Locally Advanced Non-small Cell Lung Cancer Research Articles

Pd-L1 Evaluation in Serum and Tumoral Circulating Extracellular Vescicles in Locally Advanced Nsclc After Concomitant Chemoradiation: A Surrogate of Tumor Microenviroment Change from Cold Tumor to Hot Tumor

Background: Pacific trial has revolutioned the outcome and the approach in locally advanced (LA) unresectable Non Small Cell Lung Cancer (NSCLC). In 2018 the European Medicine Agency (EMA) approved the use of Durvalumab only in adults whose tumours on biopsy specimen expresses PD-L1 on ≥ 1% of tumour cells despite this cut-off was not provided by the original randomised study. In vitro and in vivo studies have recorded the up regulation of PD-L1 expression in the tumor microenviroment (TME) after chemoradiation regrdless the expression on biopsy. Liquid biopsy could be helpful in detection of circulating PD-L1 in this set. Aim of this observational multicentre prospective study is to assess on liquid biopsy the up-regulation of PD-L1on serum and tumoral circulating extracellular vescicles (cEVS) from patients with LA NSCLC not expressing the PD-L1 on biopsy and treated with concurrent chemoradiation (CCRT). Methods: Locally advanced NSCLC PD-L1 < 1 % biopsy proven will be enrolled in this study. A blood sample will be taken the day before (T0), 14 days after CCRT (T1) and 1 months later (T2). Patients will be treated with CCRT with platinum-based doublet and 60-66 Gy total radiation dose. Soluble PD-L1 will be analysed by ELISA. PD-L1on cEVs will be isolated from serum and phenotyped by nanoparticle tracking analysis, microscopy and flow cytometry. The statistical significant improvement in PD-L1 expression in serum and cEVs at T0 -T1-T2 will be assessed by t-test for p= 0.05; for multiple test p-value will be corrected with FDR.

Unrevealing the therapeutic benefits of radiotherapy and consolidation immunotherapy using ctDNA-defined tumor clonality in unresectable locally advanced non-small cell lung cancer

Progression occurs in approximately two-thirds of patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving chemoradiation and consolidation immunotherapy. Molecular indicators for outcome prediction are under development. A novel metric, the ratio of mean to max variant allele frequency (mmVAF), was derived from 431 pre-treatment tissue biopsies from The Cancer Genome Atlas and evaluated in serial circulating tumor DNA (ctDNA) from 70 LA-NSCLC patients receiving definitive radiotherapy/chemoradiotherapy (RT/CRT) with/without immunotherapy. High mmVAFs in pre-treatment tissue biopsies, indicating clonal predominant tumors (P < 0.01), were associated with inferior overall survival [OS, hazard ratio (HR): 1.48, 95 % confidence interval (CI): 1.11–1.98]. Similar associations of mmVAF with clonality (P < 0.01) and OS (HR: 2.24, 95 % CI: 0.71–7.08) were observed in pre-treatment ctDNA. At 1-month post-RT, ctDNA mmVAF-high patients receiving consolidation immunotherapy exhibited improved progression-free survival (PFS) compared to those who did not (HR: 0.14, 95 % CI: 0.03–0.67). From the baseline to week 4 of RT and/or 1-month post-RT, survival benefits from consolidation immunotherapy were exclusively observed in ctDNA mmVAF-increased patients (PFS, HR: 0.39, 95 % CI: 0.14–1.15), especially in terms of distant metastasis (HR: 0.11, 95 % CI: 0.01–0.95). In summary, our longitudinal data demonstrated the applicability of ctDNA-defined clonality for prognostic stratification and immunotherapy benefit prediction in LA-NSCLC.

A real-world study of pneumonitis in non-small cell lung cancer patients receiving durvalumab following concurrent chemoradiation.

Locally advanced non-small cell lung cancer (LA-NSCLC) treated with the programmed death-ligand 1 inhibitor durvalumab has been associated with significant rates of pneumonitis, which has led to higher rates of discontinuation of therapy in real-world populations. Thus far there has been no consensus in the literature on the impact of pneumonitis on survival. This is a retrospective cohort study of veterans receiving durvalumab between 12/5/2017 and 4/15/2020. Participants were identified using VINCI data services. Patients were followed through 9/14/2021. Development of clinical pneumonitis was assessed through review of documentation and graded using CTCAE 4.0 criteria. Univariate logistic regression analysis evaluated for associations between body mass index (BMI), age, race, co-morbidity index, chemotherapy regimen, chronic obstructive pulmonary disease (COPD) severity, and development of clinical pneumonitis. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier methods. Cox proportional hazards models were utilized to evaluate the association between risk of death at 1 and 2 years and candidate predictor variables. A total of 284 patients were included in this study. Sixty-one patients developed clinically significant pneumonitis, 7 patients developed grade 5 pneumonitis (death from pneumonitis). The median OS in patients that developed pneumonitis was 27.8 vs. 36.9 months in patients that did not develop pneumonitis (P=0.22). BMI was found to be a clinical predictor of pneumonitis (P=0.04). COPD severity, race, age at durvalumab start date, chemotherapy regimen, and Romano comorbidity index were not significant predictors of pneumonitis. Cox proportional hazards analysis failed to demonstrate an association between the development of pneumonitis and risk of death in this population. The incidence of clinically significant pneumonitis is higher than noted in the PACIFIC trial in this cohort, however this high rate of pneumonitis does not have an impact on OS or PFS. Obesity was found to be a significant predictor of pneumonitis in this patient population.

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

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. 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. 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. Pembrolizumab and risk-adapted radiotherapy, without chemotherapy, are a promising treatment approach for patients with LA-NSCLC with a PD-L1 TPS of ≥50%.

Cardiac radiation dose is associated with inferior survival but not cardiac events in patients with locally advanced non-small cell lung cancer in the era of immune checkpoint inhibitor consolidation

PurposeWe assessed the association of cardiac radiation dose with cardiac events and survival post-chemoradiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) after adoption of modern radiation therapy (RT) techniques, stricter cardiac dose constraints, and immune checkpoint inhibitor (ICI) consolidation. Methods and MaterialsThis single-institution, multi-site retrospective study included 335 patients with LA-NSCLC treated with definitive, concurrent CRT between October 2017 and December 2021. All patients were evaluated for ICI consolidation. Planning dose constraints included heart mean dose < 20 Gy (<10 Gy if feasible) and heart volume receiving ≥ 50 Gy (V50Gy) < 25 %. Twenty-one dosimetric parameters for three different cardiac structures (heart, left anterior descending coronary artery [LAD], and left ventricle) were extracted. Primary endpoint was any major adverse cardiac event (MACE) post-CRT, defined as acute coronary syndrome, heart failure, coronary revascularization, or cardiac-related death. Secondary endpoints were: grade ≥ 3 cardiac events (per CTCAE v5.0), overall survival (OS), lung cancer-specific mortality (LCSM), and other-cause mortality (OCM). ResultsMedian age was 68 years, 139 (41 %) had baseline coronary heart disease, and 225 (67 %) received ICI consolidation. Proton therapy was used in 117 (35 %) and intensity-modulated RT in 199 (59 %). Median LAD V15Gy was 1.4 % (IQR 0–22) and median heart mean dose was 8.7 Gy (IQR 4.6–14.4). Median follow-up was 3.3 years. Two-year cumulative incidence of MACE was 9.5 % for all patients and 14.3 % for those with baseline coronary heart disease. Two-year cumulative incidence of grade ≥ 3 cardiac events was 20.4 %. No cardiac dosimetric parameter was associated with an increased risk of MACE or grade ≥ 3 cardiac events. On multivariable analysis, cardiac dose (LAD V15Gy and heart mean dose) was associated with worse OS, driven by an association with LCSM but not OCM. ConclusionsWith modern RT techniques, stricter cardiac dose constraints, and ICI consolidation, cardiac dose was associated with LCSM but not OCM or cardiac events in patients with LA-NSCLC.

Dosiomics and radiomics improve the prediction of post-radiotherapy neutrophil-lymphocyte ratio in locally advanced non-small cell lung cancer.

To develop and validate a dosiomics and radiomics model based on three-dimensional (3D) dose distribution map and computed tomography (CT) images for the prediction of the post-radiotherapy (post-RT) neutrophil-to-lymphocyte ratio (NLR). This work retrospectively collected 242 locally advanced non-small cell lung cancer (LA-NSCLC) patients who were treated with definitive radiotherapy from 2012 to 2016. The NLR collected one month after the completion of RT was defined as the primary outcome. Clinical characteristics and two-dimensional dosimetric factors calculated from the dose-volume histogram (DVH) were included. A total of 4165 dosiomics and radiomics features were extracted from the 3D dose maps and CT images within five different anatomical regions of interest (ROIs), respectively. Then, a three-step feature selection method was proposed to progressively filter features from coarse to fine: (i) model-based ranking according to individual feature's performance, (ii) maximum relevance and minimum redundancy (mRMR), (iii) select from model based on feature importance calculated with an ensemble of several decision trees. The selected feature subsets were utilized to develop the prediction model with GBDT. All patients were divided into a development set and an independent testing set (2:1). Five-fold cross-validation was applied to the development set for both feature selection and model training procedure. Finally, a fusion model combining dosiomics, radiomics and clinical features was constructed to further improve the prediction results. The area under receiver operating characteristic curve (ROC) were used to evaluate the modelperformance. The clinical-based and DVH-based models showed limited predictive power with AUCs of 0.632 (95% CI: 0.490-0.773) and 0.634 (95% CI: 0.497-0.771), respectively, in the independent testing set. The 9 feature-based dosiomics and 3 feature-based radiomics models showed improved AUCs of 0.738 (95% CI: 0.628-0.849) and 0.689 (95% CI: 0.566-0.813), respectively. The dosiomics & radiomics & clinical fusion model further improved the model's generalization ability with an AUC of 0.765 (95% CI: 0.656-0.874). Dosiomics and radiomics can benefit the prediction of post-RT NLR of LA-NSCLC patients. This can provide a reference for evaluating radiotherapy-relatedinflammation.

EP08.02-16 Higher Radiation Dose to Immune Cells is a Negative Prognostic Factor in Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC)

EP08.02-16 Higher Radiation Dose to Immune Cells is a Negative Prognostic Factor in Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC)

P1.28-06 Treatment Strategies for Locally-advanced NSCLC with Invasive T4 Tumors: A SEER Analysis in the Era of Precision Medicine

P1.28-06 Treatment Strategies for Locally-advanced NSCLC with Invasive T4 Tumors: A SEER Analysis in the Era of Precision Medicine

Effects of EGFR driver mutations on pathologic regression in resectable locally advanced non-small cell lung cancer treated with neoadjuvant chemoradiation and completion surgery.

We hypothesized that driver mutations in epidermal growth factor receptor (EGFR) are associated with decreased pathologic response to neoadjuvant chemoradiation (NA-ChRT) in locally advanced non-small cell lung cancer (LA-NSCLC). Patients with Stage IIB-IIIA NSCLC treated with NA-ChRT, completion surgery, and underwent molecular profile testing were identified in a lung cancer database. Pathologic response was quantified using: (i) major pathologic response (MPR), (ii) complete pathologic response (pCR), and (iii) mean residual viable tumor cells (MRTC). Two groups were formed based on the presence or absence of driver mutations. Clinical and pathological correlations between the groups were studied. Forty-seven patients underwent tumor molecular profile testing, NA-ChRT, and completion surgery. Compared to the no-driver mutation group, the driver mutation group had lower MPR (23% vs 71%, p = 0.003), pCR (0% vs 26%, p = 0.02), and higher MRTC (43.4% vs 15.8%, p = 0.009). Univariate analysis showed an increased MPR rate for smokers, squamous cell histology, ChRT-surgery interval >65 days, and no-driver mutations. Multivariate analysis showed that only no-driver mutations (OR 0.39, p = 0.02) remained significant for MPR. PD-L1 status did not affect MPR. At 2 years, the driver mutation group had lower rates of local control (Hazard ration [HR] 0.67, p = 0.17) and disease-free survival (HR 0.5, p = 0.001). Overall survival was similar for both groups (HR = 1.04, p = 0.86). Following 60 Gray NA-ChRT, tumors with a driver mutation had lower MPR and pCR rates than tumors without a driver mutation. PD-L1 was not associated with tumor regression. Patients with resectable LA-NSCLC and an EGFR driver mutation treated with neoadjuvant-ChRT and completion surgery have reduced pathologic regression, lower local control rates, and shorter disease-free survival than patients without a driver mutation. Evaluation of molecular testing should be introduced in LA-NSCLC intended for prognostication and treatment decisions.

Dosimetric comparison of five different radiotherapy treatment planning approaches for locally advanced non-small cell lung cancer with sequential plan changes.

The purpose of this study was to compare the dosimetric characteristics of five different treatment planning techniques for locally advanced non-small cell lung cancer (LA-NSCLC) with sequential plan changes. A total of 13 stage III NSCLC patients were enrolled in this study. These patients had both computed tomography (CT) images for initial and boost treatment plans. The latter CT images were taken if tumor shrinkage was observed after 2 weeks of treatment. The prescription dose was 60 Gy/30 Fr (initial: 40 Gy/20 Fr, and boost: 20 Gy/10 Fr). Five techniques (forward-planed 3-dimensional conformal radiotherapy [F-3DCRT] on both CT images, inverse-planned 3DCRT [I-3DCRT] on both CT images, volumetric modulated arc therapy [VMAT] on both CT images, F-3DCRT on initial CT plus VMAT on boost CT [bVMAT], and hybrid of fixed intensity-modulated radiotherapy [IMRT] beams and VMAT beams on both CT images [hybrid]) were recalculated for all patients. The accumulated doses between initial and boost plans were compared among all treatment techniques. The conformity indexes (CI) of the planning target volume (PTV) of the five planning techniques were 0.34 ± 0.10, 0.57 ± 0.10, 0.86 ± 0.08, 0.61 ± 0.12, and 0.83 ± 0.11 for F-3DCRT, I-3DCRT, VMAT, bVMAT, and hybrid, respectively. In the same manner, lung volumes receiving >20 Gy (V20Gy ) were 21.05 ± 10.56%, 20.86 ± 6.45, 19.50 ± 7.38%, 19.98 ± 10.04%, and 17.74 ± 7.86%. There was significant improvement about CI and V20Gy for hybrid compared with F-3DCRT (p < 0.05). The IMRT/VMAT hybrid technique for LA-NSCLC patients improved target CI and reduced lung doses. Furthermore, if IMRT was not available initially, starting with 3DCRT might be beneficial as demonstrated in the bVMAT procedure of this study.

Interpretable Machine Learning for Predicting Symptomatic Pneumonitis in Locally Advanced Non-Small Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy and Immune Checkpoint Inhibitor Consolidation.

The rate of grade 2 and higher pneumonitis has increased with the use of immune checkpoint inhibitors (ICI) following chemoradiotherapy (CRT) for lung cancer, which may alter previously established dose-volume constraints (DVC). In this study, we used an interpretable machine learning model with clinical and dosimetric features to predict grade 2+ pneumonitis and determine DVC associated with pneumonitis for locally advanced non-small cell lung cancer (LA-NSCLC) radiotherapy (RT). Between October 2017 and December 2021, 223 consecutively treated patients with LANSCLC treated with CRT and ICI were retrospectively reviewed. The dataset was split into training and test sets (n = 144/79). Clinical features included age, sex, smoking status, pack-years, BMI, ECOG PS, COPD, tumor location, delivered dose, RT technique, chemotherapy agent and volume of GTVp/GTVn. A total of 228 dosimetric features from the heart, contralateral/ipsilateral lung and lungs-IGTV were extracted, including the minimum/mean dose to the hottest x% volume (Dx%[Gy]/MOHx%[Gy]; x was 5-95 in 5% increments) and minimum/mean/maximum dose and percent volume receiving at least xGy (VxGy [%]; x was 5-60 in 5Gy increments), as well as the overlapping volume of each structure with PTV and the distance from each structure to GTVp/GTVn. Feature selection was performed using Boruta, followed by collinearity removal based on the variance inflation factor. The explainable boosting machine (EBM) was trained on the selected features. The performance of EBM on the test set was evaluated using the area under the receiver operating characteristic curve (AUC) and compared with that of blackbox (BB) models, including extreme gradient boosting (XGB), random forest (RF), and supporting vector machine (SVM). The global explanation of each feature's contribution to the predictions provided by the EBM was used to determine DVC. Shapley additive explanations (SHAP) were used to explain BB predictions. Selected features, ranked in order of EBM's overall feature importance, were V25Gy [%] and MOH65%[Gy] in the ipsilateral lung, the maximum dose in the heart, MOH30%[Gy] in the contralateral lung, and BMI. No dosimetric features in the lungs-IGTV were selected. The SHAP values of three BB models showed similar trends to the feature importance of the EBM. The global explanations of the EBM suggested that to mitigate the risk of pneumonitis, the ipsilateral lung should have V25Gy [%] < 36.8% and MOH65%[Gy] < 39.5Gy, and the heart should have D0.03cc [Gy] < 66.0Gy. Furthermore, an increased risk of pneumonitis was indicated with an increase in BMI, and, surprisingly, a decrease in MOH30%[Gy] in the contralateral lung. The EBM showed the best performance for predicting grade 2+ pneumonitis (AUC = 0.739), followed by RF, SVM, and XGB (AUC = 0.735, 0.733, and 0.717). EBM has the potential to predict grade 2+ pneumonitis in LA-NSCLC patients treated with CRT and ICI, while providing guidance on DVC.

Dosimetric Analysis of CBCT-Based Weekly Online Adaptive Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer

Anatomic and geometric changes are common during a radiotherapy course amongst patients receiving conventional fractionated radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). These changes may cause significant deviation from initial reference plan resulting in over-treatment of normal tissue or under-coverage of the target. Cone-beam computed tomography (CBCT)-based online adaptive radiotherapy (ART) platforms allow for response to these changes and is being increasingly used in the clinic though less so for intrathoracic disease. We hypothesized weekly CBCT-ART would improve target coverage and decrease dose to organs at risk (OAR) in patients with LA-NSCLC. Data was collected from a prospective registry of 23 LA-NSCLC patients treated to 60 Gy in 30 fractions with CBCT-ART between June 2021 and December 2022. For weekly ART (Wk-ART), online plan adaptation started on week two. The adapted plan was then used to treat patients with image guidance until the next ART. For comparison, doses were recalculated with the initial reference plan on the SCT with updated contours to derive non-adapted (non-ART) dosimetry for each week. The final dosimetric parameters were obtained by averaging weekly coverage (ITV, PTV) and critical OAR (Lung, esophagus, heart, spinal cord) doses for non-ART and weekly ART treatments respectively for each patient. Paired student t-test was performed to compare the dosimetric parameters between non-ART and Wk-ART. We observed an average 29% ± 19% (median: 26%) reduction in ITV volume through the radiotherapy course, with 48% (11/23) of patients showing >30% reduction. Most significant volume reductions (16%) were observed between the third and fourth adaptation. Weekly ART showed significant (p<1×10-3) improvements in ITV and PTV coverage, and showed improved clinically relevant lung, esophageal, cardiac, and lung dosimetry (Table 1), especially in the later stages of treatment when the tumor showed significant shrinkage. The average time from contour review to quality assurance completed is 8.5±1.2 min. CBCT-ART provides robust ART plan quality and efficient workflow. There are significant improvements in target coverage and OAR sparing in LA-NSCLC treated with weekly CBCT-ART and these are driven by the significant volume reduction of the ITV throughout treatment course.

Improved Prediction of Chemoradiation and Immune Checkpoint Blockade Efficacy with Dynamic bTMB Combined with ctDNA in Unresectable Locally Advanced NSCLC

Consolidation durvalumab after definitive chemoradiation therapy (CRT) has become the new standard of care for patients with unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). However, only a fraction of patients can benefit from it, and current decision-making procedures have limited accuracy. Blood-based tumor mutational burden (bTMB) is a promising biomarker, but whether bTMB alone or combined with circulating tumor DNA (ctDNA) can predict the efficacy of definitive CRT and immune checkpoint inhibitors (ICIs) in patients with LA-NSCLC remains unclear. This cohort study enrolled patients diagnosed with unresectable LA-NSCLC from 2018 to 2022. Patients were assigned to the cohort A receiving definitive CRT alone (intensity modulated radiation therapy or volumetric modulated arc therapy with the prescribed dose of 60 Gy, concurrently or sequentially with two or more cycles of platinum-based doublet chemotherapy), or cohort B undergoing definitive CRT and immunotherapy. Peripheral blood specimens were collected before and after CRT and subjected to next-generation sequencing panel to analyze ctDNA and bTMB. The dynamic change in bTMB (∆bTMB) was calculated as the bTMB level after CRT minus the baseline bTMB level. Potential correlations were identified by Spearman's correlation tests and expressed as R coefficients. Time-dependent receiver operating characteristic curves and areas under the curve (AUCs) were employed to evaluate the predictive power of different models on survival. A total of 73 LA-NSCLC patients were included, with 70 (95.9%) at stage III and 3 at stage II (4.1%). Thirty-six patients (49.3%) assigned to the cohort A were treated with CRT alone and 37 (50.7%) in the cohort B receiving CRT and ICIs. Patients with CRT + ICIs in the cohort B showed significantly improved overall survival (OS; P < 0.01) and progression-free survival (PFS; P = 0.02) than those with CRT alone. Baseline bTMB at cutoff values of 4 to 22 did not predict outcomes (all P > 0.10), while patients with increased bTMB (∆bTMB > 0) after CRT had significantly worse OS and PFS (both P < 0.01) than those with decreased or stable bTMB (∆bTMB ≤ 0). ∆bTMB was independent of the ctDNA level after CRT (P = 0.76, R = -0.04). Patients were further divided into 3 groups based on ∆bTMB and post-CRT ctDNA (∆bTMB > 0/detectable ctDNA vs. ∆bTMB ≤ 0/detectable ctDNA vs. ∆bTMB ≤ 0/undetectable ctDNA), and significant survival differences were observed in the pairwise comparisons of 3 groups (all P < 0.05). The model of ∆bTMB combined with post-CRT ctDNA status exhibited the optimal predictive power on both OS (AUC = 0.80) and PFS (AUC = 0.75) and outperformed each factor, which had been respectively validated in the cohort A and B as well. Dynamic bTMB (∆bTMB) combined with post-CRT ctDNA status is a novel and effective biomarker model of predicting survival outcomes in LA-NSCLC patients treated with CRT ± ICIs, and outperforms each individual feature.

Planning Considerations for the Primary Lung Tumor Stereotactic Body Radiation Therapy Followed by Concurrent Mediastinal Radiotherapy for Locally-Advanced Non-Small Cell Lung Cancer

Phase III prospective randomized trial of primary lung tumor stereotactic body radiation therapy followed by concurrent mediastinal chemoradiation for locally-advanced non-small cell lung cancer (NRG LU-008), designed to lower the rates of radiation pneumonitis and improve the progression-free survival, is expected to become active nationally in July 2023. Due to the specific nature of the cases selected for this trial, a new approach to treatment planning had to be developed to satisfy the conditions of the trial. Levice Cancer Institute (Atrium Health, North Carolina) ran the initial Phase II trial and investigated several approaches, providing recommendations for the future dosimetry planning approach. A total of 60 patients were selected for the initial trial and treated with a combination of SBRT treatment to the primary tumor (50-54 Gy in 3-5 fractions) and conventional IMRT treatment to 60 Gy to the involved lymph nodes for patients with stage 3 or unresectable stage II NSCLC, combined with chemotherapy. Depending on the location of the primary tumor, all cases could be subdivided into no overlap between the SBRT and IMRT targets, adjacent targets, and overlapping targets. All SBRT plans were done with a 6X-FFF beam, advanced dose calculation algorithm, and 0.1 cm grid size. IMRT targets were primarily treated with VMAT plans, though a minority of cases were planned with the DMLC technique, with a 6X beam, advanced dose calculation algorithm, and 0.25 cm grid size. Various approaches to the planning included target cropping, avoidance via adjusting optimization objectives and utilizing the base dose of the SBRT plan to optimize the dose for the IMRT nodal plan. Various geometries utilized in the plan included a variation in the number of arcs, covered arc angles, and the number of beams. A significant reduction in the side effects was achieved throughout the trial, with only three patients experiencing grade 3 or higher pneumonitis, 3 patients experiencing grade 3 or higher cardiotoxicity, and 1 patient experiencing grade 3 esophagitis. For targets with no significant overlap between the primary tumor and nodal target, standard planning techniques proved to be sufficient. For the overlapping targets, the planning approach of utilizing 2 arcs, >180-degree coverage, for the SBRT plan, and using ¼ of the base SBRT dose to plan the IMRT nodal plan provided the best target coverage while achieving sufficient OAR sparing. Planning the joint SBRT-IMRT plan in the cases of a significant target overlap requires a careful approach, but is feasible with the proposed guideline and should be achievable for any center electing to participate in the NRG LU-008 trial.

Left Anterior Descending Coronary Artery-Optimized Knowledge-Based Radiotherapy Planning in Patients with Locally Advanced Non-Small Cell Lung Cancer

The left anterior descending (LAD) coronary artery volume receiving 15 Gy (V15 Gy) has been associated with major adverse cardiac events and mortality in patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with radiotherapy (RT). However, coronary arteries are not routinely contoured as standard-of-care and there is limited data describing coronary-sparing planning techniques. Our objective was to evaluate whether LAD-sparing could be improved compared to real-world plans using a commercial knowledge-based planning (KBP) software without clinically unacceptable tradeoffs to other critical organs at risk (OAR). Retrospective replanning analysis was conducted on 31 RT plans developed for patients with LA-NSCLC. Each case was manually replanned with volumetric modulated arc radiotherapy (VMAT) optimized for LAD V15 Gy sparing with a prescription dose of 60 Gy. The resulting plans were used to create an LAD-optimized KBP model. The model included both KBP-generated objectives and additional point objectives to meet LAD (V15 Gy < 10%), lung (V5 Gy < 60%, V20 < 30%, mean < 17 Gy), heart (mean < 20 Gy), spinal cord (D0.03cc < 45 Gy), esophagus (V60 Gy < 17%, mean < 34 Gy), and planning target volume (PTV; D95% = 100%). The LAD-optimized model was deployed to replan 33 additional VMAT plans for LA-NSCLC with prescription dose 60 Gy, delivered between 2018 and 2022. Dose constraints or objectives were only unmet with KBP when not met in the original plan. Descriptive statistics were used to compare dosimetric parameters between original and LAD-optimized KBP plans. For the 33 plans identified for LAD-optimized KBP replanning, the original plans had a mean LAD V15 Gy of 17.9% (standard error [SE], 3.9%), while the LAD-optimized KBP plans had a significantly lower mean LAD V15 Gy of 5.9% (SE, 1.9%; p = 0.031). There was no significant difference in mean heart dose between the original and LAD-optimized KBP plans (8.4 Gy [SE 6.6 Gy] vs. 7.3 Gy [SE 5.8 Gy]; p = 0.48). Of these 33 KBP plans, 42% (n = 14) had mean reductions in LAD V15 Gy from 40.5% (SE 4.3%) to 10.5% (SE 3.5%; p = 0.0002), with 9/14 now able to meet < 10%, without affecting other critical OAR objectives (p > 0.5 for lungs, esophagus, spinal cord). 45% (n = 15) originally had an LAD V15 Gy < 1%, which were unchanged using KBP (p > 0.3). Four plans (12%) had higher LAD V15 Gy in the KBP vs. original plan (2/4 still meeting < 10%), due to the model prioritizing other OARs to a greater degree. Improvements in LAD-sparing was achievable in more than 40% of plans without apparent clinically significant tradeoffs in other critical OARs and without corresponding change in MHD. This result underscores the importance of standard implementation of LAD contouring and dose constraints, particularly given the discordance between whole heart and LAD dose exposure.

Determining the Ideal Time for Implementing Adaptive Radiation Therapy in the Treatment of Non-Small Cell Lung Cancer through the Analysis of Cone-Beam Computed Tomography Images

Radiotherapy (RT) has an important role in the management of locally advanced non-small cell lung cancer (LA-NSCLC) but is also challenging due to treatment uncertainties. Adaptive radiation therapy (ART) is a possible solution that is widely used but varied with limited consensus. Cone beam computed tomography (CBCT) is frequently used during the treatment process to confirm the accuracy of the treatment location and the changes in the tumor during treatment can be observed also from CBCT images. We collected the characteristics of patients and analysis the changes of tumor volumes from weekly CBCT images and try to predict the optimal timing for ART in modern RT. LA-NSCLC patients treated with definitive chemo-radiotherapy by volumetric modulated arc therapy (VMAT) or intensity-modulated radiation therapy (IMRT) were enrolled in this study. CBCT images during treatment in the second, fourth, and sixth weeks were collected and the region of interest (ROI) was contoured by the same experienced radiation physician. The image segmentation and processing were done using a programming environment. The change in tumor volume during mid-treatment and at the end of treatment were calculated and the regression analysis was used to evaluate the correlation of tumor volume changes during treatment course. Since 2018 to 2021, total 20 LA-NSCLC patients treated with definitive chemo-radiotherapy (CCRT) were enrolled in this study. There are 17 males and 3 females, respectively with an average age of 67 years. All patients received chemotherapy and a radiation therapy prescriptive dose of 60 Gy in 30 fractions to a planning target volume (PTV). Totally 1,760 image slices were analyzed. The average tumor volume before treatment in patients who underwent ART or without ART was 273.84 cm3 and 132.84 cm3 respectively. The median tumor volume changes were 15.04%, 35.68%, and 55.37% at 2,4, and 6 weeks, respectively. Patients who achieved a tumor volume reduction of more than 40% in the fourth week had a better final tumor reduction outcome than those who did not meet this volume reduction goal. However, no significant difference was found in the change in tumor volume from the fourth to the sixth week. This study suggests that monitoring tumor volume changes during the first half of treatment using CBCT images may be an effective way to predict the final tumor reduction outcome in patients with LA-NSCLC undergoing adaptive radiation therapy (ART) in a modern CCRT treatment setting. Specifically, the study found that a tumor volume reduction of more than 40% in the fourth week may predict a better final tumor reduction outcome. Based on this finding, the study suggests that redesigning the treatment plan based on the change in tumor volume during the first half of treatment may improve the final tumor reduction effect in patients with NSCLC undergoing ART.

Interpretable Machine Learning Models for Severe Esophagitis Prediction in LA-NSCLC Patients Treated with Chemoradiation Therapy

Radiation esophagitis is a common adverse event that may occur during chemoradiotherapy (CRT) that can adversely affect survival. This study aimed to develop interpretable machine learning (ML) models to predict grade 3 and higher radiation esophagitis in patients receiving definitive CRT therapy for locally advanced non-small cell lung cancer (LA-NSCLC). A total of 335 patients with LA-NSCLC who received definitive concurrent CRT at a single institution from 2017 to 2021 were retrospectively identified. Patients with esophagitis were identified and graded according to CTCAE v5.0. For each patient, 31 clinical features and 1093 dose-volume histogram (DVH) parameters from 19 structures were collected. The data was then randomly split into training (n = 233) and testing (n = 102) datasets. Feature selection was performed on the training dataset using the minimum redundancy maximum relevance algorithm to find a set of relevant features while controlling for the redundancy within the selected features, which were then followed by the Boruta algorithm to remove unimportant features and make the ML model more accurate. Synthetic minority oversampling technique was used to handle class-imbalanced datasets by generating synthetic samples for the minority class. Four variants of the Generalized Additive Model (GAM), including Explainable Boosting Machine (EBM), neural GAM (NODE-GAM), eXtreme Gradient Boosting (XGB)-GAM, and Spline, were built with selected features. The models' performance in predicting esophagitis was evaluated using the area under the receiver operating characteristic curve (AUC) in the test dataset. Shape plots were used to interpret the models' output and explain the selected features' contribution to the prediction. NODE-GAM yielded the highest performance (F1 score = 0.57, accuracy = 0.8, and AUC = 0.837), followed by EBM (F1 score = 0.43, accuracy = 0.8, and AUC = 0.7), Spline (F1 score = 0.42, accuracy = 0.74, and AUC = 0.737), and XGB-GAM (F1 score = 0.42, accuracy = 0.76, and AUC = 0.71). Selected features included D95%[Gy], D90%[Gy], D65%[Gy] and V40Gy [%] for the esophagus, V10Gy [%] for the pulmonary artery, and the distance from GTVn to the ascending aorta. The analysis of the selected features indicated that an increased radiation dose delivered to the esophagus and a shorter distance between the ascending aorta and GTVn were associated with a higher risk of developing esophagitis. Our study demonstrates the feasibility of developing interpretable ML models to predict esophagitis in patients with LA-NSCLC patients treated with CRT. NODE-GAM provided the best accuracy while providing insights into the driving dosimetric factors that could be used to guide optimal RT planning.

Residual ctDNA Detection Predicts Benefit From Definitive Chemoradiotherapy and Immune Checkpoint Inhibitors in Locally Advanced NSCLC

Therapeutic efficacy differs across unresectable locally advanced non-small cell lung cancer (LA-NSCLC) patients receiving definitive chemoradiotherapy (CRT), and the dynamic change in circulating tumor DNA (ctDNA) is closely associated with clinical outcomes. However, evidence for the predictive effect of ctDNA in LA-NSCLC patients with CRT and immunotherapy, the current standard of care, remains limited. It is unclear whether residual ctDNA after definitive CRT can guide clinical decisions on further use of immune checkpoint inhibitors (ICIs) consolidation. We prospectively included 73 patients with unresectable stage II-III NSCLC. All patients received definitive concurrent or sequential CRT, with the prescribed dose of 60 Gy and ≥2 cycles of platinum-based chemotherapy. Thirty-seven (50.7%) patients further underwent ICIs therapy (18 durvalumab, 9 pembrolizumab, 10 others). Peripheral blood samples were collected from all patients before any treatment (baseline), 1 month after CRT (post-CRT), and at the time of progression. All plasma specimens were analyzed with next-generation sequencing panel of 474 cancer-related genes. Plasma samples with ≥1 variant detected were defined as detectable ctDNA. The primary endpoint was progression-free survival (PFS). After the median follow-up of 25.4 months, median overall survival (OS) was not reached (NR), and median PFS was 16.7 months (95% CI, 12.4-26.6) for all patients. Compared with baseline, ctDNA abundance significantly decreased after definitive CRT (P<0.001) but relatively increased at progression (P = 0.051). Patients treated with CRT plus ICIs exhibited significantly longer OS (median, NR vs 22.1 months [95% CI, 16.7-NR]; P = 0.002) and PFS (median, 24.8 months [95% CI, 16.1-NR] vs 11.4 months [95% CI, 6.5-NR]; P = 0.016) than those with CRT alone. Post-CRT residual ctDNA was associated with significantly poorer OS (median, 18.3 months [95% CI, 14.8-NR] vs NR; P = 0.002) and PFS (median, 6.5 months [95% CI, 5.6-NR] vs 24.8 months [95% CI, 18.8-NR]; P<0.001), whereas baseline ctDNA predicted neither OS (P = 0.310) nor PFS (P = 0.570). For patients with post-CRT detectable ctDNA, further ICIs therapy brought significant benefit in both OS (median, NR vs 14.8 months [95% CI, 12.0-NR]; P = 0.012) and PFS (median, 16.1 months [95% CI, 5.8-NR] vs 6.2 months [95% CI, 4.2-NR]; P = 0.043). However, in patients with post-CRT ctDNA clearance, there was no significant difference in OS (P = 0.080) or PFS (P = 0.151) between patient with and without ICIs, which suggested less clinical benefit. Post-CRT residual ctDNA predicted worse survival in LA-NSCLC, but indicated more benefit from further ICIs therapy and thereby could facilitate personalization of consolidation immunotherapy. Further prospected studies with large sample size are warranted to validated these findings.

Adaptive Radiotherapy Guided by PET/CT in Patients with Locally Advanced Non–Small Cell Lung Cancer: A Phase II Randomized Study

The aim of this study was to determine whether adaptive radiotherapy guided by functional imaging with flourine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) can improve local tumor control in patients with locally advanced non-small cell lung cancer (LA-NSCLC). This was a phase II randomized study comparing the efficacy and safety between PET-guided adaptive radiotherapy and conventional radiotherapy. The primary end point was 2-year local-regional tumor control (LRTC) rate. Secondary end points included local-regional progression-free survival (LR-PFS), progression-free survival (PFS), overall survival (OS), and radiation-related toxicities. Between November 2012 and June 2017, 72 patients were 1:1 randomized to adaptive and conventional arms. The 2- and 5-year LRTC rates were 63.2% and 58.0% versus 43.0% and 37.6% (P = 0.035) in the adaptive and conventional arms, respectively. The median LR-PFS (14.3 versus 12.0 months; P = 0.010) and PFS (12.8 versus 8.9 months; P = 0.034) were significantly longer in the adaptive arm than in the conventional arm. The median OS was 36.3 months in the adaptive arm and 28.8 months in the conventional arm (P = 0.266). The esophageal volume of receiving ≥60 Gy (V60) in the adaptive arm was lower than that in the conventional arm (P = 0.011), while the V30 for the heart in the adaptive arm was lower than that in the conventional arm (P = 0.077). Other radiological metrological parameters of tumor, organs at risk, and the incidence of ≥grade 2 radiation-related toxicities were not significantly different between the 2 arms. Compared with conventional radiotherapy, PET-guided adaptive radiotherapy significantly improved the 2-year LRTC rate, LR-PFS, and PFS without increased risks of radiation-related toxicities in patients with LA-NSCLC.

Association of Cardiac Dose with Cardiac Events and Survival for Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC) Treated with Concurrent Chemoradiotherapy (cCRT) in the Era of Immune Checkpoint Inhibitor (ICI) Consolidation

To assess the association of cardiac dose with post-cCRT cardiac events and survival among patients (pts) with LA-NSCLC after adoption of ICI consolidation, modern radiotherapy (RT) techniques, and data-driven cardiac constraints. This single-institution, multi-site retrospective study included 335 pts with LA-NSCLC treated with definitive cCRT (60-70 Gy) from October 2017 to December 2021. Pts were evaluated for ICI consolidation. Cardiac dose constraints included heart volume receiving ≥50 Gy (V50) <25% and mean heart dose (MHD) <20 Gy. Heart, left anterior descending artery (LAD), and left ventricle were autocontoured, manually reviewed, and edited. 21 dosimetric parameters (mean dose, max dose, and min dose to the hottest x% volume [Dx%(Gy); x from 5-95 in 5% intervals]) for each were extracted, as well as LAD V15. Baseline cardiovascular disease (bCVD) was defined as heart failure (HF), coronary artery disease, peripheral vascular disease, or cerebrovascular disease. Primary endpoint was post-cCRT major adverse cardiac events (MACE), defined as acute coronary syndrome, HF hospitalization/urgent visit, coronary revascularization, or cardiac death. Secondary endpoints were grade ≥3 cardiac events (CTCAE v5.0), overall survival (OS), cancer specific mortality (CSM), and other cause mortality (OCM). Competing risk regression was used for MACE and grade ≥3 cardiac events, and Cox regression for OS, CSM, and OCM. Median age was 68 years, 139 (41%) had bCVD, and 225 (67%) received consolidation ICI. Proton therapy was used in 117 (35%), intensity-modulated RT in 199 (59%), and 3D conformal RT in 19 (6%). Median MHD was 8.7 Gy (IQR 4.6-14.4) and median LAD V15 1.4% (IQR 0-22). Median follow-up was 39.5 months. 35 MACE events occurred; 1- and 2-year cumulative incidence (CI) were 4.2% and 9.5%. No cardiac dosimetric parameter associated with MACE after adjusting for bCVD and age (e.g., MHD sHR 0.98/Gy, 95% CI 0.93-1.03, p = 0.43) or within the following 3 subgroups: no bCVD, photon therapy, and ICI consolidation. 87 grade ≥3 cardiac events occurred; 1- and 2- year CI were 12.6% and 20.4%. Heart dose was not associated with grade ≥3 cardiac events after adjusting for bCVD, ECOG, and BMI (e.g., MHD sHR 1.00/Gy, 95% CI 0.97-1.03, p = 0.85) or within the 3 aforesaid subgroups. 183 OS events occurred, including 125 CSM and 58 OCM events. Multiple cardiac dosimetric parameters associated with worse OS on multivariable analysis (e.g., LAD V15 HR 1.01/%, 95% CI 1.00-1.02, p = 0.003), driven by associations with CSM (LAD V15 HR 1.02/%, p<0.001) but not OCM (LAD V15 HR 1.00/%, p = 0.73). Median OS was worse for LAD V15 ≥10% (22.2 vs 35.1 months, p = 0.004). Among pts with LA-NSCLC treated with cCRT after adoption of ICI consolidation, modern RT techniques, and cardiac constraints, post-cCRT cardiac events were common but showed no association with cardiac dose. Cardiac dose associated with OS, driven by an association with CSM and not OCM, which may not reflect cardiac toxicity.