Circulating tumor cells reveal early predictors of disease progression in patients with stage III NSCLC undergoing chemoradiation and immunotherapy.

Circulating tumor cells (CTCs) are early signs of metastasis and can be used to monitor disease progression well before radiological detection by imaging. Using an ultrasensitive graphene oxide microfluidic chip nanotechnology built with graphene oxide sheets, we were able to demonstrate that CTCs can be specifically isolated and molecularly characterized to predict future progression in patients with stage III non-small cell lung cancer (NSCLC). We analyzed CTCs from 26 patients at six time points throughout the treatment course of chemoradiation followed by immune checkpoint inhibitor immunotherapy. We observed that CTCs decreased significantly during treatment, where a larger decrease in CTCs predicted a significantly longer progression-free survival time. Durvalumab-treated patients who have future progression were observed to have sustained higher programmed death ligand 1+ CTCs compared to stable patients. Gene expression profiling revealed phenotypically aggressive CTCs during chemoradiation. By using emerging innovative bioengineering approaches, we successfully show that CTCs are potential biomarkers to monitor and predict patient outcomes in patients with stage III NSCLC.

Selective Personalized RadioImmunotherapy for Locally Advanced Non-Small-Cell Lung Cancer Trial (SPRINT).

PURPOSE: Standard therapy for locally advanced non-small-cell lung cancer (LA-NSCLC) is concurrent chemoradiotherapy followed by adjuvant durvalumab. For biomarker-selected patients with LA-NSCLC, we hypothesized that sequential pembrolizumab and risk-adapted radiotherapy, without chemotherapy, would be well-tolerated and effective. METHODS: Patients with stage III NSCLC or unresectable stage II NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible for this trial. Patients with a PD-L1 tumor proportion score (TPS) of ≥50% received three cycles of induction pembrolizumab (200 mg, once every 21 days), followed by a 20-fraction course of risk-adapted thoracic radiotherapy (55 Gy delivered to tumors or lymph nodes with metabolic volume exceeding 20 cc, 48 Gy delivered to smaller lesions), followed by consolidation pembrolizumab to complete a 1-year treatment course. The primary study end point was 1-year progression-free survival (PFS). Secondary end points included response rates after induction pembrolizumab, overall survival (OS), and adverse events. RESULTS: Twenty-five patients with a PD-L1 TPS of ≥50% were enrolled. The median age was 71, most patients (88%) had stage IIIA or IIIB disease, and the median PD-L1 TPS was 75%. Two patients developed disease progression during induction pembrolizumab, and two patients discontinued pembrolizumab after one infusion because of immune-related adverse events. Using RECIST criteria, 12 patients (48%) exhibited a partial or complete response after induction pembrolizumab. Twenty-four patients (96%) received definitive thoracic radiotherapy. The 1-year PFS rate is 76%, satisfying our efficacy objective. One- and 2-year OS rates are 92% and 76%, respectively. The most common grade 3 adverse events were colitis (n = 2, 8%) and esophagitis (n = 2, 8%), and no higher-grade treatment-related adverse events have occurred. CONCLUSION: Pembrolizumab and risk-adapted radiotherapy, without chemotherapy, are a promising treatment approach for patients with LA-NSCLC with a PD-L1 TPS of ≥50%.

Use of machine learning to assess the prognostic utility of radiomic features for in-hospital COVID-19 mortality.

As portable chest X-rays are an efficient means of triaging emergent cases, their use has raised the question as to whether imaging carries additional prognostic utility for survival among patients with COVID-19. This study assessed the importance of known risk factors on in-hospital mortality and investigated the predictive utility of radiomic texture features using various machine learning approaches. We detected incremental improvements in survival prognostication utilizing texture features derived from emergent chest X-rays, particularly among older patients or those with a higher comorbidity burden. Important features included age, oxygen saturation, blood pressure, and certain comorbid conditions, as well as image features related to the intensity and variability of pixel distribution. Thus, widely available chest X-rays, in conjunction with clinical information, may be predictive of survival outcomes of patients with COVID-19, especially older, sicker patients, and can aid in disease management by providing additional information.

Prospective Evaluation of Limited-Stage Small Cell Lung Cancer Radiotherapy Fractionation Regimen Usage and Acute Toxicity in a Large Statewide Quality Collaborative.

PURPOSE: National guidelines on limited-stage small cell lung cancer (LS-SCLC) treatment give preference to a hyperfractionated regimen of 45 Gy in 30 fractions delivered twice daily; however, use of this regimen is uncommon compared with once-daily regimens. The purpose of this study was to characterize the LS-SCLC fractionation regimens used throughout a statewide collaborative, analyze patient and treatment factors associated with these regimens, and describe real-world acute toxicity profiles of once- and twice-daily radiation therapy (RT) regimens. METHODS AND MATERIALS: Demographic, clinical, and treatment data along with physician-assessed toxicity and patient-reported outcomes were prospectively collected by 29 institutions within the Michigan Radiation Oncology Quality Consortium between 2012 and 2021 for patients with LS-SCLC. We modeled the influence of RT fractionation and other patient-level variables clustered by treatment site on the odds of a treatment break specifically due to toxicity with multilevel logistic regression. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, incident grade 2 or worse toxicity was longitudinally compared between regimens. RESULTS: There were 78 patients (15.6% overall) treated with twice-daily RT and 421 patients treated with once-daily RT. Patients receiving twice-daily RT were more likely to be married or living with someone (65% vs 51%; P = .019) and to have no major comorbidities (24% vs 10%; P = .017). Once-daily RT fractionation toxicity peaked during RT, and twice-daily toxicity peaked within 1 month after RT. After stratifying by treatment site and adjusting for patient-level variables, once-daily treated patients had 4.11 (95% confidence interval, 1.31-12.87) higher odds of treatment break specifically due to toxicity than twice-daily treated patients. CONCLUSIONS: Hyperfractionation for LS-SCLC remains infrequently prescribed despite the lack of evidence demonstrating superior efficacy or lower toxicity of once-daily RT. With peak acute toxicity after RT and lower likelihood of a treatment break with twice-daily fractionation in real-word practice, providers may start using hyperfractionated RT more frequently.

Pelvic Recovery After Endometrial Cancer Treatment: Patient-Reported Outcomes and MRI Findings.

RATIONALE AND OBJECTIVES: Most women with endometrial cancer (EC) have an excellent prognosis and may be cured. However, treatment-related pelvic functional impacts may affect long-term quality of life. To better understand these concerns, we explored correlations between patient-reported outcomes and pelvic magnetic resonance imaging (MRI) features in women treated for EC. MATERIALS AND METHODS: Women with histologic diagnosis of EC were consented preoperatively and completed the validated Female Sexual Function Index (FSFI) and Pelvic Floor Dysfunction Index (PFDI) questionnaires at preoperative, 6-week, and 6-month follow-up visits. Pelvic MRIs with dynamic pelvic floor sequences were performed at 6 weeks and 6 months. RESULTS: A total of 33 women participated in this prospective pilot study. Only 53.7% had been asked about sexual function by providers while 92.4% thought they should have been. Sexual function became more important to women over time. Baseline FSFI was low, declined at 6 weeks, and climbed above baseline at 6 months. Hyperintense vaginal wall signal on T2-weighted images (10.9 vs. 4.8, p = .002) and intact Kegel function (9.8 vs. 4.8, p = .03) were associated with higher FSFI. PFDI scores trended toward improved pelvic floor function over time. Pelvic adhesions on MRI were associated with better pelvic floor function (23.0 vs. 54.9, p = .003). Urethral hypermobility (48.4 vs. 21.7, p = .01), cystocele (65.6 vs. 24.8, p < .0001), and rectocele (58.8 vs. 18.8, p < .0001) predicted worse pelvic floor function. CONCLUSION: Use of pelvic MRI to quantify anatomic and tissue changes may facilitate risk stratification and response assessment for pelvic floor and sexual dysfunction. Patients articulated the need for attention to these outcomes during EC treatment.

A clinical decision support system for AI-assisted decision-making in response-adaptive radiotherapy (ARCliDS).

Involvement of many variables, uncertainty in treatment response, and inter-patient heterogeneity challenge objective decision-making in dynamic treatment regime (DTR) in oncology. Advanced machine learning analytics in conjunction with information-rich dense multi-omics data have the ability to overcome such challenges. We have developed a comprehensive artificial intelligence (AI)-based optimal decision-making framework for assisting oncologists in DTR. In this work, we demonstrate the proposed framework to Knowledge Based Response-Adaptive Radiotherapy (KBR-ART) applications by developing an interactive software tool entitled Adaptive Radiotherapy Clinical Decision Support (ARCliDS). ARCliDS is composed of two main components: Artifcial RT Environment (ARTE) and Optimal Decision Maker (ODM). ARTE is designed as a Markov decision process and modeled via supervised learning. Given a patient's pre- and during-treatment information, ARTE can estimate treatment outcomes for a selected daily dosage value (radiation fraction size). ODM is formulated using reinforcement learning and is trained on ARTE. ODM can recommend optimal daily dosage adjustments to maximize the tumor local control probability and minimize the side effects. Graph Neural Networks (GNN) are applied to exploit the inter-feature relationships for improved modeling performance and a novel double GNN architecture is designed to avoid nonphysical treatment response. Datasets of size 117 and 292 were available from two clinical trials on adaptive RT in non-small cell lung cancer (NSCLC) patients and adaptive stereotactic body RT (SBRT) in hepatocellular carcinoma (HCC) patients, respectively. For training and validation, dense data with 297 features were available for 67 NSCLC patients and 110 features for 71 HCC patients. To increase the sample size for ODM training, we applied Generative Adversarial Networks to generate 10,000 synthetic patients. The ODM was trained on the synthetic patients and validated on the original dataset. We found that, Double GNN architecture was able to correct the nonphysical dose-response trend and improve ARCliDS recommendation. The average root mean squared difference (RMSD) between ARCliDS recommendation and reported clinical decisions using double GNNs were 0.61 [0.03] Gy/frac (mean [sem]) for adaptive RT in NSCLC patients and 2.96 [0.42] Gy/frac for adaptive SBRT HCC compared to the single GNN's RMSDs of 0.97 [0.12] Gy/frac and 4.75 [0.16] Gy/frac, respectively. Overall, For NSCLC and HCC, ARCliDS with double GNNs was able to reproduce 36% and 50% of the good clinical decisions (local control and no side effects) and improve 74% and 30% of the bad clinical decisions, respectively. In conclusion, ARCliDS is the first web-based software dedicated to assist KBR-ART with multi-omics data. ARCliDS can learn from the reported clinical decisions and facilitate AI-assisted clinical decision-making for improving the outcomes in DTR.

Cardiac and Pulmonary Dosimetric Parameters in Patients With Lung Cancer Undergoing Postoperative Radiation Therapy Across a Statewide Consortium.

PURPOSE: The recently published Lung Adjuvant Radiotherapy Trial (Lung ART) reported increased rates of cardiac and pulmonary toxic effects in the postoperative radiation therapy (PORT) arm. It remains unknown whether the dosimetric parameters reported in Lung ART are representative of contemporary real-world practice, which remains relevant for patients undergoing PORT for positive surgical margins. The purpose of this study was to examine heart and lung dose exposure in patients receiving PORT for non-small cell lung cancer across a statewide consortium. METHODS AND MATERIALS: From 2012 to 2022, demographic and dosimetric data were prospectively collected for 377 patients at 27 academic and community centers within the Michigan Radiation Oncology Quality Consortium undergoing PORT for nonmetastatic non-small cell lung cancer. Dosimetric parameters for target coverage and organ-at-risk exposure were calculated using data from dose-volume histograms, and rates of 3-dimensional conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) utilization were assessed. RESULTS: Fifty-one percent of patients in this cohort had N2 disease at the time of surgery, and 25% had a positive margin. Sixty-six percent of patients were treated with IMRT compared with 32% with 3D-CRT. The planning target volume was significantly smaller in patients treated with 3D-CRT (149.2 vs 265.4 cm3; P < .0001). The median mean heart dose for all patients was 8.7 Gy (interquartile range [IQR], 3.5-15.3 Gy), the median heart volume receiving at least 5 Gy (V5) was 35.2% (IQR, 18.5%-60.2%), and the median heart volume receiving at least 35 Gy (V35) was 9% (IQR, 3.2%-17.7%). The median mean lung dose was 11.4 Gy (IQR, 8.1-14.3 Gy), and the median lung volume receiving at least 20 Gy (V20) was 19.6% (IQR, 12.7%-25.4%). These dosimetric parameters did not significantly differ by treatment modality (IMRT vs 3D-CRT) or in patients with positive versus negative surgical margins. CONCLUSIONS: With increased rates of IMRT use, cardiac and lung dosimetric parameters in this statewide consortium were slightly lower than those reported in Lung ART. These data provide useful benchmarks for treatment planning in patients undergoing PORT for positive surgical margins.

The Impact of Racial Disparities on Outcome in Patients With Stage IIIC Endometrial Carcinoma: A Pooled Data Analysis.

OBJECTIVE: To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma. MATERIALS AND METHODS: A retrospective multi-institutional study included 90 black and 568 non-black patients with stage IIIC endometrial carcinoma who received adjuvant chemotherapy and radiation treatments. Overall survival (OS) and recurrence-free survival (RFS) were calculated by the Kaplan-Meier method. Propensity score matching (PSM) was conducted. Statistical analyses were conducted using SPSS version 27. RESULTS: The Median follow-up was 45.3 months. black patients were significantly older, had more nonendometrioid histology, grade 3 tumors, and were more likely to have >1 positive paraaortic lymph nodes compared with non-black patients (all P <0.0001). The 5-year estimated OS and RFS rates were 45% and 47% compared with 77% and 68% for black patients versus non-black patients, respectively ( P <0.001). After PSM, the 2 groups were well-balanced for all prognostic covariates. The estimated hazard ratios of black versus non-black patients were 1.613 ( P value=0.045) for OS and 1.487 ( P value=0.116) for RFS. After PSM, black patients were more likely to receive the "Sandwich" approach and concurrent chemoradiotherapy compared with non-black ( P =0.013) patients. CONCLUSIONS: Black patients have higher rates of nonendometrioid histology, grade 3 tumors, and number of involved paraaortic lymph nodes, worse OS, and RFS, and were more likely to receive the "Sandwich" approach compared with non-black patients. After PSM, black patients had worse OS with a nonsignificant trend in RFS. Access to care, equitable inclusion on randomized trials, and identification of genomic differences are warranted to help mitigate disparities.

Knowledge-Based Quality Assurance and Model Maintenance in Lung Cancer Radiation Therapy in a Statewide Quality Consortium of Academic and Community Practice Centers.

PURPOSE: Locally advanced lung cancer (LALC) treatment planning is often complex due to challenging tradeoffs related to large targets near organs at risk, making the judgment of plan quality difficult. The purpose of this work was to update and maintain a multi-institutional knowledge-based planning (KBP) model developed by a statewide consortium of academic and community practices for use as a plan quality assurance (QA) tool. METHODS AND MATERIALS: Sixty LALC volumetric-modulated arc therapy plans from 2021 were collected from 24 institutions. Plan quality was scored, with high-quality clinical (HQC) plans selected to update a KBP model originally developed in 2017. The model was validated via automated KBP planning, with 20 cases excluded from the model. Differences in dose-volume histogram metrics in the clinical plans, 2017 KBP model plans, and 2022 KBP model plans were compared. Twenty recent clinical cases not meeting consortium quality metrics were replanned with the 2022 model to investigate potential plan quality improvements. RESULTS: Forty-seven plans were included in the final KBP model. Compared with the clinical plans, the 2022 model validation plans improved 60%, 65%, and 65% of the lung V20Gy, mean heart dose, and spinal canal D0.03cc metrics, respectively. The 2022 model showed improvements from the 2017 model in hot spot management at the cost of greater lung doses. Of the 20 recent cases not meeting quality metrics, 40% of the KBP model-replanned cases resulted in acceptable plans, suggesting potential clinical plan improvements. CONCLUSIONS: A multi-institutional KBP model was updated using plans from a statewide consortium. Multidisciplinary plan review resulted in HQC model training plans and model validation resulted in acceptable quality plans. The model proved to be effective at identifying potential plan quality improvements. Work is ongoing to develop web-based training plan review tools and vendor-agnostic platforms to provide the model as a QA tool statewide.

Predictors of Early Hospice or Death in Patients With Inoperable Lung Cancer Treated With Curative Intent.

INTRODUCTION: Treatment for inoperable stage II to III non-small cell lung cancer (NSCLC) involves chemo-radiotherapy (CRT). However, some patients transition to hospice or die early during their treatment course. We present a model to prognosticate early poor outcomes in NSCLC patients treated with curative-intent CRT. METHODS AND MATERIALS: Across a statewide consortium, data was prospectively collected on stage II to III NSCLC patients who received CRT between 2012 and 2019. Early poor outcomes included hospice enrollment or death within 3 months of completing CRT. Logistic regression models were used to assess predictors in prognostic models. LASSO regression with multiple imputation were used to build a final multivariate model, accounting for missing covariates. RESULTS: Of the 2267 included patients, 128 experienced early poor outcomes. Mean age was 71 years and 59% received concurrent chemotherapy. The best predictive model, created parsimoniously from statistically significant univariate predictors, included age, ECOG, planning target volume (PTV), mean heart dose, pretreatment lack of energy, and cough. The estimated area under the ROC curve for this multivariable model was 0.71, with a negative predictive value of 95%, specificity of 97%, positive predictive value of 23%, and sensitivity of 16% at a predicted risk threshold of 20%. CONCLUSIONS: This multivariate model identified a combination of clinical variables and patient reported factors that may identify individuals with inoperable NSCLC undergoing curative intent chemo-radiotherapy who are at higher risk for early poor outcomes.

Executive summary of the American Radium Society appropriate use criteria for management of uterine clear cell and serous carcinomas.

BACKGROUND: Uterine clear cell and serous carcinomas have a high propensity for locoregional and distant spread, tend to be more advanced at presentation, and carry a higher risk of recurrence and death than endometrioid cancers. Limited prospective data exist to guide evidence-based management of these rare malignancies. OBJECTIVE: The American Radium Society sought to summarize evidence-based guidelines developed by a multidisciplinary expert panel that help to guide the management of uterine clear cell and serous carcinomas. METHODS: The American Radium Society Appropriate Use Criteria presented in this manuscript were developed by a multidisciplinary expert panel using an extensive analysis of current published literature from peer-reviewed journals. A well-established methodology (modified Delphi) was used to rate the appropriate use of diagnostic and therapeutic procedures for the management of uterine clear cell and serous carcinomas. RESULTS: The primary treatment for non-metastatic uterine clear cell and serous carcinomas is complete surgical staging, with total hysterectomy, salpingo-oophorectomy, omentectomy, and lymph node staging. Even in early-stage disease, patients with uterine clear cell and serous carcinomas have a worse prognosis than those with type I endometrial cancers, warranting consideration for adjuvant therapy regardless of the stage. Given the aggressive nature of these malignancies, and until further research determines the most appropriate adjuvant therapy, it may be reasonable to counsel patients about combined-modality treatment with systemic chemotherapy and radiotherapy. CONCLUSION: Patients diagnosed with uterine clear cell and serous carcinomas should undergo complete surgical staging. Multimodal adjuvant therapies should be considered in the treatment of both early-stage and advanced-stage disease. Further prospective studies or multi-institutional retrospective studies are warranted to determine optimal sequencing of therapy and appropriate management of patients based on their unique risk factors. Long-term surveillance is indicated due to the high risk of locoregional and distant recurrence.

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.

Randomized trial of laryngeal organ preservation evaluating two cycles of induction chemotherapy with platinum, docetaxel, and a novel Bcl-xL inhibitor.

BACKGROUND: Single cycle induction chemotherapy (IC) with platinum and 5-flurouracil (PF) and treatment based on clinical response predicts organ preservation in laryngeal cancer. Other agents offer intriguing alternatives with potentially increased ease of administration, reduced risk for severe toxicities, and increased platinum sensitivity. METHODS: We report the results of a phase II bioselection trial in advanced resectable laryngeal cancer utilizing an IC regimen of two cycles of platinum plus docetaxel (TP) with a Bcl-2 inhibitor. The primary endpoint was organ preservation rate at 12 weeks post chemoradiation. RESULTS: Fifty-four patients were enrolled. Response to IC was 72%. The organ preservation rate was 59% with a laryngectomy free survival of 46%. Induction related grade ≥3 toxicities were observed in 56% of patients with two grade 5 events. CONCLUSIONS: Two cycles of TP IC plus a Bcl-2 inhibitor did not improve laryngeal preservation compared to a single cycle of PF.

Uptake of Adjuvant Durvalumab After Definitive Concurrent Chemoradiotherapy for Stage III Nonsmall-cell Lung Cancer.

OBJECTIVES: The addition of adjuvant durvalumab improves overall survival in locally advanced nonsmall-cell lung cancer (NSCLC) patients treated with definitive chemoradiation, but the real-world uptake of adjuvant durvalumab is unknown. MATERIALS AND METHODS: We identified patients with stage III NSCLC treated with definitive concurrent chemoradiation from January 2018 to October 2020 from a statewide radiation oncology quality consortium, representing a mix of community (n=22 centers) and academic (n=5) across the state of Michigan. Use of adjuvant durvalumab was ascertained at the time of routine 3-month or 6-month follow-up after completion of chemoradiation. RESULTS: Of 421 patients with stage III NSCLC who completed chemoradiation, 322 (76.5%) initiated adjuvant durvalumab. The percentage of patients initiating adjuvant durvalumab increased over time from 66% early in the study period to 92% at the end of the study period. There was substantial heterogeneity by treatment center, ranging from 53% to 90%. In multivariable logistic regression, independent predictors of durvalumab initiation included more recent month (odds ratio [OR]: 1.05 per month, 95% confidence interval [CI]: 1.02-1.08, P=0.003), lower Eastern Cooperative Oncology Group score (OR: 4.02 for ECOG 0 vs. 2+, 95% CI: 1.67-9.64, P=0.002), and a trend toward significance for female sex (OR: 1.66, 95% CI: 0.98-2.82, P=0.06). CONCLUSION: Adjuvant durvalumab for stage III NSCLC treated with definitive chemoradiation was rapidly and successfully incorporated into clinical care across a range of community and academic settings in the state of Michigan, with over 90% of potentially eligible patients starting durvalumab in more recent months.

External beam management of stage I and II uterine cancer.

This review article highlights the treatment paradigms for early-stage endometrial cancer with a focus on the role of external beam radiation therapy. We aim for this review to serve as an introductory resource for gynecological oncologists, radiation oncologists, medical oncologists, and other practitioners to understand the treatments for this disease. The main treatment of endometrial cancer is surgical resection with total hysterectomy and bilateral salpingo-oophorectomy. The benefit of adjuvant radiation after surgery is primarily to prevent local recurrence. Patients with low risk of recurrence can be observed post-operatively. Vaginal cuff brachytherapy, which has been shown to be equally effective as pelvic radiation with fewer side effects, is typically recommended for high-intermediate risk patients (with characteristics such as lymphovascular space invasion, high grade, or significant myometrial invasion). In the adjuvant setting, pelvic radiation therapy is reserved for patients who have deeply invasive stage I grade 2 or 3 disease, stage II disease, and non-endometrioid histologies. In patients who are not medically operable, definitive treatment consists of brachytherapy±pelvic external beam radiation therapy. We have highlighted the main acute and long-term side effects of pelvic radiation as well as recommendations for symptom management and summarized promising evidence showing improved rates of toxicities with more conformal radiation techniques.

Racial Differences in Treatments and Toxicity in Patients With Non-Small-Cell Lung Cancer Treated With Thoracic Radiation Therapy.

PURPOSE: Historical racial disparities in lung cancer surgery rates resulted in lower survival in Black patients. Our objective was to examine racial differences in thoracic radiation treatments and toxicities in patients with non-small-cell lung cancer. METHODS AND MATERIALS: A large institutional review board-approved statewide patient-level database of patients with stage II-III non-small-cell lung cancer who received definitive thoracic radiation from March 2012 to November 2019 was analyzed to assess associations between race and other variables. Race (White or Black) was defined by patient self-report. Provider-reported toxicity was defined by Common Terminology Criteria for Adverse Events version 4.0. Patient-reported toxicity was determined by the Functional Assessment of Cancer Therapy-Lung quality-of-life instrument. Univariable and multivariable regression models were fitted to assess relationships between race and variables of interest. Spearman rank-correlation coefficients were calculated between provider-reported toxicity and similar patient-reported outcomes. RESULTS: One thousand four hundred forty-one patients from 24 institutions with mean age 68 years (range, 38-94 years) were evaluated. Race was not significantly associated with radiation or chemotherapy approach. There was significantly increased patient-reported general pain in Black patients at the preradiation and end-of-radiation time points. Black patients were significantly less likely to have provider-reported grade 2+ pneumonitis (odds ratio 0.36, P = .03), even after controlling for known patient and treatment factors. Correlation coefficients between provider- and patient-reported toxicities were generally similar across race groups except for a stronger correlation between patient- and provider-reported esophagitis in White patients. CONCLUSION: In this large multi-institutional study, we found no evidence of racial differences in radiation treatment or chemotherapy approaches. We did, however, unexpectedly find that Black race was associated with lower odds of provider-reported grade 2+ radiation pneumonitis. The stronger correlation between patient- and provider-reported esophagitis and swallowing symptoms for White patients also suggests possible under-recognition of symptoms in Black patients. Further research is needed to study the implications for Black patients.

Effect of Education and Standardization of Cardiac Dose Constraints on Heart Dose in Patients With Lung Cancer Receiving Definitive Radiation Therapy Across a Statewide Consortium.

PURPOSE: Cardiac radiation exposure is associated with an increased rate of adverse cardiac events in patients receiving radiation therapy for locally advanced non-small cell lung carcinoma (NSCLC). Previous analysis of practice patterns within the Michigan Radiation Oncology Quality Consortium (MROQC) revealed 1 in 4 patients received a mean heart dose >20 Gy and significant heterogeneity existed among treatment centers in using cardiac dose constraints. The purpose of this study is to analyze the effect of education and initiation of standardized cardiac dose constraints on heart dose across a statewide consortium. METHODS AND MATERIALS: From 2012 to 2020, 1681 patients from 27 academic and community centers who received radiation therapy for locally advanced NSCLC were included in this analysis. Dosimetric endpoints including mean heart dose (MHD), mean lung dose, and mean esophagus dose were calculated using data from dose-volume histograms. These dose metrics were grouped by year of treatment initiation for all patients. Education regarding data for cardiac dose constraints first occurred in small lung cancer working group meetings and then consortium-wide starting in 2016. In 2018, a quality metric requiring mean heart dose <20 Gy while maintaining dose coverage (D95) to the target was implemented. Dose metrics were compared before (2012-2016) versus after (2017-2020) initiation of interventions targeting cardiac constraints. Statistical analysis was performed using the Wilcoxon rank sum test. RESULTS: After education and implementation of the heart dose performance metric, mean MHD declined from an average of 12.2 Gy preintervention to 10.4 Gy postintervention (P < .0001), and the percentage of patients receiving MHD >20 Gy was reduced from 21.1% to 10.3% (P < .0001). Mean lung dose and mean esophagus dose did not increase, and target coverage remained unchanged. CONCLUSIONS: Education and implementation of a standardized cardiac dose quality measure across a statewide consortium was associated with a reduction of mean heart dose in patients receiving radiation therapy for locally advanced NSCLC. These dose reductions were achieved without sacrificing target coverage, increasing mean lung dose, or increasing mean esophagus dose. Analysis of the clinical ramifications of the reduction in cardiac doses is ongoing.

The Michigan Radiation Oncology Quality Consortium: A Novel Initiative to Improve the Quality of Radiation Oncology Care.

PURPOSE: Numerous quality measures have been proposed in radiation oncology, and initiatives to improve access to high-complexity care, quality, and equity are needed. We describe the design and evaluate effect of a voluntary statewide collaboration for quality improvement in radiation oncology initiated a decade ago. METHODS AND MATERIALS: We evaluate compliance before and since implementation of annual metrics for quality improvement, using an observational data set with information from more than 20,000 patients treated in the 28 participating radiation oncology practices. At thrice-yearly meetings, experts have spoken regarding trends within the field and inspired discussions regarding potential targets for quality improvement. Blinded data on practices at various sites have been provided. Following Standards for Quality Improvement Reporting Excellence guidelines, we describe the approach and measures the program has implemented. To evaluate effect, we compare compliance at baseline and now with active measures using mixed effects regression models with site-level random effects. RESULTS: Compliance has increased, including use of guideline-concordant hypofractionated radiation therapy, doses to targets or normal tissues, motion management, and consistency in delineating and naming contoured structures (a precondition for quality evaluation). For example, use of guideline-concordant hypofractionation for breast cancer increased from 47% to 97%, adherence to target coverage goals and heart dose limits for dose increased from 46% to 86%, motion assessment in patients with lung cancer increased from 52% to 94%, and use of standard nomenclature increased from 53% to 82% for lung patients and from 80% to 94% for breast patients (all P < .001). CONCLUSIONS: Although observational analysis cannot fully exclude secular trends, contextual data revealing slow uptake of best practices elsewhere in the United States and qualitative feedback from participants suggests that this initiative has improved the consistency, efficiency, and quality of radiation oncology care in its member practices and may be a model for oncology quality improvement more generally.