between the 2 treatment arms. The significant long-term toxicity rate also was found to be similar between the 2 arms.The addition of TPZ increased hematologic toxicity but did not improve outcomes in patients with resectable, Stage IV HNSCC using the protocol administered this small randomized study. The combination of induction and simultaneous chemoradiotherapy resulted in excellent survival in these patients.

View details for DOI 10.1002/cncr.21785

View details for Web of Science ID 000237187400010

View details for PubMedID 16532436

Lysyl oxidase is essential for hypoxia-induced metastasis NATURE Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhofer, N., Kong, C., Le, Q. T., Chi, J. T., Jeffrey, S. S., Giaccia, A. J. 2006; 440 (7088): 1222-1226


Metastasis is a multistep process responsible for most cancer deaths, and it can be influenced by both the immediate microenvironment (cell-cell or cell-matrix interactions) and the extended tumour microenvironment (for example vascularization). Hypoxia (low oxygen) is clinically associated with metastasis and poor patient outcome, although the underlying processes remain unclear. Microarray studies have shown the expression of lysyl oxidase (LOX) to be elevated in hypoxic human tumour cells. Paradoxically, LOX expression is associated with both tumour suppression and tumour progression, and its role in tumorigenesis seems dependent on cellular location, cell type and transformation status. Here we show that LOX expression is regulated by hypoxia-inducible factor (HIF) and is associated with hypoxia in human breast and head and neck tumours. Patients with high LOX-expressing tumours have poor distant metastasis-free and overall survivals. Inhibition of LOX eliminates metastasis in mice with orthotopically grown breast cancer tumours. Mechanistically, secreted LOX is responsible for the invasive properties of hypoxic human cancer cells through focal adhesion kinase activity and cell to matrix adhesion. Furthermore, LOX may be required to create a niche permissive for metastatic growth. Our findings indicate that LOX is essential for hypoxia-induced metastasis and is a good therapeutic target for preventing and treating metastases.

View details for DOI 10.1038/nature04695

View details for Web of Science ID 000237080000052

View details for PubMedID 16642001

An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers CLINICAL CANCER RESEARCH Le, Q. T., Chen, E., Salim, A., Cao, H. B., Kong, C. S., Whyte, R., Donington, J., Cannon, W., Wakelee, H., Tibshirani, R., Mitchell, J. D., Richardson, D., O'Byrne, K. J., Koong, A. C., Giaccia, A. J. 2006; 12 (5): 1507-1514


To directly assess tumor oxygenation in resectable non-small cell lung cancers (NSCLC) and to correlate tumor pO2 and the selected gene and protein expression to treatment outcomes.Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes.The median tumor pO2 ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO2 as a reflection of tumor oxygenation. The median T/L pO2 was 0.13. T/L pO2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO2 (P = 0.04), and osteopontin levels (P = 0.001).Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors.

View details for DOI 10.1158/1078-0432.CCR-05-2049

View details for Web of Science ID 000235988000016

View details for PubMedID 16533775

Comment on: Osteopontin as toxic marker RADIOTHERAPY AND ONCOLOGY Le, Q. T., Cao, H. B., Giaccia, A. 2006; 78 (2): 230-230

View details for DOI 10.1016/j.radonc.2005.12.011

View details for Web of Science ID 000236490300018

View details for PubMedID 16442647

Galectin-1: A link between tumor hypoxia and tumor immune privilege 46th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q. T., Shi, G. Y., Cao, H. B., Nelson, D. W., Wang, Y. Y., CHEN, E. Y., Zhao, S. C., Kong, C., Richardson, D., O'Byrne, K. J., Giaccia, A. J., Koong, A. C. AMER SOC CLINICAL ONCOLOGY. 2005: 893241


To identify a 15-KDa novel hypoxia-induced secreted protein in head and neck squamous cell carcinomas (HNSCC) and to determine its role in malignant progression.We used surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and tandem MS to identify a novel hypoxia-induced secreted protein in FaDu cells. We used immunoblots, real-time polymerase chain reaction (PCR), and enzyme-linked immunoabsorbent assay to confirm the hypoxic induction of this secreted protein as galectin-1 in cell lines and xenografts. We stained tumor tissues from 101 HNSCC patients for galectin-1, CA IX (carbonic anhydrase IX, a hypoxia marker) and CD3 (a T-cell marker). Expression of these markers was correlated to each other and to treatment outcomes.SELDI-TOF studies yielded a hypoxia-induced peak at 15 kDa that proved to be galectin-1 by MS analysis. Immunoblots and PCR studies confirmed increased galectin-1 expression by hypoxia in several cancer cell lines. Plasma levels of galectin-1 were higher in tumor-bearing severe combined immunodeficiency (SCID) mice breathing 10% O2 compared with mice breathing room air. In HNSCC patients, there was a significant correlation between galectin-1 and CA IX staining (P = .01) and a strong inverse correlation between galectin-1 and CD3 staining (P = .01). Expression of galectin-1 and CD3 were significant predictors for overall survival on multivariate analysis.Galectin-1 is a novel hypoxia-regulated protein and a prognostic marker in HNSCC. This study presents a new mechanism on how hypoxia can affect the malignant progression and therapeutic response of solid tumors by regulating the secretion of proteins that modulate immune privilege.

View details for DOI 10.1200/JCO.2005.02.0206

View details for Web of Science ID 000234026500004

View details for PubMedID 16219933

Identification of mitogen-activated protein kinase signaling pathways that confer resistance to endoplasmic reticulum stress in Saccharomyces cerevisiae MOLECULAR CANCER RESEARCH Chen, Y. J., Feldman, D. E., Deng, C. C., BROWN, J. A., De Giacomo, A. F., Gaw, A. F., Shi, G. Y., Le, Q. T., Brown, J. M., Koong, A. C. 2005; 3 (12): 669-677


Hypoxia activates all components of the unfolded protein response (UPR), a stress response initiated by the accumulation of unfolded proteins within the endoplasmic reticulum (ER). Our group and others have shown previously that the UPR, a hypoxia-inducible factor-independent signaling pathway, mediates cell survival during hypoxia and is required for tumor growth. Identifying new genes and pathways that are important for survival during ER stress may lead to the discovery of new targets in cancer therapy. Using the set of 4,728 homozygous diploid deletion mutants in budding yeast, Saccharomyces cerevisiae, we did a functional screen for genes that conferred resistance to ER stress-inducing agents. Deletion mutants in 56 genes showed increased sensitivity under ER stress conditions. Besides the classic UPR pathway and genes related to calcium homeostasis, we report that two additional pathways, including the SLT2 mitogen-activated protein kinase (MAPK) pathway and the osmosensing MAPK pathway, were also required for survival during ER stress. We further show that the SLT2 MAPK pathway was activated during ER stress, was responsible for increased resistance to ER stress, and functioned independently of the classic IRE1/HAC1 pathway. We propose that the SLT2 MAPK pathway is an important cell survival signaling pathway during ER stress. This study shows the feasibility of using the yeast deletion pool to identify relevant mammalian orthologues of the UPR.

View details for DOI 10.1158/1541-7786.MCR-05-0181

View details for Web of Science ID 000234499800003

View details for PubMedID 16380504

Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Koong, A. C., Christofferson, E., Le, Q. T., Goodman, K. A., Ho, A., Kuo, T., Ford, J. M., Fisher, G. A., Greco, R., Norton, J., Yang, G. P. 2005; 63 (2): 320-323


To determine the efficacy of concurrent 5-fluorouracil (5-FU) and intensity-modulated radiotherapy (IMRT) followed by body stereotactic radiosurgery (SRS) in patients with locally advanced pancreatic cancer.In this prospective study, all patients (19) had pathologically confirmed adenocarcinoma and were uniformly staged. Our treatment protocol consisted of 45 Gy IMRT with concurrent 5-FU followed by a 25 Gy SRS boost to the primary tumor.Sixteen patients completed the planned therapy. Two patients experienced Grade 3 toxicity (none had more than Grade 3 toxicity). Fifteen of these 16 patients were free from local progression until death. Median overall survival was 33 weeks.Concurrent IMRT and 5-FU followed by SRS in patients with locally advanced pancreatic cancer results in excellent local control, but does not improve overall survival and is associated with more toxicity than SRS, alone.

View details for DOI 10.1016/j.ijrobp.2005.07.002

View details for Web of Science ID 000232083700002

View details for PubMedID 16168826

Hypoxia upregulates osteopontin expression in NIH-3T3 cells via a ras-activated enhancer ONCOGENE Zhu, Y. H., Denhardt, D. T., Cao, H. B., Sutphin, P. D., Koong, A. C., Giaccia, A. J., Le, Q. T. 2005; 24 (43): 6555-6563


Osteopontin (OPN) is a secreted phosphoglycoprotein that has been linked to tumor progression and survival in several solid tumors, including head and neck cancers. Previous studies showed that OPN expression is induced by tumor hypoxia, and its plasma levels can serve as a surrogate marker for tumor hypoxia and treatment outcome in head and neck cancer patients. In this study, we investigate the transcriptional mechanism by which hypoxia enhances OPN expression. We found that OPN is induced in head and neck squamous cell carcinoma (HNSCC) cell lines and in NIH3T3 cells by hypoxia at both mRNA and protein levels in a time-dependent manner. Actinomycin D chase experiments showed that hypoxic induction of OPN was not due to increased mRNA stability. Deletion analyses of the mouse OPN promoter regions indicated that a ras-activated enhancer (RAE) located at -731 to -712 relative to the transcription start site was essential for hypoxia-enhanced OPN transcription. Using electrophoretic mobility shift assays with the RAE DNA sequence, we found that hypoxia induced sequence-specific DNA-binding complexes. Furthermore, hypoxia and ras exposure resulted in an additive induction of OPN protein and mRNA levels that appeared to be mediated by the RAE. Induction of OPN through the RAE element by hypoxia is mediated by an Akt-kinase signaled pathway as decreasing Akt levels with dominant negative constructs resulted in inhibition of OPN induction by hypoxia. Taken together, these results have identified a new hypoxia responsive transcriptional enhancer that is regulated by Akt signaling.

View details for DOI 10.1038/sj.onc.1208800

View details for Web of Science ID 000232204100009

View details for PubMedID 16007184

A comparison study of different PCR assays in measuring circulating plasma Epstein-Barr virus DNA levels in patients with nasopharyngeal carcinoma CLINICAL CANCER RESEARCH Le, Q. T., Jones, C. D., Yau, T. K., Shirazi, H. A., Wong, P. H., Thomas, E. N., Patterson, B. K., Lee, A. W., Zehnder, J. L. 2005; 11 (16): 5700-5707


To compare the performance of three PCR assays in measuring circulating Epstein-Barr virus (EBV). DNA levels in nasopharyngeal carcinoma patients and to confirm its prognostic significance.Plasma from 58 newly diagnosed nasopharyngeal carcinoma patients were collected before, during, and every 3 to 6 months after radiotherapy. EBV DNA levels were determined by real-time quantitative PCR using primer/probe sets for polymerase-1 (Pol-1), latent membrane protein 2 (Lmp2), and BamHI-W. Pretreatment levels from the three assays were correlated with each other and serial measurements from the Pol-1 assay were correlated with clinical variables.Pol-1 was more accurate than BamHI-W in predicting EBV DNA concentrations in cell lines. Of the three assays, BamHI-W yielded the highest concentrations followed by Pol-1 in plasmas (n = 23). The correlation coefficient was 0.99 (P < 0.0001) for Pol-1 and Lmp2, 0.66 (P < 0.0001) for Pol-1 and BamHI-W, and 0.55 (P < 0.0001) for BamHI-W and Lmp2. Elevated pretreatment DNA levels as detected by Pol-1 were correlated with advanced nodal stage (P = 0.04) and overall stage (P = 0.028). There was no correlation between pretreatment EBV DNA levels and freedom-from-relapse or overall survival; however, there was a significant correlation between posttreatment levels and these variables. The 2-year freedom-from-relapse and overall survival rates were 92% and 94% for patients with undetectable, and 37% and 55% for those with detectable, posttreatment levels (P < 0.0001 and P < 0.002).The three PCR assays yielded similar results in detecting EBV DNA in plasmas. The Pol-1-detected posttreatment EBV DNA level was the strongest predictor for treatment outcomes.

View details for DOI 10.1158/1078-0432.CCR-05-0648

View details for Web of Science ID 000231320000009

View details for PubMedID 16115906

A noninvasive approach for assessing tumor hypoxia in xenografts: Developing a urinary marker for hypoxia CANCER RESEARCH Nelson, D. W., Cao, H. B., Zhu, Y. H., Sunar-Reeder, B., Choi, C. Y., Faix, J. D., Brown, J. M., Koong, A. C., Giaccia, A. J., Le, Q. T. 2005; 65 (14): 6151-6158


Tumor hypoxia modifies the efficacy of conventional anticancer therapy and promotes malignant tumor progression. Human chorionic gonadotropin (hCG) is a glycoprotein secreted during pregnancy that has been used to monitor tumor burden in xenografts engineered to express this marker. We adapted this approach to use urinary beta-hCG as a secreted reporter protein for tumor hypoxia. We used a hypoxia-inducible promoter containing five tandem repeats of the hypoxia-response element (HRE) ligated upstream of the beta-hCG gene. This construct was stably integrated into two different cancer cell lines, FaDu, a human head and neck squamous cell carcinoma, and RKO, a human colorectal cancer cell line. In vitro studies showed that tumor cells stably transfected with this plasmid construct secrete beta-hCG in response to hypoxia or hypoxia-inducible factor 1alpha (HIF-1alpha) stabilizing agents. The hypoxia responsiveness of this construct can be blocked by treatment with agents that affect the HIF-1alpha pathways, including topotecan, 1-benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole (YC-1), and flavopiridol. Immunofluorescent analysis of tumor sections and quantitative assessment with flow cytometry indicate colocalization between beta-hCG and 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5) and beta-hCG and pimonidazole, two extrinsic markers for tumor hypoxia. Secretion of beta-hCG from xenografts that contain these stable constructs is directly responsive to changes in tumor oxygenation, including exposure of the animals to 10% O2 and tumor bed irradiation. Similarly, urinary beta-hCG levels decline after treatment with flavopiridol, an inhibitor of HIF-1 transactivation. This effect was observed only in tumor cells expressing a HRE-regulated reporter gene and not in tumor cells expressing a cytomegalovirus-regulated reporter gene. The 5HRE beta-hCG reporter system described here enables serial, noninvasive monitoring of tumor hypoxia in a mouse model by measuring a urinary reporter protein.

View details for Web of Science ID 000230633400024

View details for PubMedID 16024616

Nonsurgical therapy for stages I and II non-small cell lung cancer HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Le, Q. T., Petrik, D. W. 2005; 19 (2): 237-?


For patients who have stages I and II non-small cell lung cancer (NSCLC) and who are unable or unwilling to undergo surgical resection, nonsurgical treatment modalities have been used with curative intent. Conventionally fractionated radiotherapy has been the mainstay of nonsurgical therapy; however, advances in technology and the clinical application of radiobiologic principles have allowed more accurately targeted treatment that delivers higher effective doses to the tumor, while respecting the tolerance of surrounding normal tissues. This article discusses nonsurgical approaches to the treatment of early-stage NSCLC, including several promising techniques, such as radiation dose escalation, altered radiation fractionation, stereotactic radiotherapy, and radiofrequency ablation.

View details for DOI 10.1016/j.hoc.2005.02.003

View details for Web of Science ID 000228810400004

View details for PubMedID 15833405

Positron-emission tomography for surveillance of head and neck cancer LARYNGOSCOPE Ryan, W. R., Fee, W. E., Le, Q. T., Pinto, H. A. 2005; 115 (4): 645-650


To determine the diagnostic accuracy and the ideal timing of fluoro-fluorodeoxyglucose positron-emission tomography (PET) in the posttreatment surveillance of head and neck mucosal squamous cell carcinoma (HNSCC).Retrospective chart review.Our sample includes 103 adult patients with 118 posttreatment PET scans who had undergone treatment for HNSCC. We correlated PET results with surgical pathology and clinical outcome in the subsequent 6 months.For the detection of locoregional persistent or recurrent HNSCC, PET scans had a sensitivity of 82%, specificity of 92%, positive predictive value (PPV) of 64%, negative predictive value (NPV) of 97%, and overall accuracy of 90%. For the detection of distant metastases, PET scans had a sensitivity of 89%, specificity of 97%, PPV of 85%, NPV of 98%, and overall accuracy of 96%. PET scans of the head and neck region performed greater than 1 month after the completion of radiation compared with scans performed within 1 month had a significantly higher sensitivity of 95% versus 55% (P < .01) and NPV of 99% versus 90% (P < .01).PET is effective in detecting distant metastases in the posttreatment surveillance for HNSCC patients. A negative PET is highly reliable for all sites. However, a positive PET in the head and neck region is unreliable because of a high false-positivity rate. PET of the head and neck region has a statistically significant risk of a false-negative reading when performed within 1 month of radiation.

View details for DOI 10.1097/01.mlg.0000161345.23128.d4

View details for Web of Science ID 000228280300016

View details for PubMedID 15805874

Long-term results of 100 consecutive comprehensive neck dissections - Implications for selective neck dissections ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Sivanandan, R., Kaplan, M. J., Lee, K. J., Lebl, D., PINTO, H., Le, Q. T., Goffinet, D. R., Fee, W. E. 2004; 130 (12): 1369-1373


The optimal surgical procedure for the neck in patients with squamous head and neck cancers is controversial. Selective neck dissections have replaced modified radical neck dissections as the procedure of choice for the clinically negative (N0) neck and are now being considered for patients with early-stage neck disease. We report the long-term local recurrence rates in 100 consecutive patients undergoing a radical or modified radical neck dissection for clinically positive (N+) and N0 neck disease and review comprehensively the literature reporting and comparing regional control rates for both neck dissection types.The clinical records of 100 consecutive patients who underwent a comprehensive neck dissection (levels I-V) for squamous head and neck cancers with a minimum of a 2-year follow-up were retrospectively reviewed for primary site of disease, clinical and pathologic neck status, histopathologic grade, neck dissection type, and the site and time of recurrence.Complete data were available for 97 patients on whom 99 neck dissections were performed. Three patients died from unknown causes. Seventy-six patients with N+ disease underwent a therapeutic neck dissection, while 24 patients with clinically N0 disease underwent an elective dissection. The overall neck recurrence rate in patients with controlled primary disease was 7%. The neck or regional failure rate for patients completing the recommended adjuvant radiotherapy was 4%. Six (25%) of 24 patients with clinically N0 disease had occult metastases. The recurrence rate for this group was 4%.Further study is needed to determine the optimal surgical management of the N0 and limited N+ neck.

View details for Web of Science ID 000225606400002

View details for PubMedID 15611394

Sample classification from protein mass spectrometry, by 'peak probability contrasts' BIOINFORMATICS Tibshirani, R., Hastie, T., Narasimhan, B., Soltys, S., Shi, G. Y., Koong, A., Le, Q. T. 2004; 20 (17): 3034-3044


Early cancer detection has always been a major research focus in solid tumor oncology. Early tumor detection can theoretically result in lower stage tumors, more treatable diseases and ultimately higher cure rates with less treatment-related morbidities. Protein mass spectrometry is a potentially powerful tool for early cancer detection. We propose a novel method for sample classification from protein mass spectrometry data. When applied to spectra from both diseased and healthy patients, the 'peak probability contrast' technique provides a list of all common peaks among the spectra, their statistical significance and their relative importance in discriminating between the two groups. We illustrate the method on matrix-assisted laser desorption and ionization mass spectrometry data from a study of ovarian cancers.Compared to other statistical approaches for class prediction, the peak probability contrast method performs as well or better than several methods that require the full spectra, rather than just labelled peaks. It is also much more interpretable biologically. The peak probability contrast method is a potentially useful tool for sample classification from protein mass spectrometry data.

View details for DOI 10.1093/bioinformatics/bth357

View details for Web of Science ID 000225361400017

View details for PubMedID 15226172

Identification of hypoxia-regulated proteins in head and neck cancer by proteomic and tissue array profiling CANCER RESEARCH Chen, Y. J., Shi, G. Y., Wei, X., Kong, C., Zhao, S. C., Gaw, A. F., CHEN, E. Y., Yang, G. P., Giaccia, A. J., Le, Q. T., Koong, A. C. 2004; 64 (20): 7302-7310


Hypoxia within solid tumors decreases therapeutic efficacy, and identification of hypoxia markers may influence the choice of therapeutic modality. Here, we used a proteomic approach to identify hypoxia-regulated proteins and validated their use as endogenous indicators of tumor hypoxia. Using two-dimensional gel electrophoresis and PowerBlot (antibody-based array), we identified a group of 20 proteins that are increased >/=1.5-fold during hypoxia. The majority of these proteins such as IkappaB kinase beta (IKKbeta), MKK3b, highly expressed in cancer (HEC), density-regulated protein 1, P150(glued), nuclear transport factor 2, binder of ARL 2, Paxillin, and transcription termination factor I have not been previously reported to be hypoxia inducible. The increase in these proteins under hypoxia was mediated through posttranscriptional mechanisms. We additionally characterized the role of IKKbeta, a regulator of the nuclear factor-kappaB transcription factor, during hypoxia. We demonstrated that IKKbeta mediates cell survival during hypoxia and is induced in a variety of squamous cell carcinoma cell lines. Furthermore, we showed that IKKbeta expression from tumor specimens correlated with tumor oxygenation in patients with head and neck squamous cell carcinomas. These data suggest that IKKbeta is a novel endogenous marker of tumor hypoxia and may represent a new target for anticancer therapy.

View details for Web of Science ID 000224522200021

View details for PubMedID 15492250

XBP1 is essential for survival under hypoxic conditions and is required for tumor growth CANCER RESEARCH Romero-Ramirez, L., Cao, H. B., Nelson, D., Hammond, E., Lee, A. H., Yoshida, H., Mori, K., Glimcher, L. H., Denko, N. C., Giaccia, A. J., Le, Q. T., Koong, A. C. 2004; 64 (17): 5943-5947


Hypoxia within solid tumors is a major determinant of outcome after anticancer therapy. Analysis of gene expression changes during hypoxia indicated that unfolded protein response genes were one of the most robustly induced groups of genes. In this study, we investigated the hypoxic regulation of X-box binding protein (XBP1), a major transcriptional regulator of the unfolded protein response. Hypoxia induced XBP1 at the transcriptional level and activated splicing of its mRNA, resulting in increased levels of activated XBP1 protein. After exposure to hypoxia, apoptosis increased and clonogenic survival decreased in XBP1-deficient cells. Loss of XBP1 severely inhibited tumor growth due to a reduced capacity for these transplanted tumor cells to survive in a hypoxic microenvironment. Taken together, these studies directly implicate XBP1 as an essential survival factor for hypoxic stress and tumor growth.

View details for Web of Science ID 000223603200007

View details for PubMedID 15342372

Phase II double-blind randomized study comparing oral aloe vera versus placebo to prevent radiation-related mucositis in patients with head-and-neck neoplasms 39th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Su, C. K., Mehta, V., Ravikumar, L., Shah, R., PINTO, H., Halpern, J., Koong, A., Goffinet, D., Le, Q. T. ELSEVIER SCIENCE INC. 2004: 17177


In a single-institution, double-blind, prospective, randomized trial, we determined whether oral aloe vera gel can reduce radiation-induced mucositis in head-and-neck cancer patients.We randomized 58 head-and-neck cancer patients between oral aloe vera and placebo. To be included in this Phase II protocol, patients had to be treated with radiotherapy with curative intent at Stanford University between February 1999 and March 2002. We examined patients biweekly for mucositis at 15 head-and-neck subsites and administered quality-of-life questionnaires.Patients in the aloe and placebo groups were statistically identical in baseline characteristics. By the end of treatment, the two groups were also statistically identical in maximal grade of toxicity, duration of Grade 2 or worse mucositis, quality-of-life scores, percentage of weight loss, use of pain medications, hydration requirement, oral infections, and prolonged radiation breaks.In our randomized study, oral aloe vera was not a beneficial adjunct to head-and-neck radiotherapy. The mean quality-of-life scores were greater in the aloe vera group, but the differences were not statistically significant. Oral aloe vera did not improve tolerance to head-and-neck radiotherapy, decrease mucositis, reduce soreness, or otherwise improve patient well-being.

View details for DOI 10.1016/j.ijrobp.2004.02.012

View details for Web of Science ID 000223854500022

View details for PubMedID 15337553

Phase I study of tirapazamine plus cisplatin/etoposide and concurrent thoracic radiotherapy in limited-stage small cell lung cancer (S0004): A Southwest Oncology Group Study CLINICAL CANCER RESEARCH Le, Q. T., McCoy, J., Williamson, S., Ryu, J., Gaspar, L. E., EDELMAN, M. J., Dakhil, S. R., Sides, S. A., Crowley, J. J., Gandara, D. R. 2004; 10 (16): 5418-5424


To determine the feasibility and a recommended phase II dose of tirapazamine when combined with chemoradiotherapy in limited-stage small cell lung cancer (LSCLC).Concurrent chemoradiotherapy consisted of two cycles of cisplatin, etoposide, and once-daily radiation to 61 Gy. Tirapazamine (260 mg/m2) was given 1 h before cisplatin with planned dose escalation to 330 mg/m2 in the absence of dose-limiting toxicity, defined as > or =33% esophagitis (grade 3 or above). Consolidation therapy consisted of two cycles of tirapazamine (330 mg/m2), cisplatin, and etoposide. Complete responders received prophylactic cranial irradiation.Thirty patients were enrolled at the 260 mg/m2 tirapazamine dose. All had performance status of 0-1. By comparison with S9713, a predecessor Southwest Oncology Group study in LSCLC that used the same concurrent chemoradiotherapy without tirapazamine, the present trial showed a higher rate of grade 3-4 esophagitis (34% versus 22%), vomiting (34% versus 23%), and febrile neutropenia (7% versus 2%). The consolidation phase was relatively well tolerated, with grade 4 neutropenia in 44% and febrile neutropenia in 5% of patients. There were two treatment-related deaths: one from neutropenic fever and one from respiratory infection. The overall response rate was 80%, and the median survival was 22 months.Protocol-defined dose-limiting toxicity was observed at the initial tirapazamine dose, precluding dose escalation. Compared with S9713, the addition of tirapazamine increased the incidence of vomiting, neutropenia, and febrile neutropenia, although the overall toxicity profile remained acceptable. In view of the observed favorable survival, further study of tirapazamine in LSCLC is warranted.

View details for Web of Science ID 000223454600016

View details for PubMedID 15328179

Hypoxic gene expression and metastasis CANCER AND METASTASIS REVIEWS Le, Q. T., Denko, N. C., Giaccia, A. J. 2004; 23 (3-4): 293-310


Solid tumors possess malformed vasculature that results in the exposure of tumor cells to a low oxygen environment. Tumor hypoxia has been demonstrated in human and mouse tumors through the use of oxygen microelectrodes, hypoxic specific biomarkers, specific transcriptional changes induced by hypoxia, and secreted proteins. While many elegant experiments have demonstrated that hypoxia enhances metastatic potential, it is still unknown what mechanisms are involved in this enhancement. In this review, we discuss the clinical and basic science studies that support an important role for hypoxia in increasing the metastatic potential of tumor cells by promoting tissue remodeling, inducing angiogenesis and reducing apoptosis. Particular emphasis is given to recent findings that provide insight to the role of hypoxia in the metastatic process.

View details for Web of Science ID 000222017400009

View details for PubMedID 15197330

The use of plasma surface-enhanced laser desorption/ionization time-of-flight mass spectrometry proteomic patterns for detection of head and neck squamous cell cancers 45th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Soltys, S. G., Le, Q. T., Shi, G. Y., Tibshirani, R., Giaccia, A. J., Koong, A. C. AMER ASSOC CANCER RESEARCH. 2004: 480612


Our study was undertaken to determine the utility of plasma proteomic profiling using surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry for the detection of head and neck squamous cell carcinomas (HNSCCs).Pretreatment plasma samples from HNSCC patients or controls without known neoplastic disease were analyzed on the Protein Biology System IIc SELDI-TOF mass spectrometer (Ciphergen Biosystems, Fremont, CA). Proteomic spectra of mass:charge ratio (m/z) were generated by the application of plasma to immobilized metal-affinity-capture (IMAC) ProteinChip arrays activated with copper. A total of 37356 data points were generated for each sample. A training set of spectra from 56 cancer patients and 52 controls were applied to the "Lasso" technique to identify protein profiles that can distinguish cancer from noncancer, and cross-validation was used to determine test errors in this training set. The discovery pattern was then used to classify a separate masked test set of 57 cancer and 52 controls. In total, we analyzed the proteomic spectra of 113 cancer patients and 104 controls.The Lasso approach identified 65 significant data points for the discrimination of normal from cancer profiles. The discriminatory pattern correctly identified 39 of 57 HNSCC patients and 40 of 52 noncancer controls in the masked test set. These results yielded a sensitivity of 68% and specificity of 73%. Subgroup analyses in the test set of four different demographic factors (age, gender, and cigarette and alcohol use) that can potentially confound the interpretation of the results suggest that this model tended to overpredict cancer in control smokers.Plasma proteomic profiling with SELDI-TOF mass spectrometry provides moderate sensitivity and specificity in discriminating HNSCC. Further improvement and validation of this approach is needed to determine its usefulness in screening for this disease.

View details for Web of Science ID 000222840700027

View details for PubMedID 15269156

Extranodal nonorbital indolent lymphomas of the head and neck: Relationship between tumor control and radiotherapy 45th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) MacDermed, D., Thurber, L., George, T. I., Hoppe, R. T., Le, Q. T. ELSEVIER SCIENCE INC. 2004: 78895


To review our experience managing extranodal nonorbital indolent lymphomas of the head and neck.A retrospective review was made of 40 patients with indolent lymphomas of the head and neck evaluated at Stanford. The tumor head-and-neck location was Waldeyer's ring, 14; salivary glands, 16; thyroid, 4; and other sites, 6. Twenty-five were Stage I-IIE. Pathology was re-reviewed in 37. The most common histologies were marginal zone lymphoma and follicular grade 2. Patients received combinations of surgery, chemotherapy, and radiotherapy. Local therapy included surgery alone in 6 patients, radiotherapy alone in 7, and surgery plus radiotherapy in 12. Median follow-up was 70.5 months.Freedom from local progression was 86%, and freedom from progression was 61% at 5 years. Patients with radiotherapy had significantly better freedom from local progression (5-year, 100% vs. 72% for patients without radiotherapy, p = 0.006) and freedom from progression (5-year, 90% vs. 34% for patients without radiotherapy, p = 0.001). Improvement in freedom from progression with radiotherapy was statistically significant for Stage I-II patients (88% vs. 50%, p = 0.02) and of borderline significance in Stage III-IV patients (100% vs. 23%, p = 0.07). Overall survival at 10 years was 70%. Multivariate analysis revealed that significant prognostic factors for survival were tumor site (favoring salivary and thyroid, p = 0.02) and age (favoring younger, p = 0.04).Survival is excellent in patients with indolent lymphomas of the head and neck. Patients with salivary and thyroid primary tumors had better survival compared with others. Early use of radiotherapy resulted in significantly higher rates of freedom from progression and freedom from local progression in early-stage patients.

View details for DOI 10.1016/j.ijrobp.2003.11.007

View details for Web of Science ID 000221987900019

View details for PubMedID 15183482

Lens dose in MLC-based IMRT treatments of the head and neck INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Pawlicki, T., Luxton, G., Le, Q. T., Findley, D., Ma, C. M. 2004; 59 (1): 293-299


The objectives of this work are: (1) to determine typical dose to the lens during step-and-shoot intensity modulated radiotherapy (IMRT) treatments of the head and neck, and (2) to report on the dose calculation accuracy of a commercial inverse planning system in predicting lens dose.The Corvus inverse treatment planning system (Nomos, Cranberry Township, PA) was used to plan IMRT treatments for patients with head-and-neck cancers in our clinic. Patients were treated on Varian C-series linacs (Varian, Palo Alto, CA) with 4-MV or 6-MV X-rays. A Rando phantom (Alderson Laboratories, Stamford, CT) was specially modified to accommodate 1 x 1 x 1 mm(3) thermoluminescent dosimeters at the position of the lens. The IMRT treatment plans were then delivered to the modified Rando phantom. The thermoluminescent dosimeter measurements were converted to dose and taken as an estimate of the lens dose. A total of 20 cases were used in this study (15 cases with 4 MV and 5 cases with 6 MV).Expressed as a percentage of the prescription dose, the mean dose to the left and right lens for all 4-MV cases was 9.1% (range, 2.0% to 61.3%). For the 6-MV cases, the mean dose to the left and right lens was 12.8% (range, 3.6% to 41.3%). For both the 4-MV and 6-MV cases, the case of maximum dose occurred when the IMRT treatment target included volumes superior to the level of the lens. The field size and number of monitor units did not correlate with the measured lens dose. The only factor of significance affecting lens dose was the inferior-to-superior distance of the target to the lens. For target-lens distance >/=6 mm, the maximum measured lens doses were 5.9% and 9.0% relative to the prescribed dose for the 4-MV and 6-MV beams, respectively. These data are similar to those observed in conventional head-and-neck treatments. For all cases, the difference between the dose measured and that predicted by Corvus was less than 2% and 4% of the dose prescribed to the gross tumor volume for the 4-MV and 6-MV cases, respectively.In IMRT, factors such as leaf leakage and number of monitor units play a secondary role and are not more significant than what is observed in conventional head-and-neck treatment when the lens is shielded by the collimator jaws. The target-lens distance is the parameter that affects the lens dose most strongly. For cases where the tumor is at or above the level of the lens, the lens dose can amount to an appreciable fraction of the prescription dose. To keep the lens dose to a minimum, noncoplanar beams that enter or exit into the lens should not be used.

View details for DOI 10.1016/j.ijrobp.2004.01.019

View details for Web of Science ID 000221047500036

View details for PubMedID 15093926

Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Koong, A. C., Le, Q. T., Ho, A., Fong, B., Fisher, G., Cho, C., Ford, J., Poen, J., Gibbs, I. C., Mehta, V. K., Kee, S., Trueblood, W., Yang, G., Bastidas, J. A. 2004; 58 (4): 1017-1021


To determine the feasibility and toxicity of delivering stereotactic radiosurgery to patients with locally advanced pancreatic cancer.Patients with Eastern Cooperative Oncology Group performance status < or=2 and locally advanced pancreatic cancer were enrolled on this Phase I dose escalation study. Patients received a single fraction of radiosurgery consisting of either 15 Gy, 20 Gy, or 25 Gy to the primary tumor. Acute gastrointestinal toxicity was scored according to the Radiation Therapy Oncology Group criteria. Response to treatment was determined by serial high-resolution computed tomography scanning.Fifteen patients were treated at 3 dose levels (3 patients received 15 Gy, 5 patients received 20 Gy, and 7 patients received 25 Gy). At these doses, no Grade 3 or higher acute gastrointestinal toxicity was observed. This trial was stopped before any dose-limiting toxicity was reached, because the clinical objective of local control was achieved in all 6 evaluable patients treated at 25 Gy.It is feasible to deliver stereotactic radiosurgery to patients with locally advanced pancreatic cancer. The recommended dose to achieve local control without significant acute gastrointestinal toxicity is 25 Gy.

View details for DOI 10.1016/j.ijrobp.2003.11.004

View details for Web of Science ID 000220084200001

View details for PubMedID 15001240

Therapeutic exploitation of the physiological and molecular genetic alterations in head and neck cancer CLINICAL CANCER RESEARCH Le, Q. T., Giaccia, A. J. 2003; 9 (12): 4287-4295


Despite improvements in the diagnosis and management of head and neck squamous cell carcinomas, there has been minimal increase in the long-term survival in these patients over the last 30 years. Treatment intensification with concurrent chemoradiotherapy has been shown to increase survival and improve organ preservation over radiotherapy alone in patients with locally advanced tumor; however, at a cost of increased long-term toxicity. Recent advances in molecular technology have ushered in a new age of targeted therapy, which holds promise for a better outcome for these patients with potentially less normal tissue toxicity. Some of the new approaches aim to specifically inhibit tumor growth and metastasis by targeting the tumor microenvironment or vasculature, whereas others focus on specific protein or signal transduction pathways. This review will summarize these new molecular and physiological based strategies that can be used for both treatment and chemoprevention of head and neck squamous cell carcinoma.

View details for Web of Science ID 000185830700001

View details for PubMedID 14555497

Long-term outcomes after external beam irradiation and brachytherapy boost for base-of-tongue cancers INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Gibbs, I. C., Le, Q. T., Shah, R. D., Terris, D. J., Fee, W. E., Goffinet, D. R. 2003; 57 (2): 489-494


To assess long-term efficacy and toxicity associated with external beam irradiation (EBRT) and interstitial (192)Ir implantation for the treatment of squamous carcinoma of the base of tongue.Between April 1975 and December 1993, 41 patients with base-of-tongue carcinomas were treated with (192)Ir interstitial implants after EBRT at Stanford University. One patient had Stage I, 6 had Stage II, 7 had Stage III, and 27 had Stage IV tumors. Twenty-eight patients had cervical lymph node involvement at diagnosis. All received EBRT to a median dose of 50 Gy (range 48.9-68 Gy) to the primary tumor and regional lymph nodes before brachytherapy. Interstitial implant was performed 2-4 weeks after EBRT. Intraoperatively, nylon catheters were placed via steel trocars into the base of tongue, glossotonsillar groove, and pharyngo-epiglottic fold using a catheter looping technique. Twenty-three of 28 node-positive patients also underwent simultaneous neck dissections. Postoperatively, the (192)Ir seeds were inserted and allowed to remain in place for approximately 35 h to achieve a median tumor dose of 26 Gy (range 20-34 Gy) to a median volume of 73 cc. Survival, local control, and complications were assessed.With a median follow-up of 62 months (range 9-215) for all patients and 90 months for alive patients, the 5-year Kaplan-Meier survival estimate was 66%. The 5-year local control rate was 82%, with 7 patients recurring locally, 2 of whom were salvaged with surgery. Nodal control was achieved in 93% of patients with either EBRT alone or in combination with neck dissection. The 5-year freedom from distant metastasis rate was 83%. Acute complications included transient bleeding (5%) and infection (8%). Late complication included soft-tissue necrosis/ulceration (7%), osteoradionecrosis (5%), and xerostomia.Base-of-tongue carcinoma can be effectively treated with EBRT and (192)Ir implant boost. Local control is excellent and complication rates are acceptable.

View details for DOI 10.1016/S0360-3016(03)00597-2

View details for Web of Science ID 000185315200023

View details for PubMedID 12957261

Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma 44th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q. T., Tate, D., Koong, A., Gibbs, I. C., Chang, S. D., Adler, J. R., Pinto, H. A., Terris, D. J., Fee, W. E., Goffinet, D. R. ELSEVIER SCIENCE INC. 2003: 104654


Treatment of nasopharyngeal carcinoma using conventional external beam radiotherapy (EBRT) alone is associated with a significant risk of local recurrence. Stereotactic radiosurgery (STR) was used to boost the tumor site after EBRT to improve local control.Forty-five nasopharyngeal carcinoma patients received a STR boost after EBRT at Stanford University. Seven had T1, 16 had T2, 4 had T3, and 18 had T4 tumors (1997 American Joint Commission on Cancer staging). Ten had Stage II, 8 had Stage III, and 27 had Stage IV neoplasms. Most patients received 66 Gy of EBRT delivered at 2 Gy/fraction. Thirty-six received concurrent cisplatin-based chemotherapy. STR was delivered to the primary site 4-6 weeks after EBRT in one fraction of 7-15 Gy.At a medium follow-up of 31 months, no local failures had occurred. The 3-year local control rate was 100%, the freedom from distant metastasis rate was 69%, the progression-free survival rate was 71%, and the overall survival rate was 75%. Univariate and multivariate analyses revealed N stage (favoring N0-N1, p = 0.02, hazard ratio HR 4.2) and World Health Organization histologic type (favoring type III, p = 0.002, HR 13) as significant factors for freedom from distant metastasis. World Health Organization histologic type (p = 0.004, HR 10.5) and age (p = 0.01, HR 1.07/y) were significant factors for survival. Late toxicity included transient cranial nerve weakness in 4, radiation-related retinopathy in 1, and asymptomatic temporal lobe necrosis in 3 patients who originally had intracranial tumor extension.STR boost after EBRT provided excellent local control in nasopharyngeal carcinoma patients. The incidence of late toxicity was acceptable. More effective systemic treatment is needed to achieve improved survival.

View details for DOI 10.1016/S0360-3016(03)00117-2

View details for Web of Science ID 000183937500018

View details for PubMedID 12829140

HIF-alpha, a gender independent transcription factor CLINICAL CANCER RESEARCH Le, Q. T., Giaccia, A. J. 2003; 9 (7): 2391-2393

View details for Web of Science ID 000184108700002

View details for PubMedID 12855609

Radiation therapy for intracranial germ cell tumors 43rd Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Haas-Kogan, D. A., Missett, B. T., Wara, W. M., Donaldson, S. S., Lamborn, K. R., Prados, M. D., Fisher, P. G., Huhn, S. L., Fisch, B. M., Berger, M. S., Le, Q. T. ELSEVIER SCIENCE INC. 2003: 51118


To review the combined experiences of University of California, San Francisco, and Stanford University Medical Center in the treatment of intracranial germ cell tumors (GCT) and to assess the impact of craniospinal radiation (CSI) on patterns of relapse, progression-free survival (PFS), and overall survival (OS).Ninety-three patients received radiation for newly diagnosed intracranial GCTs, including 49 germinomas, 16 nongerminomatous GCTs (NGGCT), and 28 with no biopsy. Median follow-up for surviving patients was 4.5 years (range 0.25-34). Tests for variables correlating with OS and PFS were conducted using Cox proportional hazards model.Five-year PFS and OS rates were 60% +/- 15% and 68% +/- 14% for patients with NGGCT and 88% +/- 5% and 93% +/- 4% for those with germinoma. Of 6 patients with localized NGGCT who did not receive CSI, 1 experienced an isolated spinal recurrence but was salvaged. Of 41 patients with localized germinoma, 6 who received CSI and 35 who did not, no isolated spinal cord relapses occurred. Twenty-one patients with localized germinoma received neither CSI nor whole brain radiation. Of these, none of 18 with ventricular radiation relapsed. One of 3 patients with primary tumor radiation relapsed intracranially but had only received 11 Gy at initial treatment. On multivariate analysis, germinoma histology but not CSI correlated with improved PFS and OS.CSI is not indicated in the treatment of localized germinomas. For patients with localized germinomas treated with radiation alone, we recommend ventricular irradiation followed by primary tumor boost to a total of 45-50 Gy.

View details for DOI 10.1016/S0360-3016(02)04611-4

View details for Web of Science ID 000182861500026

View details for PubMedID 12738328

Comparison of the comet assay and the oxygen microelectrode for measuring tumor oxygenation in head-and-neck cancer patients Annual Meeting on Radiation Research Le, Q. T., Kovacs, M. S., Dorie, M. J., Koong, A., Terris, D. J., Pinto, H. A., Goffinet, D. R., Nowels, K., Bloch, D., Brown, J. M. ELSEVIER SCIENCE INC. 2003: 37583


To compare the Eppendorf PO2 histograph and the alkaline comet assay as methods of measuring tumor hypoxia in patients with head-and-neck squamous cell carcinomas.As part of a larger clinical trial, 65 patients with head-and-neck squamous cell carcinoma nodal metastasis underwent tumor oxygenation measurements with Eppendorf PO2 histographs and comet assays, performed on fine-needle aspirates at 1 and 2 min after 5 Gy. Fifty-four patients had sufficient tumor cells for comet analysis at 1 min and 26 at both 1 and 2 min. Individual cells were examined for DNA single-strand breaks by alkaline gel electrophoresis, and the distribution of values was quantified using median tail moment (MTM). Nonirradiated tumor cells from pretreatment fine-needle aspirates received 5 Gy in vitro to establish the oxygenated response.There was a significant correlation between the 1- and 2-min MTM (slope = 0.77 +/- 0.03). There was no relationship between DNA damage in tumor cells irradiated in vitro and in vivo. No correlation was found between Eppendorf PO2 measurements and comet MTM. There was a statistically significant correlation between the treatment response in the node studied and comet MTMs, whereas no correlation was observed between treatment response and Eppendorf measurements.Comet assays are reproducible, as shown by biopsies at 1 and 2 min. Intertumor variation in the MTM is not a result of intrinsic radiosensitivity but of tumor hypoxia. There was no correlation between Eppendorf PO2 measurements and comet MTM. Comet assays were better than Eppendorf in predicting treatment response as an end point for short-term outcome. Longer follow-up is needed to determine the role of the comet assay as a predictor for locoregional tumor control and survivals.

View details for DOI 10.1016/S0360-3016(02)04503-0

View details for Web of Science ID 000182861500010

View details for PubMedID 12738312

Patterns of patient movement during frameless image-guided radiosurgery INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Murphy, M. J., Chang, S. D., Gibbs, I. C., Le, Q. T., Hai, J., Kim, D., Martin, D. P., Adler, J. R. 2003; 55 (5): 1400-1408


Image-guided radiosurgery aligns the treatment beam to the target site by using a radiographic imaging system to locate anatomic landmarks associated with the treatment target. Because the procedure is performed without a rigid frame, the precision of dose alignment can be affected by patient movement. Movement is limited by noninvasive restraints and compensated by remeasuring the target position at short intervals throughout treatment and then realigning the beam. Frameless image-guided radiosurgery has been used at our institution to treat 250 cranial, 23 spinal, 9 lung, and 3 pancreas cases involving malignant and benign tumors as well as vascular malformations. We have analyzed the target position records for all of these cases to assess the frequency, magnitude, and case-by-case patterns of patient movement.The position of the treatment site during image-guided radiosurgery was measured at approximately 1-2-min intervals, on average, using orthogonal amorphous silicon X-ray cameras and an image registration process that determined all six degrees of freedom in the target's position. The change in position from one measurement to the next was indicative of patient movement.The treatment site position along each axis of translation was observed to vary by an average of 0.45 mm for the cranium, 0.53 mm for the cervical spine, 0.53 mm for the lumbar and thoracic spine, 1.06 mm for the lung, and 1.50 mm for the pancreas. Half of all cranial cases showed systematic drifting of the target away from the initial setup position.Using noninvasive restraints and supports, short-term movement of the head and spine during image-guided radiosurgery was limited to a radius of 0.8 mm, which satisfies the prevailing standard for radiosurgical dose alignment precision, but maintaining this margin of error throughout a treatment fraction requires regular monitoring of the target site's position.

View details for DOI 10.1016/S0360-3016(02)04597-2

View details for Web of Science ID 000181803500035

View details for PubMedID 12654453

Stereotactic radiosurgery for lung tumors: Preliminary report of a phase I trial 38th Annual Meeting of the Society-of-Thoracic-Surgeons Whyte, R. I., Crownover, R., MURPHY, M. J., Martin, D. P., Rice, T. W., DeCamp, M. M., Rodebaugh, R., Weinhous, M. S., Le, Q. T. ELSEVIER SCIENCE INC. 2003: 10971101


Stereotactic radiosurgery is well established for the treatment of intracranial neoplasms but its use for lung tumors is novel.Twenty-three patients with biopsy-proven lung tumors were recruited into a two-institution, dose-escalation, phase I clinical trial using a frameless stereotactic radiosurgery system (CyberKnife). Fifteen patients had primary lung tumors and 8 had metastatic tumors. The age range was 23 to 87 years (mean, 63 years). After undergoing computed tomography-guided percutaneous placement of two to four small metal fiducials directly into the tumor, patients received 1,500 cGY of radiation in a single fraction using a linear accelerator mounted on a computer-controlled robotic arm. Safety, feasibility, and efficacy were studied.Nine patients were treated with a breath-holding technique, and 14 with a respiratory-gating, automated, robotic technique. Tumor size ranged from 1 to 5 cm in maximal diameter. There were four complications related to fiducial placement: three pneumothoraces requiring chest tube insertion and one emphysema exacerbation. There were no grade 3 to 5 radiation-related complications. Follow-up ranged from 1 to 26 months (mean, 7.0 months). Radiographic response was scored as complete in 2 patients, partial in 15, stable in 4, and progressive in 2. Four patients died of non-treatment-related causes at 1, 5, 9, and 11 months after radiation.Single-fraction stereotactic radiosurgery is safe and feasible for the treatment of selected lung tumors. Additional studies are planned to investigate the optimal radiation dose, best motion-suppression technique, and overall treatment efficacy.

View details for Web of Science ID 000181946800007

View details for PubMedID 12683544

Identification of osteopontin as a prognostic plasma marker for head and neck squamous cell carcinomas CLINICAL CANCER RESEARCH Le, Q. T., Sutphin, P. D., Raychaudhuri, S., Yu, S. C., Terris, D. J., Lin, H. S., Lum, B., Pinto, H. A., Koong, A. C., Giaccia, A. J. 2003; 9 (1): 59-67


Tumor hypoxia modifies treatment efficacy and promotes tumor progression. Here, we investigated the relationship between osteopontin (OPN), tumor pO(2), and prognosis in patients with head and neck squamous cell carcinomas (HNSCC).We performed linear discriminant analysis, a machine learning algorithm, on the NCI-60 cancer cell line microarray expression database to identify a gene profile that best distinguish cell lines with high Von-Hippel Lindau (VHL) gene expression, an important regulator of hypoxia-related genes, from those with low expression. Plasma OPN levels in 15 volunteers, 31 VHL patients, and 54 HNSCC patients were quantitatively measured by ELISA. The relationships between plasma OPN levels, tumor pO(2) as measured by the Eppendorf microelectrode, freedom from relapse (FFR), and survival in HNSCC patients were evaluated.Microarray analysis indicated that OPN gene expression inversely correlated with that of VHL. These findings were confirmed by Northern blot analysis. ELISA studies and Western blot in a HNSCC cell line demonstrated that hypoxia exposure resulted in increased OPN secretion. Patients with VHL syndrome had significantly higher plasma OPN levels than healthy volunteers. Plasma OPN level inversely correlated with tumor pO(2) (P = 0.003, r = -0.42). OPN levels correlated with clinical outcomes. The 1-year FFR and survival rates were 80 and 100%, respectively, for patients with OPN levels 450 ng/ml (P = 0.002 and 0.0005). Multivariate analysis revealed that OPN was an independent predictor for FFR and survival.Plasma OPN levels appeared to correlate with tumor hypoxia in HNSCC patients and may serve as noninvasive tests to identify patients at high risk for tumor recurrence.

View details for Web of Science ID 000180430600008

View details for PubMedID 12538452

Tumor hypoxia is important in radiotherapy, but how should we measure it? INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Brown, J. M., Le, Q. T. 2002; 54 (5): 1299-1301

View details for Web of Science ID 000179566100002

View details for PubMedID 12459349

Estimating DNA repair by sequential evaluation of head and neck tumor radiation sensitivity using the comet assay 5th International Conference on Head and Neck Cancer of the International-Society-of-Head-Neck-Cancer Terris, D. J., Ho, E. Y., Ibrahim, H. Z., Dorie, M. J., Kovacs, M. S., Le, Q. T., Koong, A. C., Pinto, H. A., Brown, J. M. AMER MEDICAL ASSOC. 2002: 698702


The alkaline comet assay is a microelectrophoretic technique for detecting single-strand DNA breaks, and may be used as an indirect measure of hypoxia by determining the radiation sensitivity of individual cells.To assess the ability of the comet assay to estimate the rate of DNA repair after irradiation in patients with head and neck cancer.The comet assay was used to evaluate DNA damage in fine-needle aspirates of lymph nodes containing metastatic squamous cell carcinoma in patients with head and neck cancer 1, 2, and 3 minutes after treatment with 500 rad (5 Gy) of irradiation. The amount of DNA damage (measured as the "tail moment" of the comet) is proportional to the number of DNA single-strand breaks after irradiation, which in turn depends on the oxygen concentration in each cell.The mean +/- SD of the median tail moment of the 1-minute postirradiation comets was 29.4 +/- 14.2 (n = 27). After 2 minutes, the mean median tail moment decreased to 25.4 +/- 13.6 (n = 25), representing a mean decrease of 11.9% in those patients with both 1- and 2-minute comet assays. Assuming a linear rate of repair, this decrease in DNA damage corresponds to a repair half-life of 4.2 minutes. A 3-minute assay was also performed on samples from a smaller number of patients (n = 9), with a mean value not significantly different from that of the 2-minute assay of the samples from this group.The comet assay is a promising tool for evaluating radiation sensitivity in individual cells. The rate of DNA repair early after irradiation is consistent with data in the literature.

View details for Web of Science ID 000176264300013

View details for PubMedID 12049567

The effectiveness of breath-holding to stabilize lung and pancreas tumors during radiosurgery INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Murphy, M. J., Martin, D., Whyte, R., Hai, J., Ozhasoglu, C., Le, Q. T. 2002; 53 (2): 475-482


To evaluate the effect of breath-holding on the short-term reproducibility and long-term variability of tumor position during image-guided radiosurgery.Thirteen patients have undergone single-fraction radiosurgery treatments during which the tumor was repeatedly imaged radiographically to observe its position. The imaging data were used to monitor the efficacy of breath-holding and to periodically readjust the alignment of the treatment beam with the tumor. These measurements have allowed the effects of breathing, heartbeat, patient movement, and instrumental uncertainties to be separately identified in the record of tumor position.During inspiration breath-holding, the lung tumor position was reproducible to within 1 mm, on average, in the direction of maximum displacement during regular breathing, and to within 1.8 mm in three dimensions overall. The pancreas tumor position in three dimensions was reproducible to within 2.5 mm on average. Some patients showed a slow, steady drift of tumor position during the extended sequence of breath-holds, which was compensated by periodic retargeting of the treatment beam.Breath-holding can allow the reduction of tumor motion dosimetry margins to 2 mm or less for lung cancer treatments, provided that the treatment system can detect and adapt to long-term variations in the mean tumor position during a lengthy treatment fraction.

View details for Web of Science ID 000175923400025

View details for PubMedID 12023152

Primary radiotherapy for localized orbital malt lymphoma INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Le, Q. T., Eulau, S. M., George, T. I., Hildebrand, R., Warnke, R. A., Donaldson, S. S., Hoppe, R. T. 2002; 52 (3): 657-663


To define the natural history, prognosis, and radiocurability of localized orbital extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT).Clinical records and pathologic material of 40 patients treated with local radiotherapy for localized orbital lymphoma were reviewed. Treatment consisted of 30-40 Gy in 1.8-2-Gy fractions (mean 34 Gy) of irradiation using 9-20-MeV electrons for conjunctival lesions, or 6-MV photons with complex treatment planning for retrobulbar lesions. The lens was routinely shielded with the use of a suspended eye bar.Upon pathologic review, 31 cases of orbital MALT lymphoma were identified. With the median follow-up of 5.9 years (range 9 months-0.3 years), the actuarial 10-year overall survival was 73%. Local control was 100%. Five distant failures resulted in a projected 10-year freedom from relapse of 71%. Most of the failures were extranodal in sites where MALT lymphoma has previously been shown to arise. No difference in outcome was observed among patients treated to less than or equal to 34 Gy vs. those treated to higher radiation doses. Two patients experienced clinically significant retinal damage after doses > or = Gy.In this study, localized orbital MALT lymphoma was well controlled with radiotherapy. Even following relapse, patients with orbital MALT lymphoma exhibited an indolent course. Relapse occurred predominantly in extranodal mucosal sites, implying a possible homing mechanism for MALT lymphoma cells. Given the excellent local control rates, our current treatment recommendation is to use a radiation dose of 30-30.6 Gy in 1.5-.8-Gy fractions to minimize risk of late toxicity.

View details for Web of Science ID 000173999400011

View details for PubMedID 11849787

Tirapazamine: Prototype for a novel class of therapeutic agents targeting tumor hypoxia SEMINARS IN ONCOLOGY Gandara, D. R., Lara, P. N., Goldberg, Z., Le, Q. T., Mack, P. C., Lau, D. H., Gumerlock, P. H. 2002; 29 (1): 102-109


Preclinical models in vitro and in vivo have shown that tumor hypoxia alters the malignant cell phenotype, selecting for p53 mutations, stimulating angiogenesis and metastasis, and markedly reducing the efficacy of both radiotherapy and chemotherapy. Similarly, clinical studies measuring pretreatment tumor oxygen status confirm that the presence of hypoxia confers a negative impact on local control, disease-free survival, and overall survival. Despite these data and extensive past research efforts, the promise of developing selective hypoxic-cell sensitizers has been largely unfulfilled. In contrast, tirapazamine is the rationally designed prototype for a new class of therapeutic agents targeting tumor hypoxia: hypoxic cytotoxins. Tirapazamine is bioreductively activated in hypoxic cells and has been shown to potentiate the cytotoxicity of radiation and a number of chemotherapeutic drug classes, in particular platinum compounds and taxanes. This article reviews the preclinical and clinical development of tirapazamine, as well as current trials in non-small cell lung cancer designed to provide proof of principle for this new category of cancer therapeutics.

View details for DOI 10.1053/sonc.2002.31531

View details for Web of Science ID 000174419200013

View details for PubMedID 11894020

Image-guided radiosurgery in the treatment of spinal metastases. Neurosurgical focus MURPHY, M. J., Chang, S., Gibbs, I., Le, Q. T., Martin, D., Kim, D. 2001; 11 (6)


The authors describe a new method for treating metastatic spinal tumors in which noninvasive, image-guided, frameless stereotactic radiosurgery is performed. Stereotactic radiosurgery delivers a high dose of radiation in a single or limited number of fractions to a lesion while maintaining delivery of a low dose to adjacent normal structures.Image-guided radiosurgery was developed by coupling an orthogonal pair of real-time x-ray cameras to a dynamically manipulated robot-mounted linear accelerator that guides the radiation beam to treatment sites associated with radiographic landmarks. This procedure can be conducted in an outpatient setting without the use of framebased skeletal fixation. The system relies on skeletal landmarks or implanted fiducial markers to locate treatment targets. Four patients with spinal metastases underwent radiosurgery with total prescription doses of 1000 to 1600 cGy in one or two fractions. Alignment of the treatment dose with the target volume was accurate to within 1.5 mm. During the course of each treatment fraction, patient movement was less than 0.5 mm on average. Dosimetry was highly conformal, with a demonstrated ability to deliver 1600 cGy to the perimeter of an irregular target volume while keeping exposure to the cord itself below 800 cGy.These experiences indicate that frameless radiosurgery is a viable therapeutic option for metastatic spine disease.

View details for PubMedID 16463998

Image-guided hypo-fractionated stereotactic radiosurgery to spinal lesions NEUROSURGERY Ryu, S. I., Chang, S. D., Kim, D. H., MURPHY, M. J., Le, Q. T., Martin, D. P., Adler, J. R. 2001; 49 (4): 838-846


This article demonstrates the technical feasibility of noninvasive treatment of unresectable spinal vascular malformations and primary and metastatic spinal tumors by use of image-guided frameless stereotactic radiosurgery.Stereotactic radiosurgery delivers a high dose of radiation to a tumor volume or vascular malformation in a limited number of fractions and minimizes the dose to adjacent normal structures. Frameless image-guided radiosurgery was developed by coupling an orthogonal pair of x-ray cameras to a dynamically manipulated robot-mounted linear accelerator that guides the therapy beam to treatment sites within the spine or spinal cord, in an outpatient setting, and without the use of frame-based fixation. The system relies on skeletal landmarks or implanted fiducial markers to locate treatment targets. Sixteen patients with spinal lesions (hemangioblastomas, vascular malformations, metastatic carcinomas, schwannomas, a meningioma, and a chordoma) were treated with total treatment doses of 1100 to 2500 cGy in one to five fractions by use of image-guided frameless radiosurgery with the CyberKnife system (Accuray, Inc., Sunnyvale, CA). Thirteen radiosurgery plans were analyzed for compliance with conventional radiation therapy.Tests demonstrated alignment of the treatment dose with the target volume within +/-1 mm by use of spine fiducials and the CyberKnife treatment planning system. Tumor patients with at least 6 months of follow-up have demonstrated no progression of disease. Radiographic follow-up is pending for the remaining patients. To date, no patients have experienced complications as a result of the procedure.This experience demonstrates the feasibility of image-guided robotic radiosurgery for previously untreatable spinal lesions.

View details for Web of Science ID 000171279600017

View details for PubMedID 11564244

Treatment results and prognostic factors of advanced T3-4 laryngeal carcinoma: The University of California, San Francisco (UCSF) and Stanford University Hospital (SUH) experience 86th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America (RSNA) Nguyen-Tan, P. F., Le, Q. T., Quivey, J. M., Singer, M., Terris, D. J., Goffinet, D. R., Fu, K. K. ELSEVIER SCIENCE INC. 2001: 117280


To review the UCSF-SUH experience in the treatment of advanced T3--4 laryngeal carcinoma and to evaluate the different factors affecting locoregional control and survival.We reviewed the records of 223 patients treated for T3--4 squamous cell carcinoma of the larynx between October 1, 1957, and December 1, 1999. There were 187 men and 36 women, with a median age of 60 years (range, 28--85 years). The primary site was glottic in 122 and supraglottic in 101 patients. We retrospectively staged the patients according to the 1997 AJCC staging system. One hundred and twenty-seven patients had T3 lesions, and 96 had T4 lesions; 132 had N0, 29 had N1, 45 had N2, and 17 had N3 disease. The overall stage was III in 93 and IV in 130 patients. Seventy-nine patients had cartilage involvement, and 144 did not. Surgery was the primary treatment modality in 161 patients, of which 134 had postoperative radiotherapy (RT), 11 had preoperative RT, 7 had surgery followed by RT and chemotherapy (CT), and 9 had surgery alone. Forty-one patients had RT alone, and 21 had CT with RT. Locoregional control (LRC) and overall survival (OS) were estimated using the Kaplan--Meier method. Log-rank statistics were employed to identify significant prognostic factors for OS and LRC.The median follow-up was 41 months (range, 2--367 months) for all patients and 78 months (range, 6--332 months) for alive patients. The LRC rate was 69% at 5 years and 68% at 10 years. Eighty-four patients relapsed, of which 53 were locoregional failures. Significant prognostic factors for LRC on univariate analysis were primary site, N stage, overall stage, the lowest hemoglobin (Hgb) level during RT, and treatment modality. Favorable prognostic factors for LRC on multivariate analysis were lower N stage and primary surgery. The overall survival rate was 48% at 5 years and 34% at 10 years. Significant prognostic factors for OS on univariate analysis were: primary site, age, overall stage, T stage, N stage, lowest Hgb level during RT, and treatment modality. Favorable prognostic factors for OS on multivariate analysis were lower N stage and higher Hgb level during RT.Lower N-stage was a favorable prognostic factor for LRC and OS. Hgb levels > or = 12.5 g/dL during RT was a favorable prognostic factor for OS. Surgery was a favorable prognostic factor for LRC but did not impact on OS. Correcting the Hbg level before and during treatment should be investigated in future clinical trials as a way of improving therapeutic outcome in patients with advanced laryngeal carcinomas.

View details for Web of Science ID 000170266500009

View details for PubMedID 11483326

Role of beam orientation optimization in intensity-modulated radiation therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Pugachev, A., Li, J. G., Boyer, A. L., Hancock, S. L., Le, Q. T., Donaldson, S. S., Xing, L. 2001; 50 (2): 551-560


To investigate the role of beam orientation optimization in intensity-modulated radiation therapy (IMRT) and to examine the potential benefits of noncoplanar intensity-modulated beams.A beam orientation optimization algorithm was implemented. For this purpose, system variables were divided into two groups: beam position (gantry and table angles) and beam profile (beamlet weights). Simulated annealing was used for beam orientation optimization and the simultaneous iterative inverse treatment planning algorithm (SIITP) for beam intensity profile optimization. Three clinical cases were studied: a localized prostate cancer, a nasopharyngeal cancer, and a paraspinal tumor. Nine fields were used for all treatments. For each case, 3 types of treatment plan optimization were performed: (1) beam intensity profiles were optimized for 9 equiangular spaced coplanar beams; (2) orientations and intensity profiles were optimized for 9 coplanar beams; (3) orientations and intensity profiles were optimized for 9 noncoplanar beams.For the localized prostate case, all 3 types of optimization described above resulted in dose distributions of a similar quality. For the nasopharynx case, optimized noncoplanar beams provided a significant gain in the gross tumor volume coverage. For the paraspinal case, orientation optimization using noncoplanar beams resulted in better kidney sparing and improved gross tumor volume coverage.The sensitivity of an IMRT treatment plan with respect to the selection of beam orientations varies from site to site. For some cases, the choice of beam orientations is important even when the number of beams is as large as 9. Noncoplanar beams provide an additional degree of freedom for IMRT treatment optimization and may allow for notable improvement in the quality of some complicated plans.

View details for Web of Science ID 000168781000033

View details for PubMedID 11380245

Daily low-dose carboplatin as a radiation sensitizer for newly diagnosed malignant glioma JOURNAL OF NEURO-ONCOLOGY Peterson, K., Harsh, G., Fisher, P. G., Adler, J., Le, Q. 2001; 53 (1): 27-32


Surgical resection followed by local field radiotherapy is currently our most effective approach to treatment for most patients with malignant glioma. Carboplatin chemotherapy has direct cytotoxic effects on glioma cells and acts as a radiation sensitizer to enhance cell killing. Its demonstrated efficacy as a sensitizer in other solid tumors led to this clinical trial of carboplatin as a radiation sensitizer in the treatment of newly diagnosed glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). Fourteen patients (nine GBM and five AA) were treated with daily low-dose carboplatin 25 mg/m2 intravenously within 2 h of their fractionated radiotherapy to a total dose of 600 mg/m2. No significant toxicities attributable to this combined therapy were observed. All patients have progressed, with median time to progression of 16 weeks. Eleven patients have died, with median survival of 38 weeks for the entire cohort. Although this regimen appeared safe, there was no benefit in survival time compared to historical patients treated with radiotherapy. The limitations and future potential for the strategy of radiation sensitization are discussed.

View details for Web of Science ID 000170979800004

View details for PubMedID 11678427

Image-guided extracranial radiosurgery 7th International Meeting on Progress in Radio-Oncology (ICRO/OGRO 7) Sattah, M., Guerrero, T., Chang, S., Martin, D., Le, Q. T., Gibbs, I., Adler, J. MEDIMOND S R L. 2001: 153162
Pancreatic tumors show high levels of hypoxia 36th Annual Meeting of the American-Society-of-Clinical-Oncology Koong, A. C., Mehta, V. K., Le, Q. T., Fisher, G. A., Terris, D. J., Brown, J. M., Bastidas, A. J., Vierra, M. ELSEVIER SCIENCE INC. 2000: 91922


Because of the dismal outcomes of conventional therapies for pancreatic carcinomas, we postulated that hypoxia may exist within these tumors.Seven sequential patients with adenocarcinomas of the pancreas consented to intraoperative measurements of tumor oxygenation using the Eppendorf (Hamburg, Germany) polargraphic electrode.All 7 tumors demonstrated significant tumor hypoxia. In contrast, adjacent normal pancreas showed normal oxygenation.Tumor hypoxia exists within pancreatic cancers.

View details for Web of Science ID 000165238800002

View details for PubMedID 11072146

Treatment results of carcinoma in situ of the glottis - An analysis of 82 cases 41st Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO 99) Le, Q. T., Takamiya, R., Shu, H. K., Smitt, M., Singer, M., Terris, D. J., Fee, W. E., Goffinet, D. R., Fu, K. K. AMER MEDICAL ASSOC. 2000: 130512


To evaluate the results of different treatment modalities for carcinoma in situ of the glottis, and to identify important prognostic factors for outcome.Review of 82 cases treated definitively for glottic carcinoma in situ between 1958 and 1998. The median follow-up for all patients was 112 months, and 90% had more than 2 years of follow-up.Academic tertiary care referral centers.Fifteen patients were treated with vocal cord stripping (group 1), 13 with more extensive surgery (group 2) including endoscopic laser resection (11 patients) and hemilaryngectomy (2 patients), and 54 with radiotherapy (group 3). Thirty patients had anterior commissure involvement and 9 had bilateral vocal cord involvement. Radiotherapy was delivered via opposed lateral fields at 1.5 to 2.4 Gy per fraction per day (median fraction size, 2 Gy), 5 days per week. The median total dose was 64 Gy, and the median overall time was 47 days.Initial locoregional control (LRC), ultimate LRC, and larynx preservation.The 10-year initial LRC rates were 56% for group 1, 71% for group 2, and 79% for group 3. Of those who failed, the median time to relapse was 11 months for group 1, 17 months for group 2, and 41 months for group 3. Univariate analysis showed that the difference in initial LRC rates between groups 1 and 3 was statistically significant (P =.02), although it was not statistically significant on multivariate analysis (P =.07). Anterior commissure involvement was an important prognostic factor for LRC on both univariate (P =.03) and multivariate (P =.04; hazard ratio, 1.6) analysis, and its influence appeared to be mainly confined to the surgically treated patients (groups 1 and 2). The 10-year larynx preservation rates were 92% for group 1, 70% for group 2, and 85% for group 3. Anterior commissure involvement was the only important prognostic factor for larynx preservation (P =. 01) on univariate analysis. All but 2 patients in whom treatment failed underwent successful salvage surgery. Voice quality was deemed good to excellent in 73% of the patients in group 1, 40% in group 2, and 68% in group 3.Treatment of carcinoma in situ of the glottis with vocal cord stripping or more extensive surgery or radiotherapy provided excellent ultimate LRC and comparable larynx preservation rates. Anterior commissure involvement was associated with poorer initial LRC and larynx preservation, particularly in the surgically treated patients. The choice of initial treatment should be individualized, depending on patient age, reliability, and tumor extent. Pretreatment and posttreatment objective evaluation of voice quality should be helpful in determining the best therapy for these patients.

View details for Web of Science ID 000165283600001

View details for PubMedID 11074826

Head and neck cancer in cardiothoracic transplant recipients Meeting of the Western Section of the American-Laryngological-Rhinological-and-Otological-Society Pollard, J. D., Hanasono, M. M., Mikulec, A. A., Le, Q. T., Terris, D. J. JOHN WILEY & SONS INC. 2000: 125761


There is an increased incidence of cancer in patients after organ transplantation. We reviewed a large series of cardiothoracic transplant recipients to determine the incidence and natural history of head and neck malignancy.A total of 1069 heart (n = 855), heart/lung (n = 111), and lung (n = 103) transplants were performed at Stanford University from January 1968 to February 1998. Demographic data, risk factors, and disease course were evaluated in patients who developed cancer. The mean length of follow-up was 8.9+/-5.2 years.One hundred twenty patients (11.2%) developed 547 non-lymphomatous malignancies. The mean number of malignancies per cancer patient was 4.6. The average time from transplantation to development of cancer was 63.1 months. A total of 50.5% of malignancies presented in the head and neck; 96.4% of these were cutaneous in origin and 3.6% were noncutaneous. Of cutaneous malignancies, 79.3% were squamous cell carcinoma and 15.9% were basal cell carcinoma Cutaneous malignancies most commonly presented on the scalp, cheek, lip, and neck. Noncutaneous malignancies involved the oral cavity (5), thyroid (4), and parotid (1). Thirteen percent of cutaneous head and neck cancers behaved aggressively, requiring extensive management including radical surgery, radiation, and/or chemotherapy. A total of 34.2% of cancer patients developed metastases and 54.9% of cancer patients died as a direct result of cancer. A total of 68% of cancer patients were smokers and 23.8% had significant alcohol use.Transplant recipients have an increased incidence of cancer presenting in the head and neck. Malignancies in transplant patients behave more aggressively than in the general population. Recognition of this aggressive biological behavior and heightened cancer surveillance should result in improved outcomes.

View details for Web of Science ID 000088596400003

View details for PubMedID 10942122

Dosimetric effects of patient displacement and collimator and gantry angle misalignment on intensity modulated radiation therapy RADIOTHERAPY AND ONCOLOGY Xing, L., Lin, Z. X., Donaldson, S. S., Le, Q. T., Tate, D., Goffinet, D. R., Wolden, S., Ma, L. J., Boyer, A. L. 2000; 56 (1): 97-108


The primary goal of this study was to examine systematically the dosimetric effect of small patient movements and linear accelerator angular setting misalignments in the delivery of intensity modulated radiation therapy. We will also provide a method for estimating dosimetric errors for an arbitrary combination of these uncertainties.Sites in two patients (lumbar-vertebra and nasopharynx) were studied. Optimized intensity modulated radiation therapy treatment plans were computed for each patient using a commercially available inverse planning system (CORVUS, NOMOS Corporation, Sewickley, PA). The plans used nine coplanar beams. For each patient the dose distributions and relevant dosimetric quantities were calculated, including the maximum, minimum, and average doses in targets and sensitive structures. The corresponding dose volumetric information was recalculated by purposely varying the collimator angle or gantry angle of an incident beam while keeping other beams unchanged. Similar calculations were carried out by varying the couch indices in either horizontal or vertical directions. The intensity maps of all the beams were kept the same as those in the optimized plan. The change of a dosimetric quantity, Q, for a combination of collimator and gantry angle misalignments and patient displacements was estimated using Delta=Sigma(DeltaQ/Deltax(i))Deltax(i). Here DeltaQ is the variation of Q due to Deltax(i), which is the change of the i-th variable (collimator angle, gantry angle, or couch indices), and DeltaQ/Deltax(i) is a quantity equivalent to the partial derivative of the dosimetric quantity Q with respect to x(i).While the change in dosimetric quantities was case dependent, it was found that the results were much more sensitive to small changes in the couch indices than to changes in the accelerator angular setting. For instance, in the first example in the paper, a 3-mm movement of the couch in the anterior-posterior direction can cause a 38% decrease in the minimum target dose or a 41% increase in the maximum cord dose, whereas a 5 degrees change in the θ(1)=20 degrees beam only gave rise to a 1.5% decrease in the target minimum or 5.1% in the cord maximum. The effect of systematic positioning uncertainties of the machine settings was more serious than random uncertainties, which tended to smear out the errors in dose distributions.The dose distribution of an intensity modulated radiation therapy (IMRT) plan changes with patient displacement and angular misalignment in a complex way. A method was proposed to estimate dosimetric errors for an arbitrary combination of uncertainties in these quantities. While it is important to eliminate the angular misalignment, it was found that the couch indices (or patient positioning) played a much more important role. Accurate patient set-up and patient immobilization is crucial in order to take advantage fully of the technological advances of IMRT. In practice, a sensitivity check should be useful to foresee potential IMRT treatment complications and a warning should be given if the sensitivity exceeds an empirical value. Quality assurance action levels for a given plan can be established out of the sensitivity calculation.

View details for Web of Science ID 000088159100013

View details for PubMedID 10869760

Candidate genes for the hypoxic tumor phenotype CANCER RESEARCH Koong, A. C., Denko, N. C., Hudson, K. M., Schindler, C., Swiersz, L., Koch, C., Evans, S., Ibrahim, H., Le, Q. T., Terris, D. J., Giaccia, A. J. 2000; 60 (4): 883-887


In this study, we have analyzed changes induced by hypoxia at the transcriptional level of genes that could be responsible for a more aggressive phenotype. Using a series of DNA array membranes, we identified a group of hypoxia-induced genes that included plasminogen activator inhibitor-1 (PAI-1), insulin-like growth factor-binding protein 3 (IGFBP-3), endothelin-2, low-density lipoprotein receptor-related protein (LRP), BCL2-interacting killer (BIK), migration-inhibitory factor (MIF), matrix metalloproteinase-13 (MMP-13), fibroblast growth factor-3 (FGF-3), GADD45, and vascular endothelial growth factor (VEGF). The induction of each gene was confirmed by Northern blot analysis in two different squamous cell carcinoma-derived cell lines. We also analyzed the kinetics of PAI-1 induction by hypoxia in more detail because it is a secreted protein that may serve as a useful molecular marker of hypoxia. On exposure to hypoxia, there was a gradual increase in PAI-1 mRNA between 2 and 24 h of hypoxia followed by a rapid decay after 2 h of reoxygenation. PAI-1 levels were also measured in the serum of a small group of head and neck cancer patients and were found to correlate with the degree of tumor hypoxia found in these patients.

View details for Web of Science ID 000085503100022

View details for PubMedID 10706099

Lymph node metastasis in maxillary sinus carcinoma INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Le, Q. T., Fu, K. K., Kaplan, M. J., Terris, D. J., Fee, W. E., Goffinet, D. R. 2000; 46 (3): 541-549


To evaluate the incidence and prognostic significance of lymph node metastasis in maxillary sinus carcinoma.We reviewed the records of 97 patients treated for maxillary sinus carcinoma with radiotherapy at Stanford University and at the University of California, San Francisco between 1959 and 1996. Fifty-eight patients had squamous cell carcinoma (SCC), 4 had adenocarcinoma (ADE), 16 had undifferentiated carcinoma (UC), and 19 had adenoid cystic carcinoma (AC). Eight patients had T2, 36 had T3, and 53 had T4 tumors according to the 1997 AJCC staging system. Eleven patients had nodal involvement at diagnosis: 9 with SCC, 1 with UC, and 1 with AC. The most common sites of nodal involvement were ipsilateral level 1 and 2 lymph nodes. Thirty-six patients were treated with definitive radiotherapy alone, and 61 received a combination of surgical and radiation treatment. Thirty-six patients had neck irradiation, 25 of whom received elective neck irradiation (ENI) for N0 necks. The median follow-up for alive patients was 78 months.The median survival for all patients was 22 months (range: 2.4-356 months). The 5- and 10-year actuarial survivals were 34% and 31%, respectively. Ten patients relapsed in the neck, with a 5-year actuarial risk of nodal relapse of 12%. The 5-year risk of neck relapse was 14% for SCC, 25% for ADE, and 7% for both UC and ACC. The overall risk of nodal involvement at either diagnosis or on follow-up was 28% for SCC, 25% for ADE, 12% for UC, and 10% for AC. All patients with nodal involvement had T3-4, and none had T2 tumors. ENI effectively prevented nodal relapse in patients with SCC and N0 neck; the 5-year actuarial risk of nodal relapse was 20% for patients without ENI and 0% for those with elective neck therapy. There was no correlation between neck relapse and primary tumor control or tumor extension into areas containing a rich lymphatic network. The most common sites of nodal relapse were in the ipsilateral level 1-2 nodal regions (11/13). Patients with nodal relapse had a significantly higher risk of distant metastasis on both univariate (p = 0.02) and multivariate analysis (hazard ratio = 4.5, p = 0.006). The 5-year actuarial risk of distant relapse was 29% for patients with neck control versus 81% for patients with neck failure. There was also a trend for decreased survival with nodal relapse. The 5-year actuarial survival was 37% for patients with neck control and 0% for patients with neck relapse.The overall incidence of lymph node involvement at diagnosis in patients with maxillary sinus carcinoma was 9%. Following treatment, the 5-year risk of nodal relapse was 12%. SCC histology was associated with a high incidence of initial nodal involvement and nodal relapse. None of the patients presenting with SCC histology and N0 necks had nodal relapse after elective neck irradiation. Patients who had nodal relapse had a higher risk of distant metastasis and poorer survival. Therefore, our present policy is to consider elective neck irradiation in patients with T3-4 SCC of the maxillary sinus.

View details for Web of Science ID 000085412400004

View details for PubMedID 10701732

Image-guided radiosurgery for the spine and pancreas. Computer aided surgery MURPHY, M. J., Adler, J. R., Bodduluri, M., Dooley, J., Forster, K., Hai, J., Le, Q., Luxton, G., Martin, D., Poen, J. 2000; 5 (4): 278-288


A robotic image-guided radiosurgical system has been modified to treat extra-cranial sites using implanted fiducials and skeletal landmarks to locate the treatment targets. The system has been used to treat an artero-venous malformation in the cervical spine, a recurrent schwannoma of the thoracic spine, a metastatic adenocarcinoma of the lumbar spine, and three pancreatic cancers. During each treatment, the image guidance system monitored the position of the target site and relayed the target coordinates to the beam-pointing system at discrete intervals. The pointing system then dynamically aligned the therapy beam with the lesion, automatically compensating for shifts in target position. Breathing-related motion of the pancreas lesions was managed by coordinating beam gating with breath-holding by the patient. The system maintained alignment with the spine lesions to within +/- 0.2 mm on average, and to within +/- 1 mm for the pancreatic tumors. This experience has demonstrated the feasibility of using image-guided robotic radiosurgery outside the cranium.

View details for PubMedID 11029160

Computer-assisted selection of importance factors in inverse planning 13th International Conference on the Use of Computers in Radiation Therapy Le, Q. T., Li, J. G., Pugachev, A., Boyer, A. L., Xing, L. SPRINGER-VERLAG BERLIN. 2000: 2931
Estimation theory and model parameter selection for therapeutic treatment plan optimization MEDICAL PHYSICS Xing, L., Li, J. G., Pugachev, A., Le, Q. T., Boyer, A. L. 1999; 26 (11): 2348-2358


Treatment optimization is usually formulated as an inverse problem, which starts with a prescribed dose distribution and obtains an optimized solution under the guidance of an objective function. The solution is a compromise between the conflicting requirements of the target and sensitive structures. In this paper, the treatment plan optimization is formulated as an estimation problem of a discrete and possibly nonconvex system. The concept of preference function is introduced. Instead of prescribing a dose to a structure (or a set of voxels), the approach prioritizes the doses with different preference levels and reduces the problem into selecting a solution with a suitable estimator. The preference function provides a foundation for statistical analysis of the system and allows us to apply various techniques developed in statistical analysis to plan optimization. It is shown that an optimization based on a quadratic objective function is a special case of the formalism. A general two-step method for using a computer to determine the values of the model parameters is proposed. The approach provides an efficient way to include prior knowledge into the optimization process. The method is illustrated using a simplified two-pixel system as well as two clinical cases. The generality of the approach, coupled with promising demonstrations, indicates that the method has broad implications for radiotherapy treatment plan optimization.

View details for Web of Science ID 000083775800019

View details for PubMedID 10587216

Treatment of maxillary sinus carcinoma - A comparison of the 1997 and 1977 American Joint Committee on Cancer staging systems CANCER Le, Q. T., Fu, K. K., Kaplan, M., Terris, D. J., Fee, W. E., Goffinet, D. R. 1999; 86 (9): 1700-1711


This study was conducted to assess the effectiveness of the 1997 American Joint Committee on Cancer (AJCC) staging system to predict survival and local control of patients with maxillary sinus carcinoma and to identify significant factors for overall survival, local control, and distant metastases in patients with these tumors.Ninety-seven patients with maxillary sinus carcinoma were treated with radiotherapy at Stanford University and the University of California, San Francisco between 1959-1996. The histologic type of carcinoma among the 97 patients were: 58 squamous cell carcinomas, 4 adenocarcinomas, 16 undifferentiated carcinomas, and 19 adenoid cystic carcinomas. All patients were restaged clinically according to the 1977 and 1997 AJCC staging systems. The T classification of the tumors of the patients was as follows: 8 with T2, 18 with T3, and 71 with T4 according to the 1977 system and 8 with T2, 36 with T3, and 53 with T4 according to the 1997 system. Eleven patients had lymph node involvement at diagnosis. Thirty-six patients were treated with radiotherapy alone and 61 received a combination of surgical and radiation treatments. The median follow-up for surviving patients was 78 months.The 5-year and 10-year actuarial survival rates for all patients were 34% and 31%, respectively. The 5-year survival estimate by the 1977 AJCC system (P = 0.06) was 75% for Stage II, 19% for Stage III, and 34% for Stage IV and by the 1997 AJCC system (P = 0.006) was 75% for Stage II, 37% for Stage III, and 28% for Stage IV. Significant prognostic factors for survival by multivariate analysis included age (favoring younger age, P<0.001), 1997 T classification (favoring T2-3, P = 0. 001), lymph node involvement at diagnosis (favoring N0, P = 0.002), treatment modality of the primary tumor site (favoring surgery and radiotherapy, P = 0.009), and gender (favoring female patients, P = 0.04). The overall radiation time was of borderline significance (favoring shorter time, P = 0.06). The actuarial 5-year local control rate was 43%. By the 1977 AJCC system (P = 0.78) it was 62% with T2, 36% with T3, and 45% with T4 and using the 1997 AJCC system (P = 0.29) it was 62% with T2, 53% with T3, and 36% with T4. The only significant prognostic factor for local control for all patients by multivariate analysis was local therapy, favoring surgery and radiotherapy over radiotherapy alone (P< 0.001). For patients treated with surgery, pathologic margin status correlated with local control (P = 0.007) and for patients treated with radiation alone, higher tumor dose (P = 0.007) and shorter overall treatment time (P = 0.04) were associated with fewer local recurrences. The 5-year estimate of freedom from distant metastases was 66%. The 1997 T classification, N classification, and lymph node recurrence were adverse prognostic factors for distant metastases on multivariate analysis. There were 22 complications in 16 patients, representing a 30% actuarial risk of developing late complications at 10 years.The 1997 AJCC staging system was found to be superior to the 1977 AJCC staging system in predicting both survival and local control in this patient population. Combined surgical and radiation treatment to the primary tumor yielded higher survival and local control than radiotherapy alone. Other significant prognostic factors for survival were patient age, gender, and lymph node (N) classification. Prolonged overall radiation time was associated with poorer survival and local control. Late severe toxicity from the treatment of these tumors was a significant problem in long term survivors. Improved radiotherapy techniques should lead to decreased injury to the surrounding normal tissues. (c) 1999 American Cancer Society.

View details for Web of Science ID 000083430700011

View details for PubMedID 10547542

DNA damage measured by the comet assay in head and neck cancer patients treated with tirapazamine. Neoplasia Dorie, M. J., Kovacs, M. S., Gabalski, E. C., Adam, M., Le, Q. T., Bloch, D. A., Pinto, H. A., Terris, D. J., Brown, J. M. 1999; 1 (5): 461-467


Tirapazamine (TPZ) [3-amino-1,2,4-benzotriazine 1,4-dioxide, SR4233, WIN 59075, and Tirazone] is a novel anticancer drug that is selectively activated by the low oxygen environment in solid tumors. By killing the radioresistant hypoxic cells, TPZ potentiates the antitumor efficacy of fractionated irradiation of transplanted tumors in mice. As this cell kill is closely correlated with TPZ-induced DNA damage, we investigated whether human head and neck cancers would show DNA damage similar to that seen in mouse tumors following TPZ administration. TPZ-induced DNA damage in both transplanted tumors in mice and in neck nodes of 13 patients with head and neck cancer was assessed using the alkaline comet assay on cells obtained from fine-needle aspirates. The oxygen levels of the patients' tumors were also measured using a polarographic oxygen electrode. Cells from the patients' tumors showed DNA damage immediately following TPZ administration that was comparable to, or greater than, that seen with transplanted mouse tumors. The heterogeneity of DNA damage in the patients' tumors was greater than that of individual mouse tumors and correlated with tumor hypoxia. The similarity of TPZ-induced DNA damage in human and rodent tumors suggests that tirapazamine should be effective when added to radiotherapy or to cisplatin-based chemotherapy in head and neck cancers.

View details for PubMedID 10933062

View details for PubMedCentralID PMC1508108

Optimization of importance factors in inverse planning PHYSICS IN MEDICINE AND BIOLOGY Xing, L., Li, J. G., Donaldson, S., Le, Q. T., Boyer, A. L. 1999; 44 (10): 2525-2536


Inverse treatment planning starts with a treatment objective and obtains the solution by optimizing an objective function. The clinical objectives are usually multifaceted and potentially incompatible with one another. A set of importance factors is often incorporated in the objective function to parametrize trade-off strategies and to prioritize the dose conformality in different anatomical structures. Whereas the general formalism remains the same, different sets of importance factors characterize plans of obviously different flavour and thus critically determine the final plan. Up to now, the determination of these parameters has been a 'guessing' game based on empirical knowledge because the final dose distribution depends on the parameters in a complex and implicit way. The influence of these parameters is not known until the plan optimization is completed. In order to compromise properly the conflicting requirements of the target and sensitive structures, the parameters are usually adjusted through a trial-and-error process. In this paper, a method to estimate these parameters computationally is proposed and an iterative computer algorithm is described to determine these parameters numerically. The treatment plan selection is done in two steps. First, a set of importance factors are chosen and the corresponding beam parameters (e.g. beam profiles) are optimized under the guidance of a quadratic objective function using an iterative algorithm reported earlier. The 'optimal' plan is then evaluated by an additional scoring function. The importance factors in the objective function are accordingly adjusted to improve the ranking of the plan. For every change in the importance factors, the beam parameters need to be re-optimized. This process continues in an iterative fashion until the scoring function is saturated. The algorithm was applied to two clinical cases and the results demonstrated that it has the potential to improve significantly the existing method of inverse planning. It was noticed that near the final solution the plan became insensitive to small variations of the importance factors.

View details for Web of Science ID 000083120600011

View details for PubMedID 10533926

Postoperative irradiation of minor salivary gland malignancies of the head and neck 38th Annual Meeting of American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q. T., Birdwell, S., Terris, D. J., Gabalski, E. C., Varghese, A., Fee, W. E., Goffinet, D. R. ELSEVIER IRELAND LTD. 1999: 16571


(1) To review the Stanford experience with postoperative radiotherapy for minor salivary gland carcinomas of the head and neck. (2) To identify patterns of failure and prognostic factors for these tumors.Fifty-four patients with localized tumors were treated with curative intent at Stanford University between 1966 and 1995. The 1992 AJCC staging for squamous cell carcinomas was used to retrospectively stage these patients. Thirteen percent had stage I, 22% stage II, 26% stage III, and 39% stage IV neoplasms. Thirty-two patients (59%) had adenoid cystic carcinoma, 15 (28%) had adenocarcinoma, and seven (13%) had mucoepidermoid carcinoma. Thirty (55%) had positive surgical margins and seven (13%) had cervical lymph node involvement at diagnosis. The median follow-up for alive patients was 7.8 years (range: 25 months-28.9 years).The 5- and 10-year actuarial local control rates were 91 and 88%, respectively. Advanced T-stage (T3-4), involved surgical margins, adenocarcinoma histology, and sinonasal and oropharyngeal primaries were associated with poorer local control. The 5- and 10-year actuarial freedom from distant metastasis were 86 and 81%, respectively. Advanced T-stage (T3-4), lymph node involvement at diagnosis, adenoid cystic and high-grade mucoepidermoid histology were associated with a higher risk of distant metastases. The 10-year cause-specific survival (CSS) and overall survival (OS) were 81 % and 63%, respectively. On multivariate analysis, prognostic factors affecting survival were T-stage (favoring T1-2), and N-stage (favoring NO). When T- and N-stage were combined to form the AJCC stage, the latter became the most significant factor for survival. The 10-year OS was 86% for stage I-II vs. 52% for stage III-IV tumors. Late treatment-related toxicity was low (3/54); most complications were mild and no cranial nerve damage was noted.Surgical resection and carefully planned post-operative radiation therapy for minor salivary gland tumors is well tolerated and effective with high local control rates. AJCC stage was the most significant predictor for survival and should be used for staging minor salivary gland carcinomas.

View details for Web of Science ID 000082784400010

View details for PubMedID 10577702

Cell cycle proteins and the development of oral squamous cell carcinoma ORAL ONCOLOGY Schoelch, M. L., Regezi, J. A., Dekker, N. P., Ng, I. O., McMillan, A., Ziober, B. L., Le, Q. T., Silverman, S., Fu, K. K. 1999; 35 (3): 333-342


Expression of cell cycle regulatory proteins was evaluated in premalignant and malignant oral epithelial lesions, to test the hypothesis that protein regulation of the cell cycle may be altered in the development of oral squamous cell carcinoma. Archived paraffin-embedded specimens (n = 90) from 25 patients with recurrent or persistent lesions were evaluated in immunohistochemically stained sections for cell cycle regulatory proteins p53, Rb, Cyclin D1, p27, and p21. The cell cycle was also evaluated by expression of nuclear protein Ki 67. Sections were graded semiquantitatively using a 0-3 + scale to indicate the percentage of positively stained cells. The initial histologic diagnosis for 17/25 patients was either focal keratosis, mild dysplasia, or moderate dysplasia; the initial diagnosis for the remaining eight patients ranged from severe dysplasia to moderately differentiated squamous cell carcinoma. Thirty-three of 90 specimens showed positive p53 expression, 11 of which were dysplasias. Eighty-nine of 90 specimens, from all stages of disease, showed positive Rb expression. Twenty-three of 90 specimens showed positive Cyclin D1 expression, typically in the later stages (carcinoma) of a patient's disease. Eighty-four of 90 specimens showed positive p21 expression; while 55 of 90 specimens were positive for p27. In control mucosa, p27 was highly expressed, while Rb and p21 proteins were expressed at relatively low levels; p53 and Cyclin D1 proteins were largely absent. Generally, staining of p53, Rb, p21, and Ki 67 increased with time in serial biopsies, while p27 showed decreased staining with disease progression. These data show that cell cycle regulatory proteins are altered in both premalignant and malignant disease, and that protein phenotypes are heterogeneous. P53 expression is seen early, and Cyclin D1 expression is seen late in the development of oral premalignant and malignant disease. Expression of p53, Rb, p21 and Ki67 increased, while p27 decreased, with disease progression.

View details for Web of Science ID 000079456300016

View details for PubMedID 10621856

Apoptosis-associated proteins and the development of oral squamous cell carcinoma ORAL ONCOLOGY Schoelch, M. L., Le, Q. T., Silverman, S., McMillan, A., Dekker, N. P., Fu, K. K., Ziober, B. L., Regezi, J. A. 1999; 35 (1): 77-85


Expression of apoptosis-associated proteins was evaluated in premalignant and malignant oral epithelial lesions, to test the hypothesis that protein regulation of apoptosis may be altered in the development of oral squamous cell carcinoma. Ninety archived paraffin-embedded specimens from 25 patients (two or more sequential biopsies each) and eight control specimens were evaluated in immunohistochemically stained sections for tumor suppressor protein p53, p53 binding protein mdm-2, and apoptosis regulatory proteins Bcl-2, Bcl-X, Bax, and Bak. The initial histologic diagnosis for 17/25 patients was either focal keratosis, mild dysplasia, or moderate dysplasia; the initial diagnosis for the remaining eight patients ranged from severe dysplasia to moderately differentiated squamous cell carcinoma. Thirty of 90 specimens showed positive p53 expression, nine of which were dysplasias. In patients with one or more lesions displaying p53 expression, there was increased intensity of staining with disease progression. Bak was expressed in 57/90 specimens, including 27 dysplasias of various grades. There was also a significantly increased intensity of Bak staining with disease progression, which did not appear to be dependent upon p53 status. Bcl-X was expressed in 73/90 specimens, with staining displayed earlier in premalignant lesions than either p53 or Bak. Ten of 90 specimens were positive for Bcl-2 (all were dysplasias or carcinomas), and only 2/90 specimens were positive for Bax. Eleven of 90 specimens were positive for mdm-2; six of which were also positive for p53. These data show that apoptosis-associated proteins are altered in variable patterns in both premalignant and malignant oral epithelial lesions. p53 and especially Bak and Bcl-X are expressed early; Bax is largely absent; and Bcl-2 and mdm-2 show sporadic expression in the development of oral premalignant and malignant disease.

View details for Web of Science ID 000077473200012

View details for PubMedID 10211314

Post-operative irradiation of minor salivary gland malignancies of the head and neck. Radiotherapy Oncology Le QT, Birdwell S, Terris DJ, Gabalski EC, Varghese A, Fee WE, Goffinet DR. 1999; 2 (52): 165-71
A medical knowledge based system for the section of beam orientations in intensity modulated radiation therapy (IMRT). Int J Radiat Oncol Biol Phys Le QT, Xing L, Pugachev A, Li J , Donaldson S, Goffinet DR, Hancock S, Boyer A. 1998; 3S (45): 246
Soft-tissue sarcomas. In: Phillips TL, Leibel S, eds. Textbook of Radiation Oncology, 1st Edition. Philadelphia: WB Saunders Le QT, Phillips TL, Leibel S. 1998: 1047-1066.
Spinal cord dose discrepancy in IMRT treated patients at Stanford revealed by Monte Carlo dose verification: clinical summary. Int J Radiat Oncol Biol Phys Le QT, Guerrero TM, Pawlicki T, Ma CM, Forster KM, Xing L, Luxton G, Boyer AL, Goffinet DR. 1998; 3S (45): 411
Influence of fraction size, total dose, and overall time on local control of T1-T2 glottic carcinoma 38th Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology LE, Q. T., Fu, K. K., KROLL, S., Ryu, J. K., Quivey, J. M., MEYLER, T. S., Krieg, R. M., Phillips, T. L. ELSEVIER SCIENCE INC. 1997: 11526


To evaluate the influence of fraction size, overall time, total dose, and other prognostic factors on local control of T1 and T2 glottic carcinomas.Between 1956 and 1995, 398 consecutive patients with early glottic carcinoma (315 T1 and 83 T2) were treated with once-a-day definitive radiotherapy at the University of California, San Francisco, and associated institutions. Treatment was delivered 5 days per week. Minimum tumor dose ranged from 46.6 to 77.6 Gy (median: 63 Gy). The fraction size was < 1.8 Gy in 146; 1.8-1.99 Gy in 128; 2.0-2.24 Gy in 62, and > or = 2.25 Gy in 62 patients. Overall time ranged from 34 to 75 days (median: 50 days). The majority of patients treated with a fraction size of 2.25 Gy completed therapy within 43 days. Median follow-up of all alive patients was 116 months (range 3-436 months).Five-year local control was 85% for T1 and 70% for T2 glottic carcinomas (p = 0.0004). For T1 lesions, within the dose and time range evaluated, there was no apparent relationship between fraction size, overall time, total dose, and local control on multivariate analysis. Treatment era was the only significant prognostic factor (p = 0.02), and anterior commissure (AC) involvement was of borderline significance (p = 0.056). Five-year local control was 77% for patients treated between 1956-1970, 89% for between 1971-1980, and 91% for between 1981-1995; 80% for patients with AC involvement and 88% for those without. For T2 lesions, prognostic factors for local control on multivariate analysis were: overall time (p = 0.003), fraction size (p = 0.003), total dose (p = 0.01), impaired vocal cord mobility (p = 0.02), and subglottic extension (p = 0.04). Five-year local control was 100% for T2 lesions treated with overall time < or = 43 days vs. 84% for overall time > 43 days; 100% for fraction size > or = 2.25 Gy vs. 44% for fraction size < 1.8 Gy; 78% for total dose > 65 Gy vs. 60% for total dose < or = 65 Gy; 79% for normal cord mobility vs. 45% for impaired cord mobility, and 58% for lesions with subglottic extension vs. 77% for those without. The severe complication rate for the entire group was low: 1.8%.Total dose, fraction size, and overall time were significant factors for local control of T2 but not T1 glottic carcinomas. Anterior commissure involvement was associated with decreased local control for T1 but not T2 lesions. For T1 lesions, local control improved over the treatment era. For T2 lesions, local control decreased with impaired cord mobility and subglottic extension.

View details for Web of Science ID A1997XU99400014

View details for PubMedID 9300746

Adult medulloblastoma: An analysis of survival and prognostic factors CANCER JOURNAL Le, Q. T., Weil, M. D., Wara, W. M., Lamborn, K. R., Prados, M. D., Edwards, M. S., Gutin, P. H. 1997; 3 (4): 238-245


This analysis aimed to review the experience in the management of adult medulloblastoma at the University of California, San Francisco, and to identify important prognostic factors for survival and posterior fossa control.We performed a retrospective review of 34 adult patients, age > or = 15, with cerebellar medulloblastoma treated with radiotherapy at the University of California, San Francisco from 1970 to 1994. All patients underwent a surgical procedure (complete resection in 17, subtotal resection in 10, and biopsy alone in seven), followed by craniospinal irradiation. Most patients treated after 1979 also received chemotherapy. Twenty were classified as poor-risk due to either incomplete resection or evidence of disease outside of the posterior fossa at diagnosis.The 5-year posterior fossa control and overall survival rates were 61% and 58%, respectively. The majority of relapses occurred in the posterior fossa (14 of 17). Multivariate analysis revealed that age (favoring older patients), gender (favoring female patients), and extent of disease at diagnosis (favoring localized disease) were important prognostic factors for posterior fossa control. There was a trend toward improved posterior fossa control with higher radiation dose to the posterior fossa in patients with a complete resection. Gender and extent of disease at presentation were significant prognostic factors for survival. The 5-year survival rates were 92% for female patients versus 40% for male patients, and 67% for patients with localized disease versus 25% for those with disseminated disease. The prognosis following recurrence was poor; all died of the disease.Survival for adult medulloblastoma was comparable to its pediatric counterpart. In patients with localized disease at presentation, gender (favoring female patients) and age (favoring older patients) were important prognostic factors for posterior fossa control and survival. In patients with disseminated disease at presentation, the prognosis is poor, and innovative therapy is needed to improve survival.

View details for Web of Science ID A1997XN19200009

View details for PubMedID 9263630

Prognostic factors in adult soft-tissue sarcomas of the head and neck 78th Annual Meeting of the American-Radium-Society LE, Q. T., Fu, K. K., KROLL, S., Fitts, L., Massullo, V., Ferrell, L., Kaplan, M. J., Phillips, T. L. ELSEVIER SCIENCE INC. 1997: 97584


The main objectives of this study were (a) to review the treatment results of primary head and neck soft-tissue sarcoma at our institution, (b) to identify important prognostic factors in local control and survival, and (c) to assess the efficacy of salvage therapy.Sixty-five patients were treated at the University of California, San Francisco, between 1961 and 1993. Seventeen patients (27%) had low-grade, 10 (15%) had intermediate-grade, and 38 (58%) had high-grade sarcomas. Tumors were > 5 cm in 35 patients. Local management consisted of surgery alone in 14 patients (22%), surgery and radiotherapy in 40 (61%), and radiotherapy alone in 11 (17%) patients. The median follow-up was 64 months.The 5-year actuarial local control rate of the entire group was 66%. Tumor size and grade were important predictors for local control on multivariate analysis. The actuarial local control rate at 5 years was 92% for T1 vs. 40% for T2 primaries (p = 0.004), and 80% for Grade 1-2 vs. 48% for Grade 3 tumors (p = 0.01). None of the patients treated with radiotherapy alone with a dose of 50-65 Gy were controlled locally. Combined radiotherapy and surgery appeared to yield superior local control compared to surgery alone (77% vs. 59%); however, the difference was not statistically significant. The 5-year actuarial overall and cause-specific survivals were 56% and 60%, respectively. Unfavorable prognostic factors for cause-specific survival on multivariate analysis were age > 55 (p = 0.009), high tumor grade (p = 0.0002), inadequate surgery (p = 0.008), and positive surgical margins (p = 0.0009). In patients who underwent salvage therapy for treatment failure, the 5-year actuarial survival after salvage treatment was 26%.Tumor size and grade were important predictors for local control. Age, grade, adequacy of surgery, and status of surgical margins were significant prognostic factors for survival. There was a trend of improved local control with combined surgery and radiotherapy compared to either modality alone for high-risk patients. Radiotherapy alone with doses < or = 65 Gy was insufficient for control of gross disease. Aggressive salvage therapy was worthwhile in patients whose disease was uncontrolled after the initial treatment.

View details for Web of Science ID A1997XB01200002

View details for PubMedID 9169803

PATTERN OF RECURRENCE OF MEDULLOBLASTOMA AFTER LOW-DOSE CRANIOSPINAL RADIOTHERAPY 35th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Wara, W. M., LE, Q. T., Sneed, P. K., Larson, D. A., Prados, M. D., Levin, V. A., Edwards, M. S., Weil, M. D. PERGAMON-ELSEVIER SCIENCE LTD. 1994: 55156


We retrospectively evaluated relapse of medulloblastoma after low- or high-dose craniospinal radiotherapy, and after conventional or hyperfractionated posterior fossa irradiation.Ninety-two pediatric patients were treated postoperatively since 1970 at the University of California, San Francisco. Until 1989, we employed conventional fractionation with low (< or = 30 Gy) or high-dose craniospinal fields and low-dose (< or = 56 Gy) posterior fossa boosts. Recently, hyperfractionation delivered low- or high-dose to the craniospinal axis and high-dose to the posterior fossa. Most patients treated after 1979 received chemotherapy.Median follow-up was 70 months. Five-year disease-free survival was 36% (22% for poor-risk vs. 59% for good-risk patients). Five-year overall survival was 52% (43% for poor vs. 68% for good-risk). Neither the dose to the posterior fossa nor the craniospinal axis was statistically related to recurrence. Failure in the posterior fossa occurred despite boosts greater than 56 Gy. Females, over the age of 6 years, had significantly better relapse-free survival than males of the same age. Six of the 54 patients who relapsed were long-term survivors.Low-dose craniospinal radiotherapy, where the majority of patients received chemotherapy, was not associated with increased failure. High-dose posterior fossa hyperfractionation did not improve control. Long-term survival was noted in a number of patients after relapse. We recommend 60 Gy or greater with conventional fractions to the primary area, and continued study of low-dose craniospinal irradiation with adjuvant chemotherapy.

View details for Web of Science ID A1994PK60400004

View details for PubMedID 7928485