Faculty Bibliography

Purpose: The purpose of this study is to quantify interfractional dosimetric variations in radiotherapy of oropharyngeal cancer and investigate the application of statistical process control (SPC) to determine significantly deviated fractions for management.
Method(s): Thirteen oropharyngeal cancer patients treated by IMRT or VMAT with daily CBCT were retrospectively reviewed. CBCT images of every other fraction were imported to the software Velocity and registered to planning CT using the 6DOF couch shifts generated during patient setup. Using Velocity Adaptive Monitoring module, the setup-corrected CBCT was matched to planning CT using a deformable registration. The module also generated dose volume histograms (DVHs) at each CBCT from planning doses for the deformed plan structure sets. Volumes and dose metrics at each fraction were calculated and rated with plan values to evaluate interfractional dosimetric variations using a SPC framework. T-tests between plan and fraction volumes were performed to find statistically insignificant fractions. Average, upper and lower process capacity limits (UCL, LCL) of each dose metric were derived from these fractions using conventional SPC guidelines.
Result(s): GTV and OAR volumes in first 13 fractions had no significantly changes from the plan, subsequently reduced by 10% to treatment completion, except oral cavity. There were 3%-4% increases in parotid mean doses, but no significant differences in dose metrics of GTVand other OARs. The changes were organ and patient dependent. Control charts for various dose metrics were generated to assess the metrics for individual patient. The occurrences of one or several dose metrics out of the control limits warrant immediate investigation of the fraction.
Conclusion(s): Daily CBCT could be used to monitor dosimetric variations of targets and OARs resulting from volume changes and tissue deformation in oropharyngeal cancer radiotherapy. Treatment review with guidance of a SPC tool may enable objectively and consistently identify significantly deviated fractions

Purpose: Concurrent chemotherapy with radiotherapy is the standard of care for locally advanced oropharyngeal cancer patients. However, the main drawback of this approach is the high toxicities experienced by the patients. This has motivated new clinical trials that investigate the role of imaging biomarkers in dose de-escalation to mitigate the side effects of treatments.
Method(s): Ten patients from an institutional phase II clinical trial were CE-CT (Contrast-Enhanced-CT) simulated prior to starting radiotherapy treatment and at week-four as part of the protocol. A radiation oncologist manually contoured the GTVn (primary nodal disease) on both scans. Based on GTVn volume variation (>=40%) patients were eligible/ineligible for dose de-escalation. CE-CT scans and contours were transfer to IBEX for texture-feature calculation. The relative net change for 77 texture-features was calculated. The Pearson correlation coefficient (r) was used to correlate the volume change with the feature changes. Texture-features that presented an r >0.5 are possible candidates for treatment assessment. Significance level was evaluated using the t-test (P < 0.05) Results: Eight patients met criteria for mid-treatment nodal response and were de-escalated. For the two patients who proceeded with standard treatment, shape texture-features variation were low, ranging [-6% to 14%] when compared to de-escalated patients range [-0% to 60%]. Across all the patients two shape features (surface area and surface area density) showed high correlation with node-tumor volume changes, with r-values of 0.81 (P < 0.05) and -0.66 (P < 0.05). Histogram-based-likeskewness showed a medium correlation with r-value of 0.52 (P > 0.05), whereas dissimilarity feature from the Gray-Level-Occurrence-Matrix showed correlation of 0.63 (P < 0.05).
Conclusion(s): Features with high Pearson correlation values are potential candidates to be used as additional metrics for treatment assessment. The study includes other imaging modalities (e.g MRI and PET) which will be included as a future work. More analysis will be added to the study as more patients are continually enrolled in the protocol

Perineural invasion (PNI), the neoplastic invasion of nerves, is a common pathological finding in head and neck cancer that is associated with poor clinical outcomes. PNI is a histological finding of tumor cell infiltration and is distinct from perineural tumor spread (PNTS), which is macroscopic tumor involvement along a nerve extending from the primary tumor that is by definition more advanced, being radiologically or clinically apparent. Despite widespread acknowledgement of the prognostic significance of PNI/PNTS, the mechanisms underlying its pathogenesis remain largely unknown, and specific therapies targeting nerve invasion are lacking. The use of radiation therapy for PNI/PNTS can improve local control and reduce devastating failures at the skull base. However, the optimal volumes to be delineated with respect to targeting cranial nerve pathways are not well defined, and radiation may carry risks of major toxicity secondary to the location of adjacent critical structures. Here we examine the pathogenesis of these phenomena, analyze the role of radiation in PNI/PNTS, and propose guidelines for radiation treatment design based on the best available evidence and the authors' collective experience in order to advance understanding and therapy of this ominous cancer phenotype.

Oropharyngeal carcinoma associated with the human papillomavirus is increasing in incidence and represents a unique head and neck disease with favorable treatment outcomes. This review evaluates the evolving role of radiotherapy in regional management with an overall goal of treatment de-escalation in the appropriate patient. Determining the optimal approach and selection factors for treatment de-escalation is under active investigation. Response to induction chemotherapy, refining adverse pathologic factors after a primary surgical approach, decreasing radiation dose with or without chemotherapy in the definitive or adjuvant settings as well as more selective nodal level irradiation all are current strategies for treatment de-escalation. This review details the likely changes in regional radiotherapy management for oropharyngeal carcinoma in the modern human papillomavirus era and discusses future approaches to patient selection with the goal of reducing toxicities while maintaining function preservation and quality of life in group of patients who are younger and healthier than traditional head and neck cancer patients.

OBJECTIVE:Clear cell carcinoma (CCC) is a rare salivary gland malignancy, believed to be generally low grade. We investigated CCC epidemiology and clinical behavior, using the National Cancer Database (NCDB). STUDY DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:NCDB. SUBJECTS AND METHODS/METHODS:All CCCs of the salivary glands were selected between 2004 and 2015. Patient demographics, tumor characteristics, treatments, and survival were analyzed. Cox regression analyses were performed in treated patients. RESULTS:We identified 268 patients with CCC. Median age was 61 (21-90) years. Most were female (145, 54%). The most common site was oral cavity (119, 44%), followed by major salivary glands (68, 25%) and oropharynx (41, 15%). Most tumors were low grade (81, 68%) and stages I to II (117, 60.6%). Nodal (36, 17.5%) and distant metastases (6, 2.4%) were rare. Most were treated by surgery alone (134, 50.0%), followed by surgery and radiotherapy (69, 25.7%). Five-year overall survival (OS) was 77.6% (95% CI, 71.4%-84.2%). In univariate analysis, older age, major salivary gland and sinonasal site, stages III to IV, high grade, and positive margins were associated with worse OS. In multivariate analysis, only high tumor grade (hazard ratio [HR], 5.76; 95% CI, 1.39-23.85; P = .02), positive margins (HR, 4.01; 95% CI, 1.20-13.43; P = .02), and age ≥60 years (HR, 3.45; 95% CI, 1.39-8.55; P = .01) were significantly associated with OS. CONCLUSION/CONCLUSIONS:We report the largest series of clear cell carcinomas of the head and neck. Outcomes are generally favorable following surgical-based treatments. In this series, pathologic tumor grade is associated with worse survival. Routine evaluation and reporting of tumor grade might better guide physicians in recommending appropriate treatments in this rare malignancy.

OBJECTIVE:Radiobiological models have been used to calculate the outcomes of treatment plans based on dose-volume relationship. This study examines several radiobiological models for the calculation of tumor control probability (TCP) of intensity modulated radiotherapy plans for the treatment of lung, prostate, and head and neck (H&N) cancers. METHODS:Dose volume histogram (DVH) data from the intensity modulated radiotherapy plans of 36 lung, 26 prostate, and 87  H&N cases were evaluated. The Poisson, Niemierko, and Marsden models were used to calculate the TCP of each disease group treatment plan. The calculated results were analyzed for correlation and discrepancy among the three models, as well as different treatment sites under study. RESULTS:The median value of calculated TCP in lung plans was 61.9% (34.1-76.5%), 59.5% (33.5-73.9%) and 32.5% (0.0-93.9%) with the Poisson, Niemierko, and Marsden models, respectively. The median value of calculated TCP in prostate plans was 85.1% (56.4-90.9%), 81.2% (56.1-88.7%) and 62.5% (28.2-75.9%) with the Poisson, Niemierko, and Marsden models, respectively. The median value of calculated TCP in H&N plans was 94.0% (44.0-97.8%) and 94.3% (0.0-97.8%) with the Poisson and Niemierko models, respectively. There were significant differences between the calculated TCPs with the Marsden model in comparison with either the Poisson or Niemierko model (p < 0.001) for both lung and prostate plans. The TCPs calculated by the Poisson and Niemierko models were significantly correlated for all three tumor sites. CONCLUSION/CONCLUSIONS:There are variations with different radiobiological models. Understanding of the correlation and limitation of a TCP model with dosimetric parameters can help develop the meaningful objective functions for plan optimization, which would lead to the implementation of outcome-based planning. More clinical data are needed to refine and consolidate the model for accuracy and robustness. Advances in knowledge: This study has tested three radiobiological models with varied disease sites. It is significant to compare different models with the same data set for better understanding of their clinical applicability.

Background/UNASSIGNED:Annually, over 65,000 persons are diagnosed with head and neck cancer in the United States. During treatment, up to 50% of patients become severely symptomatic with pain, fatigue, mouth sores, and inability to eat. Long term complications are lymphedema, fibrosis, dysphagia, and musculoskeletal impairment. Patients' ability to perform daily activities and to interact socially may be impaired, resulting in poor quality of life. A pragmatic, clinically useful assessment is needed to ensure early detection and intervention for patients to report symptoms and functional limitations over time. We developed the Electronic Patient Visit Assessment (ePVA) that enables patients to report 42 symptoms related to head and neck cancer and 17 limitations of functional status. This manuscript reports (I) the development of the ePVA, (II) the content validity of the ePVA, and (III) the usability and reliability of the ePVA. Methods/UNASSIGNED:Usability was evaluated using the "Think Aloud" technique to guide the iterative process to refine the ePVA based on participants' evaluations. After signing the informed consent, 30 participants with head and neck cancer completed the ePVA using digital tablet devices while thinking aloud about ease of use. All patient conversations were recorded and professionally transcribed. Reliability of the ePVA symptom and functional limitation measures was estimated using the Kuder-Richardson test. Convergent validity of the ePVA was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 global QoL/health scale. Transcribed qualitative data were analyzed using directed content analysis approach. Quantitative analyses consisted of descriptive statistics and correlation analyses. Results/UNASSIGNED:Among participants, 90% strongly agreed or agreed that the ePVA system was easy to use and 80% were very satisfied. Only minor usability problems were reported due to formatting and software "bugs". Reporting of usability problems decreased in frequency over the study period and no usability problems were reported by the last 3 participants who completed the ePVA. Based on participants' suggestions during the iterative process, refinement of the ePVA included increased touch sensitivity of the touch screen technology and customized error messages to improve ease of use. The ePVA also recorded patient reported symptoms (mouth symptoms: 93%, fibrosis: 60%, fatigue: 60%). The ePVA demonstrated acceptable reliability (alpha =0.82-0.85) and convergent validity (ePVA total number of reported symptoms and function limitations was negatively correlated with EORTC QLQ-C30 global QOL/health scale: r=-0.55038, P<0.01). Conclusions/UNASSIGNED:The ePVA was rigorously developed, accepted by patients with satisfaction, and demonstrated acceptable reliability and convergent validity. Future research will use data generated by the ePVA to determine the impact of symptom trajectories on functional status, treatment interruptions and terminations, and health resource use in head and neck cancer.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To assess patterns of care and outcomes with the use of neoadjuvant chemotherapy followed by definitive radiation in local-regionally advanced nasopharyngeal carcinoma. STUDY DESIGN/METHODS:Retrospective database analysis. METHODS:We queried the National Cancer Database for patients with T3-4N2 or T1-4N3 nasopharyngeal carcinoma who received concurrent chemoradiotherapy or neoadjuvant chemotherapy followed by radiation. Overall survival (OS) was analyzed using the Kaplan-Meier method, propensity-score matching, and a Cox proportional hazards model adjusting for demographic and disease-specific prognostic factors. RESULTS:P = .001). At a median follow-up of 36.6 months, patients had 3-year OS of 66% in the neoadjuvant group compared with 70% in those who received concurrent chemoradiotherapy (log rank P = .29). On subgroup analysis by histology, T stage, and N stage, there remained no differences in OS between the two groups. On multivariable analysis, there was no significant survival difference associated with neoadjuvant chemotherapy (adjusted hazard ratio [HR]: 1.05, 95% confidence interval [CI]: 0.89-1.25, P = .54). In a propensity score-matched population of 1,008 patients (504 with neoadjuvant therapy and 504 without), there was no significant survival difference associated with neoadjuvant chemotherapy (H: 1.13, 95% CI: 0.93-1.38, P = .22). CONCLUSIONS:Neoadjuvant chemotherapy was used in over 25% of patients, and its use is increasing. However, neoadjuvant chemotherapy was not associated with any differences in survival compared to concurrent chemoradiotherapy. LEVEL OF EVIDENCE/METHODS:4 Laryngoscope, 2018.