Beth Beadle, MD

Abstract

BACKGROUND: We conducted the current systemic review to provide up-to-date literature summary and optimal evidence-based recommendations for ipsilateral radiation for squamous cell carcinoma of the tonsil.METHODS: We performed literature search of peer-reviewed journals through PubMed. The search strategy and subject-specific keywords were developed based on the expert panel's consensus. Articles published from January 2000 to May 2020 with full text available on PubMed and restricted to the English language and human subjects were included. Several prespecified search terms were used to identify relevant publications and additional evidence published since the initial American College of Radiology Appropriateness Criteria Ipsilateral Tonsil Radiation recommendation was finalized in 2012. The full bibliographies of identified articles were reviewed and irrelevant studies were removed.RESULTS: The initial search and review returned 46 citations. The authors added three citations from bibliographies, websites, or books not found in the literature search. Of the 49 citations, 30 citations were retained for further detailed review, and 14 of them were added to the evidence table. Articles were removed from the bibliography if they were not relevant or generalizable to the topic, or focused on unknown primary disease. Several commonly encountered clinical case variants were created and panelists anonymously rated each treatment recommendation. The results were reviewed and disagreements discussed.CONCLUSIONS: The panel provided updated evidence and recommendations for ipsilateral radiation for squamous cell carcinoma of the tonsil in the setting of primary radiation-based therapy and postoperative adjuvant radiotherapy. This committee did not reach agreements for some case variants due to a lack of strong evidence supporting specific treatment decisions, indicating a further need for research in these topics.

View details for DOI 10.1002/hed.26492

View details for PubMedID 33068064

View details for Web of Science ID 000579885400098

View details for Web of Science ID 000579885400093

Abstract

Purpose: Our institution cancelled all in-person clerkships owing to the coronavirus disease 2019 pandemic. In response, we designed a virtual radiation oncology medical student clerkship.Methods and Materials: We convened an advisory panel to design a virtual clerkship curriculum. We implemented clerkship activities using a cloud-based learning management system, video web conferencing systems, and a telemedicine portal. Students completed assessments pre- and postclerkship to provide data to improve future versions of the clerkship.Results: The virtual clerkship spans 2 weeks and is graded pass or fail. Students attend interactive didactic sessions during the first week and participate in virtual clinic and give talks to the department during the second week. Didactic sessions include lectures, case-based discussions, treatment planning seminars, and material adapted from the Radiation Oncology Education Collaborative Study Group curriculum. Students also attend virtual departmental quality assurance rounds, cancer center seminars, and multidisciplinary tumor boards. The enrollment cap was met during the first virtual clerkship period (April 27 through May 8, 2020), with a total of 12 students enrolling.Conclusions: Our virtual clerkship can increase student exposure and engagement in radiation oncology. Data on clerkship outcomes are forthcoming.

View details for DOI 10.1016/j.adro.2020.05.006

View details for PubMedID 32775783

Abstract

Primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid is a rare and aggressive neoplasm. Fewer than 50 cases have been reported in the literature, and the genetic driving mutations are unknown. Herein, we present a case of this rare disease along with the results of molecular profiling via targeted next generation sequencing. The patient is an 85-year-old man who presented with left eyelid swelling initially thought to be a chalazion. After no response to incision and drainage and antibiotics, an incisional biopsy was performed. Histologic sections revealed a proliferation of cells with signet-ring and histiocytoid morphology arranged singly and in cords infiltrating the dermis, subcutaneous tissue, and muscle. The lesional cells strongly expressed cytoplasmic cytokeratin 7 and nuclear androgen receptor. Next generation sequencing revealed a CDH1 mutation, which is known to confer signet-ring morphology in other carcinomas. Pathogenic mutations in NTRK3, CDKN1B and PIK3CA were also detected. To our knowledge, this is the first documented genetic analysis of this rare disease with findings that offer insights into disease pathogenesis and potential therapeutic targets. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/cup.13733

View details for PubMedID 32358805

Abstract

PURPOSE: We evaluated the impact of a virtual radiation oncology clerkship.METHODS AND MATERIALS: We developed a 2-week virtual radiation oncology clerkship that launched on April 27, 2020. Clerkship components included a virtual clinic with radiation oncology faculty and residents, didactic lectures, student talks, and supplemental sessions such as tumor boards and chart rounds. Medical students completed pre- and post-clerkship self-assessments. Faculty and resident participants also completed surveys on their experience with virtual lectures and clinics. Pre- and post-clerkship results were compared using a 2-sided paired t test. An analysis of variance model was used to analyze the clerkship components.RESULTS: Twenty-six medical students, including 4 visiting students, enrolled over 2 clerkship periods (4 weeks). All students completed the pre- and post-clerkship self-assessments and agreed that the clerkship improved their understanding of radiation oncology. Compared with 3 (11.5%) students who agreed that they understood the daily responsibilities of a radiation oncologist before the clerkship, 22 (84.6%) students agreed and 3 (11.5%) strongly agreed that they understood the daily responsibilities of a radiation oncologist after the clerkship (P < .0001). Although 15 students (57.7%) reported an increased interest in radiation oncology because of the clerkship, the mean level of interest in radiation oncology as a career remained the same, with pre- and post-clerkship scores of 3.0 (0.9) and 3.0 (1.1) on a 5-point scale, respectively (P = .7). Students found virtual clinic and didactic lectures to be the most valuable components of the clerkship. Most respondents agreed (30.8%) or strongly agreed (65.4%) to recommend the clerkship to their classmates.CONCLUSIONS: Our virtual clerkship was effective in increasing medical student interest in and knowledge about radiation oncology. These data will help optimize a new paradigm of virtual radiation oncology education for medical students during COVID-19 and beyond.

View details for DOI 10.1016/j.ijrobp.2020.06.050

View details for PubMedID 32890529

Abstract

Wet (neovascular) age-related macular degeneration (AMD) is the leading cause of blindness in the USA. The mainstay treatment requires monthly intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs, associated with multiple visits, high cost, and the risk of procedural injury and infection. Anti-VEGF drugs inhibit the formation of neovasculature but do not directly attack it. Radiotherapy can destroy neovasculature and potentially also inhibit wet-AMD associated inflammation and fibrosis not addressed by VEGF inhibitors. However, the current collimation-based radiotherapy device uses fixed 4 mm beams, which are prone to overtreat or undertreat the choroidal neovascularization (CNV) lesions because of their various sizes and shapes. This simulation study evaluates personalized conformal treatment with focused kV radiation using cutting-edge polycapillary x-ray optics.Simulation of the polycapillary optics was achieved via Monte Carlo (MC)-based 3D geometric ray tracing. Phase-space files modeling the focused photons were generated. The method was previously verified by phantom measurements. The ultrasmall ~0.2 mm beam focal spot perpendicular to the beam direction enables spatially fractionated grid therapy, which has been shown to preferentially damage abnormal neovascular blood vessels vs normal ones. Geant4-based MC simulations of scanning while rotating beam delivery were performed to conformally treat three clinical cases of large, medium, and small CNV lesions with regular and grid deliveries. Dose delivery uncertainties due to positioning errors were analyzed, including 0.75 mm displacement in the three orthogonal directions and 5 vertical/horizontal rotation of the eyeball.The simulated CNV treatments by 60 kVp focused x-ray beams show highly-conformal delivery of dose to the lesion plus margin (0.75 mm) with sharp dose fall-offs and controllable spatial modulation patterns. The 90%-10% isodose penumbra is <0.5 mm. With a 16 Gy prescription dose to the lesions, the critical structure doses are well below the tolerance. The average CNV dose varies within 10% (mostly within 4%) due to 0.75-mm linear displacements and 5-degree gaze angle rotation of the eyeball.Focused kV technique allows personalized treatment of CNV lesions and reduces unwanted radiation to adjacent healthy tissue. The simulated dose distribution is superior to currently available techniques.

View details for DOI 10.1002/mp.14404

View details for PubMedID 32683708

Abstract

This study aimed to compare outcomes in patients with head and neck lymphedema receiving either a home-based lymphedema treatment program or a hybrid approach including both home-based treatment and regular clinical visits.Outcomes were assessed in patients receiving head and neck lymphedema rehabilitation. Baseline measures of neck, submental, and facial edema were obtained and repeated following treatment. A home program was recommended for all patients, and those receiving hybrid care received the same recommendations as well as a visit with the lymphedema therapist for additional treatment. Their outcomes were compared using standard statistical analysis.Fifty consecutive individuals were included, 25 in each group. Adherence to at least 50% of recommended treatment was reported in 68% of those receiving home-based treatment and 84% of those receiving hybrid care. Significant improvement was demonstrated for 66% of patients. There was no statistically significant difference between treatment groups with regard to clinically significant improvement (P = .15). Patients receiving hybrid therapy demonstrated treatment advantages regarding facial edema (P = .037). Adherence to treatment was associated with clinical improvement (P = .047).Comparable benefits were observed regardless of whether patients had a home-based or hybrid lymphedema treatment approach. These data suggest a home-based treatment approach may be appropriate for patients unable to participate in clinical sessions. However, for patients with significant facial edema, a hybrid approach may be preferable. Adherence was associated with better outcomes. Given these findings, future investigations should consider strategies to improve adherence to optimize the outcomes lymphedema treatment.3b Laryngoscope, 2020.

View details for DOI 10.1002/lary.28549

View details for PubMedID 32068894

Abstract

Oncology has undergone rapid progress, with emerging developments in areas including cancer stem cells, molecularly targeted therapies, genomic analyses, and individually tailored immunotherapy. These advances have expanded the tools available in the fight against cancer. Some of these have seen broad media coverage resulting in justified public attention. However, these achievements have only been possible due to rapid developments in the expanding field of biomedical informatics and information technology (IT). Artificial intelligence, radiomics, electronic health records, and electronic patient-reported outcome measures (ePROMS) are only a few of the developments enabling further progress in oncology. The promising impact of IT in oncology will only become reality through a multidisciplinary approach to the complex challenges ahead.

View details for DOI 10.1159/000507586

View details for PubMedID 32408309

Abstract

The aims of this systematic review are to (a) evaluate the current literature on the impact of postoperative therapy for resected squamous cell carcinoma of the head and neck (SCCHN) on oncologic and non-oncologic outcomes and (b) identify the optimal evidence-based postoperative therapy recommendations for commonly encountered clinical scenarios.An analysis of the medical literature from peer-reviewed journals was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Prospective studies and methodology-based systematic reviews and meta-analyses of postoperative therapy for SCCHN were identified by searching Medline (OVID) and EMBASE (Elsevier) using controlled vocabulary terms (ie, National Library of Medicine Medical Subject Headings [MeSH], EMTREE). Study screening and selection was performed with Covidence software and full-text review. The RAND/UCLA appropriateness method was used by the expert panel to rate the appropriate use of postoperative therapy, and the modified Delphi method was used to come to consensus.A total of 5660 studies were identified and screened using the title and abstract, leading to 201 studies assessed for relevance using full-text review. After limitation to the eligibility criteria, 101 studies from 1977 to 2020 were identified, including 77 with oncologic endpoints and 24 with function and quality of life endpoints. All studies reported staging prior to the implementation of American Joint Committee on Cancer (AJCC-8).Prospective clinical studies and systematic reviews identified through the PRISMA systematic review provided good evidence for consensus statements regarding the appropriate use of postoperative therapy for resected SCCHN. Further research is needed in domains where consensus by the expert panel could not be achieved for the appropriateness of specific postoperative therapeutic interventions.

View details for DOI 10.1002/hed.26490

View details for PubMedID 33098180

Abstract

OBJECTIVE: For patients with head and neck squamous cell carcinoma (HNSCC), delays in the initiation of radiotherapy (RT) have been closely associated with worse outcomes. We sought to investigate whether RT modality (proton vs. photon) is associated with differences in the time to initiation of RT.METHODS: The National Cancer Database was queried for patients diagnosed with nonmetastatic HNSCC between 2004 and 2015 who received either proton or photon RT as part of their initial treatment. Wilcoxon rank-sum and chi-square tests were used to compare continuous and categorical variables, respectively. Multivariable logistic regression was used to determine the association between use of proton RT and delayed RT initiation.RESULTS: A total of 175,088 patients with HNSCC receiving either photon or proton RT were identified. Patients receiving proton RT were more likely to be white, reside in higher income areas, and have private insurance. Proton RT was associated with delayed RT initiation compared to photon RT (median 59days vs. 45, P <0.001). Receipt of proton therapy was independently associated with RT initiation beyond 6weeks after diagnosis (adjusted OR [aOR, definitive RT] = 1.69; 95% confidence interval [CI] 1.26-2.30) or surgery (aOR [adjuvant RT] = 4.08; 95% CI 2.64-6.62). In the context of adjuvant proton RT, increases in treatment delay were associated with worse overall survival (weeks, adjusted hazard ratio =1.099, 95% CI 1.011-1.194).CONCLUSION: Use of proton therapy is associated with delayed RT in both the definitive and adjuvant settings for patients with HNSCC and could be associated with poorer outcomes.LEVEL OF EVIDENCE: 2b Laryngoscope, 122:0000-0000, 2019 Laryngoscope, 2019.

View details for DOI 10.1002/lary.28458

View details for PubMedID 31837165

View details for DOI 10.1002/mp.13814]

View details for Web of Science ID 000494894600035

Abstract

PURPOSE: To develop a head and neck normal structures auto-contouring tool that could be used to automatically detect the errors in auto-contours from a clinically-validated auto-contouring tool.METHODS: An auto-contouring tool based on convolutional neural networks (CNN) was developed for 16 normal structures of the head and neck and tested to identify the contour errors from a clinically-validated multi-atlas-based auto-contouring system (MACS). The CT scans and clinical contours from 3495 patients were semi-automatically curated and used to train and validate the CNN-based auto-contouring tool. The final accuracy of the tool was evaluated by calculating the Sorensen-Dice similarity coefficients (DSC) and Hausdorff distances between the automatically generated contours and physician-drawn contours on 174 internal and 24 external CT scans. Lastly, the CNN-based tool was evaluated on 60 patients' CT scans to investigate the possibility to detect contouring failures. The contouring failures on these patients were classified as either minor or major errors. The criteria to detect contouring errors were determined by analyzing the DSC between the CNN- and MACS-based contours under two independent scenarios: 1. contours with minor error are clinically acceptable and 2. contours with minor errors are clinically unacceptable.RESULTS: The average DSC and Hausdorff distance of our CNN-based tool were 98.4%/1.23cm for brain, 89.1%/0.42cm for eyes, 86.8%/1.28cm for mandible, 86.4%/0.88cm for brainstem, 83.4%/0.71cm for spinal cord, 82.7%/1.37cm for parotids, 80.7%/1.08cm for esophagus, 71.7%/0.39cm for lenses, 68.6%/0.72 for optic nerves, 66.4%/0.46cm for cochleas, and 40.7%/0.96cm for optic chiasm. With the error detection tool, the proportions of the clinically unacceptable MACS contours that were correctly detected were 0.99/0.80 on average except for the optic chiasm, when contours with minor errors are clinically acceptable/unacceptable respectively. The proportions of the clinically acceptable MACS contours that were correctly detected were 0.81/0.60 on average except for the optic chiasm, when contours with minor errors are clinically acceptable/unacceptable respectively.CONCLUSION: Our CNN-based auto-contouring tool performed well on both the publically-available and the internal datasets. Furthermore, our results show that CNN-based algorithms are able to identify ill-defined contours from a clinically-validated and used multi-atlas-based auto-contouring tool. Therefore, our CNN-based tool can effectively perform automatic verification of MACS contours.

View details for DOI 10.1002/mp.13814

View details for PubMedID 31505046

Abstract

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rapidly increasing. Disease stage and smoking history are often used in current clinical trials to select patients for de-intensification therapy, but these features lack sufficient accuracy for predicting disease relapse. Purpose: To develop an imaging signature to assess early response and predict outcomes of OPSCC. Methods: We retrospectively analyzed 162 OPSCC patients treated with concurrent chemoradiotherapy, equally divided into separate training and validation cohorts with similar clinical characteristics. A robust consensus clustering approach was used to spatially partition the primary tumor and involved lymph nodes into subregions (i.e., habitats) based on fluorine 18 (18F) fluorodeoxyglucose (FDG) PET and contrast CT imaging. We proposed quantitative image features to characterize the temporal volumetric change of the habitats and peritumor/nodal tissue between baseline and mid-treatment. The reproducibility of these features was evaluated. We developed an imaging signature to predict progression-free survival (PFS) by fitting an L1-regularized Cox regression model. Results: We identified three phenotypically distinct intratumoral habitats, which were (1) metabolically active and heterogeneous, (2) enhancing and heterogeneous, and (3) metabolically inactive and homogeneous. The final Cox model consisted of four habitat evolution-based features. In both cohorts, this imaging signature significantly outperformed traditional imaging metrics including mid-treatment metabolic tumor volume for predicting PFS, with C-index: 0.72 vs 0.67 (training) and 0.66 vs 0.56 (validation). The imaging signature stratified patients into high-risk vs low-risk groups with 2-year PFS rates: 59.1% vs 89.4% (HR=4.4, 95% CI: 1.4-13.4, training), and 61.4% vs 87.8% (HR=4.6, 95% CI: 1.7-12.1, validation). It remained an independent predictor of PFS in multivariable analysis adjusting for stage, human papillomavirus status, and smoking history. Conclusion: The proposed imaging signature allows more accurate prediction of disease progression and, if prospectively validated, may refine OPSCC patient selection for risk-adaptive therapy.

View details for DOI 10.2967/jnumed.119.230037

View details for PubMedID 31420498

View details for DOI 10.1002/lary.27544

View details for Web of Science ID 000471915700026

Abstract

PURPOSE: Prognostic biomarkers of disease relapse are needed for risk-adaptive therapy of oropharyngeal cancer (OPC). This work aims to identify an imaging signature to predict distant metastasis in OPC.MATERIALS/METHODS: This single-institution retrospective study included 140 patients treated with definitive concurrent chemoradiotherapy, for whom both pre and mid-treatment contrast-enhanced CT scans were available. Patients were divided into separate training and testing cohorts. Forty-five quantitative image features were extracted to characterize tumor and involved lymph nodes at both time points. By incorporating both imaging and clinicopathological features, a random survival forest (RSF) model was built to predict distant metastasis-free survival (DMFS). The model was optimized via repeated cross-validation in the training cohort, and then independently validated in the testing cohort.RESULTS: The most important features for predicting DMFS were the maximum distance among nodes, maximum distance between tumor and nodes at mid-treatment, and pre-treatment tumor sphericity. In the testing cohort, the RSF model achieved good discriminability for DMFS (C-index=0.73, P=0.008), and further divided patients into two risk groups with different 2-year DMFS rates: 96.7% vs. 67.6%. Similar trends were observed for patients with p16+ tumors and smoking 10 pack-years. The RSF model based on pre-treatment CT features alone achieved lower performance (C-index=0.68, P=0.03).CONCLUSION: Integrating tumor and nodal imaging characteristics at baseline and mid-treatment CT allows prediction of distant metastasis in OPC. The proposed imaging signature requires prospective validation, and if successful, may help identify high-risk HPV-positive patients who should not be considered for de-intensification therapy.

View details for PubMedID 30940529

View details for Web of Science ID 000462612300026

Abstract

PURPOSE: The purpose of this study was to validate a fully automatic treatment planning system for conventional radiotherapy of cervical cancer. This system was developed to mitigate staff shortages in low-resource clinics.METHODS: In collaboration with hospitals in South Africa and the United States, we have developed the Radiation Planning Assistant (RPA), which includes algorithms for automating every step of planning: delineating the body contour, detecting the marked isocenter, designing the treatment-beam apertures, and optimizing the beam weights to minimize dose heterogeneity. First, we validated the RPA retrospectively on 150 planning computed tomography (CT) scans. We then tested it remotely on 14 planning CT scans at two South African hospitals. Finally, automatically planned treatment beams were clinically deployed at our institution.RESULTS: The automatically and manually delineated body contours agreed well (median mean surface distance, 0.6 mm; range, 0.4 to 1.9 mm). The automatically and manually detected marked isocenters agreed well (mean difference, 1.1 mm; range, 0.1 to 2.9 mm). In validating the automatically designed beam apertures, two physicians, one from our institution and one from a South African partner institution, rated 91% and 88% of plans acceptable for treatment, respectively. The use of automatically optimized beam weights reduced the maximum dose significantly (median, -1.9%; P < .001). Of the 14 plans from South Africa, 100% were rated clinically acceptable. Automatically planned treatment beams have been used for 24 patients with cervical cancer by physicians at our institution, with edits as needed, and its use is ongoing.CONCLUSION: We found that fully automatic treatment planning is effective for cervical cancer radiotherapy and may provide a reliable option for low-resource clinics. Prospective studies are ongoing in the United States and are planned with partner clinics.

View details for PubMedID 30629457

Abstract

To develop and implement an automated plan check (APC) tool using a Six Sigma methodology with the aim of improving safety and efficiency in external beam radiotherapy.The Six Sigma define-measure-analyze-improve-control (DMAIC) framework was used by measuring defects stemming from treatment planning that were reported to the departmental incidence learning system (ILS). The common error pathways observed in the reported data were combined with our departmental physics plan check list, and AAPM TG-275 identified items. Prioritized by risk priority number (RPN) and severity values, the check items were added to the APC tool developed using Varian Eclipse Scripting Application Programming Interface (ESAPI). At 9months post-APC implementation, the tool encompassed 89 check items, and its effectiveness was evaluated by comparing RPN values and rates of reported errors. To test the efficiency gains, physics plan check time and reported error rate were prospectively compared for 20 treatment plans.The APC tool was successfully implemented for external beam plan checking. FMEA RPN ranking re-evaluation at 9 months post-APC demonstrated a statistically significant average decrease in RPN values from 129.2 to 83.7 (P<.05). After the introduction of APC, the average frequency of reported treatment-planning errors was reduced from 16.1% to 4.1%. For high-severity errors, the reduction was 82.7% for prescription/plan mismatches and 84.4% for incorrect shift note. The process shifted from 4 to 5 quality for isocenter-shift errors. The efficiency study showed a statistically significant decrease in plan check time (10.17.3min, P=.005) and decrease in errors propagating to physics plan check (80%).Incorporation of APC tool has significantly reduced the error rate. The DMAIC framework can provide an iterative and robust workflow to improve the efficiency and quality of treatment planning procedure enabling a safer radiotherapy process.

View details for DOI 10.1002/acm2.12678

View details for PubMedID 31423729

Abstract

To assess the risk of failure of a recently developed automated treatment planning tool, the Radiation Planning Assistant (RPA) and to determine the reduction in these risks with implementation of a quality assurance (QA) program specifically designed for the RPA.We used failure mode and effects analysis (FMEA) to assess the risk of the RPA. The steps involved in the workflow of planning a 4-field box treatment of cervical cancer with the RPA were identified. Then, the potential failure modes at each step and their causes were identified and scored according to their likelihood of occurrence, severity, and likelihood of going undetected. Additionally, the impact of the components of the QA program on the detectability of the failure modes was assessed. The QA program was designed to supplement a clinic's standard QA processes and consisted of 3 components: (1) automatic, independent verification of the results of automated planning; (2) automatic comparison of treatment parameters to expected values; and (3) guided manual checks of the treatment plan. A risk priority number (RPN) was calculated for each potential failure mode with and without use of the QA program.In the RPA automated treatment planning workflow, we identified 68 potential failure modes with 113 causes. The average RPN was 91 without the QA program and 68 with the QA program (maximum RPNs were 504 and 315, respectively). The reduction in RPN was due to an improvement in the likelihood of detecting failures, resulting in lower detectability scores. The top-ranked failure modes included incorrect identification of the marked isocenter, inappropriate beam aperture definition, incorrect entry of the prescription into the RPA plan directive, and lack of a comprehensive plan review by the physician.Using FMEA, we assessed the risks in the clinical deployment of an automated treatment planning workflow and showed that a specialized QA program for the RPA, which included automatic QA techniques, improved the detectability of failures, reducing this risk. However, some residual risks persisted, which were similar to those found in manual treatment planning, and human error remained a major cause of potential failures. Through the risk analysis process, we identified 3 key aspects of safe deployment of automated planning: (1) user training on potential failure modes; (2) comprehensive manual plan review by physicians and physicists; and (3) automated QA of the treatment plan. This article is protected by copyright. All rights reserved.

View details for PubMedID 31002389

Abstract

Over the course of the last several decades, the treatment options for early laryngeal cancers (T1 and T2) have evolved; however, simultaneously the mortality rate has increased. As larynx preservation approaches have become the standard of care, the selection of the proper treatment modality has become paramount. Radiation therapy or transoral laser microsurgery are the most common options for treatment of these early lesions. Oncologic and functional outcomes are considered equivalent between the two modalities for early glottic cancers; however, no direct comparisons exist for robust analysis. In terms of larynx preservation, there also is not compelling data favoring one treatment option or another. For early stage lesions, the goal for any larynx-sparing technique, either radiation or surgery, should be the intent to cure with single modality treatment and minimal short- and long-term toxicity. This article is designed to create a frame of reference for managing early stage disease with respect to lesions of the glottis and supraglottis while weighing treatment implications from an oncologic, functional, and cost perspective.

View details for PubMedID 30527248

Abstract

OBJECTIVES/HYPOTHESIS: Based on current guidelines, surgical and nonsurgical therapies are viable frontline treatment for patients with locoregional oropharyngeal carcinoma (OPC). We sought to compare financial parameters between chemoradiation and transoral robotic surgery (TORS) in this patient population.STUDY DESIGN: Case-control study.METHODS: In this study we identified patients with selected American Joint Committee on Cancer 7th Edition stage II to IVa OPC treated with TORS between January 2013 and December 2014. Fifteen patients who underwent TORS were stage matched with 15 patients treated with chemoradiation. Total charges and cost data for each patient were analyzed at 4-month and 1-year time points; functional and oncologic outcomes were assessed.RESULTS: There were no significant differences in functional and oncologic outcomes. Patients undergoing TORS had a longer inpatient hospital stay, and most required a nasogastric tube for an average of 3.5 days. There were no local or regional recurrences. Across all time points, the TORS group had lower charges and costs compared to the chemoradiation group, with 14% lower costs at 1 year. In the chemoradiation group, nearly two-thirds of costs came from radiation therapy and pharmacy expenses. Chemotherapy accounted for most pharmacy costs. The costs of operating the surgical robot accounted for a about half of surgical costs.CONCLUSIONS: Selected patients with stage II to IVa oropharyngeal carcinoma treated with TORS may incur lower costs than those treated nonsurgically. With rising healthcare spending, the financial impact of treatment might be considered for those patients eligible for treatment regimens with comparable functional and oncologic outcomes.LEVEL OF EVIDENCE: 3b Laryngoscope, 2018.

View details for PubMedID 30485445

View details for Web of Science ID 000446532700487

View details for Web of Science ID 000432447200033

Abstract

Dysphagia following treatment for head and neck cancer is one of the most significant morbidities impacting quality of life. Despite the value of prophylactic exercises to mitigate the impact of radiation on long-term swallowing function, adherence to treatment is limited. The purpose of this investigation was to explore the feasibility of a mobile health application to support patient adherence to swallowing therapy during radiation-based treatment. 36 patients undergoing radiation therapy were provided with the Vibrent mobile application as an adjunct to standard swallowing therapy. The application included exercise videos, written instructions, reminders, exercise logging, and educational content. 80% of participants used the app during treatment and logged an average of 102 exercise sessions over the course of treatment. 25% of participants logged at least two exercise sessions per day over the 7-week treatment period, and 53% recorded at least one session per day. Exit interviews regarding the patient experience with the Vibrent mobile application were largely positive, but also provided actionable strategies to improve future versions of the application. The Vibrent mobile application appears to be a tool that can be feasibly integrated into existing patient care practices and may assist patients in adhering to treatment recommendations and facilitate communication between patients and providers between encounters.

View details for PubMedID 28965209

View details for PubMedID 29485069

Abstract

The purpose of this study was to present our experience with retropharyngeal node reirradiation using highly conformal radiotherapy (RT).A retrospective screen of 2504 consecutively irradiated patients with head and neck malignancies between 2005 and 2015 identified 19 patients who underwent reirradiation for retropharyngeal node metastasis. Clinical and toxicity outcomes were assessed in these patients.Thirteen patients (68%) had squamous cell carcinoma. Eleven patients (58%) received conventionally fractionated intensity-modulated radiotherapy (IMRT) or proton therapy, and 8 patients (42%) received single-fractionated or hypofractionated stereotactic RT. Fourteen patients (74%) received chemotherapy. Median follow-up was 14.7 months. The 1-year local control, locoregional control, overall survival, and progression-free survival rates were 100%, 94%, 92%, and 92%, respectively. Three patients (16%) experienced acute grade 3 toxicity and occurred in those treated with IMRT. There was no late grade 3 toxicity.Retropharyngeal node reirradiation with conformal therapy is well tolerated and associated with excellent short-term disease control.

View details for PubMedID 28741749

Abstract

Purpose: The primary cause of death due to head and neck squamous cell carcinoma (HNSCC) is local treatment failure. The goal of this study was to examine this phenomenon using an unbiased approach.Experimental Design: We utilized human papilloma virus (HPV)-negative cell lines rendered radiation-resistant (RR) via repeated exposure to radiation, a panel of HPV-negative HNSCC cell lines and three cohorts of HPV-negative HNSCC tumors (n = 68, 97, and 114) from patients treated with radiotherapy and subjected to genomic, transcriptomic, and proteomic analysis.Results: RR cell lines exhibited upregulation of several proteins compared with controls, including increased activation of Axl and PI3 kinase signaling as well as increased expression of PD-L1. Additionally, inhibition of either Axl or PI3 kinase led to decreased PD-L1 expression. When clinical samples were subjected to RPPA and mRNA expression analysis, PD-L1 was correlated with both Axl and PI3K signaling as well as dramatically associated with local failure following radiotherapy. This finding was confirmed examining a third cohort using immunohistochemistry. Indeed, tumors with high expression of PD-L1 had failure rates following radiotherapy of 60%, 70%, and 50% compared with 20%, 25%, and 20% in the PD-L1-low expression group (P = 0.01, 1.9 10(-3), and 9 10(-4), respectively). This finding remained significant on multivariate analysis in all groups. Additionally, patients with PD-L1 low/CD8(+) tumor-infiltrating lymphocytes high had no local failure or death due to disease (P = 5 10(-4) and P = 4 10(-4), respectively).Conclusions: Taken together, our data point to a targetable Axl-PI3 kinase-PD-L1 axis that is highly associated with radiation resistance. Clin Cancer Res; 23(11); 2713-22. 2017 AACR.

View details for DOI 10.1158/1078-0432.CCR-16-2586

View details for PubMedID 28476872

Abstract

The purpose of this study was to determine the impact of CT-determined pretreatment primary tumor volume on survival and disease control in T4a laryngeal squamous cell carcinoma (SCC).We retrospectively reviewed 124 patients with T4a laryngeal cancer from 2000-2011. Tumor volume measurements were collected and correlated with outcomes.Five-year overall survival (OS) for patients with tumor volume 21 cm(3) treated with larynx preservation (n = 26 of 41) was significantly inferior compared to <21 cm(3) (42% vs 64%, respectively; P = .003). Five-year OS for patients with tumor volumes 21 cm(3) in the cohort treated with total laryngectomy followed by radiotherapy (RT; n = 42 of 83) was not statistically significant when compared to <21 cm(3) (50% vs 63%, respectively; P = .058). On multivariate analysis, tumor volume 21 cm(3) was a significant independent correlate of worse disease-specific survival (DSS; P = .004), event-free survival (P = .005), recurrence-free survival (RFS; P = .04), noncancer cause-specific survival (P = .02), and OS (P = .0002).Pretreatment CT-based tumor volume is an independent prognostic factor of outcomes in T4a laryngeal cancer.

View details for DOI 10.1002/hed.24804

View details for PubMedID 28464542

View details for DOI 10.1002/hed.24666

View details for Web of Science ID 000397856000004

View details for DOI 10.1002/lary.26153

View details for Web of Science ID 000397572700020

View details for DOI 10.1016/j.ijrobp.2016.06.010

View details for Web of Science ID 000397913400012

Abstract

Conditional survival (CS), the survival beyond a pre-defined time interval, can identify periods of higher mortality risk for patients with locally advanced laryngeal cancer who face treatment-related toxicity and comorbidities related to alcohol and smoking in the survivorship setting. Using Weibull regression modeling, we analyzed retrospectively abstracted data from 638 records of patients who received radiation to identify prognostic factors for overall survival (OS) and recurrence free survival (RFS) for the first 3 years of survival and for OS conditional upon 3 years of survival. The CS was iteratively calculated, stratifying on variables that were statistically significant on multivariate regression. Predictive nomograms were generated. The median total follow up time was 175 months. The 3- and 6- year actuarial overall survival (OS) was 68% (95% confidence interval [CI] 65-72%) and 49% (CI 45-53%). The 3-year conditional overall survival (COS) at 3 years was 72% (CI 65-74%). Black patients had worse COS over time. Nodal disease was significantly associated with recurrence, but after 3 years, the 3-year conditional RFS converged for all nodal groups. In conclusion, the CS analysis in this patient cohort identified subgroups and time intervals that may represent opportunities for intervention.

View details for DOI 10.1038/srep43928

View details for Web of Science ID 000395799900001

View details for PubMedID 28276466

Abstract

The purpose is to examine the relationship between mandibular osteoradionecrosis (ORN) and chronic dysphagia in long-term oropharynx cancer (OPC) survivors, and to determine the perceived symptom burden associated with ORN.Medical records of 349 OPC patients treated with bilateral IMRT and systemic therapy were reviewed. ORN was graded using a published 4-point classification schema. Patients were considered to have chronic dysphagia if they had aspiration pneumonia, stricture or aspiration detected by fluoroscopy or endoscopy, and/or feeding tube dependence in long-term follow-up 1year following radiotherapy. MD Anderson Symptom Inventory - Head and Neck Module (MDASI-HN) scores were analyzed in a nested cross-sectional survey sample of 118 patients.34 (9.7%, 95% CI: 6.8-13.3%) patients developed ORN and 45 (12.9%, 95% CI: 9.6-16.9%) patients developed chronic dysphagia. Prevalence of chronic dysphagia was significantly higher in ORN cases (12/34, 35%) compared to those who did not develop ORN (33/315, 11%, p<0.001). ORN grade was also significantly associated with prevalence of dysphagia (p<0.001); the majority of patients with grade 4 ORN requiring major surgery (6 patients, 75%) were found to have chronic dysphagia. Summary MDASI-HN symptom scores did not significantly differ by ORN grade. Significantly higher symptom burden was reported, however, among ORN cases compared to those without ORN for MDASI-HN swallowing (p=0.033), problems with teeth and/or gums (p=0.016) and change in activity (p=0.015) item scores.ORN is associated with excess burden of chronic dysphagia and higher symptom severity related to swallowing, dentition and activity limitations.

View details for DOI 10.1016/j.oraloncology.2017.01.006

View details for PubMedID 28249651

View details for DOI 10.1002/cncy.21842

View details for PubMedID 28241100

View details for DOI 10.1002/cncr.30350

View details for Web of Science ID 000394719200015

View details for DOI 10.1002/acm2.12024

View details for Web of Science ID 000393176200028

Abstract

Endoscopic examinations are frequently-used procedures for patients with head and neck cancer undergoing radiotherapy, but radiation treatment plans are created on computed tomography (CT) scans. Image registration between endoscopic video and CT could be used to improve treatment planning and analysis of radiation-related normal tissue toxicity. The purpose of this study was to explore the feasibility of endoscopy-CT image registration without prospective physical tracking of the endoscope during the examination.A novel registration technique called Location Search was developed. This technique uses physical constraints on the endoscope's view direction to search for the virtual endoscope coordinates that maximize the similarity between the endoscopic video frame and the virtual endoscopic image. Its performance was tested on phantom and patient images and compared to an established registration technique, Frame-To-Frame Tracking.In phantoms, Location Search had average registration errors of 0.55 0.60 cm for point measurements and 0.29 0.15 cm for object surface measurements. Frame-To-Frame Tracking achieved similar results on some frames, but it failed on others due to the virtual endoscope becoming lost. This weakness was more pronounced in patients, where Frame-To-Frame tracking could not make it through the nasal cavity. On successful patient video frames, Location Search was able to find endoscope positions with an average distance of 0.98 0.53 cm away from the ground truth positions. However, it failed on many frames due to false similarity matches caused by anatomical structural differences between the endoscopic video and the virtual endoscopic images.Endoscopy-CT image registration without prospective physical tracking of the endoscope is possible, but more development is required to achieve an accuracy suitable for clinical translation.

View details for DOI 10.1371/journal.pone.0177886

View details for PubMedID 28542331

Abstract

We focused on a cohort of radiation nave patients who had recurrent oral cavity cancer (recurrent OCC) to assess their outcomes with salvage multimodal therapy.A retrospective single institutional study was performed of patients with recurrent OCC. Disease recurrence and survival outcomes were assessed.Seventy-eight patients were analyzed. All patients had salvage surgery and intensity-modulated radiotherapy (IMRT) and 74% had chemotherapy. Five-year overall survival, recurrence-free survival, and locoregional control rates were 59%, 60%, and 74%, respectively.Outcomes of radiation nave patients with recurrent OCC are fair, and seem similar with patients with locally advanced nonrecurrent OCC treated with multimodal therapy. 2016 Wiley Periodicals, Inc. Head Neck, 2016.

View details for DOI 10.1002/hed.24666

View details for PubMedID 28006086

Abstract

Our department has a long-established comprehensive quality assurance (QA) planning clinic for patients undergoing radiation therapy (RT) for head and neck cancer. Our aim is to assess the impact of a real-time peer review QA process on the quantitative and qualitative radiation therapy plan changes in the era of intensity modulated RT (IMRT).Prospective data for 85 patients undergoing head and neck IMRT who presented at a biweekly QA clinic after simulation and contouring were collected. A standard data collection form was used to document alterations made during this process. The original pre-QA clinical target volumes (CTVs) approved by the treating-attending physicians were saved before QA and compared with post-QA consensus CTVs. Qualitative assessment was done according to predefined criteria. Dice similarity coefficients (DSC) and other volume overlap metrics were calculated for each CTV level and were used for quantitative comparison. Changes are categorized as major, minor, and trivial according to the degree of overlap. Patterns of failure were analyzed and correlated to plan changes.All 85 patients were examined by at least 1 head and neck subspecialist radiation oncologist who was not the treating-attending physician; 80 (94%) were examined by 3 faculty members. New clinical findings on physical examination were found in 12 patients (14%) leading to major plan changes. Quantitative DSC analysis revealed significantly better agreement in CTV1 (0.940.10) contours than in CTV2 (0.820.25) and CTV3 (0.860.2) contours (P=.0002 and P=.03, respectively; matched-pair Wilcoxon test). The experience of the treating-attending radiation oncologist significantly affected DSC values when all CTV levels were considered (P=.012; matched-pair Wilcoxon text). After a median follow-up time of 38months, only 10 patients (12%) had local recurrence, regional recurrence, or both, mostly in central high-dose areas.Comprehensive peer review planning clinic is an essential component of IMRT QA that led to major changes in one-third of the study population. This process ensured safety related to target definition and led to favorable disease control profiles, with no identifiable recurrences attributable to geometric misses or delineation errors.

View details for DOI 10.1016/j.ijrobp.2016.11.019

View details for PubMedID 28258898

Abstract

Head and neck squamous cell carcinoma (HNSCC) is commonly treated with radiotherapy, and local failure after treatment remains the major cause of disease-related mortality. To date, human papillomavirus (HPV) is the only known clinically validated, targetable biomarkers of response to radiation in HNSCC.We performed proteomic and transcriptomic analysis of targetable biomarkers of radioresistance in HPV-negative HNSCC cell lines in vitro, and tested whether pharmacologic blockade of candidate biomarkers sensitized cells to radiotherapy. Candidate biomarkers were then investigated in several independent cohorts of patients with HNSCC.Increased expression of several targets was associated with radioresistance, including FGFR, ERK1, EGFR, and focal adhesion kinase (FAK), also known as PTK2. Chemical inhibition of PTK2/FAK, but not FGFR, led to significant radiosensitization with increased G2-M arrest and potentiated DNA damage. PTK2/FAK overexpression was associated with gene amplification in HPV-negative HNSCC cell lines and clinical tumors. In two independent cohorts of patients with locally advanced HPV-negative HNSCC, PTK2/FAK amplification was highly associated with poorer disease-free survival (DFS; P = 0.012 and 0.034). PTK2/FAK mRNA expression was also associated with worse DFS (P = 0.03). Moreover, both PTK2/FAK mRNA (P = 0.021) and copy number (P = 0.063) were associated with DFS in the Head and Neck Cancer subgroup of The Cancer Genome Atlas.Proteomic analysis identified PTK2/FAK overexpression is a biomarker of radioresistance in locally advanced HNSCC, and PTK2/FAK inhibition radiosensitized HNSCC cells. Combinations of PTK2/FAK inhibition with radiotherapy merit further evaluation as a therapeutic strategy for improving local control in HPV-negative HNSCC. Clin Cancer Res; 22(18); 4643-50. 2016 AACR.

View details for DOI 10.1158/1078-0432.CCR-15-2785

View details for PubMedID 27036135

Abstract

Reirradiation of head and neck (H&N) cancer is a clinical challenge. Proton radiation therapy (PRT) offers dosimetric advantages for normal tissue sparing and may benefit previously irradiated patients. Here, we report our initial experience with the use of PRT for H&N reirradiation, with focus on clinical outcomes and toxicity.We retrospectively reviewed the records of patients who received H&N reirradiation with PRT from April 2011 through June 2015. Patients reirradiated with palliative intent or without prior documentation of H&N radiation therapy were excluded. Radiation-related toxicities were recorded according to the Common Terminology Criteria for Adverse Events Version 4.0.The conditions of 60 patients were evaluated, with a median follow-up time of 13.6months. Fifteen patients (25%) received passive scatter proton therapy (PSPT), and 45 (75%) received intensity modulated proton therapy (IMPT). Thirty-five patients (58%) received upfront surgery, and 44 (73%) received concurrent chemotherapy. The 1-year rates of locoregional failure-free survival, overall survival, progression-free survival, and distant metastasis-free survival were 68.4%, 83.8%, 60.1%, and 74.9%, respectively. Eighteen patients (30%) experienced acute grade 3 (G3) toxicity, and 13 (22%) required a feeding tube at the end of PRT. The 1-year rates of late G3 toxicity and feeding tube independence were 16.7% and 2.0%, respectively. Three patients may have died of reirradiation-related effects (1 acute and 2 late).Proton beam therapy can be a safe and effective curative reirradiation strategy, with acceptable rates of toxicity and durable disease control.

View details for DOI 10.1016/j.ijrobp.2016.03.053

View details for PubMedID 27325480

Abstract

The purpose of this study was to evaluate the long-term outcomes after initial definitive or adjuvant radiotherapy (RT) for T3 laryngeal cancers.We reviewed 412 patients treated for T3 laryngeal squamous cell cancer from 1985 to 2011.The 10-year overall survival (OS) was 35%; disease-specific-survival (DSS) was 61%; locoregional control was 76%; and freedom from distant metastasis was 83%. Chemotherapy, age, performance status <2, node-negative status, and glottic subsite were associated with improved survival (all p < .03). Larynx preservation with induction and/or concurrent chemoradiotherapy (LP-CRT) had better laryngectomy-free survival than RT alone (LP-RT; hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.47-0.81; p = .0005); 10-year laryngectomy-free survival rates of the LP-CRT cohort (37%) were higher than those of the LP-RT cohort (18%). The 5-year DSS and OS rates of the LP-CRT cohort (79% and 67%) were better after total laryngectomy with postoperative RT (TL-PORT; 61% and 50%) and LP-RT (64% and 46%; p < .006 for all).In patients with T3 laryngeal cancers, LP-CRT provides better functional, oncologic, and survival outcomes than historical TL-PORT or LP-RT does. 2016 Wiley Periodicals, Inc. Head Neck 38: 1739-1751, 2016.

View details for DOI 10.1002/hed.24532

View details for PubMedID 27466789

Abstract

The aim of this study is to develop a methodology to standardize the analysis and reporting of the patterns of loco-regional failure after IMRT of head and neck cancer.Twenty-one patients with evidence of local and/or regional failure following IMRT for head-and-neck cancer were retrospectively reviewed under approved IRB protocol. Manually delineated recurrent gross disease (rGTV) on the diagnostic CT documenting recurrence (rCT) was co-registered with the original planning CT (pCT) using both deformable (DIR) and rigid (RIR) image registration software. Subsequently, mapped rGTVs were compared relative to original planning target volumes (TVs) and dose using a centroid-based approaches. Failures were then classified into five types based on combined spatial and dosimetric criteria; A (central high dose), B (peripheral high dose), C (central elective dose), D (peripheral elective dose), and E (extraneous dose).A total of 26 recurrences were identified. Using DIR, recurrences were assigned to more central TVs compared to RIR as detected using the spatial centroid-based method (p=0.0002). rGTVs mapped using DIR had statistically significant higher mean doses when compared to rGTVs mapped rigidly (mean dose 70 vs. 69Gy, p=0.03). According to the proposed classification 22 out of 26 failures were of type A (central high dose) as assessed by DIR method compared to 18 out of 26 for the RIR because of the tendencey of RIR to assign failures more peripherally.RIR tends to assigns failures more peripherally. DIR-based methods showed that the vast majority of failures originated in the high dose target volumes and received full prescribed doses suggesting biological rather than technology-related causes of failure. Validated DIR-based registration is recommended for accurate failure characterization and a novel typology-indicative taxonomy is recommended for failure reporting in the IMRT era.

View details for DOI 10.1186/s13014-016-0678-7

View details for PubMedID 27460585

Abstract

To determine the factors associated with longitudinal patient-reported dysphagia as measured by the MD Anderson Dysphagia Inventory (MDADI) in locoregionally advanced oropharyngeal carcinoma (OPC) survivors treated with split-field intensity modulated radiotherapy (IMRT).Retrospective patient analysis.A retrospective analysis combined data from three single-institution clinical trials for stage III/IV head and neck carcinoma. According to trial protocols, patients had prospectively collected MDADI at baseline, 6, 12, and 24 months after treatment. OPC patients with baseline and at least one post-treatment MDADI were included. Longitudinal analysis was completed with multivariate linear mixed effects modeling.There were 116 patients who met inclusion criteria. Mean baseline MDADI composite was 88.3, dropping to 73.8 at 6 months, and rising to 78.6 and 83.3 by 12 and 24 months, respectively (compared to baseline, all P < .0001). Tumor stage and smoking status were significant predictors of longitudinal MDADI composite scores. Patients with T1, T2, and T3 tumors had 15.9 (P = .0001), 10.9 (P = .0049), and 7.5 (P = .0615), respectively, higher mean MDADI composite than those with T4 tumors, and current smokers had a 9.4 (P = .0007) lower mean MDADI composite than never smokers.Patients report clinically meaningful dysphagia early after split-field IMRT for locoregionally advanced OPC that remains apparent 6 months after treatment. MDADI scores recover slowly thereafter, but remain depressed at 24 months compared to baseline. Higher tumor stage and smoking status are important markers of patient-reported function through the course of treatment, suggesting these are important groups for heightened surveillance and more intensive interventions to optimize swallowing outcomes.4 Laryngoscope, 2016.

View details for DOI 10.1002/lary.26153

View details for PubMedID 27440393

Abstract

Toreview our 15-year institutional experience using intensity modulated radiation therapy (IMRT) to reirradiate patients with head and neck squamous cell carcinomas (HNSCC) and identify predictors of outcomes and toxicity.We retrospectively reviewed the records of 227 patients who received head and neck reirradiation using IMRT from 1999 to 2014. Patients treated with noncurative intent were excluded. Radiation-related acute and late toxicities were recorded. Prognostic variables included performance status, disease site, disease-free interval, chemotherapy, and RT dose and volume. Correlative analyses were performed separately for surgery and nonsurgery patients.Two hundred six patients (91%) were retreated with curative intent, and 173 had HNSCC histology; 104 (50%) underwent salvage resection, and 135 (66%) received chemotherapy. Median follow-up after reirradiation was 24.7months. Clinical outcomes were worse for HNSCC patients, with 5-year locoregional control, progression-free survival, and overall survival rates of 53%, 22%, and 32%, respectively, compared with 74%, 59%, and 79%, respectively, for non-HNSCC patients. On multivariate analysis, concurrent chemotherapy and retreatment site were associated with tumor control, whereas performance status was associated with survival. Favorable prognostic factors specific to surgery patients were neck retreatment and lack of extracapsular extension, whereas for nonsurgery patients, these were a nasopharynx subsite and complete response to induction chemotherapy. Actuarial rates of grade 3 toxicity were 32% at 2years and 48% at 5years, with dysphagia or odynophagia being most common. Increased grade 3 toxicity was associated with retreatment volume >50cm(3) and concurrent chemotherapy.Reirradiation with IMRT either definitively or after salvage surgery can produce promising local control and survival in selected patients with head and neck cancers. Treatment-related toxicity remains significant. Prognostic factors are emerging to guide multidisciplinary treatment approaches and clinical trial design.

View details for DOI 10.1016/j.ijrobp.2016.03.015

View details for PubMedID 27354127

Abstract

Although adjuvant radiation to the tumor bed has been reported to improve the clinic outcomes of esthesioneuroblastoma (ENB) patients, the role of elective neck irradiation (ENI) in clinically node-negative (N0) patients remains controversial. Here, we evaluated the effects of ENI on neck nodal relapse risk in ENB patients treated with radiation therapy as a component of multimodality treatment.Seventy-one N0 ENB patients irradiated at the University of Texas MD Anderson Cancer Center between 1970 and 2013 were identified. ENI was performed on 22 of these patients (31%). Survival analysis was performed with focus on comparative outcomes of those patients who did and did not receive ENI.The median follow-up time for our cohort is 80.8 months (range, 6-350 months). Among N0 patients, 13 (18.3%) developed neck nodal relapses, with a median time to progression of 62.5 months. None of these 13 patients received prophylactic neck irradiation. ENI was associated with significantly improved regional nodal control at 5 years (regional control rate of 100% for ENI vs 82%, P < .001), but not overall survival or disease-free survival. Eleven patients without ENI developed isolated neck recurrences. All had further treatment for their neck disease, including neck dissection (n = 10), radiation (n = 10), or chemotherapy (n = 5). Six of these 11 patients (54.5%) demonstrated no evidence of further recurrence with a median follow-up of 55.5 months.ENI significantly reduces the risk of cervical nodal recurrence in ENB patients with clinically N0 neck, but this did not translate to a survival benefit. Multimodality treatment for isolated neck recurrence provides a reasonable salvage rate. The greatest benefit for ENI appeared to be among younger patients who presented with Kadish C disease. Further studies are needed to confirm these findings.

View details for DOI 10.1016/j.prro.2015.10.023

View details for PubMedID 26979544

Abstract

To characterize long-term MD Anderson Dysphagia Inventory (MDADI) results after primary intensity modulated radiation therapy (IMRT) for oropharyngeal carcinoma (OPC) among patients with "low-intermediate risk" OPC who would be eligible for current trials (eg, ECOG 3311, NRG HN002, CRUK PATHOS).A retrospective pooled analysis combined data from 3 single-institution clinical trials for advanced-stage head and neck carcinoma. Inclusion criteria were clinical stage III/IV OPC (T1-2/N1-2b, T3/N0-2b) treated with definitive split-field IMRT and prospectively collected MDADI at baseline and at least 1 posttreatment interval available in trial databases. Patients were sampled to represent likely human papillomavirus (HPV)-associated disease (HPV(+)/p16(+) or <10 pack-years if HPV/p16 unknown). The MDADI composite scores were collected at baseline and 6, 12, and 24months after treatment. Pairwise tests were Bonferroni corrected for multiple comparisons.Forty-six patients were included. All received bilateral neck irradiation with a median dose of 70Gy and systemic therapy (57% concurrent, 43% induction only). Overall the mean baseline MDADI composite score was 90.1, dropping to 74.6 at 6months (P<.0001) and rising to 78.5 (P<.0001) and 83.1 (P=.002) by 12 and 24months relative to baseline, respectively, representing a clinically meaningful drop in MDADI scores at 6months that partially recovers by 24months (6 vs 24months, P=.05). Poor MDADI scores (composite <60) were reported in 4%, 11%, 15%, and 9% of patients at baseline and 6, 12, and 24months, respectively. Fifteen percent of patients had a persistently depressed composite score by at least 20 points at the 24-month interval."Low-intermediate risk" patients with OPC treated with laryngeal/esophageal inlet dose-optimized split-field IMRT are highly likely to report recovery of acceptable swallowing function in long-term follow-up. Only 15% report poor swallowing function and/or persistently depressed MDADI at 12months or more after IMRT. These data serve as a benchmark future trial design and endpoint interpretation.

View details for DOI 10.1016/j.ijrobp.2016.06.010

View details for PubMedID 27485284

Abstract

The present study was undertaken to evaluate osteoradionecrosis (ORN) in patients with salivary gland malignancies (SGM) after treatment with radiation therapy.The medical records of 172 patients treated with radiation therapy for SGM during a 12-year period (August 2001 to November 2013) were reviewed. Incidence, time to event, staging and management of ORN were analyzed.Of the 172 patients, 7 patients (4%) developed ORN (median latency: 19months, range: 4-72months). Of those 7 patients, 4 required major surgery, 1 required hyperbaric oxygen therapy (HBO), one required minor debridement, and one required conservative management. Total prescribed radiation dose varied from 50Gy (1 case) to 70Gy (1 case) among those patients who developed ORN, and radiotherapy was delivered postoperatively after osseous resection in 4 of 7 cases. Three of the 7 cases of ORN occurred after traumatic injury to the bone. Of the 7 patients who developed ORN, 3 had SGM of the major glands, 3 had other sites of the oral cavity, and 1 had a sinonasal location.While the rate of ORN after radiotherapy for SGM was somewhat lower (4%) than previously published data on patients with squamous cell carcinomas of the head and neck treated with radiation therapy (8-14%), ORN necessitating major surgery remains a clinically significant, possible late effect of radiotherapy in SGM survivors. Location of SGM is very important, with cases that developed ORN disproportionally having primary disease arising in the oral cavity.

View details for DOI 10.1016/j.oraloncology.2016.03.006

View details for PubMedID 27208837

Abstract

Favorable outcomes for human papillomavirus-associated oropharyngeal cancer have led to interest in identifying a subgroup of patients with the lowest risk of disease recurrence after therapy. De-intensification of therapy for this group may result in survival outcomes that are similar to those associated with current therapy but with less toxicity. To advance this effort, this study analyzed the outcomes of oropharyngeal cancer patients treated with or without systemic therapy.This was a retrospective study of patients with oropharyngeal cancer treated between 1985 and 2012. The criteria for inclusion were 10 pack-years of cigarette smoking and stage III/IVA cancer limited to T1-3, N1-N2b, and T3N0 disease. A survival analysis was performed with the primary endpoint of progression-free survival (PFS).The cohort included 857 patients. Systemic therapy was given to 439 patients (51%). The median survival was 80 months. The 2-year PFS rate was 91%. When the analysis was limited to 324 patients irradiated without systemic therapy, the 2- and 5-year PFS rates were 90% and 85%, respectively. Furthermore, for these 324 patients, the 5-year PFS rates for T1, T2, and T3 disease were 90%, 83%, and 70%, respectively. The 5-year PFS rate for patients treated with systemic therapy for T3 disease was 77% (P = .07).According to the low-risk definition currently established in cooperative trials, the patients had a 2-year PFS rate approximating 90%. When patients who were treated with radiation alone were evaluated, no compromise was observed in this high rate of PFS, which is higher than the 2-year PFS thresholds used in current cooperative trials. Cancer 2016;122:1702-7. 2016 American Cancer Society.

View details for DOI 10.1002/cncr.29965

View details for PubMedID 27019396

Abstract

Major weight loss is common in patients with head and neck squamous cell carcinoma (HNSCC) who undergo radiotherapy (RT). How baseline and posttreatment body composition affects outcome is unknown.To determine whether lean body mass before and after RT for HNSCC predicts survival and locoregional control.Retrospective study of 2840 patients with pathologically proven HNSCC undergoing curative RT at a single academic cancer referral center from October 1, 2003, to August 31, 2013. One hundred ninety patients had computed tomographic (CT) scans available for analysis of skeletal muscle (SM). The effect of pre-RT and post-RT SM depletion (defined as a CT-measured L3 SM index of less than 52.4 cm2/m2 for men and less than 38.5 cm2/m2 for women) on survival and disease control was evaluated. Final follow-up was completed on September 27, 2014, and data were analyzed from October 1, 2014, to November 29, 2015.Primary outcomes were overall and disease-specific survival and locoregional control. Secondary analyses included the influence of pre-RT body mass index (BMI) and interscan weight loss on survival and recurrence.Among the 2840 consecutive patients who underwent screening, 190 had whole-body positron emission tomography-CT or abdominal CT scans before and after RT and were included for analysis. Of these, 160 (84.2%) were men and 30 (15.8%) were women; their mean (SD) age was 57.7 (9.4) years. Median follow up was 68.6 months. Skeletal muscle depletion was detected in 67 patients (35.3%) before RT and an additional 58 patients (30.5%) after RT. Decreased overall survival was predicted by SM depletion before RT (hazard ratio [HR], 1.92; 95% CI, 1.19-3.11; P=.007) and after RT (HR, 2.03; 95% CI, 1.02-4.24; P=.04). Increased BMI was associated with significantly improved survival (HR per 1-U increase in BMI, 0.91; 95% CI, 0.87-0.96; P<.001). Weight loss without SM depletion did not affect outcomes. Post-RT SM depletion was more substantive in competing multivariate models of mortality risk than weight loss-based metrics (Bayesian information criteria difference, 7.9), but pre-RT BMI demonstrated the greatest prognostic value.Diminished SM mass assessed by CT imaging or BMI can predict oncologic outcomes for patients with HNSCC, whereas weight loss after RT initiation does not predict SM loss or survival.

View details for DOI 10.1001/jamaoncol.2015.6339

View details for PubMedID 26891703

Abstract

Conflicting results are reported regarding the impact of neck dissection on radiation-associated dysphagia. The purpose of this study was to reexamine this question specific to oropharyngeal intensity-modulated radiotherapy (IMRT).Three hundred forty-nine patients with oropharyngeal cancer treated with bilateral IMRT with systemic therapy (induction and/or concurrent) were reviewed. Chronic dysphagia was defined by aspiration, stricture, pneumonia, and/or gastrostomy dependence 12 months post-IMRT.Selective neck dissection was performed after IMRT in 75 patients (21%). Overall, 41 patients (12%) developed chronic dysphagia. Neck dissection did not increase the rate of chronic dysphagia (9% neck dissection; 12% no neck dissection; p=.464) or gastrostomy duration (p=.482). On multivariate analysis, age (odds ratio [OR] per 5-year=1.25; 95% confidence interval [CI]=1.04-1.51), baseline abnormal diet (OR=2.78; 95% CI=1.31-5.88), and IMRT dose (OR per 5-Gy=5.11; 95% CI=1.77-14.81) significantly predicted dysphagia.In the setting of selective neck dissection for residual adenopathy after IMRT, neck dissection did not impact dysphagia. 2015 Wiley Periodicals, Inc. Head Neck 38: 886-893, 2016.

View details for DOI 10.1002/hed.24195

View details for PubMedID 26339764

Abstract

Postoperative radiation is often indicated in the treatment of malignant epithelial tumors of the orbit and ocular adnexa. We present details of radiation technique and toxicity data after orbit-sparing surgery followed by adjuvant proton radiation therapy.Twenty patients underwent orbit-sparing surgery followed by proton therapy for newly diagnosed malignant epithelial tumors of the lacrimal gland (n=7), lacrimal sac/nasolacrimal duct (n=10), or eyelid (n=3). Tumor characteristics, treatment details, and visual outcomes were obtained from medical records. Acute and chronic toxicity were prospectively scored using Common Terminology Criteria for Adverse Events version 4.0.The median radiation dose was 60 Gy(RBE) (relative biological effectiveness; [range 50-70 Gy]); 11 patients received concurrent chemotherapy. Dose to ipsilateral anterior optic structures was reduced in 13 patients by having them gaze away from the target during treatment. At a median follow-up time of 27.1 months (range 2.6-77.2 months), no patient had experienced local recurrence; 1 had regional and 1 had distant recurrence. Three patients developed chronic grade 3 epiphora, and 3 developed grade 3 exposure keratopathy. Four patients experienced a decrease in visual acuity from baseline but maintained vision sufficient to perform all activities of daily living without difficulty. Patients with grade 3 chronic ocular toxicity had higher maximum dose to the ipsilateral cornea (median 46.3 Gy[RBE], range 36.6-52.7 Gy[RBE] vs median 37.4 Gy[RBE], range 9.0-47.3 Gy(RBE); P=.017).Orbit-sparing surgery for epithelial tumors of the orbit and ocular adnexa followed by proton therapy successfully achieved disease control and was well tolerated. No patient required orbital exenteration or enucleation. Chronic grade 3 toxicity was associated with high maximum dose to the cornea. An eye-deviation technique can be used to limit the maximum corneal dose to <35 Gy(RBE).

View details for DOI 10.1016/j.ijrobp.2015.08.008

View details for PubMedID 26454680

Abstract

To compare the complication rate for osseointegrated hearing aids (OIHA) in patients with or without irradiation.Retrospective case review.We studied patients with OIHAs implanted between January 1, 2005, and July 15, 2013 in a tertiary university center with a referral otology and neurotology practice. Demographics, history of oncologic surgery, follow-up length after OIHA implantation, radiation history and dosage, postoperative complications, and chronologic relationship between oncologic resection, OIHA implantation, and irradiation were reviewed to collect information. Soft tissue complications were graded according to a modified Holgers classification.The study included 48 patients. Twenty-nine patients (32 implants) did not undergo radiotherapy and 19 patients (19 implants) did. In the radiotherapy group, six patients had OIHAs implanted before radiotherapy, and 13 had OIHAs implanted in irradiated bone. Of these 13 patients, one had OIHA implanted during primary oncologic surgery; 11 had OIHA implanted during secondary surgery; and one patient did not have oncologic surgery. Patients with both OIHA implantation and radiotherapy had more complications than patients without radiotherapy (31.6% vs. 24.1%, P > 0.05) and more major complications than patients without radiotherapy (26.3% vs. 3.4%, P > 0.05). Patients with OIHAs implanted before radiotherapy did not have any complications. There were significantly fewer and less severe complications in patients with OIHAs implanted during primary oncologic resection than in patients with OIHAs implanted secondarily (0/8 vs. 8/11, P < 0.05).The rate and severity of complications of OIHAs can be minimized by implanting the device before irradiation, ideally at the time of primary oncologic surgery.4. Laryngoscope, 126:1187-1192, 2016.

View details for DOI 10.1002/lary.25592

View details for PubMedID 26371776

Abstract

A single-institution prospective study was conducted to assess disease control and toxicity of proton therapy for patients with head and neck cancer.Disease control, toxicity, functional outcomes, and patterns of failure for the initial cohort of patients with oropharyngeal squamous carcinoma (OPC) treated with intensity modulated proton therapy (IMPT) were prospectively collected in 2 registry studies at a single institution. Locoregional failures were analyzed by using deformable image registration.Fifty patients with OPC treated from March 3, 2011, to July 2014 formed the cohort. Eighty-four percent were male, 50% had never smoked, 98% had stage III/IV disease, 64% received concurrent therapy, and 35% received induction chemotherapy. Forty-four of 45 tumors (98%) tested for p16 were positive. All patients received IMPT (multifield optimization to n=46; single-field optimization to n=4). No Common Terminology Criteria for Adverse Events grade 4 or 5 toxicities were observed. The most common grade 3 toxicities were acute mucositis in 58% of patients and late dysphagia in 12%. Eleven patients had a gastrostomy (feeding) tube placed during therapy, but none had a feeding tube at last follow-up. At a median follow-up time of 29 months, 5 patients had disease recurrence: local in 1, local and regional in 1, regional in 2, and distant in 1. The 2-year actuarial overall and progression-free survival rates were 94.5% and 88.6%.The oncologic, toxicity, and functional outcomes after IMPT for OPC are encouraging and provide the basis for ongoing and future clinical studies.

View details for DOI 10.1016/j.ijrobp.2016.02.021

View details for PubMedID 27084653

Abstract

This was a retrospective study of patients with human papillomavirus (HPV)-associated oropharyngeal cancer treated with concurrent systemic therapy and radiation.Data were extracted through chart review, and statistical analyses included frequency tabulation, chi-square, and Kaplan-Meier tests.Three hundred thirty-nine patients were analyzed; 166 received neoadjuvant chemotherapy. One hundred thirty-six patients were treated with cisplatin, 123 with cetuximab, and 59 with carboplatin. The 2-, 3-, and 5-year actuarial overall survival rates were 92%, 88%, and 78%, respectively. There were no significant differences in survival or disease control when analyzed by systemic agent. Platin-treated patients had greater hematologic toxicity, and required more intravenous hydration. The incidence of confluent mucositis was highest among patients treated with cetuximab.Platin and cetuximab seem to have similar efficacy when delivered concurrently with radiation in our retrospective population study. Although platin did cause greater hematologic toxicity, radiation-specific side effects seemed relatively comparable. 2015 Wiley Periodicals, Inc. Head Neck 38: E1554-E1561, 2016.

View details for DOI 10.1002/hed.24278

View details for PubMedID 26595157

Abstract

This study assessed outcomes of patients with hypopharyngeal carcinoma treated with organ-preservation therapy utilizing intensity-modulated radiation therapy (IMRT).The medical records of 98 patients treated with definitive IMRT +/- chemotherapy from 2001 to 2013 for nonmetastatic hypopharyngeal cancer were retrospectively reviewed.Patients were treated to doses of 66 to 72 Gy. Eighty-three patients (85%) received chemotherapy. With median follow-up of 35 months, 2-year overall survival (OS), locoregional control, progression-free survival (PFS), and laryngectomy-free survival rates were 74%, 77%, 67%, and 65%, respectively. Functional laryngeal preservation rate was 76% at 2 years. N3 disease correlated with worse OS (p < .01). Concurrent chemotherapy correlated with improved locoregional control (p = .03) and complete response to induction chemotherapy correlated with improved OS and PFS (p = .02). Actuarial 2-year and 5-year grade 3 treatment toxicities were 17% and 21%, respectively.Favorable disease outcomes and functional laryngeal preservation rates can be achieved with IMRT for patients with hypopharyngeal cancer. 2016 Wiley Periodicals, Inc. Head Neck 38: E2091-E2099, 2016.

View details for DOI 10.1002/hed.24387

View details for PubMedID 26920665

Abstract

The purpose of this study was to assess outcomes of patients with orbital carcinomas treated with orbital exenteration and intensity-modulated radiation therapy (IMRT).Twenty-nine patients were treated with orbital exenteration and postoperative IMRT between 2002 through 2011; their medical records were retrospectively reviewed.Adenoid cystic carcinoma represented the most common histology (41%) followed by squamous cell carcinoma (21%). Perineural invasion (PNI) was identified in 22 patients (76%). The median radiation dose was 60 Gy (range, 60-70). Seven patients (24%) received neck radiation. The median follow-up was 43 months (range, 5-102 months). Five-year local control, overall survival (OS), and disease-free survival rates were 83%, 60%, and 55%, respectively. PNI (p=.01) and especially involvement of a named nerve (p=.001) significantly correlated with worse OS.Favorable disease control rates for orbital carcinomas are achievable with IMRT after orbital exenteration even for patients with advanced disease. Toxicity for the contralateral eye was minimal. 2015 Wiley Periodicals, Inc. Head Neck 38: E580-E587, 2016.

View details for DOI 10.1002/hed.24044

View details for PubMedID 25782700

Abstract

Overexpression of p16 is associated with improved outcomes among patients with oropharyngeal carcinoma. However, its role in the outcomes of patients with nasopharyngeal cancer (NPC) remains unclear.Eighty-six patients with NPC treated at MD Anderson Cancer Center from 2000 to 2014 were identified. Epstein-Barr virus (EBV) and human papillomavirus (HPV) status were determined by in situ hybridization (ISH) and p16 by immunohistochemical staining.EBV positivity was associated with extended overall survival (OS; median, 95.0 vs 44.9 months; p < .004), progression-free survival (PFS; median, 80.4 vs 28.1 months; p < .013), and locoregional control (median, 104.4 vs 65.5 months; p < .043). In patients with EBV-positive tumors, p16 overexpression correlated with improved PFS (median, 106.3 vs 27.1 months; p < .02) and locoregional control (median, 93.6 vs 64.5 months; p < .02).P16 overexpression is associated with improved PFS and locoregional control in patients with EBV-positive NPC. P16 expression may complement EBV status in predicting treatment outcomes for patients with NPC. 2015 Wiley Periodicals, Inc. Head Neck 38: E1459-E1466, 2016.

View details for DOI 10.1002/hed.24258

View details for PubMedID 26560893

Abstract

The purpose of this study was to report the outcomes of patients with Merkel cell carcinoma (MCC) of the head and neck using a radiation-based treatment approach.We reviewed records of 106 consecutive patients with MCC of the head and neck treated with radiation therapy (RT) at our institution between 1988 and 2011. The Kaplan-Meier method was used to estimate outcomes and hazard ratios (HRs) were calculated.The 5-year actuarial local and regional control rates were 96% and 96%, respectively. There were no regional recurrences in 22 patients treated with RT to gross nodal disease without neck dissection. The 5-year cause-specific survival rate was 76%. Lymphadenopathy at presentation impacted distant metastatic-free survival outcomes (p<.001). Treatment was well tolerated with only 5 patients having grade 3 toxicities.For MCC of the head and neck, a management strategy that includes RT offers excellent locoregional control. Gross nodal disease can be successfully treated with RT. 2015 Wiley Periodicals, Inc. Head Neck 38: E452-E458, 2016.

View details for DOI 10.1002/hed.24017

View details for Web of Science ID 000375116400047

View details for PubMedID 25645649

Abstract

Treatment of T4 nasopharyngeal carcinoma (NPC) is challenging because of the proximity of the tumor to the central nervous system. The purpose of this study was to present our evaluation of disease control and toxicity outcomes for patients with T4 NPC treated with intensity-modulated radiation therapy (IMRT) and chemotherapy.The medical records of 66 patients with T4 NPC treated from 2002 to 2012 with IMRT were reviewed. Endpoints included tumor control and toxicity outcomes (Common Terminology Criteria for Adverse Events [CTCAE v4.0]).Median follow-up was 38 months. Five-year rates of locoregional control, distant metastasis-free survival, progression-free survival (PFS), and overall survival (OS) were 80%, 62%, 57%, and 69%, respectively. Nodal involvement was associated with worse PFS (p=.015). Gross target volume (GTV) volume >100 cm and planning target volume (PTV) volume >400 cm were associated with worse OS (p=.038 and p=.004, respectively). Four patients had significant cognitive impairment, and 9 had MRI evidence of brain necrosis.For patients with T4 NPC treated with IMRT and chemotherapy, survival and locoregional disease control rates have improved; however, late treatment toxicity remains a concern. 2015 Wiley Periodicals, Inc. Head Neck 38: E925-E933, 2016.

View details for DOI 10.1002/hed.24128

View details for PubMedID 25994561

View details for DOI 10.1016/j.radonc.2016.01.019

View details for Web of Science ID 000373420000015

Abstract

A questionnaire-based study was conducted to assess long-term patient reported outcomes (PROs) following definitive IMRT-based treatment for early stage carcinomas of the tonsillar fossa.Participants had received IMRT with or without systemic therapy for squamous carcinoma of the tonsillar fossa (T1-2 and N0-2b) with a minimum follow-up of 2years. Patients completed a validated head and neck cancer-specific PRO instrument, the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN). Symptoms were compared between treatment groups of interest and overall symptom burden was evaluated.Of 139 participants analyzed, 51% had received ipsilateral neck IMRT, and 62% single modality IMRT alone (no systemic therapy). There were no differences in mean severity ratings for the top-ranked individual symptoms or symptom interference for those treated with bilateral versus ipsilateral neck IMRT alone. However, 40% of those treated with bilateral versus 25% of those treated with ipsilateral neck RT alone reported moderate-to-severe levels of dry mouth (p=0.03). Fatigue, numbness/tingling, and constipation were rated more severe for those who had received systemic therapy (p<0.05 for each), but absolute differences were small. Overall, 51% had no more than mild symptom ratings across all 22 symptoms assessed.The long-term patient reported symptom profile in this cohort of tonsil cancer survivors treated with definitive IMRT-based treatment showed a majority of patients with no more than mild symptoms, low symptom interference, and provides an opportunity for future comparison studies with other treatment approaches.

View details for DOI 10.1016/j.radonc.2015.09.007

View details for PubMedID 26403258

Abstract

To develop an automatic segmentation algorithm integrating imaging information from computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) to delineate target volume in head and neck cancer radiotherapy.Eleven patients with unresectable disease at the tonsil or base of tongue who underwent MRI, CT, and PET/CT within two months before the start of radiotherapy or chemoradiotherapy were recruited for the study. For each patient, PET/CT and T1-weighted contrast MRI scans were first registered to the planning CT using deformable and rigid registration, respectively, to resample the PET and magnetic resonance (MR) images to the planning CT space. A binary mask was manually defined to identify the tumor area. The resampled PET and MR images, the planning CT image, and the binary mask were fed into the automatic segmentation algorithm for target delineation. The algorithm was based on a multichannel Gaussian mixture model and solved using an expectation-maximization algorithm with Markov random fields. To evaluate the algorithm, we compared the multichannel autosegmentation with an autosegmentation method using only PET images. The physician-defined gross tumor volume (GTV) was used as the "ground truth" for quantitative evaluation.The median multichannel segmented GTV of the primary tumor was 15.7 cm(3) (range, 6.6-44.3 cm(3)), while the PET segmented GTV was 10.2 cm(3) (range, 2.8-45.1 cm(3)). The median physician-defined GTV was 22.1 cm(3) (range, 4.2-38.4 cm(3)). The median difference between the multichannel segmented and physician-defined GTVs was -10.7%, not showing a statistically significant difference (p-value = 0.43). However, the median difference between the PET segmented and physician-defined GTVs was -19.2%, showing a statistically significant difference (p-value =0.0037). The median Dice similarity coefficient between the multichannel segmented and physician-defined GTVs was 0.75 (range, 0.55-0.84), and the median sensitivity and positive predictive value between them were 0.76 and 0.81, respectively.The authors developed an automated multimodality segmentation algorithm for tumor volume delineation and validated this algorithm for head and neck cancer radiotherapy. The multichannel segmented GTV agreed well with the physician-defined GTV. The authors expect that their algorithm will improve the accuracy and consistency in target definition for radiotherapy.

View details for DOI 10.1118/1.4928485

View details for PubMedID 26328980

Abstract

Both iodine-125 ((125)I) Collaborative Ocular Melanoma Study and ruthenium-106 ((106)Ru) eye plaques can achieve excellent tumor control in patients diagnosed with uveal melanoma. We analyzed our single institutional experience in the management of ocular melanoma treated with either (125)I or (106)Ru plaque brachytherapy.The records of 107 patients with uveal melanoma treated with either (106)Ru (n = 40) or (125)I (n = 67) plaque brachytherapy between 2000 and 2008 were retrospectively reviewed. Tumor control parameters and toxicity were assessed.Actuarial 5-year rates of local control, progression-free survival, and overall survival with (106)Ru were 97%, 94%, and 92%, respectively. For (125)I, these values were 83%, 65%, and 80%. In the subset of patients with tumor apex height 5 mm (36 (125)I and 40 (106)Ru), there was no difference in overall survival; however, progression-free survival was significantly improved with (106)Ru (P = .02). Enucleation-free survival was significantly different between the 2 subsets, with no enucleations in the (106)Ru cohort (P = .02). Patients treated with (106)Ru experienced reduced retinopathy (P = .03) and cataracts (P < .01).Both (125)I and (106)Ru eye plaque brachytherapy treatment result in encouraging tumor control for patients with uveal melanoma. We demonstrate that (106)Ru offers these benefits with reduced toxicity in patients treated for uveal melanomas 5 mm in apical height.

View details for DOI 10.1016/j.prro.2014.09.005

View details for PubMedID 25423888

Abstract

TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations.

View details for DOI 10.1158/0008-5472.CAN-14-2735

View details for Web of Science ID 000351948900037

View details for PubMedID 25634208

Abstract

We sought to characterize the pattern of lymph node regression and morphology following definitive radiation therapy (RT) for human papilloma virus (HPV)-associated oropharyngeal carcinoma in patients with disease control.Radiographically positive cervical lymph nodes from patients treated with definitive RT for HPV-associated oropharyngeal carcinoma were segmented on initial pre- and subsequent post-RT contrast enhanced CT images. Pre-specified quantitative nodal parameters were calculated. Initial nodal parameter correlates of final nodal size, final nodal volume, and time to <1 cm short-axis diameter were determined.Sixty-six radiographically positive lymph node were analyzed in 36 patients. Lymph nodes exhibited initial volume decreases with size stabilization at 4 months. Fifteen nodes (23%) underwent complete radiographic response (median 6.4 months following RT; range 2.9-25.6 months). On multivariate time-to-event analysis, initial hypodense/fat component, nodal volume, and short-axis diameter exhibited inverse association, while higher HU standard deviation exhibited a positive association, with reaching <1 cm short-axis diameter (all p<0.05).Our results showed a substantial decrease in nodal volume within the first 1-2 months following RT. These findings support our current nodal imaging paradigm, propose a quantitative methodology, and describe a reference dataset for further validation and comparison studies.

View details for DOI 10.1016/j.oraloncology.2014.11.001

View details for Web of Science ID 000347901800019

View details for PubMedID 25444304

Abstract

Sleep disturbance is a prominent complaint of cancer patients. Most studies have focused on insomnia and cancer-related fatigue. Obstructive sleep apnea (OSA) has been reported in small studies and case reports.In a retrospective review of patients who underwent formal sleep evaluation and polysomnography (PSG) from 2006 to 2011, 56 patients with tumors in the head and neck region were identified. Clinical characteristics, sleep-related history, and PSG data were reviewed.Most patients had active cancer (80%), and the majority had squamous pathology (68%). Prominent symptoms included daytime fatigue (93%), daytime sleepiness (89%), and snoring (82%). Comorbid conditions primarily included hypertension (46%) and hypothyroidism (34%). Significant sleep-related breathing disorder was noted in 93% of patients, and 84% met clinical criteria for OSA. A male predominance (77%) was noted, and patients were not obese (body mass index <30 kg/m(2) in 52%). The majority of patients (79%) underwent radiation prior to sleep study, of which 88% had OSA, and in the group without prior radiation, 67% had OSA. Adherence to positive airway pressure (PAP) therapy was slightly better when compared with the general population. A subset of patients with persistent hypoxia despite advanced forms of PAP required tracheostomy. Multivariate analysis revealed that patients with active disease and radiation prior to PSG were more likely to have OSA.Sleep-related breathing disorder was common in patients with tumors in the head and neck region referred for evaluation of sleep disruption, and most met clinical criteria for OSA. Daytime fatigue and sleepiness were the most common complaints. OSA was prevalent in male patients, and most with OSA were not obese. Architectural distortion from the malignancy and/or treatment may predispose these patients to OSA by altering anatomic and neural factors. A heightened clinical suspicion for sleep-related breathing disorder and referral to a sleep specialist would be beneficial for patients with these complaints.

View details for DOI 10.1634/theoncologist.2014-0176

View details for Web of Science ID 000346601600017

View details for PubMedID 25273079

Abstract

Radiation therapy (RT), with or without chemotherapy, can cause significant acute toxicity among patients treated for head and neck cancer (HNC), but predicting, before treatment, who will experience a particular toxicity or symptom is difficult. We created and evaluated 2 multivariate models and generated a nomogram to predict symptom severity during RT based on a patient-reported outcome (PRO) instrument, the MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN).This was a prospective, longitudinal, questionnaire-based study.Tertiary cancer care center.Subjects were 264 patients with HNC (mostly oropharyngeal) who had completed the MDASI-HN before and during therapy. Pretreatment variables were correlated with MDASI-HN symptom scores during therapy with multivariate modeling and then were correlated with the composite MDASI-HN score during week 5 of therapy.A multivariate model incorporating pretreatment PROs better predicted MDASI-HN symptom scores during treatment than did a model based on clinical variables and physician-rated patient performance status alone (Akaike information criterion = 1442.5 vs 1459.9). In the most parsimonious model, pretreatment MDASI-HN symptom severity (P < .001), concurrent chemotherapy (P = .006), primary tumor site (P = .016), and receipt of definitive (rather than adjuvant) RT (P = .044) correlated with MDASI-HN symptom scores during week 5. That model was used to construct a nomogram.Our model demonstrates the value of incorporating baseline PROs, in addition to disease and treatment characteristics, to predict patient symptom burden during therapy. Although additional investigation and validation are required, PRO-inclusive prediction tools can be useful for improving symptom interventions and expectations for patients being treated for HNC.

View details for DOI 10.1177/0194599814545746

View details for Web of Science ID 000342982900015

View details for PubMedID 25104816

Abstract

The goal of the current study was to assess the rates of recurrence in the neck for patients with lymph node-positive human papillomavirus-associated cancer of the oropharynx who were treated with definitive radiotherapy (with or without chemotherapy).This is a single-institution retrospective study. Methodology included database search, and statistical testing including frequency analysis, Kaplan-Meier tests, and comparative tests including chi-square, logistic regression, and log-rank.The cohort consisted of 401 patients with lymph node-positive disease who underwent radiotherapy between January 2006 and June 2012. A total of 388 patients had computed tomography restaging, and 251 had positron emission tomography and/or ultrasound as a component of their postradiation staging. Eighty patients (20%) underwent neck dissection, and 21 patients (26%) had a positive specimen. The rate of neck dissection increased with increasing lymph node stage, and was lower in patients who had positron emission tomography scans or ultrasound in addition to computed tomography restaging. The median follow-up was 30 months. The 2-year actuarial neck recurrence rate was 7% and 5%, respectively, in all patients and those with local control. Lymph node recurrence rates were greater in current smokers (P =.008). There was no difference in lymph node recurrence rates noted between patients who did and those who did not undergo a neck dissection (P =.4) CONCLUSIONS: A treatment strategy of (chemo)radiation with neck dissection performed based on response resulted in high rates of regional disease control in patients with human papillomavirus-associated oropharyngeal cancer.

View details for DOI 10.1002/cncr.28831

View details for Web of Science ID 000342630000022

View details for PubMedID 24898672

Abstract

To create models that forecast longitudinal trends in changing tumor morphology and to evaluate and compare their predictive potential throughout the course of radiation therapy.Two morphology feature vectors were used to describe 35 gross tumor volumes (GTVs) throughout the course of intensity-modulated radiation therapy for oropharyngeal tumors. The feature vectors comprised the coordinates of the GTV centroids and a description of GTV shape using either interlandmark distances or a spherical harmonic decomposition of these distances. The change in the morphology feature vector observed at 33 time points throughout the course of treatment was described using static, linear, and mean models. Models were adjusted at 0, 1, 2, 3, or 5 different time points (adjustment points) to improve prediction accuracy. The potential of these models to forecast GTV morphology was evaluated using leave-one-out cross-validation, and the accuracy of the models was compared using Wilcoxon signed-rank tests.Adding a single adjustment point to the static model without any adjustment points decreased the median error in forecasting the position of GTV surface landmarks by the largest amount (1.2 mm). Additional adjustment points further decreased the forecast error by about 0.4 mm each. Selection of the linear model decreased the forecast error for both the distance-based and spherical harmonic morphology descriptors (0.2 mm), while the mean model decreased the forecast error for the distance-based descriptor only (0.2 mm). The magnitude and statistical significance of these improvements decreased with each additional adjustment point, and the effect from model selection was not as large as that from adding the initial points.The authors present models that anticipate longitudinal changes in tumor morphology using various models and model adjustment schemes. The accuracy of these models depended on their form, and the utility of these models includes the characterization of patient-specific response with implications for treatment management and research study design.

View details for DOI 10.1118/1.4887815

View details for PubMedID 25086518

View details for DOI 10.1118/1.4887815

View details for Web of Science ID 000341068100010

Abstract

Ruthenium-106 ((106)Ru) eye plaques have the potential to achieve excellent tumor control with acceptable radiation toxicity. We evaluated our experience in the management of uveal melanoma treated with (106)Ru brachytherapy.The records of 40 patients with uveal melanoma treated with brachytherapy using (106)Ru plaques from 2003 to 2007 at University of Texas MD Anderson Cancer Center were reviewed. Endpoints assessed included tumor control and toxicity.Median ophthalmologic follow-up was 67 months. Actuarial 5-year rates of local control (LC), progression-free survival (PFS), and overall survival (OS) were 97%, 94%, and 92%. There were 3 deaths, 2 related to melanoma. Fifteen patients experienced clinically significant visual loss; no patients were diagnosed with neovascular glaucoma, and 1 patient developed a clinically significant radiation-associated cataract. No patient required enucleation.We report the largest published US cohort of patients treated with (106)Ru plaque brachytherapy for uveal melanoma. Tumor control was excellent, and toxicity was acceptably low. These data support the reintroduction of (106)Ru into clinical practice for ocular melanoma.

View details for DOI 10.1016/j.prro.2013.08.004

View details for PubMedID 25012839

Abstract

Human papillomavirus (HPV) is a causative factor in squamous cell carcinomas of the anus, penis, vagina, vulva, and head and neck, and adenocarcinoma of the cervix. We examined the demographics, clinical characteristics, and timing of multiple potentially HPV-related cancers in individual patients.One hundred forty-three patients were identified with 300 potentially HPV-related cancers. The median follow-up from index and second cancer was 18.5 years and 3.2 years, respectively.Median age at index and second cancer was 45 and 60.5 years of age, respectively, with a median interval of 11 years. Cervical cancer was the most common initial diagnosis (61.7%), whereas head and neck squamous cell carcinoma (HNSCC) was the most common second cancer (57.6%).These data suggest differential patterns for development of multiple HPV-related cancers based upon clinical characteristics. Prospective longitudinal and population-based studies are warranted to understand the impact of these findings and opportunities for intervention and screening.

View details for DOI 10.1002/hed.23379

View details for Web of Science ID 000336493200012

View details for PubMedID 23720126

Abstract

The purpose of this work was to develop and evaluate the accuracy of several predictive models of variation in tumor volume throughout the course of radiation therapy.Nineteen patients with oropharyngeal cancers were imaged daily with CT-on-rails for image-guided alignment per an institutional protocol. The daily volumes of 35 tumors in these 19 patients were determined and used to generate (1) a linear model in which tumor volume changed at a constant rate, (2) a general linear model that utilized the power fit relationship between the daily and initial tumor volumes, and (3) a functional general linear model that identified and exploited the primary modes of variation between time series describing the changing tumor volumes. Primary and nodal tumor volumes were examined separately. The accuracy of these models in predicting daily tumor volumes were compared with those of static and linear reference models using leave-one-out cross-validation.In predicting the daily volume of primary tumors, the general linear model and the functional general linear model were more accurate than the static reference model by 9.9% (range: -11.6%-23.8%) and 14.6% (range: -7.3%-27.5%), respectively, and were more accurate than the linear reference model by 14.2% (range: -6.8%-40.3%) and 13.1% (range: -1.5%-52.5%), respectively. In predicting the daily volume of nodal tumors, only the 14.4% (range: -11.1%-20.5%) improvement in accuracy of the functional general linear model compared to the static reference model was statistically significant.A general linear model and a functional general linear model trained on data from a small population of patients can predict the primary tumor volume throughout the course of radiation therapy with greater accuracy than standard reference models. These more accurate models may increase the prognostic value of information about the tumor garnered from pretreatment computed tomography images and facilitate improved treatment management.

View details for DOI 10.1118/1.4870437

View details for Web of Science ID 000336053100008

View details for PubMedID 24784371

Abstract

To investigate potential dose-response relationship between radiation-associated nausea and vomiting (RANV) reported during radiotherapy and candidate nausea/vomiting-associated regions of interest (CNV-ROIs) in head and neck (HNC) squamous cell carcinomas.A total of 130 patients treated with IMRT with squamous cell carcinomas of head and neck were evaluated. For each patient, CNV-ROIs were segmented manually on planning CT images. Clinical on-treatment RANV data were reconstructed by a review of the records for all patients. Dosimetric data parameters were recorded from dose-volume histograms. Nausea and vomiting reports were concatenated as a single binary "Any N/V" variable, and as a "CTC-V2+" variable.The mean dose to CNV-ROIs was higher for patients experiencing RANV events. For patients receiving IMRT alone, a dose-response effect was observed with varying degrees of magnitude, at a statistically significant level for the area postrema, brainstem, dorsal vagal complex, medulla oblongata, solitary nucleus, oropharyngeal mucosa and whole brain CNV-ROIs.RANV is a common therapy-related morbidity facing patients receiving HNC radiotherapy, and, for those receiving radiotherapy-alone, is associated with modifiable dose to specific CNS structures.

View details for DOI 10.1016/j.radonc.2014.02.019

View details for Web of Science ID 000339150100019

View details for PubMedID 24746582

View details for Web of Science ID 000331454200011

Abstract

To investigate atlas-based auto-segmentation methods to improve the quality of the delineation of low-risk clinical target volumes (CTVs) of unilateral tonsil cancers.Sixteen patients received intensity modulated radiation therapy for left tonsil tumors. These patients were treated by a total of 8 oncologists, who delineated all contours manually on the planning CT image. We chose 6 of the patients as atlas cases and used atlas-based auto-segmentation to map each the atlas CTV to the other 10 patients (test patients). For each test patient, the final contour was produced by combining the 6 individual segmentations from the atlases using the simultaneous truth and performance level estimation algorithm. In addition, for each test patient, we identified a single atlas that produced deformed contours best matching the physician's manual contours. The auto-segmented contours were compared with the physician's manual contours using the slice-wise Hausdorff distance (HD), the slice-wise Dice similarity coefficient (DSC), and a total volume overlap index.No single atlas consistently produced good results for all 10 test cases. The multiatlas segmentation achieved a good agreement between auto-segmented contours and manual contours, with a median slice-wise HD of 7.4 1.0 mm, median slice-wise DSC of 80.2% 5.9%, and total volume overlap of 77.8% 3.3% over the 10 test cases. For radiation oncologists who contoured both the test case and one of the atlas cases, the best atlas for a test case had almost always been contoured by the oncologist who had contoured that test case, indicating that individual physician's practice dominated in target delineation and was an important factor in optimal atlas selection.Multiatlas segmentation may improve the quality of CTV delineation in clinical practice for unilateral tonsil cancers. We also showed that individual physician's practice was an important factor in selecting the optimal atlas for atlas-based auto-segmentation.

View details for DOI 10.1016/j.prro.2013.03.003

View details for PubMedID 24621429

Abstract

The purpose of this work was to determine the expansions in 6 anatomic directions that produced optimal margins considering nonrigid setup errors and tissue deformation for patients receiving image-guided radiation therapy (IGRT) of the oropharynx.For 20 patients who had received IGRT to the head and neck, we deformably registered each patient's daily images acquired with a computed tomography (CT)-on-rails system to his or her planning CT. By use of the resulting vector fields, the positions of volume elements within the clinical target volume (CTV) (target voxels) or within a 1-cm shell surrounding the CTV (normal tissue voxels) on the planning CT were identified on each daily CT. We generated a total of 15,625 margins by dilating the CTV by 1, 2, 3, 4, or 5 mm in the posterior, anterior, lateral, medial, inferior, and superior directions. The optimal margins were those that minimized the relative volume of normal tissue voxels positioned within the margin while satisfying 1 of 4 geometric target coverage criteria and 1 of 3 population criteria.Each pair of geometric target coverage and population criteria resulted in a unique, anisotropic, optimal margin. The optimal margin expansions ranged in magnitude from 1 to 5 mm depending on the anatomic direction of the expansion and on the geometric target coverage and population criteria. Typically, the expansions were largest in the medial direction, were smallest in the lateral direction, and increased with the demand of the criteria. The anisotropic margin resulting from the optimal set of expansions always included less normal tissue than did any isotropic margin that satisfied the same pair of criteria.We demonstrated the potential of anisotropic margins to reduce normal tissue exposure without compromising target coverage in IGRT to the head and neck.

View details for DOI 10.1016/j.ijrobp.2013.06.2036

View details for Web of Science ID 000325165300034

View details for PubMedID 23906931

Abstract

Data support proactive swallowing therapy during radiotherapy (RT) or chemoradiotherapy (CRT) for pharyngeal cancers. The benefits of adherence to a regimen of swallowing exercises and maintaining oral intake throughout treatment are reported, but independent effects are unclear.To evaluate the independent effects of maintaining oral intake throughout radiotherapy and adherence to preventive swallowing exercise.Retrospective observational study.The University of Texas MD Anderson Cancer Center, Houston.The study included 497 patients treated with definitive RT or CRT for pharyngeal cancer (458 oropharynx, 39 hypopharynx) between 2002 and 2008.Swallowing-related end points were final diet after RT or CRT and duration of gastrostomy dependence. Primary independent variables included oral intake status at the end of RT or CRT (no oral intake, partial oral intake, or full oral intake) and adherence to a swallowing exercise regimen. Multiple linear regression and ordered logistic regression models were analyzed.At the conclusion of RT or CRT, 131 patients (26%) had no oral intake and 74% maintained oral intake (167 partial [34%], 199 full [40%]). Fifty-eight percent (286 of 497) reported adherence to swallowing exercises. Maintenance of oral intake during RT or CRT and swallowing exercise adherence were independently associated with better long-term diet after RT or CRT (P = .045 and P < .001, respectively) and shorter duration of gastrostomy dependence (P < .001 and P = .007, respectively) in models adjusted for tumor and treatment burden.The data indicate independent, positive associations of maintenance of oral intake throughout RT or CRT and swallowing exercise adherence with long-term swallowing outcomes. Patients who either eat or exercise fare better than those who do neither. Patients who both eat and exercise have the highest rate of return to a regular diet and shortest duration of gastrostomy dependence.

View details for DOI 10.1001/jamaoto.2013.4715

View details for Web of Science ID 000328944900006

View details for PubMedID 24051544

Abstract

As a first step toward developing effective strategies to control symptoms associated with head and neck cancer (HNC) and its treatment, we sought to describe the pattern of symptoms experienced before radiation therapy.Subjects completed the MD Anderson Symptom Inventory-Head and Neck Module before beginning radiation therapy.In all, 270 patients participated. Symptom severity and interference varied between treatment-nave patients and those with prior treatment. Cluster analyses revealed that 33% of patients had high symptom burden. Symptoms most often rated moderate-to-severe were fatigue, sleep disturbance, distress, pain, and problems chewing and swallowing. Poorer performance status, higher T classification, and receipt of previous treatment correlated with higher symptom burden.A substantial proportion of patients were experiencing high symptom burden. Because few interventions currently exist for several of the most problematic symptoms, research in symptom reduction that targets the pattern of symptoms described here is greatly needed.

View details for DOI 10.1002/hed.23181

View details for Web of Science ID 000325091000030

View details for PubMedID 23169304

Abstract

Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in frequency. We reviewed patients with advanced-stage OPSCC treated with chemoradiation to assess the impact of residual neck disease on survival.We reviewed 202 patients with OPSCC between 1990 and 2010 treated with primary chemoradiation followed by neck dissection. Imaging was analyzed using RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 criteria. Survival was evaluated using both univariate and multivariate analyses.Overall survival at 5 years was 89%. Forty-two patients (21%) had residual disease in the neck (pN+). pN+ was associated with greater locoregional recurrence (LRR) and distant metastasis (DM) and decreased survival. No clinicopathologic factors were predictive of pN+. Contrasted posttreatment CT had low sensitivity and specificity.In advanced OPSCC pN+, patients have higher rates of LRR and DM. Neither clinicopathologic factors nor posttreatment imaging was predictive of pN+, although increased use of modern imaging may reduce the rate of negative neck dissections.

View details for DOI 10.1002/hed.23173

View details for Web of Science ID 000325091000024

View details for PubMedID 23018868

Abstract

We performed this study to define the incidence of radiographic retropharyngeal lymph node (RPLN) involvement in oropharyngeal cancer (OPC) and its impact on clinical outcomes, neither of which has been well established to date.Our departmental database was queried for patients irradiated for OPC between 2001 and 2007. Analyzable patients were those with imaging data available for review to determine radiographic RPLN status. Demographic, clinical, and outcome data were retrieved and analyzed.The cohort consisted of 981 patients. The median follow-up was 69 months. The base of the tongue (47%) and the tonsil (46%) were the most common primary sites. The majority of patients had stage T1 to T2 primary tumors (64%), and 94% had stage 3 to 4B disease. Intensity-modulated radiation therapy was used in 77% of patients, and systemic therapy was administered in 58% of patients. The incidence of radiographic RPLN involvement was 10% and was highest for the pharyngeal wall (23%) and lowest for the base of the tongue (6%). RPLN adenopathy correlated with several patient and tumor factors. RPLN involvement was associated with poorer 5-year outcomes on univariate analysis (P<.001 for all) for local control (79% vs 92%), nodal control (80% vs 93%), recurrence-free survival (51% vs 81%), distant metastases-free survival (66% vs 89%), and overall survival (52% vs 82%) and maintained significance on multivariate analysis for local control (P=.023), recurrence-free survival (P=.001), distant metastases-free survival (P=.003), and overall survival (P=.001).In this cohort of nearly 1000 patients investigating [corrected] radiographic RPLN adenopathy in OPC, RPLN involvement was observed in 10% of patients and portends [corrected] a negative influence on disease recurrence, distant relapse, and survival. In this cohort of nearly 1000 patients investigating radiographic RPLN adenopathy in OPC, RPLN involvement was observed in 10% of patients and portends a negative influence on disease recurrence, distant relapse, and survival.

View details for DOI 10.1002/cncr.28195

View details for Web of Science ID 000323255600010

View details for PubMedID 23733178

Abstract

A number of studies have previously assessed the role of teaching interventions to improve organ-at-risk (OAR) delineation. We present a preliminary study demonstrating the benefit of a combined atlas and real time software-based feedback intervention to aid in contouring of OARs in the head and neck.The study consisted of a baseline evaluation, a real-time feedback intervention, atlas presentation, and a follow-up evaluation. At baseline evaluation, 8 resident observers contoured 26 OARs on a computed tomography scan without intervention or aid. They then received feedback comparing their contours both statistically and graphically to a set of atlas-based expert contours. Additionally, they received access to an atlas to contour these structures. The resident observers were then asked to contour the same 26 OARs on a separate computed tomography scan with atlas access. In addition, 6 experts (5 radiation oncologists specializing in the head and neck, and 1 neuroradiologist) contoured the 26 OARs on both scans. A simultaneous truth and performance level estimation (STAPLE) composite of the expert contours was used as a gold-standard set for analysis of OAR contouring.Of the 8 resident observers who initially participated in the study, 7 completed both phases of the study. Dice similarity coefficients were calculated for each user-drawn structure relative to the expert STAPLE composite for each structure. Mean dice similarity coefficients across all structures increased between phase 1 and phase 2 for each resident observer, demonstrating a statistically significant improvement in overall OAR-contouring ability (P < .01). Additionally, intervention improved contouring in 16/26 delineated organs-at-risk across resident observers at a statistically significant level (P .05) including all otic structures and suprahyoid lymph node levels of the head and neck.Our data suggest that a combined atlas and real-time feedback-based educational intervention detectably improves contouring of OARs in the head and neck.

View details for DOI 10.1016/j.prro.2012.11.002

View details for PubMedID 24674363

Abstract

The traditional Fletcher-Williamson tandem and ovoid brachytherapy applicators for treatment of cervical cancer have ovoid shields that reduce the dose to the bladder and rectum. However, these shields produce artifact on computed tomography (CT) that prevents acquisition of high-quality images. To address this limitation, we designed and tested a novel CT-compatible applicator with movable shields, called MDA(3).Fifteen patients with stage IB1-IIB cervical cancer requiring definitive radiation therapy were enrolled in a prospective pilot study to evaluate image quality with the MDA(3). Image quality was assessed by comparing an initial scan obtained with the shields shifted to minimize shield artifact to a second scan obtained with the shields in treatment position. The 2 scans were then compared by a radiation oncologist blinded to the image source. In addition, image quality was assessed by analysis of Hounsfield values in the normal tissues.The MDA(3) was successfully employed for intracavitary brachytherapy in 15 patients. CT images obtained with the shields shifted were superior to CT images obtained with the shields in treatment position in every case as evaluated by the radiation oncologist (P < .0001). The presence of the shields in the treatment position significantly increased the mean Hounsfield values within the bladder (P = .002) and rectum (P = .001) due to high-density image artifact.This novel applicator provides a clinically feasible solution to overcome the limitation of lack of ovoid shields on currently available CT-compatible applicators.

View details for DOI 10.1016/j.prro.2012.03.014

View details for PubMedID 24674314

Abstract

To report mature results of a large cohort of patients diagnosed with squamous cell carcinoma of the oropharynx who were treated with intensity modulated radiation therapy (IMRT).The database of patients irradiated at The University of Texas, M.D. Anderson Cancer Center was searched for patients diagnosed with oropharyngeal cancer and treated with IMRT between 2000 and 2007. A retrospective review of outcome data was performed.The cohort consisted of 776 patients. One hundred fifty-nine patients (21%) were current smokers, 279 (36%) former smokers, and 337 (43%) never smokers. T and N categories and American Joint Committee on Cancer group stages were distributed as follows: T1/x, 288 (37%); T2, 288 (37%); T3, 113 (15%); T4, 87 (11%); N0, 88(12%); N1/x, 140 (18%); N2a, 101 (13%); N2b, 269 (35%); N2c, 122 (16%); and N3, 56 (7%); stage I, 18(2%); stage II, 40(5%); stage III, 150(19%); and stage IV, 568(74%). Seventy-one patients (10%) presented with nodes in level IV. Median follow-up was 54 months. The 5-year overall survival, locoregional control, and overall recurrence-free survival rates were 84%, 90%, and 82%, respectively. Primary site recurrence developed in 7% of patients, and neck recurrence with primary site control in 3%. We could only identify 12 patients (2%) who had locoregional recurrence outside the high-dose target volumes. Poorer survival rates were observed in current smokers, patients with larger primary (T) tumors and lower neck disease.Patients with oropharyngeal cancer treated with IMRT have excellent disease control. Locoregional recurrence was uncommon, and most often occurred in the high dose volumes. Parotid sparing was accomplished in nearly all patients without compromising tumor coverage.

View details for DOI 10.1016/j.ijrobp.2012.08.004

View details for Web of Science ID 000315809300025

View details for PubMedID 22975604

Abstract

We performed this study to assess outcomes of patients with oropharyngeal cancer treated with modern therapy approaches.Demographics, treatments and outcomes of patients diagnosed with Stage 3- 4B squamous carcinoma of the oropharynx, between 2000-2007 were tabulated and analyzed.The cohort consisted of 1046 patients. The 5-year actuarial overall survival, recurrence-free survival and local-regional control rates for the entire cohort were 78%, 77% and 87% respectively. More advanced disease, increasing T-stage and smoking were associated with higher rates of local-regional recurrence and poorer survival.Patients with locally advanced oropharyngeal cancer have a relatively high survival rate. Patients' demographics and primary tumor volume were very influential on these favorable outcomes. In particular, patients with small primary tumors did very well even when treatment was not intensified with the addition of chemotherapy.

View details for DOI 10.1186/1748-717X-8-21

View details for Web of Science ID 000315408100001

View details for PubMedID 23360540

View details for DOI 10.1016/j.currproblcancer.2012.07.002

View details for Web of Science ID 000311879800001

View details for PubMedID 22986060

Abstract

High-dose radiotherapy can cause contracture of the anophthalmic socket, but the incidence of this complication in patients with enucleation for uveal melanoma has not been reported previously. The authors reviewed the surgical management and outcomes in terms of successful prosthesis wear in patients with severe contracture of the anophthalmic socket treated with high-dose radiotherapy for high-risk uveal melanoma, and they estimated the relative risk of this complication.The medical records of all consecutive patients enrolled in a prospective uveal-melanoma tissue-banking protocol at the authors' institution who underwent enucleation between January 2003 and December 2010 were reviewed. Patients who underwent adjuvant radiotherapy of the enucleated socket were further studied.Of the 68 patients enrolled in the prospective tissue-banking protocol, 12 had high-risk histologic features (e.g., extrascleral spread or vortex vein invasion) and were treated with 60 Gy of external beam radiotherapy after enucleation. Five of these patients (41.7%) experienced severe socket contracture precluding prosthesis wear. The median time to onset of contracture following completion of radiotherapy was 20 months. Three patients underwent surgery, which entailed scar tissue release, oral mucous membrane grafting, and socket reconstruction; 2 patients declined surgery. All 3 patients who had surgery experienced significant improvement of socket contracture that enabled patients to wear a prosthesis again.High-dose radiotherapy after enucleation in patients with uveal melanoma caused severe socket contracture and inability to wear a prosthesis in approximately 40% of patients. Surgical repair of the contracted socket using oral mucous membrane grafting can allow resumption of prosthesis wear.

View details for DOI 10.1097/IOP.0b013e31824dd9b8

View details for Web of Science ID 000304530700024

View details for PubMedID 22581085

Abstract

To assess, through a retrospective review, clinical outcomes of patients with squamous cell carcinoma of the tonsil treated at the M. D. Anderson Cancer Center with unilateral radiotherapy techniques that irradiate the involved tonsil region and ipsilateral neck only.Of 901 patients with newly diagnosed squamous cell carcinoma of the tonsil treated with radiotherapy at our institution, we identified 102 that were treated using unilateral radiotherapy techniques. All patients had their primary site of disease restricted to the tonsillar fossa or anterior pillar, with <1 cm involvement of the soft palate. Patients had TX (n = 17 patients), T1 (n = 52), or T2 (n = 33) disease, with Nx (n = 3), N0 (n = 33), N1 (n = 23), N2a (n = 21), or N2b (n = 22) neck disease.Sixty-one patients (60%) underwent diagnostic tonsillectomy before radiotherapy. Twenty-seven patients (26%) underwent excision of a cervical lymph node or neck dissection before radiotherapy. Median follow-up for surviving patients was 38 months. Locoregional control at the primary site and ipsilateral neck was 100%. Two patients experienced contralateral nodal recurrence (2%). The 5-year overall survival and disease-free survival rates were 95% and 96%, respectively. The 5-year freedom from contralateral nodal recurrence rate was 96%. Nine patients required feeding tubes during therapy. Of the 2 patients with contralateral recurrence, 1 experienced an isolated neck recurrence and was salvaged with contralateral neck dissection only and remains alive and free of disease. The other patient presented with a contralateral base of tongue tumor and involved cervical lymph node, which may have represented a second primary tumor, and died of disease.Unilateral radiotherapy for patients with TX-T2, N0-N2b primary tonsil carcinoma results in high rates of disease control, with low rates of contralateral nodal failure and a low incidence of acute toxicity requiring gastrostomy.

View details for DOI 10.1016/j.ijrobp.2011.06.1975

View details for Web of Science ID 000302993900052

View details for PubMedID 22019242

Abstract

Mortality of patients with head and neck squamous cell carcinoma (HNSCC) is primarily driven by tumor cell radioresistance leading to locoregional recurrence (LRR). In this study, we use a classification of TP53 mutation (disruptive vs. nondisruptive) and examine impact on clinical outcomes and radiation sensitivity.Seventy-four patients with HNSCC treated with surgery and postoperative radiation and 38 HNSCC cell lines were assembled; for each, TP53 was sequenced and the in vitro radioresistance measured using clonogenic assays. p53 protein expression was inhibited using short hairpin RNA (shRNA) and overexpressed using a retrovirus. Radiation-induced apoptosis, mitotic cell death, senescence, and reactive oxygen species (ROS) assays were carried out. The effect of the drug metformin on overcoming mutant p53-associated radiation resistance was examined in vitro as well as in vivo, using an orthotopic xenograft model.Mutant TP53 alone was not predictive of LRR; however, disruptive TP53 mutation strongly predicted LRR (P = 0.03). Cell lines with disruptive mutations were significantly more radioresistant (P < 0.05). Expression of disruptive TP53 mutations significantly decreased radiation-induced senescence, as measured by SA--gal staining, p21 expression, and release of ROS. The mitochondrial agent metformin potentiated the effects of radiation in the presence of a disruptive TP53 mutation partially via senescence. Examination of our patient cohort showed that LRR was decreased in patients taking metformin.Disruptive TP53 mutations in HNSCC tumors predicts for LRR, because of increased radioresistance via the inhibition of senescence. Metformin can serve as a radiosensitizer for HNSCC with disruptive TP53, presaging the possibility of personalizing HNSCC treatment.

View details for DOI 10.1158/1078-0432.CCR-11-2260

View details for Web of Science ID 000298758900031

View details for PubMedID 22090360

Abstract

Multiple studies have shown that breast-conserving therapy (BCT) and mastectomy have equivalent outcomes for large populations of women with early-stage breast cancer. For individual treatment decisions, however, it is important to appreciate the heterogeneity of disease. Recent molecular studies have suggested that "breast cancer" includes biologically distinct classes of disease; although these molecular distinctions are important, other patient-related factors also affect outcome and influence prognosis. One of the most important of these patient factors is the age of the patient at diagnosis. Numerous studies have shown very different breast cancer outcomes based on patient age; younger women typically have more aggressive tumors that are more likely to recur both locoregionally and distantly, and older women more commonly have less aggressive disease. The overall disease-specific outcomes, techniques, and doses for adjuvant radiation therapy and toxicity of treatments should be discussed within the context of age because breast cancer is a very different disease based on this factor. Arguments can be made that more aggressive locoregional therapy is warranted in populations of young women with breast cancer and perhaps less aggressive therapy in the elderly.

View details for DOI 10.1016/j.semradonc.2010.09.001

View details for Web of Science ID 000285775600005

View details for PubMedID 21134651

Abstract

To determine the patterns of regional recurrence in patients treated with definitive radiotherapy (RT) for cervical cancer.The records of 198 patients treated with definitive RT for cervical cancer between 1980 and 2000 who experienced a regional recurrence without a central or distal vaginal recurrence were reviewed. All patients received a combination of external-beam RT and intracavitary brachytherapy. In the 180 patients with a documented location of regional recurrence, the relationship between the recurrence and the radiation fields was determined.The median time to regional recurrence was 13 months (range, 2-85 months). Of the 180 patients who had an evaluable regional recurrence, 119 (66%) had a component of marginal failure; 71 patients recurred above-the-field, 2 patients occurred in the inguinal nodes, and 2 patients recurred above-the-field and in the inguinal nodes. In addition, 105 patients (58%) had a component of in-field failure; 59 patients recurred in-field only, 39 patients recurred in-field and above-the-field, 2 patients recurred in-field, above-the-field, and in the inguinal nodes, and 5 patients recurred in-field and in the inguinal nodes. The median survival after regional recurrence was 8 months (range, 0-194 months).Most regional recurrences after definitive RT for cervical cancer include a component of marginal failure, usually immediately superior to the radiation field. These recurrences suggest a deficiency in target volume. Recurrences also occur in-field, suggesting a deficiency in dose. Developments in pretreatment staging, field delineation, dose escalation, and posttreatment surveillance may help to improve outcome in these patients.

View details for DOI 10.1016/j.ijrobp.2009.04.009

View details for Web of Science ID 000276675300020

View details for PubMedID 19581056

Abstract

To compare treatment-related outcomes and toxicity for patients with axillary lymph node metastases from malignant melanoma treated with postoperative radiation therapy (RT) to either the axilla only or both the axilla and supraclavicular fossa (extended field [EF]).The medical records of 200 consecutive patients treated with postoperative RT for axillary lymph node metastases from malignant melanoma were retrospectively reviewed. All patients received postoperative hypofractionated RT for high-risk features; 95 patients (48%) received RT to the axilla only and 105 patients (52%) to the EF.At a median follow-up of 59 months, 111 patients (56%) had sustained relapse, and 99 patients (50%) had died. The 5-year overall survival, disease-free survival, and distant metastasis-free survival rates were 51%, 43%, and 46%, respectively. The 5-year axillary control rate was 88%. There was no difference in axillary control rates on the basis of the treated field (89% for axilla only vs. 86% for EF; p = 0.4). Forty-seven patients (24%) developed treatment-related complications. On both univariate and multivariate analyses, only treatment with EF irradiation was significantly associated with increased treatment-related complications.Adjuvant hypofractionated RT to the axilla only for metastatic malignant melanoma with high-risk features is an effective method to control axillary disease. Limiting the radiation field to the axilla only produced equivalent axillary control rates to EF and resulted in lower treatment-related complication rates.

View details for DOI 10.1016/j.ijrobp.2008.06.1910

View details for Web of Science ID 000264728000013

View details for PubMedID 18774657

Abstract

Some evidence suggests that women with pregnancy-associated breast cancers (PABC) have a worse outcome compared with historical controls. However, young age is a worse prognostic factor independently, and women with PABC tend to be young. The purpose of the current study was to compare locoregional recurrence (LRR), distant metastases (DM), and overall survival (OS) in young patients with PABC and non-PABC.Data for 668 breast cancers in 652 patients aged

View details for DOI 10.1002/cncr.24165

View details for Web of Science ID 000264148300008

View details for PubMedID 19204903

Abstract

Young women with breast cancer have higher locoregional recurrence (LRR) rates than older patients. The goal of this study is to determine the impact of locoregional treatment strategy, breast-conserving therapy (BCT), mastectomy alone (M), or mastectomy with adjuvant radiation (MXRT), on LRR for patients 35 years or younger.Data for 668 breast cancers in 652 young patients with breast cancer were retrospectively reviewed; 197 patients were treated with BCT, 237 with M, and 234 with MXRT.Median follow-up for all living patients was 114 months. In the entire cohort, 10-year actuarial LRR rates varied by locoregional treatment: 19.8% for BCT, 24.1% for M, and 15.1% for MXRT (p = 0.05). In patients with Stage II disease, 10-year actuarial LRR rates by locoregional treatment strategy were 17.7% for BCT, 22.8% for M, and 5.7% for MXRT (p = 0.02). On multivariate analysis, M (hazard ratio, 4.45) and Grade III disease (hazard ratio, 2.24) predicted for increased LRR. In patients with Stage I disease, there was no difference in LRR rates based on locoregional treatment (18.0% for BCT, 19.8% for M; p = 0.56), but chemotherapy use had a statistically significant LRR benefit (13.5% for chemotherapy, 27.9% for none; p = 0.04).Young women have high rates of LRR after breast cancer treatment. For patients with Stage II disease, the best locoregional control rates were achieved with MXRT. For patients with Stage I disease, similar outcomes were achieved with BCT and mastectomy; however, chemotherapy provided a significant benefit to either approach.

View details for DOI 10.1016/j.ijrobp.2008.04.078

View details for Web of Science ID 000263440900016

View details for PubMedID 18707822

Abstract

To evaluate the magnitude of cervix regression and motion during external beam chemoradiation for cervical cancer.Sixteen patients with cervical cancer underwent computed tomography scanning before, weekly during, and after conventional chemoradiation. Cervix volumes were calculated to determine the extent of cervix regression. Changes in the center of mass and perimeter of the cervix between scans were used to determine the magnitude of cervix motion. Maximum cervix position changes were calculated for each patient, and mean maximum changes were calculated for the group.Mean cervical volumes before and after 45 Gy of external beam irradiation were 97.0 and 31.9 cc, respectively; mean volume reduction was 62.3%. Mean maximum changes in the center of mass of the cervix were 2.1, 1.6, and 0.82 cm in the superior-inferior, anterior-posterior, and right-left lateral dimensions, respectively. Mean maximum changes in the perimeter of the cervix were 2.3 and 1.3 cm in the superior and inferior, 1.7 and 1.8 cm in the anterior and posterior, and 0.76 and 0.94 cm in the right and left lateral directions, respectively.Cervix regression and internal organ motion contribute to marked interfraction variations in the intrapelvic position of the cervical target in patients receiving chemoradiation for cervical cancer. Failure to take these variations into account during the application of highly conformal external beam radiation techniques poses a theoretical risk of underdosing the target or overdosing adjacent critical structures.

View details for DOI 10.1016/j.ijrobp.2008.03.064

View details for Web of Science ID 000261820200036

View details for PubMedID 18513882

Abstract

To determine the national surgical practice patterns of care for operable lung cancer patients treated with radiation.A nationwide survey of a stratified random sample of institutions was conducted for patients who had non-metastatic lung cancer, Karnofsky Performance Scores (KPS) > or =60, and who had received radiation therapy as definitive or adjuvant treatment. Among 541 patients, representing a weighted sample size of 42,335 patients nationwide, 131 (19.8%) underwent surgery as part of their therapy. Pearson chi statistics were used to analyze characteristics of this subset of patients.Of the 131 patients who underwent surgery, 126 patients who had non-small cell lung cancer (NSCLC) were analyzed. Surgical patients were younger, had less weight loss, higher KPS, and higher forced expiratory volume within 1 second (FEV1) values than those treated without surgery. Surgical patients had more stage I/II (53.5% vs 32.2%; p = 0.0004) and less clinical N2/N3 disease (28.8% vs 47.5%; p = 0.002) than nonsurgical patients. Surgery consisted of lobectomy or bilobectomy in 63.2% of patients, pneumonectomy in 23.5%, and wedge resection in 5.9%. Of the patients, 80.4% received radiation in the adjuvant setting and 9.9% in the neoadjuvant setting.Patients with non-metastatic lung cancer who are treated surgically and with radiation have clinically less advanced disease than those treated with radiation alone. Most radiation therapy in this setting is administrated postoperatively and secondary to hilar and/or mediastinal nodal involvement undetected before surgery. Improved preoperative nodal staging and neoadjuvant approaches may alter these practice patterns.

View details for Web of Science ID 000239191500005

View details for PubMedID 17409912

Abstract

To determine how imipenem inhibits the class C beta-lactamase AmpC, the X-ray crystal structure of the acyl-enzyme complex was determined to a resolution of 1.80 A. In the complex, the lactam carbonyl oxygen of imipenem has flipped by approximately 180 degrees compared to its expected position; the electrophilic acyl center is thus displaced from the point of hydrolytic attack. This conformation resembles that of imipenem bound to the class A enzyme TEM-1 but is different from that of moxalactam bound to AmpC.

View details for DOI 10.1128/AAC.46.12.3978-3980.2002

View details for Web of Science ID 000179376000041

View details for PubMedID 12435704

Abstract

The structures of enzymes reflect two tendencies that appear opposed. On one hand, they fold into compact, stable structures; on the other hand, they bind a ligand and catalyze a reaction. To be stable, enzymes fold to maximize favorable interactions, forming a tightly packed hydrophobic core, exposing hydrophilic groups, and optimizing intramolecular hydrogen-bonding. To be functional, enzymes carve out an active site for ligand binding, exposing hydrophobic surface area, clustering like charges, and providing unfulfilled hydrogen bond donors and acceptors. Using AmpC beta-lactamase, an enzyme that is well-characterized structurally and mechanistically, the relationship between enzyme stability and function was investigated by substituting key active-site residues and measuring the changes in stability and activity. Substitutions of catalytic residues Ser64, Lys67, Tyr150, Asn152, and Lys315 decrease the activity of the enzyme by 10(3)-10(5)-fold compared to wild-type. Concomitantly, many of these substitutions increase the stability of the enzyme significantly, by up to 4.7kcal/mol. To determine the structural origins of stabilization, the crystal structures of four mutant enzymes were determined to between 1.90A and 1.50A resolution. These structures revealed several mechanisms by which stability was increased, including mimicry of the substrate by the substituted residue (S64D), relief of steric strain (S64G), relief of electrostatic strain (K67Q), and improved polar complementarity (N152H). These results suggest that the preorganization of functionality characteristic of active sites has come at a considerable cost to enzyme stability. In proteins of unknown function, the presence of such destabilized regions may indicate the presence of a binding site.

View details for DOI 10.1016/S0022-2836(02)00599-5

View details for Web of Science ID 000177488000009

View details for PubMedID 12144785

Abstract

Beta-lactamases hydrolyze beta-lactam antibiotics and are the leading cause of bacterial resistance to these drugs. Although beta-lactamases have been extensively studied, structures of the substrate-enzyme and product-enzyme complexes have proven elusive. Here, the structure of a mutant AmpC in complex with the beta-lactam cephalothin in its substrate and product forms was determined by X-ray crystallography to 1.53 A resolution. The acyl-enzyme intermediate between AmpC and cephalothin was determined to 2.06 A resolution. The ligand undergoes a dramatic conformational change as the reaction progresses, with the characteristic six-membered dihydrothiazine ring of cephalothin rotating by 109 degrees. These structures correspond to all three intermediates along the reaction path and provide insight into substrate recognition, catalysis, and product expulsion.

View details for Web of Science ID 000174409600016

View details for PubMedID 12005439

Abstract

Beta-lactamases hydrolyze beta-lactam antibiotics, including penicillins and cephalosporins; these enzymes are the most widespread resistance mechanism to these drugs and pose a growing threat to public health. beta-Lactams that contain a bulky 6(7)alpha substituent, such as imipenem and moxalactam, actually inhibit serine beta-lactamases and are widely used for this reason. Although mutant serine beta-lactamases have arisen that hydrolyze beta-lactamase resistant beta-lactams (e.g., ceftazidime) or avoid mechanism-based inhibitors (e.g., clavulanate), mutant serine beta-lactamases have not yet arisen in the clinic with imipenemase or moxalactamase activity. Structural and thermodynamic studies suggest that the 6(7)alpha substituents of these inhibitors form destabilizing contacts within the covalent adduct with the conserved Asn152 in class C beta-lactamases (Asn132 in class A beta-lactamases). This unfavorable interaction may be crucial to inhibition. To test this destabilization hypothesis, we replaced Asn152 with Ala in the class C beta-lactamase AmpC from Escherichia coli and examined the mutant enzyme's thermodynamic stability in complex with imipenem and moxalactam. Consistent with the hypothesis, the Asn152 --> Ala substitution relieved 0.44 and 1.10 kcal/mol of strain introduced by imipenem and moxalactam, respectively, relative to the wild-type complexes. However, the kinetic efficiency of AmpC N152A was reduced by 6300-fold relative to that of the wild-type enzyme. To further investigate the inhibitor's interaction with the mutant enzyme, the X-ray crystal structure of moxalactam in complex with N152A was determined to a resolution of 1.83 A. Moxalactam in the mutant complex is significantly displaced from its orientation in the wild-type complex; however, moxalactam does not adopt an orientation that would restore competence for hydrolysis. Although Asn152 forces beta-lactams with 6(7)alpha substituents out of a catalytically competent configuration, making them inhibitors, the residue is essential for orienting beta-lactam substrates and cannot simply be replaced with a much smaller residue to restore catalytic activity. Designing beta-lactam inhibitors that interact unfavorably with this conserved residue when in the covalent adduct merits further investigation.

View details for DOI 10.1021/bi010641m

View details for Web of Science ID 000169833400006

View details for PubMedID 11434768

Abstract

Penicillin-binding proteins (PBPs) catalyze the final stages of bacterial cell wall biosynthesis. PBPs form stable covalent complexes with beta-lactam antibiotics, leading to PBP inactivation and ultimately cell death. To understand more clearly how PBPs recognize beta-lactam antibiotics, it is important to know their energies of interaction. Because beta-lactam antibiotics bind covalently to PBPs, these energies are difficult to measure through binding equilibria. However, the noncovalent interaction energies between beta-lactam antibiotics and a PBP can be determined through reversible denaturation of enzyme-antibiotic complexes. Escherichia coli PBP 5, a D-alanine carboxypeptidase, was reversibly denatured by temperature in an apparently two-state manner with a temperature of melting (T(m)) of 48.5 degrees C and a van't Hoff enthalpy of unfolding (H(VH)) of 193 kcal/mole. The binding of the beta-lactam antibiotics cefoxitin, cloxacillin, moxalactam, and imipenem all stabilized the enzyme significantly, with T(m) values as high as +4.6 degrees C (a noncovalent interaction energy of +2.7 kcal/mole). Interestingly, the noncovalent interaction energies of these ligands did not correlate with their second-order acylation rate constants (k(2)/K'). These rate constants indicate the potency of a covalent inhibitor, but they appear to have little to do with interactions within covalent complexes, which is the state of the enzyme often used for structure-based inhibitor design.

View details for Web of Science ID 000168914700018

View details for PubMedID 11369864

Abstract

Despite decades of intense study, the complementarity of beta-lactams for beta-lactamases and penicillin binding proteins is poorly understood. For most of these enzymes, beta-lactam binding involves rapid formation of a covalent intermediate. This makes measuring the equilibrium between bound and free beta-lactam difficult, effectively precluding measurement of the interaction energy between the ligand and the enzyme. Here, we explore the energetic complementarity of beta-lactams for the beta-lactamase AmpC through reversible denaturation of adducts of the enzyme with beta-lactams. AmpC from Escherichia coli was reversibly denatured by temperature in a two-state manner with a temperature of melting (Tm) of 54.6 degrees C and a van't Hoff enthalpy of unfolding (deltaH(VH)) of 182 kcal/mol. Solvent denaturation gave a Gibbs free energy of unfolding in the absence of denaturant (deltaG(u)H2O) of 14.0 kcal/mol. Ligand binding perturbed the stability of the enzyme. The penicillin cloxacillin stabilized AmpC by 3.2 kcal/mol (deltaTm = +5.8 degrees C); the monobactam aztreonam stabilized the enzyme by 2.7 kcal/mol (deltaTm = +4.9 degrees C). Both acylating inhibitors complement the active site. Surprisingly, the oxacephem moxalactam and the carbapenem imipenem both destabilized AmpC, by 1.8 kcal/mol (deltaTm = -3.2 degrees C) and 0.7 kcal/mol (deltaTm = -1.2 degrees C), respectively. These beta-lactams, which share nonhydrogen substituents in the 6(7)alpha position of the beta-lactam ring, make unfavorable noncovalent interactions with the enzyme. Complexes of AmpC with transition state analog inhibitors were also reversibly denatured; both benzo(b)thiophene-2-boronic acid (BZBTH2B) and p-nitrophenyl phenylphosphonate (PNPP) stabilized AmpC. Finally, a catalytically inactive mutant of AmpC, Y150F, was reversibly denatured. It was 0.7 kcal/mol (deltaTm = -1.3 degrees C) less stable than wild-type (WT) by thermal denaturation. Both the cloxacillin and the moxalactam adducts with Y150F were significantly destabilized relative to their WT counterparts, suggesting that this residue plays a role in recognizing the acylated intermediate of the beta-lactamase reaction. Reversible denaturation allows for energetic analyses of the complementarity of AmpC for beta-lactams, through ligand binding, and for itself, through residue substitution. Reversible denaturation may be a useful way to study ligand complementarity to other beta-lactam binding proteins as well.

View details for Web of Science ID 000082424200011

View details for PubMedID 10493583

Abstract

Several models have been proposed to explain the high temperatures required to denature enzymes from thermophilic organisms; some involve greater maximum thermodynamic stability for the thermophile, and others do not. To test these models, we reversibly melted two analogous protein domains in a two-state manner. E2cd is the isolated catalytic domain of cellulase E2 from the thermophile Thermomonospora fusca. CenAP30 is the analogous domain of the cellulase CenA from the mesophile Cellulomonas fimi. When reversibly denatured in a common buffer, the thermophilic enzyme E2cd had a temperature of melting (Tm) of 72.2 degrees C, a van't Hoff enthalpy of unfolding (DeltaHVH) of 190 kcal/mol, and an entropy of unfolding (DeltaSu) of 0.55 kcal/(mol*K); the mesophilic enzyme CenAP30 had a Tm of 56.4 degrees C, a DeltaHVH of 107 kcal/mol, and a DeltaSu of 0. 32 kcal/(mol*K). The higher DeltaHVH and DeltaSu values for E2cd suggest that its free energy of unfolding (DeltaGu) has a steeper dependence on temperature at the Tm than CenAP30. This result supports models that predict a greater maximum thermodynamic stability for thermophilic enzymes than for their mesophilic counterparts. This was further explored by urea denaturation. Under reducing conditions at 30 degrees C, E2cd had a concentration of melting (Cm) of 5.2 M and a DeltaGu of 11.2 kcal/mol; CenAP30 had a Cm of 2.6 M and a DeltaGu of 4.3 kcal/mol. Under nonreducing conditions, the Cm and DeltaGu of CenAP30 were increased to 4.5 M and 10.8 kcal/mol at 30 degrees C; the Cm for E2cd was increased to at least 7.4 M at 32 degrees C. We were unable to determine a DeltaGu value for E2cd under nonreducing conditions due to problems with reversibility. These data suggest that E2cd attains its greater thermal stability (DeltaTm = 15.8 degrees C) through a greater thermodynamic stability (DeltaDeltaGu = 6.9 kcal/mol) compared to its mesophilic analogue CenAP30.

View details for Web of Science ID 000078971300038

View details for PubMedID 10029552