Prospective Evaluation of Swallowing Symptoms in Human Papillomavirus-Associated Oropharynx Cancer.

To demonstrate that the lack of significant swallowing-related symptoms in patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma is attributable to smaller mucosal primaries. A validated dysphagia symptom questionnaire and eating assessment tool was prospectively provided to patients presenting with untreated human papillomavirus-associated oropharyngeal cancer at the University of Maryland from July 2017 to December 2018. A 10-item Eating Assessment Tool (EAT-10) was completed by each patient prior to intervention. All EAT-10 data were collected prospectively. Patient demographic and oncologic characteristics were also obtained. Seventy consecutive patients were enrolled and included in the study. This study cohort included 66 (94%) male patients. Sixty (86%) of patients were Caucasian. The mean EAT-10 score was 3.77 (95% CI 2.04, 5.50). Fifty-two (74.3%) patients presented with normal swallowing (EAT-10 scores less than 3). Spearman correlation indicated there was a significant positive association between tumor size and EAT-10 score (r(68) = 0.429, p < 0.005), with larger tumors associated with increased swallowing-related symptoms. The majority of patients presenting with HPV-associated oropharyngeal squamous cell carcinoma do not report any swallowing difficulties. Dysphagia-related symptoms are associated with large size tumors when they do occur.

Reproducibility of a novel, vacuum-assisted immobilization for breast stereotactic radiotherapy.

A novel, breast-specific stereotactic radiotherapy device has been developed for delivery of highly conformal, accelerated partial breast irradiation. This device employs a unique, vacuum-assisted, breast cup immobilization system that applies a gentle, negative pressure to the target breast with the patient in the prone position. A device-specific patient loader is utilized for simulation scanning and device docking. Prior to clinical activation, a prospective protocol enrolled 25 patients who had been or were to be treated with breast conservation surgery and adjuvant radiotherapy for localized breast cancer. The patients underwent breast cup placement and two separate CT simulation scans. Surgical clips within the breast were mapped and positions measured against the device's integrated stereotactic fiducial/coordinate system to confirm reproducible and durable immobilization during the simulation, treatment planning, and delivery process for the device. Of the enrolled 25 patients, 16 were deemed eligible for analysis. Seventy-three clips (median, 4; mean, 4.6; range, 1-8 per patient) were mapped in these selected patients on both the first and second CT scans. X, Y, and Z coordinates were determined for the center point of each clip. Length of vector change in position was determined for each clip between the two scans. The mean displacement of implanted clips was 1.90 mm (median, 1.47 mm; range, 0.44-6.52 mm) (95% CI, 1.6-2.20 mm). Additional analyses stratified clips by position within the breast and depth into the immobilization cup. Overall, this effort validated the clinically utilized 3-mm planning target volume margin for accurate, reliable, and precise employment of the device.

Comparison of longitudinal change in sST2 vs BNP to predict major adverse cardiovascular events in asymptomatic patients in the community.

Biomarker-based preventative and monitoring strategies are increasingly used for risk stratification in cardiovascular (CV) disease. The aim of this study was to investigate the utility of longitudinal change in B-type natriuretic peptide (BNP) and sST2 concentrations for predicting incident major adverse CV events (MACE) (heart failure, myocardial infarction, arrhythmia, stroke/transient ischaemic attack and CV death) in asymptomatic community-based patients with risk factors but without prevalent MACE at enrolment. The study population consisted of 282 patients selected from the longitudinal STOP-HF study of asymptomatic patients with risk factors for development of MACE. Fifty-two of these patients developed a MACE. The study was run in two phases comprising of an initial investigative cohort (n = 195), and a subsequent 2:1 (No MACE: MACE) propensity matched verification cohort (n = 87). BNP and sST2 were quantified in all patients at two time points a median of 2.5 years apart. Results highlighted that longitudinal change in sST2 was a statistically significant predictor of incident MACE, (AUC 0.60). A one-unit increment in sST2 change from baseline to follow up corresponded to approximately 7.99% increase in the rate of one or more incident MACE, independent of the baseline or follow-up concentration. In contrast, longitudinal change value of BNP was not associated with MACE. In conclusion, longitudinal change in sST2 but not BNP was associated with incident MACE in asymptomatic, initially event-free patients in the community. Further work is required to evaluate the clinical utility of change in sST2 in risk prediction and event monitoring in this setting.

Beyond the dermis-high-risk invasive squamous cell carcinoma: a retrospective review.

OBJECTIVE: Most cutaneous squamous cell carcinomas (cSCC) are low risk and can be treated with simple excision or ablation. High-risk cSCC require invasive treatment, including radical surgery. We present our experience in treating invasive cSCC of the pelvis and extremities. METHOD: A retrospective review of the data of patients with invasive cSCC, indicated for surgery between 2014 and 2018, from a single institution was carried out. RESULTS: A total of 19 patients (nine men, 10 women) were included in the study. Mean age was 62 years; mean tumour size was 8.6cm). Of the 19 patients, five patients with paraplegia with cSCC arising from hard-to-heal ulcers died of infection or bleeding after surgery or systemic therapy. Also, nine patients with localised cSCC underwent margin-negative resection with or without radiation; one patient experienced disease relapse. Of the participants, two patients with previous transplants and multifocal aggressive cSCC underwent numerous resections but succumbed to disease, and two patients who presented with locally recurrent disease after previous positive margin resection and radiation underwent re-resection but developed recurrent disease. CONCLUSIONS: Prognosis for invasive cSCC largely depends on clinical setting. Tumours arising from ulcers in patients with paraplegia have a poor prognosis regardless of treatment. Invasive cSCC in transplant patients are often multifocal and often recur. Debulking procedures are associated with local recurrence despite radiation. Patients presenting with localised disease have a favourable prognosis with wide resection, flap coverage and adjuvant therapy.

Utilization of hypofractionated whole-breast radiation therapy in patients receiving chemotherapy: a National Cancer Database analysis.

PURPOSE: Results from four major hypofractionated whole-breast radiotherapy (HF-WBRT) trials have demonstrated equivalence in select patients with early-stage breast cancer when compared with conventionally fractionated WBRT (CF-WBRT). Because relatively little data were available on patients receiving neoadjuvant or adjuvant chemotherapy, consensus guidelines published in 2011 did not endorse the use of HF-WBRT in this population. Our goal is to evaluate trends in utilization of HF-WBRT in patients receiving chemotherapy. METHODS AND MATERIALS: We retrospectively analyzed data from 2004 to 2013 in the National Cancer DataBase on breast cancer patients treated with HF-WBRT who met the clinical criteria proposed by consensus guidelines (i.e., age >0 years, T1-2N0, and breast-conserving surgery), regardless of receipt of chemotherapy. We employed logistic regression to delineate and compare clinical and demographic factors associated with utilization of HF-WBRT and CF-WBRT. RESULTS: A total of 56,836 women were treated with chemotherapy and WBRT (without regional nodal irradiation) from 2004 to 2013; 9.0% (n = 5093) were treated with HF-WBRT. Utilization of HF-WBRT increased from 4.6% in 2004 to 18.2% in 2013 (odds ratio [OR] 1.21/year; P < 0.001). Among patients receiving chemotherapy, factors most dramatically associated with increased odds of receiving HF-WBRT on multivariate analysis were academic facilities (OR 2.07; P < 0.001), age >80 (OR 2.58; P < 0.001), west region (OR 1.91; P < 0.001), and distance >50 miles from cancer reporting facility (OR 1.43; P < 0.001). Factors associated with decreased odds of receiving HF-WBRT included white race, income <$48,000, lack of private insurance, T2 versus T1, and higher grade (all P < 0.02). CONCLUSIONS: Despite the absence of consensus guideline recommendations, the use of HF-WBRT in patients receiving chemotherapy has increased fourfold (absolute = 13.6%) over the last decade. Increased utilization of HF-WBRT should result in institutional reports verifying its safety and efficacy.

Increasing utilization of regional nodal irradiation in elderly node-positive women and declining emphasis on demographic factors.

PURPOSE: To evaluate the practice patterns for the use of regional nodal irradiation (RNI) in treatment of elderly women with low volume node-positive breast cancer in the setting of breast conservation surgery (BCS). METHODS: Women aged 70-89 diagnosed with unilateral, pathologic T1-2N1M0 breast cancer from 2004 to 2013, who underwent BCS and received radiotherapy were identified from the National Cancer Database. In 2011, two major trials were presented that helped define indications for RNI. Patients were dichotomized into "early", i.e. diagnosed up to 2010, and "late" cohorts. Patient and treatment characteristics were compared between the cohorts and logistic regression used to determine independent factors associated with the receipt of RNI. RESULTS: 7228 women met inclusion criteria; 4330 (59.9%) in early and 2898 (40.1%) in late cohorts. Utilization of RNI increased from 33.9% in early to 42.5% in late cohorts (P ≤ 0.001) and was independent of a general increase in RNI utilization. RNI in the early and late cohorts was not different between the study population and younger women (P > 0.05). RNI utilization increased in both cohorts with increasing number of positive lymph nodes. In the early cohort, RNI was also associated with higher grade, white race and lower income. In the late cohort, RNI increased with the presence of multiple, predefined risk factors. CONCLUSIONS: There was an increase in utilization of RNI for elderly patients from 2004 to 2013. In more recent years, the primary factors associated with receipt of RNI were tumor related with declining importance of demographic factors.

Dosimetric Improvements with a Novel Breast Stereotactic Radiotherapy Device for Delivery of Preoperative Partial-Breast Irradiation.

OBJECTIVE: Partial-breast irradiation (PBI) with external-beam radiotherapy has produced higher than expected rates of fair-to-poor cosmesis. Worsened outcomes have been correlated with larger volumes of breast tissue exposed to radiation. A novel breast-specific stereotactic radiotherapy (BSRT) device (BSRTD) has been developed at our institution and has shown promise in delivering highly conformal dose distributions. We compared normal tissue sparing with this device with that achieved with intensity-modulated radiation therapy (IMRT)-PBI. METHODS: Fifteen women previously treated with breast conservation therapy were enrolled on an institutional review board-approved protocol. Each of them underwent CT simulation in the prone position using the BSRTD-specific immobilization system. Simulated postoperative and preoperative treatment volumes were generated based on surgical bed/clip position. Blinded planners generated IMRT-PBI plans and BSRT plans for each set of volumes. These plans were compared based on clinically validated markers for cosmetic outcome and toxicity using a Wilcoxon rank-sum test. RESULTS: The BSRT plans consistently reduced the volumes receiving each of several dose levels (Vx) to breast tissue, the chest wall, the lung, the heart, and the skin in both preoperative and postoperative settings (p < 0.05). Preoperative BSRT yielded particularly dramatic improvements. CONCLUSION: The novel BSRTD has demonstrated significant dosimetric benefits over IMRT-PBI. Further investigation is currently proceeding through initial clinical trials.

Hyperthermia and radiotherapy in bladder cancer.

Hyperthermia represents a unique, safe, and advantageous methodology for improving therapeutic strategies in the management of bladder cancer. This modality has shown promise in contributing to treatment regimens for both superficial and muscle-invasive disease. Especially in conjunction with intravesical chemotherapy, systemic therapy, and radiotherapy, hyperthermia shows particular synergistic benefit. As such, it should be explored further through clinical use and clinical trial in conjunction with currently available techniques and emerging technologies. However, to conceptualise the way forward, it is particularly important to understand the current challenges to widespread use of non-invasive, bladder-sparing approaches and the current state of bladder cancer care. As such, in the following article, we have focused on not only the rationale for concurrent radiotherapy and hyperthermia, but also the clinical landscape in bladder cancer as a whole.

Characterization of Photon Intensity Modulated Radiation Therapy Robustness in Patients With Prostate Cancer as a Proposed Benchmark for Proton Therapy Robustness Evaluation.

PURPOSE: Robustness evaluation is increasingly used in particle therapy planning to assess clinical target volume (CTV) coverage in the setting of setup and range uncertainty. However, no clear standard exists as to an acceptable degree of plan robustness. The aim of this study is to quantify x-ray robustness parameters, as this could inform proton planning when held to a similar standard. METHODS AND MATERIALS: Consecutive patients with prostate adenocarcinoma treated with definitive x-irradiation to the prostate alone at a single institution in 2019 were retrospectively reviewed. CTV to planned target volume (PTV) margins of 7 mm in all directions, except 4 mm posteriorly, were used in the main cohort. Plans were normalized to PTV V100% ≥ 95%. Patient setup errors were simulated by shifting the isocenter relative to the patient in each of the cardinal directions. The magnitude of each shift equaled the magnitude of the CTV to PTV expansion in that direction. Range uncertainty was set to 0%. RESULTS: A total of 27 patients were evaluated. The mean (SD) nominal plan CTV V100% was 99.6% (1.1%). The mean (SD) worst-case shift CTV V100% was 97.2% (2.8%). The mean (SD) nominal and worst-case CTV V95% were 100% (0%) and 99.7% (0.5%), respectively. A worst-case CTV V100% > 90% and a worst-case CTV V95% > 99% were achieved in over 95% of plans. The mean (SD) nominal and worst-case rectal V70 Gy were 2.37 cc (1.00 cc) and 11.60 cc (3.16 cc), respectively. The mean (SD) nominal and worst-case bladder V60 Gy were 7.8% (4.8%) and 14.5% (9.3%), respectively. Paired 2-tailed t tests comparing the nominal to worst-case dose-volume histograms were significant for each dosimetric parameter (P < .01). CONCLUSIONS: X-ray planning uses PTV margins to inherently provide robustness to patient setup errors. Although the prostate remains well covered in various setup uncertainty scenarios, organs at risk routinely exceeded nominal treatment plan institutional constraints in the worst-case scenarios. Robustness metrics obtained from x-ray plans could serve as a benchmark for proton therapy robust optimization and evaluation.

Practice Patterns of Spatially Fractionated Radiation Therapy: A Clinical Practice Survey.

Purpose: Spatially fractionated radiation therapy (SFRT) is increasingly used for bulky advanced tumors, but specifics of clinical SFRT practice remain elusive. This study aimed to determine practice patterns of GRID and Lattice radiation therapy (LRT)-based SFRT. Methods and Materials: A survey was designed to identify radiation oncologists' practice patterns of patient selection for SFRT, dosing/planning, dosimetric parameter use, SFRT platforms/techniques, combinations of SFRT with conventional external beam radiation therapy (cERT) and multimodality therapies, and physicists' technical implementation, delivery, and quality procedures. Data were summarized using descriptive statistics. Group comparisons were analyzed with permutation tests. Results: The majority of practicing radiation oncologists (United States, 100%; global, 72.7%) considered SFRT an accepted standard-of-care radiation therapy option for bulky/advanced tumors. Treatment of metastases/recurrences and nonmetastatic primary tumors, predominantly head and neck, lung cancer and sarcoma, was commonly practiced. In palliative SFRT, regimens of 15 to 18 Gy/1 fraction predominated (51.3%), and in curative-intent treatment of nonmetastatic tumors, 15 Gy/1 fraction (28.0%) and fractionated SFRT (24.0%) were most common. SFRT was combined with cERT commonly but not always in palliative (78.6%) and curative-intent (85.7%) treatment. SFRT-cERT time sequencing and cERT dose adjustments were variable. In curative-intent treatment, concurrent chemotherapy and immunotherapy were found acceptable by 54.5% and 28.6%, respectively. Use of SFRT dosimetric parameters was highly variable and differed between GRID and LRT. SFRT heterogeneity dosimetric parameters were more commonly used (P = .008) and more commonly thought to influence local control (peak dose, P = .008) in LRT than in GRID therapy. Conclusions: SFRT has already evolved as a clinical practice pattern for advanced/bulky tumors. Major treatment approaches are consistent and follow the literature, but SFRT-cERT combination/sequencing and clinical utilization of dosimetric parameters are variable. These areas may benefit from targeted education and standardization, and knowledge gaps may be filled by incorporating identified inconsistencies into future clinical research.

Overview and Recommendations for Prospective Multi-institutional Spatially Fractionated Radiation Therapy Clinical Trials.

PURPOSE: The highly heterogeneous dose delivery of spatially fractionated radiation therapy (SFRT) is a profound departure from standard radiation planning and reporting approaches. Early SFRT studies have shown excellent clinical outcomes. However, prospective multi-institutional clinical trials of SFRT are still lacking. This NRG Oncology/American Association of Physicists in Medicine working group consensus aimed to develop recommendations on dosimetric planning, delivery, and SFRT dose reporting to address this current obstacle toward the design of SFRT clinical trials. METHODS AND MATERIALS: Working groups consisting of radiation oncologists, radiobiologists, and medical physicists with expertise in SFRT were formed in NRG Oncology and the American Association of Physicists in Medicine to investigate the needs and barriers in SFRT clinical trials. RESULTS: Upon reviewing the SFRT technologies and methods, this group identified challenges in several areas, including the availability of SFRT, the lack of treatment planning system support for SFRT, the lack of guidance in the physics and dosimetry of SFRT, the approximated radiobiological modeling of SFRT, and the prescription and combination of SFRT with conventional radiation therapy. CONCLUSIONS: Recognizing these challenges, the group further recommended several areas of improvement for the application of SFRT in cancer treatment, including the creation of clinical practice guidance documents, the improvement of treatment planning system support, the generation of treatment planning and dosimetric index reporting templates, and the development of better radiobiological models through preclinical studies and through conducting multi-institution clinical trials.

Remote, tablet-based assessment of gaze following: a nationwide infant twin study.

Introduction: Much of our understanding of infant psychological development relies on an in-person, laboratory-based assessment. This limits research generalizability, scalability, and equity in access. One solution is the development of new, remotely deployed assessment tools that do not require real-time experimenter supervision. Methods: The current nationwide (Sweden) infant twin study assessed participants remotely via their caregiver's tablets (N = 104, ages 3 to 17 months). To anchor our findings in previous research, we used a gaze-following task where experimental and age effects are well established. Results: Closely mimicking results from conventional eye tracking, we found that a full head movement elicited more gaze following than isolated eye movements. Furthermore, predictably, we found that older infants followed gaze more frequently than younger infants. Finally, while we found no indication of genetic contributions to gaze-following accuracy, the latency to disengage from the gaze cue and orient toward a target was significantly more similar in monozygotic twins than in dizygotic twins, an indicative of heritability. Discussion: Together, these results highlight the potential of remote assessment of infants' psychological development, which can improve generalizability, inclusion, and scalability in developmental research.

Evaluation of a New Aptamer-Based Array for Soluble Suppressor of Tumorgenicity (ST2) and N-terminal Pro-B-Type Natriuretic Peptide (NTproBNP) in Heart Failure Patients.

BACKGROUND: Recent advances in multi-marker platforms offer faster data generation, but the fidelity of these methods compared to the ELISA is not established. We tested the correlation and predictive performance of SOMAscan vs. ELISA methods for NTproBNP and ST2. METHODS: Patients ≥ 18 years with heart failure and ejection fraction < 50% were enrolled. We tested the correlation between SOMA and ELISA for each biomarker and their association with outcomes. RESULTS: There was good correlation of SOMA vs. ELISA for ST2 (ρ = 0.71) and excellent correlation for NTproBNP (ρ = 0.94). The two versions of both markers were not significantly different regarding survival association. The two ST2 assays and NTproBNP assays were similarly associated with all-cause mortality and cardiovascular mortality. These associations remained statistically significant when adjusted for MAGGIC risk score (all p < 0.05). CONCLUSION: SOMAscan quantifications of ST2 and NTproBNP correlate to ELISA versions and carry similar prognosis.

An International Consensus on the Design of Prospective Clinical-Translational Trials in Spatially Fractionated Radiation Therapy.

PURPOSE: Spatially fractionated radiation therapy (SFRT), which delivers highly nonuniform dose distributions instead of conventionally practiced homogeneous tumor dose, has shown high rates of clinical response with minimal toxicities in large-volume primary or metastatic malignancies. However, prospective multi-institutional clinical trials in SFRT are lacking, and SFRT techniques and dose parameters remain variable. Agreement on dose prescription, technical administration, and clinical and translational design parameters for SFRT trials is essential to enable broad participation and successful accrual to rigorously test the SFRT approach. We aimed to develop a consensus for the design of multi-institutional clinical trials in SFRT, tailored to specific primary tumor sites, to help facilitate development and enhance the feasibility of such trials. METHODS AND MATERIALS: Primary tumor sites with sufficient pilot experience in SFRT were identified, and fundamental trial design questions were determined. For each tumor site, a comprehensive consensus effort was established through disease-specific expert panels. Clinical trial design criteria included eligibility, SFRT technology and technique, dose and fractionation, target- and normal-tissue dose parameters, systemic therapies, clinical trial endpoints, and translational science considerations. Iterative appropriateness rank voting, expert panel consensus reviews and discussions, and public comment posting were used for consensus development. RESULTS: Clinical trial criteria were developed for head and neck cancer and soft-tissue sarcoma. Final consensus among the 22 trial design categories each (a total of 163 criteria) was high to moderate overall. Uniform patient cohorts of advanced bulky disease, standardization of SFRT technologies and dosimetry and physics parameters, and collection of translational correlates were considered essential to trial design. Final guideline recommendations and the degree of agreement are presented and discussed. CONCLUSIONS: This consensus provides design guidelines for the development of prospective multi-institutional clinical trials testing SFRT in advanced head and neck cancer and soft-tissue sarcoma through in-advance harmonization of the fundamental clinical trial design among SFRT experts, potential investigators, and the SFRT community.

Factors associated with loss to follow-up after radiation therapy for head and neck cancer.

OBJECTIVES: Head and neck cancer (HNC) patients are at high risk for late occurring radiation-related morbidity and recurrence, necessitating close long-term medical surveillance. This study identified factors associated with becoming lost to follow-up (LTFU) at a comprehensive cancer center. MATERIALS AND METHODS: Patients were drawn from survivors who received radiation for HNC at a single institution between 2001 and 2018. LTFU was defined as living patients without a clinical encounter within 2 years of the data query. RESULTS: In total, 537 patients met the inclusion criteria and 57 (10.6%) were identified as LTFU. Individual comparisons identified time since completing radiation, non-White race and being unmarried as associated with LTFU. Multiple regression identified time since treatment and being unmarried as factors associated with LTFU. A decision tree correctly sorted 89.4% using time, distance, and marital status. CONCLUSION: Time since radiation, distance to clinic, and being unmarried were factors associated with becoming LTFU.

An International Consensus on the Design of Prospective Clinical-Translational Trials in Spatially Fractionated Radiation Therapy for Advanced Gynecologic Cancer.

Despite the unexpectedly high tumor responses and limited treatment-related toxicities observed with SFRT, prospective multi-institutional clinical trials of SFRT are still lacking. High variability of SFRT technologies and methods, unfamiliar complex dose and prescription concepts for heterogeneous dose and uncertainty regarding systemic therapies present major obstacles towards clinical trial development. To address these challenges, the consensus guideline reported here aimed at facilitating trial development and feasibility through a priori harmonization of treatment approach and the full range of clinical trial design parameters for SFRT trials in gynecologic cancer. Gynecologic cancers were evaluated for the status of SFRT pilot experience. A multi-disciplinary SFRT expert panel for gynecologic cancer was established to develop the consensus through formal panel review/discussions, appropriateness rank voting and public comment solicitation/review. The trial design parameters included eligibility/exclusions, endpoints, SFRT technology/technique, dose/dosimetric parameters, systemic therapies, patient evaluations, and embedded translational science. Cervical cancer was determined as the most suitable gynecologic tumor for an SFRT trial. Consensus emphasized standardization of SFRT dosimetry/physics parameters, biologic dose modeling, and specimen collection for translational/biological endpoints, which may be uniquely feasible in cervical cancer. Incorporation of brachytherapy into the SFRT regimen requires additional pre-trial pilot investigations. Specific consensus recommendations are presented and discussed.

The Reality of Randomized Controlled Trials for Assessing the Benefit of Proton Therapy: Critically Examining the Intent-to-Treat Principle in the Presence of Insurance Denial.

PURPOSE: This study hypothesized that insurance denial would lead to bias and loss of statistical power when evaluating the results from an intent-to-treat (ITT), per-protocol, and as-treated analyses using a simulated randomized clinical trial comparing proton therapy to intensity modulated radiation therapy where patients incurred increasing rates of insurance denial. METHODS AND MATERIALS: Simulations used a binary endpoint to assess differences between treatment arms after applying ITT, per-protocol, and as-treated analyses. Two scenarios were developed: 1 with clinical success independent of age and another assuming dependence on age. Insurance denial was assumed possible for patients <65 years. All scenarios considered an age distribution with mean ± standard deviation: 55 ± 15 years, rates of insurance denial ranging from 0%-40%, and a sample of N = 300 patients (150 per arm). Clinical success rates were defined as 70% for proton therapy and 50% for intensity modulated radiation therapy. The average treatment effect, bias, and power were compared after applying 5000 simulations. RESULTS: Increasing rates of insurance denial demonstrated inherent weaknesses among all 3 analytical approaches. With clinical success independent of age, a per-protocol analysis demonstrated the least bias and loss of power. When clinical success was dependent on age, the per-protocol and ITT analyses resulted in a similar trend with respect to bias and loss of power, with both outperforming the as-treated analysis. CONCLUSIONS: Insurance denial leads to misclassification bias in the ITT analysis, a missing data problem in the per-protocol analysis, and covariate imbalance between treatment arms in the as-treated analysis. Moreover, insurance denial forces the critical appraisal of patient features (eg, age) affected by the denial and potentially influencing clinical success. In the presence of insurance denial, our study suggests cautious reporting of ITT and as-treated analyses, and placing primary emphasis on the results of the per-protocol analysis.

Work Outcomes after Intensity-Modulated Proton Therapy (IMPT) versus Intensity-Modulated Photon Therapy (IMRT) for Oropharyngeal Cancer.

PURPOSE: We compared work outcomes in patients with oropharyngeal cancer (OPC), randomized to intensity-modulated proton (IMPT) versus intensity-modulated photon therapy (IMRT) for chemoradiation therapy (CRT). PATIENTS AND METHODS: In 147 patients with stage II-IVB squamous cell OPC participating in patient-reported outcomes assessments, a prespecified secondary aim of a randomized phase II/III trial of IMPT (n = 69) versus IMRT (n = 78), we compared absenteeism, presenteeism (i.e., the extent to which an employee is not fully functional at work), and work productivity losses. We used the work productivity and activity impairment questionnaire at baseline (pre-CRT), at the end of CRT, and at 6 months, 1 year, and 2 years. A one-sided Cochran-Armitage test was used to analyze within-arm temporal trends, and a χ2 test was used to compare between-arm differences. Among working patients, at each follow-up point, a 1-sided Wilcoxon rank-sum test was used to compare work-productivity scores. RESULTS: Patient characteristics in IMPT versus IMRT arms were similar. In the IMPT arm, within-arm analysis demonstrated that an increasing proportion of patients resumed working after IMPT, from 60% (40 of 67) pre-CRT and 71% (30 of 42) at 1 year to 78% (18 of 23) at 2 years (P = 0.025). In the IMRT arm, the proportion remained stable, with 57% (43 of 76) pre-CRT, 54% (21 of 39) at 1 year, and 52% (13 of 25) working at 2 years (P = 0.47). By 2 years after CRT, the between-arm difference between patients who had IMPT and those who had IMRT trended toward significance (P = 0.06). Regardless of treatment arm, among working patients, the most severe work impairments occurred from treatment initiation to the end of CRT, with significant recovery from absenteeism, presenteeism, and productivity impairments by the 2-year follow-up (P < 0.001 for all). Higher magnitudes of recovery from absenteeism (at 1 year, P = 0.05; and at 2 years, P = 0.04) and composite work impairment scores (at 1 year, P = 0.04; and at 2 years, P = 0.04) were seen in patients treated with IMPT versus those treated with IMRT. CONCLUSION: In patients with OPC receiving curative CRT, patients randomized to IMPT demonstrated increasing work and productivity recovery trends. Studies are needed to identify mechanisms underlying head and neck CRT treatment causing work disability and impairment.

When saliva becomes a problem: the challenges and palliative care for patients with sialorrhea.

Sialorrhea, or relative excess of salivary excretion, is a vexing problem for many patients. This symptom is precipitated by dysfunction in one of two interrelated processes-salivary production and oropharyngeal clearance. While medications primarily precipitate the former, dysphagia, often due to neurologic dysfunction, often causes the latter. This overabundance of saliva coupled with difficulty swallowing can predispose patients to respiratory issues, infections, and poor quality of life. There are, however, a myriad of treatment options that have shown clinical efficacy in treating this dysfunction. The purpose of this article is to present some background and etiology behind sialorrhea as well as present treatment options-non-pharmacologic, pharmacologic, surgical, and radiotherapeutic-that can help to ameliorate symptoms and improve quality of life for patients.

Sticky stuff: xerostomia in patients undergoing head and neck radiotherapy-prevalence, prevention, and palliative care.

Xerostomia remains one of the most common and impactful side effects associated with radiotherapy for head and neck malignancies. With improvements in oncologic therapy and an improved prognosis for patients with head and neck squamous cell carcinoma (HNSCC) overall, the long-standing effects of therapy have become even more significant. Recent efforts have primarily focused on prevention of this morbidity through technological advances, reductions in radiotherapy fields, and radioprotectants. The promises of de-intensified strategies and proton radiation warrant ongoing investigation. However, palliative care for and active management of xerostomia before, during, and after treatment deserve further attention and research to define optimal approaches.