Phase II Trial Assessing Toxicity of Personalized Response-Based Radiation Treatment in Patients with Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Local failure rates after treatment for locally advanced non-small-cell lung cancer (NSCLC) remain high. Efforts to improve local control with uniform dose-escalation or dose-escalation to mid-treatment PET-avid residual disease have been limited by heightened toxicity. This trial aimed to refine response-based adaptive radiation (RT) and minimize toxicity by incorporating FDG-PET and V/Q SPECT imaging mid-treatment. METHODS: 47 patients with Stage IIA-III unresectable NSCLC were prospectively enrolled in this single-institution trial (NCT02492867). Patients received concurrent chemoradiation with personalized response-based adaptive RT over 30 fractions incorporating V/Q SPECT and FDG-PET. The first 21 fractions (46.2Gy at 2.2 Gy/fraction) were delivered to the tumor while minimizing dose to SPECT-defined functional lung. The plan was then adapted for the final 9 fractions (2.2-3.8Gy/fraction) up to a total of 80.4Gy, based on mid-treatment FDG-PET tumor response to escalate dose to residual tumor while minimizing dose to SPECT-defined functional lung. Non-progressing patients received consolidative carboplatin/paclitaxel or durvalumab. The primary endpoint of the study was ≥ grade 2 lung and esophageal toxicities. Secondary endpoints included time to local progression, tumor response, and overall survival. RESULTS: At one year post-treatment, the rates of grade 2 and grade 3 pneumonitis were 21.3% and 2.1%, respectively, with no difference in pneumonitis rates among patients who received and did not receive adjuvant durvalumab (p=0.74). While there were no grade 3 esophageal-related toxicities, 66.0% of patients experienced grade 2 esophagitis. 1- and 2-year local control rates were 94.5% (95% CI, 87.4% - 100%) and 87.5% (95% CI, 76.7% - 100%), respectively. Overall survival was 82.8% (95% CI, 72.6% -94.4%) at 1 year and 62.3% (95% CI, 49.6%-78.3%) at 2 years. CONCLUSIONS: Response-based adaptive dose-escalation accounting for tumor change and normal tissue function during treatment provided excellent local control, comparable toxicity to standard chemoradiation, and did not increase toxicity with adjuvant immunotherapy.

Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection.

Lung cancer screening via annual low-dose computed tomography (LDCT) has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by an LDCT. Changes in genome-wide cell-free DNA (cfDNA) fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples, and then validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer, and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a five-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths.

Radiation for Early Glottic Cancer.

Multidisciplinary evaluation of early-stage glottic cancer facilitates optimal treatment with either surgery or radiation therapy. Standard of care radiation treatment of early-stage glottic cancer continues to be three-dimensional opposed lateral fields to include the whole larynx. Modern radiation treatment techniques are allowing studies to examine the efficacy and toxicity of altered doses and treatment volumes. Advanced techniques, such as stereotactic body radiation therapy or single-vocal cord irradiation, are not yet considered standard of care for early-stage glottic cancer and should be performed at institutions with clinical trials to ensure adequate expertise and quality assurance.

Tumor immune microenvironment alterations using induction cetuximab in a phase II trial of deintensified therapy for p16-positive oropharynx cancer.

BACKGROUND: We sought to characterize early changes in CD8+ tumor-infiltrating lymphocytes and tumor transcriptomes after induction cetuximab in a cohort with p16-positive oropharyngeal cancer on a phase II clinical de-escalation trial. METHODS: Tumor biopsies were obtained before and 1 week after a single cetuximab loading dose in eight patients enrolled in a phase II trial of cetuximab and radiotherapy. Changes in CD8+ tumor-infiltrating lymphocytes and transcriptomes were assessed. RESULTS: One week after cetuximab, five patients (62.5%) had an increase in CD8+ cell infiltration with a median (range) fold change of +5.8 (2.5-15.8). Three (37.5%) had unchanged CD8+ cells (median [range] fold change of -0.85 [0.8-1.1]). In two patients with evaluable RNA, cetuximab induced rapid tumor transcriptome changes in cellular type 1 interferon signaling and keratinization pathways. CONCLUSIONS: Within 1 week, cetuximab induced measurable changes in pro-cytotoxic T-cell signaling and immune content.

Initial Feasibility and Acute Toxicity Outcomes From a Phase 2 Trial of 18F-Fluorodeoxyglucose Positron Emission Tomography Response-Based De-escalated Definitive Chemoradiotherapy for p16+ Oropharynx Cancer: A Planned Interim Analysis.

PURPOSE: 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) parameters are prognostic of oncologic outcomes in human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). We used FDG-PET imaging biomarkers to select patients for de-escalated chemoradiotherapy (CRT), hypothesizing that acute toxicity will be improved with de-escalation. METHODS AND MATERIALS: This is a planned interim initial feasibility and acute toxicity report from a phase 2, prospective, nonrandomized study, which enrolled patients with stage I-II p16+ OPSCC. All patients started definitive CRT to 70 Gy in 35 fractions, and those who met de-escalation criteria on midtreatment FDG-PET at fraction 10 completed treatment at 54 Gy in 27 fractions. We report the acute toxicity and patient-reported outcomes for 59 patients with a minimum follow-up of 3 months. RESULTS: There were no statistically significant differences between baseline patient characteristics in the standard and de-escalated cohorts. There were 28 of 59 (47.5%) patients who met FDG-PET de-escalation criteria and collectively received 20% to 30% less dose to critical organs at risk known to affect toxicity. At 3 months posttreatment, patients who received de-escalated CRT lost significantly less weight (median, 5.8% vs 13.0%; P < .001), had significantly less change from baseline in penetration-aspiration scale score (median, 0 vs 1; P = .018), and had significantly fewer aspiration events on repeat swallow study (8.0% vs 33.3%, P = .037) compared with patients receiving standard CRT. CONCLUSIONS: Approximately half of patients with early-stage p16+ OPSCC are selected for de-escalation of definitive CRT using midtreatment FDG-PET biomarkers, which resulted in significantly improved rates of observed acute toxicity. Further follow-up is ongoing and will be required to determine whether this de-escalation approach preserves the favorable oncologic outcomes for patients with p16+ OPSCC before adoption.

Development and Clinical Implementation of an Automated Virtual Integrative Planner for Radiation Therapy of Head and Neck Cancer.

Purpose: Head and neck (HN) radiation (RT) treatment planning is complex and resource intensive. Deviations and inconsistent plan quality significantly affect clinical outcomes. We sought to develop a novel automated virtual integrative (AVI) knowledge-based planning application to reduce planning time, increase consistency, and improve baseline quality. Methods and Materials: An in-house write-enabled script was developed from a library of 668 previously treated HN RT plans. Prospective hazard analysis was performed, and mitigation strategies were implemented before clinical release. The AVI-planner software was retrospectively validated in a cohort of 52 recent HN cases. A physician panel evaluated planning limitations during initial deployment, and feedback was enacted via software refinements. A final second set of plans was generated and evaluated. Kolmogorov-Smirnov test in addition to generalized evaluation metric and weighted experience score were used to compare normal tissue sparing between final AVI planner versus respective clinically treated and historically accepted plans. A t test was used to compare the interactive time, complexity, and monitor units for AVI planner versus manual optimization. Results: Initially, 86% of plans were acceptable to treat, with 10% minor and 4% major revisions or rejection recommended. Variability was noted in plan quality among HN subsites, with high initial quality for oropharynx and oral cavity plans. Plans needing revisions were comprised of sinonasal, nasopharynx, P-16 negative squamous cell carcinoma unknown primary, or cutaneous primary sites. Normal tissue sparing varied within subsites, but AVI planner significantly lowered mean larynx dose (median, 18.5 vs 19.7 Gy; P < .01) compared with clinical plans. AVI planner significantly reduced interactive optimization time (mean, 2 vs 85 minutes; P < .01). Conclusions: AVI planner reliably generated clinically acceptable RT plans for oral cavity, salivary, oropharynx, larynx, and hypopharynx cancers. Physician-driven iterative learning processes resulted in favorable evolution in HN RT plan quality with significant time savings and improved consistency using AVI planner.

Randomized Phase II Study of Physiologic MRI-Directed Adaptive Radiation Boost in Poor Prognosis Head and Neck Cancer.

PURPOSE: We conducted a randomized phase II multicenter clinical trial to test the hypothesis that physiologic MRI-based radiotherapy (RT) dose escalation would improve the outcome of patients with poor prognosis head and neck cancer. PATIENTS AND METHODS: MRI was acquired at baseline and at RT fraction 10 to create low blood volume/apparent diffusion coefficient maps for RT boost subvolume definition in gross tumor volume. Patients were randomized to receive 70 Gy (standard RT) or 80 Gy to the boost subvolume (RT boost) with concurrent weekly platinum. The primary endpoint was disease-free survival (DFS) with significance defined at a one-sided 0.1 level, and secondary endpoints included locoregional failure (LRF), overall survival (OS), comparison of adverse events and patient reported outcomes (PRO). RESULTS: Among 81 randomized patients, neither the primary endpoint of DFS (HR = 0.849, P = 0.31) nor OS (HR = 1.19, P = 0.66) was significantly improved in the RT boost arm. However, the incidence of LRF was significantly improved with the addition of the RT boost (HR = 0.43, P = 0.047). Two-year estimates [90% confidence interval (CI)] of the cumulative incidence of LRF were 40% (27%-53%) in the standard RT arm and 18% (10%-31%) in the RT boost arm. Two-year estimates (90% CI) for DFS were 48% (34%-60%) in the standard RT arm and 57% (43%-69%) in the RT boost arm. There were no significant differences in toxicity or longitudinal differences seen in EORTC QLQ30/HN35 subscales between treatment arms in linear mixed-effects models. CONCLUSIONS: Physiologic MRI-based RT boost decreased LRF without a significant increase in grade 3+ toxicity or longitudinal PRO differences, but did not significantly improve DFS or OS. Additional improvements in systemic therapy are likely necessary to realize improvements in DFS and OS.

Direct incorporation of patient-specific efficacy and toxicity estimates in radiation therapy plan optimization.

PURPOSE: Current radiation therapy (RT) treatment planning relies mainly on pre-defined dose-based objectives and constraints to develop plans that aim to control disease while limiting damage to normal tissues during treatment. These objectives and constraints are generally population-based, in that they are developed from the aggregate response of a broad patient population to radiation. However, correlations of new biologic markers and patient-specific factors to treatment efficacy and toxicity provide the opportunity to further stratify patient populations and develop a more individualized approach to RT planning. We introduce a novel intensity-modulated radiation therapy (IMRT) optimization strategy that directly incorporates patient-specific dose response models into the planning process. In this strategy, we integrate the concept of utility-based planning where the optimization objective is to maximize the predicted value of overall treatment utility, defined by the probability of efficacy (e.g., local control) minus the weighted sum of toxicity probabilities. To demonstrate the feasibility of the approach, we apply the strategy to treatment planning for non-small cell lung cancer (NSCLC) patients. METHODS AND MATERIALS: We developed a prioritized approach to patient-specific IMRT planning. Using a commercial treatment planning system (TPS), we calculate dose based on an influence matrix of beamlet-dose contributions to regions-of-interest. Then, outside of the TPS, we hierarchically solve two optimization problems to generate optimal beamlet weights that can then be imported back to the TPS. The first optimization problem maximizes a patient's overall plan utility subject to typical clinical dose constraints. In this process, we facilitate direct optimization of efficacy and toxicity trade-off based on individualized dose-response models. After optimal utility is determined, we solve a secondary optimization problem that minimizes a conventional dose-based objective subject to the same clinical dose constraints as the first stage but with the addition of a constraint to maintain the optimal utility from the first optimization solution. We tested this method by retrospectively generating plans for five previously treated NSCLC patients and comparing the prioritized utility plans to conventional plans optimized with only dose metric objectives. To define a plan utility function for each patient, we utilized previously published correlations of dose to local control and grade 3-5 toxicities that include patient age, stage, microRNA levels, and cytokine levels, among other clinical factors. RESULTS: The proposed optimization approach successfully generated RT plans for five NSCLC patients that improve overall plan utility based on personalized efficacy and toxicity models while accounting for clinical dose constraints. Prioritized utility plans demonstrated the largest average improvement in local control (16.6%) when compared to plans generated with conventional planning objectives. However, for some patients, the utility-based plans resulted in similar local control estimates with decreased estimated toxicity. CONCLUSION: The proposed optimization approach, where the maximization of a patient's RT plan utility is prioritized over the minimization of standardized dose metrics, has the potential to improve treatment outcomes by directly accounting for variability within a patient population. The implementation of the utility-based objective function offers an intuitive, humanized approach to biological optimization in which planning trade-offs are explicitly optimized.

Investigating the Incidence of Pulmonary Abnormalities as Identified by Parametric Response Mapping in Patients With Lung Cancer Before Radiation Treatment.

Purpose: Parametric response mapping (PRM) of high-resolution, paired inspiration and expiration computed tomography (CT) scans is a promising analytical imaging technique that is currently used in diagnostic applications and offers the ability to characterize and quantify certain pulmonary pathologies on a patient-specific basis. As one of the first studies to implement such a technique in the radiation oncology clinic, the goal of this work was to assess the feasibility for PRM analysis to identify pulmonary abnormalities in patients with lung cancer before radiation therapy (RT). Methods and Materials: High-resolution, paired inspiration and expiration CT scans were acquired from 23 patients with lung cancer as part of routine treatment planning CT acquisition. When applied to the paired CT scans, PRM analysis classifies lung parenchyma, on a voxel-wise basis, as normal, small airways disease (SAD), emphysema, or parenchymal disease (PD). PRM classifications were quantified as a percent of total lung volume and were evaluated globally and regionally within the lung. Results: PRM analysis of pre-RT CT scans was successfully implemented using a workflow that produced patient-specific maps and quantified specific phenotypes of pulmonary abnormalities. Through this study, a large prevalence of SAD and PD was demonstrated in this lung cancer patient population, with global averages of 10% and 17%, respectively. Moreover, PRM-classified normal and SAD in the region with primary tumor involvement were found to be significantly different from global lung values. When present, elevated levels of PD and SAD abnormalities tended to be pervasive in multiple regions of the lung, indicating a large burden of underlying disease. Conclusions: Pulmonary abnormalities, as detected by PRM, were characterized in patients with lung cancer scheduled for RT. Although further study is needed, PRM is a highly accessible CT-based imaging technique that has the potential to identify local lung abnormalities associated with chronic obstructive pulmonary disease and interstitial lung disease. Further investigation in the radiation oncology setting may provide strategies for tailoring RT planning and risk assessment based on pre-existing PRM-based pathology.

Improved prediction of radiation pneumonitis by combining biological and radiobiological parameters using a data-driven Bayesian network analysis.

Grade 2 and higher radiation pneumonitis (RP2) is a potentially fatal toxicity that limits efficacy of radiation therapy (RT). We wished to identify a combined biomarker signature of circulating miRNAs and cytokines which, along with radiobiological and clinical parameters, may better predict a targetable RP2 pathway. In a prospective clinical trial of response-adapted RT for patients (n = 39) with locally advanced non-small cell lung cancer, we analyzed patients' plasma, collected pre- and during RT, for microRNAs (miRNAs) and cytokines using array and multiplex enzyme linked immunosorbent assay (ELISA), respectively. Interactions between candidate biomarkers, radiobiological, and clinical parameters were analyzed using data-driven Bayesian network (DD-BN) analysis. We identified alterations in specific miRNAs (miR-532, -99b and -495, let-7c, -451 and -139-3p) correlating with lung toxicity. High levels of soluble tumor necrosis factor alpha receptor 1 (sTNFR1) were detected in a majority of lung cancer patients. However, among RP patients, within 2 weeks of RT initiation, we noted a trend of temporary decline in sTNFR1 (a physiological scavenger of TNFα) and ADAM17 (a shedding protease that cleaves both membrane-bound TNFα and TNFR1) levels. Cytokine signature identified activation of inflammatory pathway. Using DD-BN we combined miRNA and cytokine data along with generalized equivalent uniform dose (gEUD) to identify pathways with better accuracy of predicting RP2 as compared to either miRNA or cytokines alone. This signature suggests that activation of the TNFα-NFκB inflammatory pathway plays a key role in RP which could be specifically ameliorated by etanercept rather than current therapy of non-specific leukotoxic corticosteroids.

Investigating the SPECT Dose-Function Metrics Associated With Radiation-Induced Lung Toxicity Risk in Patients With Non-small Cell Lung Cancer Undergoing Radiation Therapy.

PURPOSE: Dose to normal lung has commonly been linked with radiation-induced lung toxicity (RILT) risk, but incorporating functional lung metrics in treatment planning may help further optimize dose delivery and reduce RILT incidence. The purpose of this study was to investigate the impact of the dose delivered to functional lung regions by analyzing perfusion (Q), ventilation (V), and combined V/Q single-photon-emission computed tomography (SPECT) dose-function metrics with regard to RILT risk in patients with non-small cell lung cancer (NSCLC) patients who received radiation therapy (RT). METHODS AND MATERIALS: SPECT images acquired from 88 patients with locally advanced NSCLC before undergoing conventionally fractionated RT were retrospectively analyzed. Dose was converted to the nominal dose equivalent per 2 Gy fraction, and SPECT intensities were normalized. Regional lung segments were defined, and the average dose delivered to each lung region was quantified. Three functional categorizations were defined to represent low-, normal-, and high-functioning lungs. The percent of functional lung category receiving ≥20 Gy and mean functional intensity receiving ≥20 Gy (iV20) were calculated. RILT was defined as grade 2+ radiation pneumonitis and/or clinical radiation fibrosis. A logistic regression was used to evaluate the association between dose-function metrics and risk of RILT. RESULTS: By analyzing V/Q normalized intensities and functional distributions across the population, a wide range in functional capability (especially in the ipsilateral lung) was observed in patients with NSCLC before RT. Through multivariable regression models, global lung average dose to the lower lung was found to be significantly associated with RILT, and Q and V iV20 were correlated with RILT when using ipsilateral lung metrics. Through a receiver operating characteristic analysis, combined V/Q low-function receiving ≥20 Gy (low-functioning V/Q20) in the ipsilateral lung was found to be the best predictor (area under the curce: 0.79) of RILT risk. CONCLUSIONS: Irradiation of the inferior lung appears to be a locational sensitivity for RILT risk. The multivariable correlation between ipsilateral lung iV20 and RILT, as well as the association of low-functioning V/Q20 and RILT, suggest that irradiating low-functioning regions in the lung may lead to higher toxicity rates.

Patient Burden with Current Surveillance Paradigm and Factors Associated with Interest in Altered Surveillance for Early Stage HPV-Related Oropharyngeal Cancer.

INTRODUCTION: Optimal surveillance paradigms for survivors of early stage human papillomavirus (HPV)-related oropharyngeal cancer are not well defined. This study aimed to characterize patient interest in and factors associated with an altered surveillance paradigm. MATERIALS AND METHODS: We surveyed patients with Stage I or II HPV-related oropharyngeal cancer treated at a tertiary care institution from 2016 to 2019. Primary outcomes were descriptive assessment of patient knowledge, interest in altered surveillance, burdens of in-person appointments, and priorities for surveillance visits. Ordinal regression was used to identify correlates of interest in altered surveillance. RESULTS: Sixty-seven patients completed surveys from February to April 2020 at a median of 21 months since completing definitive treatment. A majority (61%) of patients were interested in a surveillance approach that decreased in-person clinic visits. Patients who self-identified as medical maximizers, had higher worry of cancer recurrence, or were in long-term relationships were less likely to be interested. Patients reported significant burdens associated with surveillance visits, including driving distance, time off work, and nonmedical costs. Patients were most concerned with discussing cancer recurrence (76%), physical quality of life (70%), mortality (61%), and mental quality of life (52%) with their providers at follow-up visits. CONCLUSION: Patients with early stage HPV-related oropharyngeal cancers are interested in altered surveillance approaches, experience significant burdens related to surveillance visits, and have concerns that are not well addressed with current surveillance approaches, including physical and mental quality of life. Optimized surveillance approaches should incorporate patient priorities and minimize associated burdens. IMPLICATIONS FOR PRACTICE: The number of patients with HPV-related oropharyngeal cancers is increasing, and numerous clinical trials are investigating novel approaches to treating these good-prognosis patients. There has been limited work assessing optimal surveillance paradigms in these patients. Patients experience significant appointment-related burdens and have concerns such as physical and mental quality of life. Additionally, patients with early stage HPV-related oropharyngeal cancers express interest in altered surveillance approaches that decrease in-person clinic visits. Optimization of surveillance paradigms to promote broader survivorship care in clinical practice is needed.

Particle Beam Therapy for Cardiac-Sparing Radiotherapy in Non-Small Cell Lung Cancer.

Radiation therapy plays an integral role in the treatment of all stages of non-small cell lung cancer. Survival outcomes are improving, but radiation therapy remains associated with long-term toxicity. Recently, it has become evident that the heart is an important organ at risk for treatment-related morbidity. In this review, we discuss the hypothesis that particle radiation therapy offers superior dosimetry compared with photon-based treatment, and that this comparative advantage translates into clinically meaningful cardiac toxicity reduction with similar local tumor control. We discuss the evidence in non-small cell lung cancer to date, the ongoing prospective trials that may provide additional insight, and the opportunities to optimally integrate particle therapy into future prospective investigation.

Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination.

Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.

CT and FDG-PET radiologic biomarkers in p16+ oropharyngeal squamous cell carcinoma patients treated with definitive chemoradiotherapy.

PURPOSE: To assess associations between imaging biomarkers from standard of care pre-treatment CT and FDG-PET scans and locoregional (LR) and distant metastatic (DM) recurrences in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive chemoradiotherapy (CRT). METHODS: An institutional database from a single NCI-designated cancer center identified 266 patients with p16+ OPSCC treated with definitive CRT in our department from 2005 to 2016 with evaluable pre-treatment FDG-PET scans. Quantitative SUV metrics and qualitative imaging metrics were determined from FDG-PET and CT scans, while clinical characteristics were abstracted from the medical record. Associations between clinical/imaging features and time to LR (TTLRF) or DM (TTDMF) failure and overall survival (OS) were assessed using univariable Cox regression and penalized stepwise regression for multivariable analyses (MVA). RESULTS: There were 27 LR and 32 DM recurrences as incident failures. Imaging biomarkers were significantly associated with TTLRF, TTDMF and OS. FDG-PET metrics outperformed CT and clinical metrics for TTLRF, with metabolic tumor volume being the only significant feature selected on MVA: C-index = 0.68 (p = 0.01). Radiographic extranodal extension (rENE), positive retropharyngeal nodes (RPN+), and clinical stage were significant on MVA for TTDMF: C-index = 0.84 (p < 0.001). rENE, group stage, and RPN+ were significant on MVA for OS: C-index = 0.77 (p < 0.001). CONCLUSIONS: In the largest study to date of uniformly treated patients with CRT to evaluate both pretreatment CT and FDG-PET, radiographic biomarkers were significantly associated with TTLRF, TTDMF and OS among patients with p16+ OPSCC treated with CRT. CT metrics performed best to predict TTDMF, while FDG-PET metrics showed improved prediction for LRRFS. These metrics may help identify candidates for treatment intensification or de-escalation of therapy. STATEMENT OF TRANSLATIONAL RELEVANCE: Pre-treatment imaging features from standard-of-care PET/CT imaging show promise for predicting long-term outcomes following HPV-associated oropharynx cancer (HPV-OPC) therapy. This study comprehensively characterizes qualitative and quantitative pre-treatment imaging metrics associated with time to pattern-specific failure in a cohort of 266 patients treated uniformly with definitive chemoradiation. Multivariate analysis (MVA) for time to locoregional failure (TTLRF), time to distant metastatic failure (TTDMF), and overall survival (OS) was performed. FDG-PET metrics outperformed CT and clinical metrics for TTLRF. CT radiographic extranodal extension, positive retropharyngeal nodes, and stage strongly predicted TTDMF (combined C-index = 0.84, log rank p < 0.001). Number of smoking pack-years complemented clinical and imaging features only in patients without radiographic extranodal extension or positive retropharyngeal nodes. Time to pattern-specific failure is important for guiding treatment de-escalation strategies, which intend to reduce treatment-related toxicity in patients with relatively long expected survival times. This study suggests that PET/CT features should play a crucial role in future de-escalation trials and management of HPV-OPC patients.

Characterization of very late dysphagia after chemoradiation for oropharyngeal squamous cell carcinoma.

OBJECTIVES: Improved prognosis for p16+ oropharyngeal squamous cell carcinoma (OPSCC) has led to efforts to mitigate long-term complications of treatment, which remains poorly defined in late survivors. Here we characterize very late dysphagia in OPSCC. MATERIALS AND METHODS: Long-term review of 93 p16+ OPSCC patients treated with chemoradiation was performed. We scored videofluoroscopic swallow studies (VFSS) according to the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale. Very late dysphagia was defined >2.5 years from end of treatment. Fine-Gray regression models were used to assess dysphagia with competing risk of death. RESULTS: Median follow up was 10.5 years. 402 total VFSS were assessed (median 4 per patient, range 0-8). 15.1% of patients had a DIGEST score ≥2 very late after treatment. Very late DIGEST score ≥2 correlated with T-stage (HR 1.7, p = 0.049), second cancer (HR 6.5, p = 0.004), superior pharyngeal constrictor dose (HR 1.11, p = 0.050), total tongue dose (HR 1.07, p = 0.045), but not hypoglossal nerve dose (p > 0.2). Seven patients (7.5%) had late progressive dysphagia, defined as DIGEST score that increased by ≥2 beyond one year after treatment, and this correlated with higher ipsilateral hypoglossal nerve D1cc dose (75 vs 72 Gy, p = 0.037). CONCLUSION: In p16+ OPSCC patients treated with definitive chemoradiation, at least 7.5% developed late progressive dysphagia, and 15.1% experienced moderate dysphagia >2.5 years from treatment. Our study suggests that dose to tongue musculature may be associated with very late dysphagia, and hypoglossal nerve dose may be associated with late progressive dysphagia. More intensive long-term dysphagia survivorship monitoring is suggested.

The impact of treatment package time on locoregional control for HPV+ oropharyngeal squamous cell carcinoma treated with surgery and postoperative (chemo)radiation.

BACKGROUND: For patients with head and neck squamous cell carcinoma (SCC) undergoing surgery followed by postoperative radiotherapy (PORT), time from surgery to completion of adjuvant therapy, "package time" impacts locoregional control (LRC). However, the significance of package time in HPV+ oropharyngeal SCC (OPSCC) is unknown. METHODS: We examined patients undergoing TORS resection with PORT for HPV+ OPSCC from January 2010 to December 2015 with ≥18 months follow-up (n = 267). A cutoff of 15 weeks was used to delineate patients into short and long package time groups. LRC loss was defined as any recurrence after surgery. RESULTS: Prolonged package time >15 weeks was associated with inferior LRC in this HPV+ OPSCC cohort, driven primarily by interval from surgery to PORT initiation. Multivariate analysis showed that package time and T classification are both independently associated with LRC. CONCLUSIONS: Among HPV+ OPSCC, prolongation of package time appears to compromise LRC, but not survival.

Five-year Long-term Outcomes of Stereotactic Body Radiation Therapy for Operable Versus Medically Inoperable Stage I Non-small-cell Lung Cancer: Analysis by Operability, Fractionation Regimen, Tumor Size, and Tumor Location.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is standard for medically inoperable stage I non-small-cell lung cancer (NSCLC) and is emerging as a surgical alternative in operable patients. However, limited long-term outcomes data exist, particularly according to operability. We hypothesized long-term local control (LC) and cancer-specific survival (CSS) would not differ by fractionation schedule, tumor size or location, or operability status, but overall survival (OS) would be higher for operable patients. PATIENTS AND METHODS: All consecutive patients with stage I (cT1-2aN0M0) NSCLC treated with SBRT from June 2009 to July 2013 were assessed. Thoracic surgeon evaluation determined operability. Local failure was defined as growth following initial tumor shrinkage or progression on consecutive scans. LC, CSS, and OS were calculated using Cox proportional hazards regression. RESULTS: A total of 186 patients (204 lesions) were analyzed. Most patients were inoperable (82%) with Eastern Cooperative Oncology Group performance status of 1 (59%) or 2 (26%). All lesions received biological effective doses ≥ 100 Gy most commonly (94%) in 3 to 5 fractions. The median follow-up was 4.0 years. LC at 2 and 5 years were 95.6% (95% confidence interval, 92%-99%) and 93.7% (95% confidence interval, 90%-98%), respectively. Compared with operable patients, inoperable patients did not have significant differences in 5-year LC (93.1% vs. 96.7%; P = .49), nodal failure (31.4% vs. 11.0%; P = .12), distant failure (12.2% vs. 10.4%; P = .98), or CSS (80.6% vs. 91.0%; P = .45) but trended towards worse OS (34.2% vs. 45.3%; P = .068). Tumor size, location, and fractionation did not significantly influence outcomes. CONCLUSIONS: SBRT has excellent, durable LC and CSS rates for early-stage NSCLC, although inoperable patients had somewhat lower OS than operable patients, likely owing to greater comorbidities.

Impact of Enlarged Nonhypermetabolic Lymph Nodes on Outcomes After Stereotactic Body Radiotherapy for Early-Stage Non-Small-Cell Lung Cancer.

BACKGROUND: Up to 15% of patients undergoing positron emission tomography (PET)/computed tomography (CT) before stereotactic body radiotherapy (SBRT) harbor occult nodal disease. In the absence of invasive mediastinal staging, the clinical significance of enlarged nonhypermetabolic lymph nodes (LNs) remains unclear. We performed what is to our knowledge the first study to address whether enlarged nonhypermetabolic LNs were associated with higher post-SBRT failure rates. PATIENTS AND METHODS: Two academic centers assessed 157 consecutive patients treated with SBRT for cT1-2aN0M0 non-small-cell lung cancer who underwent PET/CT without pathologic nodal staging. The cutoff of an enlarged node was ≥ 1.0 cm, although a 7 mm threshold was also evaluated. Local recurrence-free survival (RFS), regional RFS, distant metastasis-free survival, RFS, and overall survival (OS) were calculated by Kaplan-Meier methodology. Multivariate Cox modeling addressed factors associated with RFS and OS. RESULTS: There were 120 patients (76%) with LNs < 1 cm and 37 (24%) with nodes ≥ 1 cm. Most patients had peripheral and/or T1 tumors. Median follow-up was 25.5 months. There were no differences between cohorts in actuarial local RFS, regional RFS, distant metastasis-free survival, RFS, or OS (P > .05 for all). Thirteen percent of patients experienced any nodal relapse, 15% of which occurred in the same station as that of the largest pre-SBRT LN. Stratification by largest LN location in an N1 versus N2 station showed no differences in RFS or OS (P > .05 for both). A 7 mm cutoff also showed no differences in outcomes (P > .05 for all). LN size was not correlated with RFS/OS on multivariable analysis (P > .05 for both). CONCLUSION: The presence of enlarged nonhypermetabolic LNs on PET/CT is not associated with increased post-SBRT failure rates.