A prospective study of the feasibility of FDG-PET/CT imaging to quantify radiation-induced lung inflammation in locally advanced non-small cell lung cancer patients receiving proton or photon radiotherapy.

PURPOSE: This prospective study assessed the feasibility of 18F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) to quantify radiation-induced lung inflammation in patients with locally advanced non-small cell lung cancer (NSCLC) who received radiotherapy (RT), and compared the differences in inflammation in the ipsilateral and contralateral lungs following proton and photon RT. METHODS: Thirty-nine consecutive patients with NSCLC underwent FDG-PET/CT imaging before and after RT on a prospective study. A novel quantitative approach utilized regions of interest placed around the anatomical boundaries of the lung parenchyma and provided lung mean standardized uptake value (SUVmean), global lung glycolysis (GLG), global lung parenchymal glycolysis (GLPG) and total lung volume (LV). To quantify primary tumor metabolic response to RT, an adaptive contrast-oriented thresholding algorithm was applied to measure metabolically active tumor volume (MTV), tumor uncorrected SUVmean, tumor partial volume corrected SUVmean (tumor-PVC-SUVmean), and total lesion glycolysis (TLG). Parameters of FDG-PET/CT scans before and after RT were compared using two-tailed paired t-tests. RESULTS: All tumor parameters after either proton or photon RT decreased significantly (p < 0.001). Among the 21 patients treated exclusively with proton RT, no significant increase in PVC-SUVmean or PVC-GLPG was observed in ipsilateral lungs after the PVC parameters of primary tumor were subtracted (p = 0.114 and p = 0.453, respectively). Also, there were no significant increases in SUVmean or GLG of contralateral lungs of patients who received proton RT (p = 0.841, p = 0.241, respectively). In contrast, among the nine patients who received photon RT, there was a statistically significant increase in PVC-GLPG of ipsilateral lung (p < 0.001) and in GLG of contralateral (p = 0.036) lung. In the subset of nine patients who received a combined proton and photon RT, there was a statistically significant increase in PVC-GLPG of ipsilateral lung (p < 0.001). CONCLUSION: Our data suggest less induction of inflammatory response in both the ipsilateral and contralateral lungs of patients treated with proton compared to photon or combined proton-photon RT.

Prospective MRI-based imaging study to assess feasibility of proton therapy for post-prostatectomy radiation.

PURPOSE/OBJECTIVES: To optimize delivery of post-prostatectomy radiation (PPRT) with protons by examining dosimetric effects of variations in physician contouring, organ motion, and patient alignment during a course of PPRT. MATERIAL AND METHODS: We enrolled 10 patients receiving PPRT in a prospective imaging study. All patients underwent combined computed tomography (CT)/magnetic resonance imaging (MRI) simulation with endorectal balloon (ERB) and received intensity modulated radiation therapy (IMRT) per institutional standards. Study patients underwent weekly MRI verification scans in the treatment position. Three radiation oncologists contoured clinical target volumes (CTV) on initial and verification scans using two consensus guidelines (RTOG and EORTC). We generated IMRT, double scattering (DS), and pencil beam scanning (PBS) proton plans and examined the dosimetric impact of contour variations, inter-fraction motion, and patient alignment techniques. RESULTS: Inter-observer variations in contouring reduced median CTV coverage (D100) by 0.9% for IMRT plans, 2.8% for DS proton plans, 3.4-4.9% for PBS Proton Plans. Inter-fraction changes in target volumes due to internal organ motion resulted in a median loss of target dose coverage (D98) of 0% with IMRT, 3.5% with DS, and 8.1-8.3% with PBS. Median bladder V65Gy increased during the treatment course with all techniques (6.0-7.5%). Changes in the median rectal V60Gy remained small regardless of the treatment technique (0.5-3.1% increase). Alignment to the ERB after cranio-caudal bony alignment reduced CTV displacement compared to bony alignment alone, and as a result CTV coverage (D98) changed <2% with IMRT, DS, and PBS. CONCLUSION: Proton-based treatments are more sensitive to changes in inter-fraction organ motion during PPRT compared to IMRT, and therefore motion management and patient alignment methods are critical. Patient alignment using bony anatomy as well as the ERB minimizes displacement of the CTV, and reduces variation in target dose coverage particularly for PBS proton therapy.

Guideline familiarity predicts variation in self-reported use of routine surveillance PET/CT by physicians who treat head and neck cancer.

BACKGROUND: Use of routine surveillance testing beyond guideline recommended levels is common in many oncologic disciplines, including head and neck cancer. The impact of guideline familiarity and other physician characteristics on surveillance imaging use are not well understood. METHODS: A cross-sectional national survey was performed of physicians responsible for surveillance of patients with head and neck squamous cell carcinoma (HNSCC). The primary outcome was self-reported use of routine surveillance PET/CT in asymptomatic patients. A secondary outcome was familiarity with guideline recommendations. Using multivariable regression, the impact of guideline familiarity and other physician characteristics on PET/CT use was examined. RESULTS: Of the 502 responders, 79% endorsed ever using PET/CT scans for routine surveillance imaging, and 39% were high imaging users (used PET/CT scans on more than half of their asymptomatic patients); 76% were familiar with the NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers recommending against routine surveillance PET/CT scans. Although guideline familiarity was associated with being a low imaging user or a never-user, among those who were familiar with guidelines, 31% were nonetheless high imaging users and 73% endorsed ever using PET/CT scans. In multivariable analysis controlling for physician characteristics, guideline familiarity was the strongest predictor of PET/CT use. CONCLUSIONS: Familiarity with the NCCN Guidelines predicts self-reported routine surveillance PET/CT use among physicians who treat patients with HNSCC. However, given the observed variation and high levels of imaging even among physicians who are familiar with the guidelines, further research should examine the reasons physicians choose to use surveillance PET/CT scans.

Low rates of adjuvant radiation in patients with nonmetastatic prostate cancer with high-risk pathologic features.

BACKGROUND: The 2013 American Urological Association/American Society for Radiation Oncology consensus guidelines recommend offering adjuvant radiotherapy (RT) after radical prostatectomy in patients with high-risk pathologic features for recurrence. In the current study, the authors examined practice patterns of adjuvant RT use in patients with elevated pathologic risk factors over a time period spanning the publication of supporting randomized evidence. METHODS: Using the National Cancer Data Base, a total of 130,681 patients were identified who underwent surgical resection for prostate cancer between 2004 and 2011 with at least 1 of the following pathologic risk factors for early biochemical failure: pT3a disease or higher, positive surgical margins and/or lymph node-positive disease. Using multivariable logistic regression, the authors examined factors associated with adjuvant RT use including patient, clinical, demographic, and temporal characteristics. RESULTS: Adjuvant RT was administered to 9.9% of the patients with at least 1 pathologic risk factor. Use of adjuvant RT did not change over the study period (P = .23). On multivariable analysis, we found that patients treated at high-volume surgical facilities were less likely to receive adjuvant RT (15.9% vs 7.8%; odds ratio, 0.58 [95% confidence interval, 0.50-0.65]; P < .0001). Older age, comorbidities, black race, lower income, and lower population density were also associated with lower rates of adjuvant RT. CONCLUSIONS: Use of adjuvant RT is uncommon and remained unchanged between 2004 and 2011. Patients treated at high-volume surgical facilities are less likely to receive adjuvant RT, irrespective of margin status.

Applicability of randomized trials in radiation oncology to standard clinical practice.

BACKGROUND: Randomized controlled trials (RCTs) are commonly used to inform clinical practice; however, it is unclear how generalizable RCT data are to patients in routine clinical practice. The authors of this report assessed the availability and applicability of randomized evidence guiding medical decisions in a cohort of patients who were evaluated for consideration of definitive management in a radiation oncology clinic. METHODS: The medical records of consecutive, new patient consultations between January and March 2007 were reviewed. Patient medical decisions were classified as those with (Group 1) or without (Group 2) available, relevant level I evidence (phase 3 RCT) supporting recommended treatments. Group 1 medical decisions were further divided into 3 groups based on the extent of fulfilling eligibility criteria for each RCT: Group 1A included decisions that fulfilled all eligibility criteria; Group 1B, decisions that did not fulfill at least 1 minor eligibility criteria; or Group 1C, decisions that did not fulfill at least 1 major eligibility criteria. Patient and clinical characteristics were tested for correlations with the availability of evidence. RESULTS: Of the 393 evaluable patients, malignancies of the breast (30%), head and neck (18%), and genitourinary system (14%) were the most common presenting primary disease sites. Forty-seven percent of all medical decisions (n = 451) were made without available (36%) or applicable (11%) randomized evidence to inform clinical decision making. Primary tumor diagnosis was significantly associated with the availability of evidence (P < .0001). CONCLUSIONS: A significant proportion of medical decisions in an academic radiation oncology clinic were made without available or applicable level I evidence, underscoring the limitations of relying solely on RCTs for the development of evidence-based health care.

Radical cystectomy versus bladder-preserving therapy for muscle-invasive urothelial carcinoma: examining confounding and misclassification biasin cancer observational comparative effectiveness research.

OBJECTIVES: Radical cystectomy (RC) is the standard treatment for muscle-invasive urothelial carcinoma of the bladder. Trimodality bladder-preserving therapy (BPT) is an alternative to RC, but randomized comparisons of RC versus BPT have proven infeasible. To compare RC versus BPT, we undertook an observational cohort study using registry and administrative claims data from the Surveillance, Epidemiology and End Results-Medicare database. METHODS: We identified patients age 65 years or older diagnosed between 1995 and 2005 who received RC (n = 1426) or BPT (n = 417). We examined confounding and stage misclassification in the comparison of RC and BPT by using multivariable adjustment, propensity score-based adjustment, instrumental variable (IV) analysis, and simulations. RESULTS: Patients who received BPT were older and more likely to have comorbid disease. After propensity score adjustment, BPT was associated with an increased hazard of death from any cause (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.05-1.53) and from bladder cancer (HR 1.31; 95% CI 0.97-1.77). Using the local area cystectomy rate as an instrument, IV analysis demonstrated no differences in survival between BPT and RC (death from any cause HR 1.06; 95% CI 0.78-1.31; death from bladder cancer HR 0.94; 95% CI 0.55-1.18). Simulation studies for stage misclassification yielded results consistent with the IV analysis. CONCLUSIONS: Survival estimates in an observational cohort of patients who underwent RC versus BPT differ by analytic method. Multivariable and propensity score adjustment revealed greater mortality associated with BPT relative to RC, while IV analysis and simulation studies suggest that the two treatments are associated with similar survival outcomes.

External beam radiotherapy for thyroid cancer: Patients, complications, and survival.

BACKGROUND: Patterns of utilization of external beam radiation therapy (EBRT) in thyroid cancer are incompletely described. We characterize therapeutic intent, complications, and survival in thyroid cancer treated with EBRT. METHODS: In this retrospective study of 105 thyroid cancer patients treated with EBRT at one institution (2008-2018), the primary outcome was overall survival. Secondary outcomes included incomplete treatment, emergency department (ED) visits, weight change, and gastrostomy placement. RESULTS: Dominant histopathology was differentiated (44%), anaplastic (45%) and poorly-differentiated (11%) disease. EBRT was mainly utilized for locoregional control (differentiated 87%, poorly-differentiated 75%, anaplastic 92%). Palliative EBRT was more common in poorly-differentiated disease (42%). Weight loss was greater in aggressive/advanced disease (differentiated 10 lb, poorly-differentiated 27 lb, anaplastic 18 lb). Anaplastic cancer had higher rates of gastrostomy (34%) and lowest rates of treatment completion (83%). ED encounters were common (differentiated 44%, poorly-differentiated 50%, anaplastic 45%). Gastrostomy was associated with mortality on multivariable analysis in non-anaplastic malignancy. CONCLUSIONS: EBRT was most frequently administered for locoregional control in thyroid cancer. Despite complications, the majority of patients completed EBRT therapy.

Tubarial salivary gland sparing with proton therapy.

The recently identified bilateral macroscopic tubarial salivary glands present a potential opportunity for further toxicity mitigation for patients receiving head and neck radiotherapy. Here, we show superior dosimetric sparing of the tubarial salivary glands with proton radiation therapy (PRT) compared to intensity-modulated radiotherapy (IMRT) for patients treated postoperatively for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). This was a retrospective, single institutional study of all patients treated with adjuvant PRT for HPV-associated OPSCC from 2015 to 2019. Each patient had a treatment-approved, equivalent IMRT plan to serve as a reference. The main end point was dose delivered to the tubarial salivary glands by modality, assessed via a 2-tailed, paired t-test. We also report disease outcomes for the entire cohort, via the Kaplan-Meier method. Sixty-four patients were identified. The mean RT dose to the tubarial salivary glands was 23.6 Gy (95% confidence interval (CI) 21.7 to 25.5) and 30.4 Gy (28.6 to 32.2) for PRT and IMRT plans (p < 0.0001), respectively. With a median follow-up of 25.2 months, the two-year locoregional control, progression-free survival and overall survival were 97.8% (95% CI 85.6% to 99.7%), 94.1% (82.8% to 98.1%) and 98.1% (87.4% to 99.7%), respectively. Our study suggests that meaningful normal tissue sparing of the recently identified tubarial salivary glands is achievable with PRT. The apparent gains with PRT did not impact disease outcomes, with only 1 observed locoregional recurrence (0 local, 1 regional). Further studies are warranted to explore the impact of the improved dosimetric sparing of the tubarial salivary glands conveyed by PRT on patient toxicity and quality of life.

Dosimetric Results for Adjuvant Proton Radiation Therapy of HPV-Associated Oropharynx Cancer.

Purpose: One significant advantage of proton therapy is its ability to improve normal tissue sparing and toxicity mitigation, which is relevant in the treatment of oropharyngeal squamous cell carcinoma (OPSCC). Here, we report our institutional experience and dosimetric results with adjuvant proton radiation therapy (PRT) versus intensity-modulated radiotherapy (IMRT) for Human Papilloma Virus (HPV)-associated OPSCC. Materials and Methods: This was a retrospective, single institutional study of all patients treated with adjuvant PRT for HPV-associated OPSCC from 2015 to 2019. Each patient had a treatment-approved equivalent IMRT plan to serve as a reference. Endpoints included dosimetric outcomes to the organs at risk (OARs), local regional control (LRC), progression-free survival (PFS), and overall survival (OS). Descriptive statistics, a 2-tailed paired t test for dosimetric comparisons, and the Kaplan-Meier method for disease outcomes were used. Results: Fifty-three patients were identified. Doses delivered to OARs compared favorably for PRT versus IMRT, particularly for the pharyngeal constrictors, esophagus, larynx, oral cavity, and submandibular and parotid glands. The achieved normal tissue sparing did not negatively impact disease outcomes, with 2-year LRC, PFS, and OS of 97.0%, 90.3%, and 97.5%, respectively. Conclusion: Our study suggests that meaningful normal tissue sparing in the postoperative setting is achievable with PRT, without impacting disease outcomes.

Prognostic significance of conventional and volumetric PET parameters with and without partial volume correction in the assessment of head and neck squamous cell carcinoma.

BACKGROUND: The optimal quantification of PET in assessment of head and neck squamous cell carcinoma (HNSCC) is still under development. The effect of partial volume correction (PVC) on the evaluation of survival in the HNSCC patients has not been investigated yet. METHODOLOGY: Pretreatment 18F-FDG-PET/CT scans of a selected group of 57 patients with advanced stage HNSCC were collected. Conventional (SUVmean and SUVmax) and volumetric [total lesion glycolysis (TLG) and metabolic tumor volume (MTV)] PET metrics were calculated. The ROVER software (ABX GmbH, Radeberg, Germany) automatically applied PVC to the PET metrics. Cox proportional hazards regression model calculated hazard ratio (HR) for assessment of predictive parameters of progression-free survival (PFS). RESULTS: In multivariate Cox regression analysis, including age, gender, race, human papillomavirus status, and stage, the only significant predictors of PFS were the volumetric PET parameters (TLG: HR, 1.003; 95% CI, 1.001-1.005; P = 0.02), pvcTLG (HR, 1.002; 95% CI, 1.001-1.004; P = 0.01) and MTV (HR, 1.050; 95% CI, 1.024-1.077; P < 0.01). The partial volume-corrected values were significantly higher than the noncorrected values (Wilcoxon sign test; P < 0.05). However, there was not a statistically significant difference between the nonpartial volume corrected and partial volume-corrected PET metrics for assessment of PFS. CONCLUSION: Volumetric PET metrics were predictors of PFS in Cox regression analysis. Applying PVC could not significantly improve the accuracy of PET metrics for assessment of PFS.

Early Changes in Physical Activity and Quality of Life With Thoracic Radiation Therapy in Breast Cancer, Lung Cancer, and Lymphoma.

PURPOSE: The effects of thoracic radiation therapy (RT) on physical functioning and quality of life (QoL) are incompletely defined. We determined the associations between thoracic RT dose volume metrics, physical activity, and QoL in patients with cancer. METHODS AND MATERIALS: Participants with breast cancer, lung cancer, or mediastinal lymphoma treated with radiation with or without chemotherapy were enrolled in a prospective, longitudinal cohort study. Data were collected pre-RT, immediately post-RT, and 5 to 9 months post-RT. At each timepoint, self-reported physical activity was assessed via the Godin-Shephard Leisure-Time Physical Activity Questionnaire, and QoL metrics were assessed via Functional Assessment of Chronic Illness Therapy Fatigue and Dyspnea Scales. Multivariable adjusted linear regression models were stratified by breast cancer alone and lung cancer and lymphoma combined. RESULTS: One hundred thirty participants were included in the study. In breast cancer (n = 80), each 1-Gy increase in mean heart dose was associated with worse Functional Assessment of Chronic Illness Therapy Fatigue scores (-1.0; 95% confidence interval [CI], -1.9 to -0.2; P = .021); similar associations were observed between V5 and fatigue (-2.5; 95% CI, -4.4 to -0.6; P = .010 for each 10% increase in V5). In lung cancer and lymphoma (n = 50), each 10% increase in V5 was associated with decreased physical activity (Godin-Shephard Leisure-Time Physical Activity Questionnaire score -2.3; 95% CI, -4.3 to -0.4; P = .017). Although the associations between baseline levels of physical activity and fatigue and dyspnea were of borderline significance in breast cancer alone (P < .10), increased physical activity over time was associated with improvements in fatigue and dyspnea across all cancer types (P < .05 for all). CONCLUSIONS: Higher cardiac RT dose was associated with worse fatigue and physical activity across breast cancer, lung cancer, and mediastinal lymphoma. Longitudinal increases in physical activity were associated with concurrent improvements in QoL measures. Strategies to increase physical activity and decrease cardiac RT dose may improve physical functioning and QoL for patients with cancer.

Disparities and guideline adherence for HPV testing among patients with oropharyngeal squamous cell carcinoma, NCDB, and SEER.

BACKGROUND: Human papilloma virus testing for oropharyngeal squamous-cell carcinoma has been recommended by the National Comprehensive Cancer Network since 2012. We examine disparities, reported rates of human papillomavirus (HPV) testing, and the impact on these findings of limitations with the variable in database registries. METHODS: The HPV variable was queried for patients with oropharyngeal squamous carcinoma (OPSCC) from 2013 to 2016 in National Cancer Data Base (NCDB) and Surveillance, Epidemiology, and End Results (SEER). Multivariable regression was used to identify disparities based on sociodemographic variables. Sensitivity analyses were used to investigate limitations of the variable. RESULTS: Despite limitations in the HPV variable in the databases, there was less than 100% adherence to recommended testing, and there were significant disparities in multiple sociodemographic variables. For example, in NCDB 70% of white versus 60.4% of black patients were tested (odds ratio [OR] 0.75, confidence interval [CI] 0.66-0.85, p ≤ 0.0001); in SEER 59.8% of white and 47.6% of black patients were tested (OR 0.73, CI 0.67-0.81; p ≤ 0.0001). CONCLUSIONS: Disparities exist among patients undergoing testing for HPV-associated OPSCC and adherence to guideline recommended HPV testing has been suboptimal. In addition, the HPV variable definition, especially as it relates to p16 positivity, and use in these two registries should be improved.

Dual-Energy Computed Tomography Proton-Dose Calculation with Scripting and Modified Hounsfield Units.

PURPOSE: To describe an implementation of dual-energy computed tomography (DECT) for calculation of proton stopping-power ratios (SPRs) in a commercial treatment-planning system. The process for validation and the workflow for safe deployment of DECT is described, using single-energy computed tomography (SECT) as a safety check for DECT dose calculation. MATERIALS AND METHODS: The DECT images were acquired at 80 kVp and 140 kVp and were processed with computed tomography scanner software to derive the electron density and effective atomic number images. Reference SPRs of tissue-equivalent plugs from Gammex (Middleton, Wisconsin) and CIRS (Computerized Imaging Reference Systems, Norfolk, Virginia) electron density phantoms were used for validation and comparison of SECT versus DECT calculated through the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, California) application programming interface scripting tool. An in-house software was also used to create DECT SPR computed tomography images for comparison with the script output. In the workflow, using the Eclipse system application programming interface script, clinical plans were optimized with the SECT image set and then forward-calculated with the DECT SPR for the final dose distribution. In a second workflow, the plans were optimized using DECT SPR with reduced range-uncertainty margins. RESULTS: For the Gammex phantom, the root mean square error in SPR was 1.08% for DECT versus 2.29% for SECT for 10 tissue-surrogates, excluding the lung. For the CIRS Phantom, the corresponding results were 0.74% and 2.27%. When evaluating the head and neck plan, DECT optimization with 2% range-uncertainty margins achieved a small reduction in organ-at-risk doses compared with that of SECT plans with 3.5% range-uncertainty margins. For the liver case, DECT was used to identify and correct the lipiodol SPR in the SECT plan. CONCLUSION: It is feasible to use DECT for proton-dose calculation in a commercial treatment planning system in a safe manner. The range margins can be reduced to 2% in some sites, including the head and neck.

Photobiomodulation Therapy in Head and Neck Cancer-Related Lymphedema: A Pilot Feasibility Study.

PURPOSE: Lymphedema is a common debilitating late effect among patients post-head and neck cancer (HNC) treatment. Head and neck lymphedema was associated with symptom burden, functional impairment, and decreased quality of life. The objective of this study was to determine the feasibility and potential efficacy of the use of photobiomodulation (PBM) therapy for head and neck lymphedema, symptom burden, and neck range of motion among HNC survivors. METHODS: This was a single-arm, pre- and post-design clinical trial. Eligible patients included those with lymphedema after completion of complete decongestive therapy (CDT) and 3 to 18 months after completion of cancer therapy. The intervention included PBM therapy 2 times a week for 6 weeks for a total of 12 treatments. Lymphedema, symptom burden, and neck range of motion were measured at baseline, end-of-intervention, and 4-week post-intervention. RESULTS: Of the 12 patients enrolled in the study, 91.7% (n = 11) completed the study intervention and assessment visits, and no adverse events were reported. When comparing the baseline to 4-week post-intervention, we found statistically significant improvements in the severity of external lymphedema, symptom burden, and neck range of motion (all P < .05). CONCLUSION: PBM therapy was feasible and potentially effective for the treatment of head and neck lymphedema. Future randomized controlled trials are warranted to examine the efficacy of PBM therapy for HNC-related lymphedema. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: ClinicalTrials.gov Identifier: NCT03738332; date of registration: November 13, 2018.

Increased rate of recurrence and high rate of salvage in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma with adverse features treated with primary surgery without recommended adjuvant therapy.

BACKGROUND: Some patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) do not receive guideline-recommended postoperative radiation therapy (PORT) following primary transoral robotic surgery (TORS). METHODS: Three-hundred and sixty-four patients with treatment-naïve, HPV-associated OPSCC were recommended to receive PORT based on clinicopathological features following TORS. Patients were stratified based on if they received PORT. Oncologic outcomes were compared. RESULTS: The 3-year locoregional failure (LRF) was 32% in patients who did not receive PORT and 4% in patients who received PORT (P < .001). Despite increased LRF, avoiding PORT was not associated with increased 3-year distant metastasis rates (8% vs 4%, P = .56) or worse 3-year survival (95% vs 98%, P = .34). Recurrences in the surgery alone cohort varied between local and regional sites and were often successfully salvaged. CONCLUSIONS: Patients with HPV-associated OPSCC who do not receive indicated PORT have an increased risk of LRF but similar survival due to high salvage rates.

Sex-based differences in outcomes among surgically treated patients with HPV-related oropharyngeal squamous cell carcinoma.

OBJECTIVES: Sex differences in surgically treated HPV-associated oropharyngeal squamous cell carcinoma are not defined due to the low number of affected women. We explored the oncologic outcomes of men and women with p16-positive oropharyngeal squamous cell carinoma treated with primary surgery. MATERIALS AND METHODS: Retrospective analysis of patients with HPV-related oropharyngeal cancer treated with surgery and pathology guided adjuvant therapy from 2007 to 2017. Primary end point was recurrence-free and overall survival. RESULTS: Of 468 men (86.7%) and 72 women (13.3%), women presented more often with clinical N0 nodal disease (25% vs 12.2%). There were no differences in adverse pathologic features or T stage, although women were more likely to present with N0 disease (16.7% vs 10%), less N2 disease (6.9% vs 17.7%, p = 0.03), and more stage I disease (88.9% vs 75%). As a result, women were more likely to undergo surgery alone (30.6% vs 14.1%) while men were more likely to require adjuvant radiation therapy (47.2% vs 36.1%). Four women (5.6%) and 30 men (6.4%, p = 0.8) died during follow-up. Multivariate analysis controlling for age, sex, treatment, and pathologic stage demonstrated no differences in overall survival between men and women. There were no differences in recurrence-free or overall survival between men and women at two and five years. CONCLUSIONS: Although women undergoing transoral robotic surgery for HPV+ oropharyngeal squamous cell carcinoma may have less advanced disease, upfront surgery with pathology-guided adjuvant therapy produces similar oncologic results in men and women while accounting for disease burden.

Association of Antibiotic Exposure With Survival and Toxicity in Patients With Melanoma Receiving Immunotherapy.

BACKGROUND: Gut microbial diversity is associated with improved response to immune checkpoint inhibitors (ICI). Based on the known detrimental impact that antibiotics have on microbiome diversity, we hypothesized that antibiotic receipt prior to ICI would be associated with decreased survival. METHODS: Patients with stage III and IV melanoma treated with ICI between 2008 and 2019 were selected from an institutional database. A window of antibiotic receipt within 3 months prior to the first infusion of ICI was prespecified. The primary outcome was overall survival (OS), and secondary outcomes were melanoma-specific mortality and immune-mediated colitis requiring intravenous steroids. All statistical tests were two-sided. RESULTS: There were 568 patients in our database of which 114 received antibiotics prior to ICI. Of the patients, 35.9% had stage III disease. On multivariable Cox proportional hazards analysis of patients with stage IV disease, the antibiotic-exposed group had statistically significantly worse OS (hazard ratio [HR] = 1.81, 95% confidence interval [CI] = 1.27 to 2.57; P <.001). The same effect was observed among antibiotic-exposed patients with stage III disease (HR = 2.78, 95% CI = 1.31 to 5.87; P =.007). When limited to only patients who received adjuvant ICI (n = 89), antibiotic-exposed patients also had statistically significantly worse OS (HR = 4.84, 95% CI = 1.09 to 21.50; P =.04). The antibiotic group had a greater incidence of colitis (HR = 2.14, 95% CI = 1.02 to 4.52; P =.046). CONCLUSION: Patients with stage III and IV melanoma exposed to antibiotics prior to ICI had statistically significantly worse OS than unexposed patients. Antibiotic exposure was associated with greater incidence of moderate to severe immune-mediated colitis. Given the large number of antibiotics prescribed annually, physicians should be judicious with their use in cancer populations likely to receive ICI.

Oncologic outcomes of transoral robotic surgery for HPV-negative oropharyngeal carcinomas.

BACKGROUND: Patients with human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) continue to experience disappointing outcomes following chemoradiotherapy (CRT) and appreciable morbidity following historical surgical approaches. We aimed to investigate the oncologic outcomes and perioperative morbidity of a transoral robotic surgery (TORS) approach to surgically resectable HPV-negative OPSCC. METHODS: Retrospective analysis HPV-negative OPSCC patients who underwent TORS, neck dissection and pathology-guided adjuvant therapy (2005-2017). RESULTS: Fifty-six patients (91.1% stage III/IV) were included. Three-year overall survival, locoregional control, and disease-free survival were 85.5%, 84.4%, and 73.6%, respectively (median follow-up 30.6 months, interquartile range 18.4-66.6). Eighteen (32.1%) patients underwent adjuvant radiotherapy and 20 (39.3%) underwent adjuvant CRT. Perioperative mortality occurred in one (1.8%) patient and hemorrhage occurred in two (3.6%) patients. Long-term gastrostomy and tracheostomy rates were 5.4% and 0.0%, respectively. CONCLUSION: The TORS approach for resectable HPV-negative OPSCC can achieve encouraging oncologic outcomes with infrequent morbidity.

Survival and toxicity in patients with human papilloma virus-associated oropharyngeal squamous cell cancer receiving trimodality therapy including transoral robotic surgery.

BACKGROUND: Patients with oropharyngeal cancer who undergo transoral robotic surgery (TORS) and have high-risk features generally receive adjuvant chemoradiotherapy or trimodality therapy (TMT). The notion that TMT leads to high toxicity is largely based on studies that included human papilloma virus (HPV)-negative cancers and/or nonrobotic surgery; we sought to describe outcomes in HPV-associated oropharyngeal squamous cell cancer (HPV + OPSCC) undergoing TORS-TMT. METHODS: In consecutive patients with HPV + OPSCC receiving TMT at an academic center from 2010 to 2017, survival was estimated using Kaplan-Meier methodology, and toxicities were ascertained via chart review. RESULTS: In our cohort of 178 patients, 5-year survival was 93.6%. Feeding tube rates were 25.8% at therapy completion and 0.7% at 1 year. Rates of grade ≥ 3 kidney injury, anemia, and neutropenia in cisplatin-treated patients were 2.7%, 3.4%, and 11.0%, respectively. CONCLUSIONS: Patients with HPV + OPSCC who underwent TORS-TMT had excellent survival and low rates of toxicity and feeding tube dependence. These outcomes compare favorably to historical cohorts treated with definitive chemoradiotherapy.

Definitive tumor directed therapy confers a survival advantage for metachronous oligometastatic HPV-associated oropharyngeal cancer following trans-oral robotic surgery.

OBJECTIVES: To assess the prognostic significance of oligometastatic versus polymetastatic disease in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC), and to evaluate the impact of definitive tumor directed therapy on the survival outcomes for patients with oligometastatic disease when compared to systemic therapy. MATERIALS AND METHODS: This was a retrospective observational cohort study of patients with HPV-associated OPSCC who developed distant metachronous metastatic disease after undergoing initial primary surgical management from 2008 to 2017. We classified patients based on the extent of metastatic disease [Oligometastatic (≤5 metastases) and polymetastatic (>5 metastases)], and the initial treatment of metastatic disease [definitive tumor directed therapy (all metastases treated with surgery or radiotherapy) versus upfront systemic therapy]. RESULTS: Among 676 patients undergoing primary surgical management for HPV-associated OPSCC, 39 patients (5.8%) developed metastases after a median follow-up of 29.6 months (range 4.5-127.0). Of the 34 metastatic patients who met study criteria, 26 (76.5%) were oligometastatic and 8 (23.5%) were polymetastatic. Oligometastatic patients had improved median overall survival (OS) compared to polymetastatic patients (47.9 vs. 22.7 months, p = 0.036). For oligometastatic patients, definitive tumor directed therapy was associated with an improved median progression free survival (not reached vs 6.13 months, p = 0.001) and median OS (not reached vs 40.7 months, p = 0.004). CONCLUSION: In a cohort of patients surgically treated for HPV-associated OPSCC, metachronous metastatic disease was uncommon and, in most cases, considered oligometastatic. Oligometastasis portends a favorable prognosis and definitive tumor directed therapy may be associated with improved overall survival in these patients. Future multi-institutional efforts are warranted to further demonstrate the impact of definitive tumor directed therapy on disease outcomes.