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\u27 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

Four-Year Outcomes From a Prospective Phase II Clinical Trial of Moderately Hypofractionated Proton Therapy for Localized Prostate Cancer

Purpose: Moderately hypofractionated radiation therapy represents an effective treatment for localized prostate cancer (PC). Although large randomized trials have reported the efficacy of photon-based hypofractionated therapy, hypofractionated proton therapy (HFPT) has not been extensively studied. This study was performed to determine the clinical and patient-reported outcomes for patients with PC treated with HFPT. Methods and Materials: Between 2010 and 2017, 184 men were enrolled on a trial of 70 Gy in 28 fractions of HFPT for low- to intermediate-risk PC. Acute and late toxicity was evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Patient-reported outcomes were measured by International Prostate Symptom Score, International Index of Erectile Function Questionnaire, and Expanded Prostate Cancer Index Composite scores. Results: Median follow-up was 49.2 months. Enrolled patients had low-risk (n = 18), favorable intermediate-risk (n = 78), and unfavorable intermediate-risk (n = 88) PC. Four-year rates of biochemical-clinical failure-free survival were 93.5% (95% confidence interval, 89%-98%), 94.4% (89%-100%), 92.5% (86%-100%), and 93.8% (88%-100%) in the overall group and the low-risk, favorable intermediate-risk, and unfavorable intermediate-risk cohorts, respectively (log-rank P > .4). The incidence of acute grade 2 or higher gastrointestinal (GI) and urologic toxicities were 3.8% and 12.5%, respectively. The 4-year incidence of late grade 2 or higher urologic and GI toxicity was 7.6% (4%-13%) and 13.6% (9%-20%), respectively. One late grade 3 GI toxicity was reported. All late toxicities were transient. Patient-reported International Prostate Symptom, International Index of Erectile Function, and Expanded Prostate Cancer Index Composite scores had no significant long-term changes after completion of HFPT (Supplementary Table 1, available at https://doi.org/10.1016/j.ijrobp.2019.05.069). Conclusions: HFPT is associated with low rates of toxicity and does not appear to negatively affect 4-year patient reported urinary and bowel health. Further comparative analyses are warranted to better understand differences between proton and photon HFRT. (C) 2019 Elsevier Inc. All rights reserved

Feasibility of function‐guided lung treatment planning with parametric response mapping

PurposeRecent advancements in functional lung imaging have been developed to improve clinicians’ knowledge of patient pulmonary condition prior to treatment. Ultimately, it may be possible to employ these functional imaging modalities to tailor radiation treatment plans to optimize patient outcome and mitigate pulmonary complications. Parametric response mapping (PRM) is a computed tomography (CT)–based functional lung imaging method that utilizes a voxel‐wise image analysis technique to classify lung abnormality phenotypes, and has previously been shown to be effective at assessing lung complication risk in diagnostic applications. The purpose of this work was to demonstrate the implementation of PRM guidance in radiotherapy treatment planning.Methods and materialsA retrospective study was performed with 18 lung cancer patients to test the incorporation of PRM into a radiotherapy planning workflow. Paired inspiration/expiration pretreatment CT scans were acquired and PRM analysis was utilized to classify each voxel as normal, parenchymal disease, small airway disease, and emphysema. Density maps were generated for each PRM classification to contour high density regions of pulmonary abnormalities. Conventional volumetric‐modulated arc therapy and PRM‐guided treatment plans were designed for each patient.ResultsPRM guidance was successfully implemented into the treatment planning process. The inclusion of PRM priorities resulted in statistically significant (p < 0.05) improvements to the V20Gy within the PRM avoidance contours. On average, reductions of 5.4% in the V20Gy(%) were found. The PRM‐guided treatment plans did not significantly increase the dose to the organs at risk or result in insufficient planning target volume coverage, but did increase plan complexity.ConclusionsPRM guidance was successfully implemented into a treatment planning workflow and shown to be effective for dose redistribution within the lung. This work has provided a framework for the potential clinical implementation of PRM‐guided treatment planning.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170991/1/acm213436.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170991/2/acm213436_am.pd

Early vs. Late Chemoradiation Therapy and the Postoperative Interval to Adjuvant Therapy Do Not Correspond to Local Recurrence in Resected Pancreatic Cancer

Objective: Standard postoperative therapy for pancreatic cancer consists of both chemotherapy alone and chemoradiation. We sought to investigate whether the sequence of chemotherapy and chemoradiation and overall time to initiation of adjuvant therapy would impact local vs. distant recurrence. Methods: After Institutional Review Board approval, resected pancreas cancer patient charts were evaluated for medical background, surgical, pathological, chemoradiation (CRT), and follow-up. Local recurrence (LR) was defined as failures occurring in the postoperative bed and regional lymph nodes. Early vs. late CRT was defined by whether CRT was given early (within 1–2 cycles of adjuvant chemotherapy) or late in the course of adjuvant chemotherapy (after the 3rd cycle of chemotherapy). The postoperative interval variance was compared to LR factors such as progression-free survival (PFS) and overall survival (OS). Results: Of the 34 eligible patients, 47% (n=16) underwent early CRT and 41% (n=14) underwent late CRT. 12% (n=14) did not undergo any induction chemotherapy. At median follow-up of 22 months, 53% (n=18) had metastases, 24% (n=8) had LR, and 24% (n=8) were disease free. Kaplan-Meier curves revealed that early vs. late CRT did not appear to significantly impact OS (p=0.63), PFS (p=0.085) or LR (p=0.19). Postoperative interval did not affect PFS (p=0.42) or OS (p=0.93). Conclusions: Early vs. late CRT and the time to initiation of adjuvant therapy were not significantly associated with LR in patients with resected pancreatic cancer. Future prospective studies are required to determine if sequencing of chemotherapy, CRT, or the postoperative interval impact survival and patterns of recurrence

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

PurposeCurrent 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 materialsWe 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.ResultsThe 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.ConclusionThe 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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175082/1/mp15940.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175082/2/mp15940_am.pd

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

IntroductionOptimal 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 MethodsWe 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.ResultsSixty‐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.ConclusionPatients 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 PracticeThe 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.Patient input is critical to improve surveillance options for human papillomavirus (HPV)‐related oropharyngeal cancer. This article assesses patient interest in and factors associated with alternative surveillance approaches, including patient knowledge, burdens of in‐person appointments, and priorities for follow‐up visits.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/169305/1/onco13784-sup-0001-Supinfo01.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169305/2/onco13784.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169305/3/onco13784_am.pd

Predictors of Pneumonitis After Conventionally Fractionated Radiotherapy for Locally Advanced Lung Cancer

PURPOSE: Multiple factors influence the risk of developing pneumonitis after radiation therapy (RT) for lung cancer, but few resources exist to guide clinicians in predicting risk in an individual patient treated with modern techniques. We analyzed toxicity data from a state-wide consortium to develop an integrated pneumonitis risk model. METHODS AND MATERIALS: All patients (N = 1302) received conventionally fractionated RT for stage II-III non-small cell lung cancer between April 2012 and July 2019. Pneumonitis occurring within 6 months of treatment was graded by local practitioners and collected prospectively from 27 academic and community clinics participating in a state-wide quality consortium. Pneumonitis was modeled as either grade ≥2 (G2+) or grade ≥3 (G3+). Logistic regression models were fit to quantify univariable associations with dose and clinical factors, and stepwise Akaike information criterion-based modeling was used to build multivariable prediction models. RESULTS: The overall rate of pneumonitis of any grade in the six months following RT was 16% (208 cases). 7% (94 cases) were G2+ and \u3c1% (11 cases) were G3+. Adjusting for incomplete follow-up, estimated rates for G2+ and G3+ were 14% and 2%, respectively. In univariate analyses, gEUD, V5, V10, V20, V30, and Mean Lung Dose (MLD) were positively associated with G2+ pneumonitis risk, while current smoking status was associated with lower odds of pneumonitis. G2+ pneumonitis risk of ≥22% was independently predicted by MLD of ≥20 Gy, V20 of ≥35%, and V5 of ≥75%. In multivariate analyses, the lung V5 metric remained a significant predictor of G2+ pneumonitis even when controlling for MLD, despite their close correlation. For G3+ pneumonitis, MLD and V20 were statistically significant predictors. Number of comorbidities was an independent predictor of G3+, but not G2+ pneumonitis. CONCLUSIONS: We present an analysis of pneumonitis risk after definitive RT for lung cancer using a large, prospective dataset. We incorporate comorbidity burden, smoking status, and dosimetric parameters in an integrated risk model. These data may guide clinicians in assessing pneumonitis risk in individual patients

Prognostic value of CD103+ tumor-infiltrating lymphocytes and programmed death ligand-1 (PD-L1) combined positive score in recurrent laryngeal squamous cell carcinoma.

OBJECTIVES: In an evolving era of immunotherapeutic options for persistent or recurrent laryngeal squamous cell carcinoma (LSCC), there is a need for improved biomarkers of treatment response and survival to inform optimal treatment selection and prognostication. Herein, our primary objective was to explore correlations between tumor infiltrating lymphocytes (TILs) and PD-L1 Combined Positive Score (CPS). Secondarily, we sought to explore their combined association with survival outcomes in patients with persistent or recurrent LSCC treated with salvage surgery. MATERIALS AND METHODS: This was a retrospective cohort study at a single academic medical center. Immunohistochemistry staining for TILs and PD-L1 was performed on a tissue microarray of persistent or recurrent LSCC pathologic specimens. Correlations between TIL subsets and PD-L1 CPS were examined using Pearsons correlation coefficient and survival outcomes were analyzed with the Kaplan-Meier method and log-rank tests. RESULTS: Only CD103+ TILs showed a statistically significant, weakly-positive correlation with PD-L1 CPS (r2&nbsp;=&nbsp;0.264, p&nbsp;&lt;&nbsp;0.015). No other TIL subsets correlated with PD-L1 CPS in our cohort. The most favorable survival outcomes were seen in patients with pathologic N0 tumors showing high CD103+ TILs and/or high PD-L1 CPS staining. CONCLUSION: Among patients with persistent or recurrent LSCC, CD103+ TILs only modestly correlated with PD-L1 CPS. A combined biomarker score incorporating CD103+ TILs and PD-L1 CPS greatly enhanced survival discrimination. This model may have additional utility in predicting the clinical benefit of immunotherapies in persistent or recurrent LSCC in the future

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