Locally Advanced Non-small Cell Lung Cancer Patients Research Articles

Predictors of Early Durvalumab Discontinuation After Chemoradiotherapy for Non-Small Cell Lung Cancer

Based on the PACIFIC trial, adjuvant durvalumab is now recommended after concurrent chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC), with an intended course duration of one year. In PACIFIC, approximately 50% of subjects did not complete the planned durvalumab course. Here, we explore causes and predictors of early durvalumab discontinuation to test the hypothesis that extent of normal tissue irradiation may be associated with durvalumab treatment duration.We reviewed patients treated for LA-NSCLC with definitive CRT at our institution who began adjuvant durvalumab between 2017 and 2020. Duration of durvalumab receipt and causes for early discontinuation (defined as a course duration shorter than 11.5 months) were tabulated. Cox proportional hazards models were utilized to test clinical factors (age, performance status, tumor histology, presence of known driver mutations, PD-L1 expression), measures of disease burden (stage, metabolic tumor volume [MTV] on pre-treatment FDG-PET), and treatment characteristics (mean radiotherapy doses received by the esophagus, heart, and lungs) as predictors of early durvalumab discontinuation. These variables were also tested as predictors of progression-free survival (PFS) duration after durvalumab initiation. The Kaplan-Meier method was utilized to estimate rates of durvalumab completion and PFS for the entire cohort and for patient subgroups.Fifty-three patients met inclusion criteria. Nineteen patients completed a one-year course of durvalumab, twenty-eight patients discontinued durvalumab early, and six are still receiving durvalumab. The actuarial rate of completing a one-year durvalumab course was 36%. Reasons for early durvalumab discontinuation were disease progression (n = 10), lung toxicity (n = 8), other toxicity (n = 6), and death unrelated to cancer progression or treatment toxicity (n = 4). Univariate and multivariate Cox models identified mean heart dose as the only statistically significant predictor of early immunotherapy discontinuation (HR 1.11 per Gy, 95% CI 1.01 to 1.21, P = 0.025). The rate of durvalumab completion for patients with mean heart dose below the cohort median (9.7 Gy) was 55%, compared to only 20% for patients with higher mean heart doses (log rank P = 0.020). Mean heart dose was also the only statistically significant predictor of PFS after immunotherapy initiation in a multivariable Cox model (HR 1.19 per Gy, 95% CI 1.07 to 1.32, P = 0.001). Median PFS duration for patients with mean heart dose below the cohort median was 32 months, compared to only 8 months for patients with higher mean heart doses (log rank P < 0.001).For LA-NSCLC patients treated with chemoradiotherapy followed by immunotherapy, extent of cardiac irradiation may be a risk factor for early immunotherapy discontinuation and disease recurrence or death. A multi-institutional validation study is underway.

Prognostic impact of pneumonitis after durvalumab therapy in patients with locally advanced non-small cell lung cancer

SummaryBackground. Prognostic data on Japanese patients receiving durvalumab after chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC) are insufficient. Whether pneumonitis has prognostic implications in patients with LA-NSCLC who have received durvalumab also remains unclear. Methods. We retrospectively assessed the data of 82 consecutive patients who had received durvalumab after CRT at our institution between May 2018 and August 2020. A multi-state model was used to establish the associations between co-variables and progression-free survival (PFS). Results. The median observation period for all the censored cases was 14.5 months (5.7–28.9 months), the median PFS was 22.7 months, and the 12-month PFS rate was 62.3% (95% CI: 50.2%-72.3%). The median percentage of the lung volume receiving a radiation dose in excess of 20 Gray (V20) was 22% (4%-35%). Thirteen patients (16%) had Grade 1 pneumonitis before receiving durvalumab, and 62 patients developed pneumonitis after durvalumab (Grades 1, 2, and 3 in 25 [30%], 32 [39%], and 4 [5%], respectively). Twenty-four patients (29%) completed the 1-year durvalumab treatment period, 16 patients (20%) were continuing to receive treatment, and 42 (51%) had discontinued treatment. In a multi-state analysis, patients with pneumonitis before durvalumab therapy had a poorer PFS than those without pneumonitis (HR: 4.29, p = 0.002). The development of Grade 2 or higher pneumonitis after durvalumab was not a significant prognostic factor for PFS (HR: 0.71, p = 0.852). Conclusion. Grade 2 or higher pneumonitis after durvalumab was not a prognostic factor of PFS in LA-NSCLC patients received durvalumab.

Optimal surgical timing and radiotherapy dose for trimodality therapy in locally advanced non‐small cell lung cancer

Purpose/ObjectivesData are conflicting on the effects of time interval from neoadjuvant chemoradiation (NCRT) to surgery for locally advanced non‐small‐cell lung cancer (LA‐NSCLC). This study investigated the impact of surgical timing after NCRT and radiation dose on postoperative mortality and overall survival (OS).Materials and MethodsUsing the National Cancer Database, we identified 3489 LA‐NSCLC patients treated with NCRT and surgery. Multivariate Cox proportional hazards analysis (MVA) was used to examine the effects of surgery >7 weeks from NCRT completion on OS. Propensity score (PS)‐matched survival analysis for surgery ≤7 and >7 weeks was performed. Postoperative mortality was assessed.ResultsMedian OS for surgery ≤7 weeks and >7 weeks after NCRT were 56.9 versus 45.6 months (hazard ratio, HR 1.18 [1.07–1.30]; p < 0.001). Surgery >7 weeks correlated with decreased OS on MVA (HR 1.15 [1.04–1.27]; p = 0.009) and PS matching (HR 1.16 [1.049–1.29]; p = 0.004). Time as a continuous variable correlated with OS on MVA (HR 1.003 [1.001–1.006]; p = 0.0056) and PS matching (HR 1.004 [1.001–1.006]; p = 0.004). Among 2902 lobectomy patients, the mortality rate for surgery ≤66 days was 5.2% versus 8.1% for >66 days (MVA HR 1.59 [1.02–2.49]; p = 0.04). Higher neoadjuvant radiotherapy dose correlated with surgery >7 weeks and lobectomy >66 days on MVA.ConclusionsIncreased interval >7 weeks from NCRT to surgery for LA‐NSCLC is correlated with worse OS and lobectomy ≤66 days correlated with improved OS. Surgery ≤7weeks may improve tumor control, whereas higher mortality for surgery >66 days may relate to late NCRT manifestations. Neoadjuvant doses of 44–50.4 Gy may minimize risks of radiation‐induced lung injury and surgical complications and facilitate surgery within the optimal 7‐week interval.

Feasibility of intensity modulated radiotherapy with involved field radiotherapy for Japanese patients with locally advanced non-small cell lung cancer

The feasibility of intensity modulated radiotherapy (IMRT) with involved field radiotherapy (IFRT) for Japanese patients with locally advanced non-small cell lung cancer (LA-NSCLC) remains unclear. Here we reviewed our initial experience of IMRT with IFRT for Japanese patients with LA-NSCLC to evaluate the feasibility of the treatment. Twenty LA-NSCLC patients who were treated with IMRT with IFRT during November 2019 to October 2020 were retrospectively analyzed. All patients received 60 Gy in 30 fractions of IMRT and were administered concurrent platinum-based chemotherapy. The median patient age was 71 years old and the group included 15 men and 5 women. The patient group included 2 patients with stage IIB, 11 patients with stage IIIA, 5 patients with stage IIIB, and 2 patients with stage IIIC disease. Histological diagnosis was squamous cell carcinoma in 14 patients, adenocarcinoma in 5 patients, and non-small cell lung cancer in 1 patient. The median follow-up period was 8 months. The incidence of grade 3 or greater pneumonitis was 5%, and grade 3 or greater esophagitis was not observed. None of the patients developed regional lymph node, with only recurrence reported so far. These findings indicate that IMRT with IFRT for Japanese patients with LA-NSCLC is feasible in terms of acute toxicity. Further study with a larger number of patients and longer follow-up to clarify the effect of treatment on patient prognosis is required.

Cardiac-sparing radiotherapy for locally advanced non-small cell lung cancer

BackgroundWe have carried out a study to determine the scope for reducing heart doses in photon beam radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC).Materials and methodsBaseline VMAT plans were created for 20 LA-NSCLC patients following the IDEAL-CRT isotoxic protocol, and were re-optimized after adding an objective limiting heart mean dose (MDHeart). Reductions in MDHeart achievable without breaching limits on target coverage or normal tissue irradiation were determined. The process was repeated for objectives limiting the heart volume receiving ≥ 50 Gy (VHeart-50-Gy) and left atrial wall volume receiving ≥ 63 Gy (VLAwall-63-Gy).ResultsFollowing re-optimization, mean MDHeart, VHeart-50-Gy and VLAwall-63-Gy values fell by 4.8 Gy and 2.2% and 2.4% absolute respectively. On the basis of associations observed between survival and cardiac irradiation in an independent dataset, the purposefully-achieved reduction in MDHeart is expected to lead to the largest improvement in overall survival. It also led to useful knock-on reductions in many measures of cardiac irradiation including VHeart-50-Gy and VLAwall-63-Gy, providing some insurance against survival being more strongly related to these measures than to MDHeart. The predicted hazard ratio (HR) for death corresponding to the purposefully-achieved mean reduction in MDHeart was 0.806, according to which a randomized trial would require 1140 patients to test improved survival with 0.05 significance and 80% power. In patients whose baseline MDHeart values exceeded the median value in a published series, the average MDHeart reduction was particularly large, 8.8 Gy. The corresponding predicted HR is potentially testable in trials recruiting 359 patients enriched for greater MDHeart values.ConclusionsCardiac irradiation in RT of LA-NSCLC can be reduced substantially. Of the measures studied, reduction of MDHeart led to the greatest predicted increase in survival, and to useful knock-on reductions in other cardiac irradiation measures reported to be associated with survival. Potential improvements in survival can be trialled more efficiently in a population enriched for patients with greater baseline MDHeart levels, for whom larger reductions in heart doses can be achieved.

The Prognostic Value of Programmed Death-ligand 1 (PD-L1) in Patients who Received Neoadjuvant Chemoradiation Therapy Followed by Surgery for Locally Advanced Non-small Cell Lung Cancer.

We analyzed the prognostic efficacy of programmed death-ligand 1 (PD-L1) in locally advanced non-small cell lung cancer (LA-NSCLC) patients. During 2005-2016, 211 patients underwent neoadjuvant concurrent chemoradiation therapy (CCRT) followed by surgical resection for LA-NSCLC at Asan Medical Center. PD-L1 expression and CD8+ tumor-infiltrating lymphocytes (TIL) were measured pre- and post-neoadjuvant CCRT and analyzed using immuno - histochemical staining. In total, 39 patients were enrolled. Overall survival (OS) and disease-free survival (DFS) were significantly longer in patients with increased PD-L1 expression and increased CD8+ TIL density post-neoadjuvant CCRT. Univariate Cox regression analysis confirmed that increased levels of PD-L1 and increased CD8+ TIL density were prognostic factors for OS and DFS. Multivariate Cox regression analysis confirmed that increased levels of PD-L1 was a prognostic factor for OS and increased CD8+ TIL density for DFS. Relative changes in PD-L1 expression post-neoadjuvant CCRT can be utilized to predict the prognosis of LA-NSCLC patients.

Treatment strategies for locally advanced non-small cell lung cancer in elderly patients: Translating scientific evidence into clinical practice.

Treatment of locally advanced NSCLC (LA-NSCLC) is focused on multimodal strategy, including chemotherapy and radiotherapy (in combination or as alternative treatments), followed by surgery in selected cases. Recently, durvalumab consolidation after definitive chemo-radiation has shown a meaningful overall survival benefit. However, it is important to note that elderly patients represent a high proportion of NSCLC population and frailty and comorbidities can significantly limit treatment options. Indeed, elderly patients are under-represented in clinical trials and data to drive treatment selection in this category of patients are scanty. Available data, main issues and controversies on multimodal treatment in elderly LA-NSCLC patients will be reviewed in this paper.

Efficacy and Safety of Thoracic Radiotherapy in Locally Advanced Non-Small Cell Lung Cancer Patients With Pre-Existing Interstitial Lung Diseases: A Single Center Experience of 85 Cases

Background: Whether thoracic radiotherapy (TRT) could be applied to interstitial lung diseases and lung cancer(ILD-LC) patients safely remains unclear. This retrospective study aims to evaluate the efficacy and safety of definitive TRT in locally advanced non-small cell lung cancer (LA-NSCLC) patients with pre-existing ILD, and to analyze the associated risk factors for radiation induced lung toxicities (RILTs) in the clinical setting. Methods: Patients with histologically confirmed LA-NSCLC and pre-existing ILD treated definitive TRT between 2010 and 2019 were retrospectively reviewed. Patient, tumor, and treatment characteristics were evaluated to determine the risk factors for RILTs. Pre-radiation CT of all patients were reviewed by two radiologists and one pulmonologist and are scored according to Muller’s thin-section CT scoring system for IPF: 0-no discrete honeycombing, with interlobular septal thickening; 1-honeycombing involving 0-5% of the lobe; 2-honeycombing 6-24%; 3-honeycombing 25-49%; 4-honeycombing 50-74%;5-honeycombing >75%. Univariate and multivariate analyses with logistic regression models and cox proportional hazards approach were performed to identify the risk factor(s) of RILTs and overall survival(OS) respectively. Findings: Among 1261 LA-NSCLC patients, 85 were found with pre-existing ILD and enrolled in the analysis. 36·5% of them were scored more than 1 point on CT. 20% patients developed G3+ RILTs within 1 year after the last irradiation, with remarkably 11·8% dying from lung toxicities. And the incidence of symptomatic (G3+) RILTs abruptly dropped to 11·1%(6/54),3·8%(1/26),and 0%(0/19)for patients with CT score≤1, V20 1 and V20≥20% were independently associated with higher risk of G3+ RILTs. The median OS and PFS were 14·0 months and 7·4 month respectively. In the univariate analysis for OS, clinical stage and G3+RILT were evaluated as risk factors while patients in low-risk group, defined as honeycombing score<1 and V20<20%, had shown a protective tendency(HR=0·52,95%CI:0·27-1·04,P=0·063). In multivariate analysis, G3+RILT was the only independent risk factor associated with OS(HR=2·40,95%CI:1·32-4·36,P=0·004). However, the median OS of low-risk group was quite longer than the whole group (26·5 months versus 14·5 months), indicating that patients at low risk might benefit from thoracic radiation therapy. Interpretation: Honeycombing score >1 and V20≥20% were significantly associated with high incidence of severe lung toxicities, leading to poor survival. However, patients at low risk might benefit from TRT with a considerable overall survival. Funding: None to declare Declaration of Interest: None to declare. Ethical Approval: The study was approved by the institutional review board of National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College (IRB No·NCC2612).

Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Locally Advanced Non-small-cell Lung Cancer Treated with Trimodality Therapy.

Current evidence suggests that the neutrophil-to-lymphocyte ratio (NLR) is a prognostic factor in several types of cancer. In this study, we aimed to evaluate the prognostic impact of clinicopathological factors, including postoperative NLR, in patients with locally advanced non-small-cell lung cancer (LA-NSCLC) who underwent surgery after chemoradiotherapy (CRT) with or without postoperative adjuvant chemotherapy. The medical records of LA-NSCLC patients treated with trimodality therapy at our institution between June 1999 and May 2019 were reviewed. The association between several clinicopathological factors and overall survival (OS) was analyzed. A total of 168 patients were included in this study. Regarding the prognosis, the 5-year OS rate was 68.1%, and the 2-year recurrence-free survival rate was 66.1% in the entire population. In multivariate analysis, we identified that high postoperative NLR, not pretreatment or preoperative NLR, was one of the independent factors for unfavorable OS (NLR high vs NLR low; hazard ratio = 2.45, 95% confidence interval: 1.53-3.94, p < 0.001). In addition, among patients with high postoperative NLR, patients who received postoperative adjuvant chemotherapy showed significantly better 5-year OS compared with those who did not (p = 0.016). On the other hand, postoperative adjuvant chemotherapy had no impact on the prognosis in patients with low NLR (p = 0.19). Our results suggest that high postoperative NLR was not only an independent unfavorable prognostic factor in patients with LA-NSCLC who were treated with trimodality therapy, but also a promising indicator for postoperative treatment in this population.

Impact of Cardiac Dose on Overall Survival in Lung Stereotactic Body Radiotherapy (SBRT) Compared to Conventionally Fractionated Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC).

Purpose:To examine possible association between heart irradiation and Overall Survival (OS) in lung SBRT patients and to compare observed associations with cardiac toxicity models previously derived in LA-NSCLC patient studies.Materials and Methods:197 Patients treated with lung SBRT at Mayo Clinic Arizona were selected for this IRB-approved study. Multivariate Cox model with Akaike Information Criterion (AIC) was used to select patient specific covariates associated with OS. Heart dosimetry was represented by VD indices, which is a percentage of volume exposed to dose D or greater. Multivariate Cox models with patient specific covariates and single VD index per model was used to find a range of doses which were predictive for OS. A digital subdivision of the heart was further used to determine the spatial distribution of doses which were predictive for OS. A coarse subdivision divided heart into 4 segments, while the fine subdivision divided heart into 64 segments. Knowledge constrained Fused Lasso operator was used to derive a more complete model which correlated heart dosimetry with OS. Results of statistical analysis were compared to predictions of a model of cardiac toxicity in LA-NSCLC patients.Results:Higher age (p < 0.001), higher stage (p < 0.001) and squamous cell histology (p = 0.001) were associated with reduced OS. Whole heart DVH analysis did not reveal associations between heart irradiation and reduced OS. Coarse subdivision of the heart into four segments revealed that the irradiation of two inferior segments of the heart with low doses was associated with reduced OS, V2Gy in the right-inferior segment (HR = 1.012/1%, p = 0.02), and V1Gy in the left-inferior segment (HR = 1.01/1%, p = 0.04). Maximum dose in the right-inferior segment of the heart was also associated with reduced OS (HR = 1.02/Gy, p = 0.02). Fine subdivision of the heart into 64 segments revealed that approximately 25% of heart volume in the inferior part of the heart (15/64 segments), when irradiated to doses in the 1 Gy - 5 Gy range, were predictive for reduced OS (HR = 1.01/1%, p = 0.01). A previously derived model of cardiac toxicity in LA-NSCLC patients did not predict a reduction of OS due to heart irradiation in lung SBRT patients, because of relatively low doses to the heart in most lung SBRT patients.Conclusions:Doses lower than 5 Gy in the inferior segments of the heart may be associated with reduced overall survival in patients treated for lung lesions with SBRT. Stage and histology of the disease, as well as patients’ age, were also associated with overall survival. Comparisons of cardiac toxicity patterns in LA-NSCLC patients and lung SBRT patients suggest different etiology of cardiac toxicity in the two groups.

Effect of durvalumab on local control after concurrent chemoradiotherapy for locally advanced non-small cell lung cancer in comparison with chemoradiotherapy alone.

BackgroundDurvalumab after concurrent chemoradiotherapy (CCRT) for locally advanced non‐small cell lung cancer (LA‐NSCLC) has been found to significantly improve overall survival (OS). However, the effect of durvalumab on local control remains unclear. Here, we evaluated the effect of the durvalumab on local control in comparison with the clinical result of patients treated with CCRT alone.MethodsA total of 120 LA‐NSCLC patients including 76 patients with CCRT alone and 44 patients with CCRT followed by durvalumab were analyzed. Baseline patient characteristics of CCRT alone cohort and durvalumab cohort were compared with student's t test or Mann–Whitney U test for continuous variables and with chi‐squared test for categorical variables. Local control (LC), progression free survival (PFS) and OS rates were estimated using the Kaplan–Meier method and compared with the log‐rank test.ResultsThere were 19 patients with stage II disease and 101 patients with stage III disease. Age, sex, histopathological type, T classification, N classification, clinical stage, tumor volume and dose fractionation schedule were not significantly different between the CCRT alone and durvalumab cohorts. The one‐year LC rate was significantly higher in the durvalumab cohort (86%) compared with the CCRT alone cohort (62%) (P = 0.005), whereas no significant difference was observed in either PFS (P = 0.864) or OS (P = 0.443) between the CCRT and durvalumab cohorts.ConclusionsThe one‐year LC rate was significantly higher in the durvalumab cohort compared with the CCRT alone cohort. Although the follow‐up period was too short to draw definitive conclusions, the study revealed that durvalumab might have a significant effect on LC.Key pointsSignificant findings of the studyEffect of durvalumab on local control after chemoradiotherapy for locally advanced non‐small cell lung cancer is unclearWhat this study addsThe one‐year local control rate of chemoradiotherapy followed by durvalumab was significantly higher compared with chemoradiotherapy alone.

Implications of pneumonitis after chemoradiation and durvalumab for locally advanced non-small cell lung cancer.

BackgroundConsolidation durvalumab improved overall survival (OS) in locally advanced non-small cell lung cancer (LA-NSCLC) treated with chemoradiotherapy (CRT) in the PACIFIC trial; however, pneumonitis was increased with durvalumab. We sought to examine real-world outcomes with the PACIFIC paradigm, especially factors associated with pneumonitis, using a multi-institutional review.MethodsPatients with LA-NSCLC treated with CRT followed by durvalumab from January 2017–February 2019 were identified at 2 institutions. We characterized demographics, tumor factors, radiotherapy, and duration of durvalumab. We examined pneumonitis outcomes including re-challenge success, with secondary endpoints of progression-free survival (PFS) and OS.ResultsThirty-four patients were included with median follow-up of 12 months (range, 3 to 20 months); 94% had stage III disease. The cumulative grade >2 pneumonitis rate was 26.5% with 2 patients developing grade 3 pneumonitis and no grade 4/5 events. Median time to pneumonitis after RT was 2.4 months (range, 0 to 4.9 months). Pneumonitis management included median prednisone dose of 60 mg for median taper of 6 weeks with durvalumab held for median of 4.5 weeks (range, 2 to 8 weeks); 70% of pneumonitis patients received durvalumab re-challenge, with pneumonitis recurring in 14% of patients. 3-month and 6-month pneumonitis-free-survival were 76.9% and 73.6%, respectively; 9- and 12-month OS were 96% (75.1–99.8%), 86.6% (63.5–95.5%), respectively; 9- and 12-month PFS were 68% (47.5–82.5%), 48.7% (25.3–68.3%). Pneumonitis development did not significantly impact PFS or OS (P>0.05).ConclusionsAmong LA-NSCLC patients treated with CRT followed by consolidation durvalumab, more than 25% developed symptomatic pneumonitis. In this small case series, pneumonitis did not appear to negatively impact survival, and durvalumab re-challenge appeared feasible after pneumonitis treatment with steroids.

Integrative Nomogram of CT-based Radiomics and Clinical Features for Predicting Oligometastases at Recurrent after Definitive Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer

To develop and validate a radiomics-based nomogram for predicting oligometastases at recurrent after definitive chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC). The study consisted of 118 LA-NSCLC patients treated with definitive CRT between January 1, 2014 and December 31, 2017. 96 and 22 patients were allocated to the primary cohort and the validation cohort, respectively. Baseline clinical features data were collected from the medical records. Computed tomography (CT) radiomics features were quantitatively extracted by the 3D slicer software and “pyradiomics” package. Least absolute shrinkage and selection operator (LASSO) Cox regression model was applied for date dimension reduction, feature selection and developing the radiomics signature. The discrimination of the radiomics signature was calculated by the area under the curve (AUC). Univariate and multivariate Cox regression analysis was utilized to evaluate independent predictors of oligometastases at recurrent. Finally, the model was developed and presented as the nomogram that incorporated both radiomics signature and independent clinical risk factors. Nomogram performance was assessed via the Harrell concordance index (C-index), calibration and clinical usefulness. With a median follow-up of 21.5 months (range: 6.5 to 58.8 months), oligometastases at recurrent was detected by follow-up imaging in 26 patients (21 patients were assigned to the primary cohort). For those who experienced oligometastases, the first metastases were in lung (38.5%), followed by brain, bone, and adrenal (19.2% each). The median time to oligometastases was 11.3 months (range: 2.0 to 41.3 months). The radiomics signature, which was based on selected 9 selected radiomics features, showed good discrimination in the primary cohort (AUC = 0.865) and the validation cohort (AUC = 0.659). Multivariate Cox proportional hazards testing revealed that histology subtype was an independent clinical risk factor (p-value < 0.05). After uni- and multivariate analysis, a nomogram was built based on histology subtype and radiomics signature. The model showed good discrimination in both the primary cohort and the validation cohort, with a C-index of 0.869 (95% CI, 0.776 to 0.962) and 0.797 (95% CI, 0.664 to 0.930), respectively. The calibration curve showed agreement between predicted and actual values for the probability of oligometastases of recurrent at 1, 2, or 3 years. Decision curve analysis demonstrated that the radiomics nomogram was clinically useful. The signature based on CT radiomics features can be used as an imaging marker for predicting oligometastases at recurrent after definitive CRT for LA-NSCLC. Nomograms combining radiomics signature and the independent clinical risk factor may constitute a usefully clinical tool to guide subsequent personalized treatments.

Predicting Clinical Outcomes of Patients with Stage III Non-Small-Cell Lung Cancer Treated with Concurrent Chemoradiation with and without PD-1/PD-L1 Inhibitors Using Cone Beam Computed Tomography

Currently, there are no standardized biomarkers that predict response to consolidative therapy with Programmed cell Death receptor -1(PD-1) or Programmed cell Death receptor -Ligand 1 (PD-L1) inhibitors used after concurrent chemoradiation therapy (CCRT) for patients with stage III unresectable locally advanced non-small-cell lung cancer (LA-NSCLC).We hypothesized that tumor volume reduction during CCRT may be predictive of response to consolidative PD-1/PDL-1 inhibitors. We retrospectively reviewed the medical records of patients treated with definitive CCRT, both with and without consolidative PD-1/PD-L1 inhibitors. CCRT consisted of 60Gy in 30 fractions with platinum-based chemotherapy doublet. Primary gross tumor volumes (GTV) of all patients were contoured on set-up cone-beam computed tomography (CBCT) scans acquired on day 1, 15, 29, and 43 of CCRT, as well as on follow-up CT at 1 month. GTV reduction was quantified as the percent difference in volume on each CBCT and follow-up CT, relative to CBCT Day 1. Mid-treatment shrinkage (MTS) and End of Treatment Tumor Shrinkage (ETTS) were defined at day 29 and 43, respectively. Progression-free survival (PFS) was calculated using Kaplan-Meier curves and the log-rank test was used for statistical evaluation. 93 LA-NSCLC patients completed definitive CCRT, of which 24 received consolidative PD-1/PD-L1 inhibitors. For the entire cohort, the median age was 66.5 years (range: 51-84 years) and 54% were males. Adenocarcinoma represented 51%, squamous cell carcinoma 40% and undifferentiated histology 9%. 32% had stage IIIA and 68% had stage IIIB (AJCC 7th edition). Median follow-up was 43 months (range: 36-53 months). Patients who received PD-1/PD-L1 inhibitors achieved significantly longer PFS than CCRT-only group (22.5 vs. 9.5 months, p = 0.014). For the 93 patients, median ETTS was 40.6% (range: 39.3-50.3). Median ETTS was comparable between PD-1/PD-L1 inhibitors and CCRT-only group (41.2% vs. 40%). Patients who received PD-1/PD-L1 inhibitors and achieved ETTS > 35% demonstrated a trend toward improved PFS compared to those who had ETTS ≤ 35% (median PFS was not reached vs. 11.03 months, p = 0.059). Similarly, patients who received PD-1/PD-L1 inhibitors and achieved MTS of > 35% were associated with numerically better PFS compared to patients who did not achieve the same cut off (median PFS was not reached vs. 13.15 months, p = 0.059). Patients who achieved a significant reduction in their tumor volume during CCRT are more likely to benefit from consolidative PD-1/PD-L1 inhibitors. Measuring tumor volume dynamics using the readily available CBCT images acquired during CCRT may serve as a potential biomarker to predict response to PD-1/PD-L1 inhibition therapy.

Early Prediction of Acute Esophagitis Using Accumulated Dose and Local Volume Change of Esophagus

Acute esophagitis (AE) is a common dose-limiting toxicity with significant impact on quality of life in patients with locally advanced non-small cell lung cancer (LA-NSCLC). In this study, we performed early AE prediction using weekly accumulated esophagus dose and its associated local volumetric change. The study included 60 LA-NSCLC patients consecutively treated (2017 to 2019) via IMRT to 50-72Gy in 2 Gy-fractions with concurrent chemotherapy and had weekly cone beam CTs (CBCTs). In addition, nine of the patients also had weekly respiratory triggered T2-weighted MRIs (3T) during the RT course. A total of 35 patients (58%) developed grade 2 AE (AE2; requiring medication cf. CTCAE) at a median of 4 weeks post-RT start. The weekly esophagus dose was accumulated on the contours delineated by a radiation oncologist on CBCTs and MRIs. Week to week esophagus changes were calculated using determinant of the gradient of the deformation vector field as Jacobian map obtained via a regularized diffeomorphic registration. The Jacobian at each voxel measures the percentage of local esophagus volume expansion/shrinkage. Parameters quantifying esophagus volume changes were the net volume change, maximum percentage of expansion (ExMax%) and volumes with ≥5%,10% and 15% local expansions (VE5%, VE10%, VE15%) at the current week with respect to the previous week. For the 51 patients with CBCTs only, a multivariate logistic regression model was built with 5-fold cross-validation to perform early prediction of AE2 using a combination of the accumulated Mean Esophagus Dose at week two (MEDW2) and VE10% from week one to two (w1→2). The model was externally validated on the nine patients who had MRI; and compared to a previously published model using only planned mean dose (MEDPlan). Performance was assessed using AUC and the Hosmer-Lemeshow test (PHL). Univariate analysis showed VE10% (p = 0.003), VE5% (p = 0.006) and ExMax% (p = 0.02) significantly predicted AE2 (p<0.05 after Bonferroni correction). A model combining MEDW2 and w1→2 VE10% from CBCT data had the highest accuracy (AUC = 0.74) with good calibration (PHL = 0.27) and was considerably better than the MEDPlan model (AUC = 0.64; PHL = 0.09). When externally validated on the MRI data, the combined model showed high accuracy (AUC = 0.79). The population average w1→2 VE10% and MEDW2 for AE2 vs. non-AE2 patients were 2.5cm3 vs. 0.6cm3 and 5.4Gy vs. 4Gy, respectively. According to the model, w1→2 VE10% >2.8cm3 and MEDW2 >8.1Gy correspond to a 50% complication probability of AE2. A cross-validated model with a combination of local volume change and accumulated dose of esophagus from the first two weeks of RT significantly improved the prediction of AE compared to previously published model using only the planned dose. This model could inform plan adaptation early during the treatment to lower the risk of esophagitis.

Chronic Lung Injury After Trimodality Therapy for Locally Advanced Non-Small Cell Lung Cancer

Trimodality therapy is a treatment option for patients with locally advanced non-small cell lung cancer (LA-NSCLC). Thoracic radiation has both early (radiation pneumonitis) and late (chronic lung injury [CLI]) adverse effects on the lung. While CLI is expected to result in various problems in long-term survivors, these manifestations have not been precisely investigated. We enrolled 112 LA-NSCLC patients who had received induction chemoradiotherapy followed by surgery, and then undergone follow-up computed tomography (CT) every 6 months for greater than 1 year. All chest CT images were reviewed to evaluate any injury of the pulmonary parenchyma. CLI at 1 year after surgery and its progression were observed in 94 (84%) and 38 (34%) patients, respectively. Progressive lung fibrosis as the first manifestation of CLI progression was most frequent after right middle and lower lobectomy. Cavity formation was the subsequent manifestation after progressive lung fibrosis , and chronic infection was the final stage of CLI. The cumulative rate of chronic infection was 76.4% at 10 years in patients with cavity formation. Ten patients with chronic infection included 7 cases of pulmonary aspergillosis and 2 cases of cavity infections with methicillin-resistant Staphylococcus aureus or Stenotrophomonas maltophilia. Among them, 4 patients required surgical interventions including completion pneumonectomy or fenestration. CLI is a common incidence after trimodality therapy for LA-NSCLC. CLI frequently results in cavity formation, which is a precursor of highly refractory chronic infections requiring surgical intervention. Appropriate management needs to be established for CLI developing after trimodality therapy.

Multiple Immune Features-Based Signature for Predicting Recurrence and Survival of Inoperable LA-NSCLC Patients.

IntroductionThe immune status of the tumor microenvironment is extremely complex. One single immune feature cannot reflect the integral immune status, and its prognostic value was limited. We postulated that the immune signature based on multiple immuno-features could markedly improve the prediction of post-chemoradiotherapeutic survival in inoperable locally advanced non-small-cell lung cancer (LA-NSCLC) patients.MethodsIn this study, 100 patients who were diagnosed as having inoperable LA-NSCLC between January 2005 and January 2016 were analyzed. A five immune features-based signature was then constructed using the nested repeat 10-fold cross validation with least absolute shrinkage and selection operator (LASSO) Cox regression model. Nomograms were then established for predicting prognosis.ResultsThe immune signature combining five immuno-features was significantly associated with overall survival (OS) and progression-free survival (PFS) (P = 0.002 and P = 0.014, respectively) in patients with inoperable LA-NSCLC, and at a cutoff of −0.05 stratified patients into two groups with 5-year OS rates of 39.8 and 8.8%, and 2-year PFS rates of 22.2 and 5.5% for the high- and low-immune signature groups, respectively. Integrating immune signature, we proposed predictive nomograms that were better than the traditional TNM staging system in terms of discriminating ability (OS: 0.692 vs. 0.588; PFS: 0.672 vs. 0.586, respectively) or net weight classification (OS: 32.96%; PFS: 9.22%), suggesting that the immune signature plays a significant role in improving the prognostic value.ConclusionMultiple immune features-based immune signature could effectively predict recurrence and survival of inoperable LA-NSCLC patients and complemented the prognostic value of the TNM staging system.

Higher Dose Volumes May Be Better for Evaluating Radiation Pneumonitis in Lung Proton Therapy Patients Compared With Traditional Photon-Based Dose Constraints

PurposeThe dosimetric parameters used clinically to reduce the likelihood of radiation pneumonitis (RP) for lung cancer radiation therapy have traditionally been V20Gy ≤ 30% to 35% and mean lung dose ≤ 20 to 23 Gy; however, these parameters are derived based on studies from photon therapy. The purpose of this study is to evaluate whether such dosimetric predictors for RP are applicable for locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with proton therapy. Methods and MaterialsIn the study, 160 (78 photon, 82 proton) patients with LA-NSCLC treated with chemoradiotherapy between 2011 and 2016 were retrospectively identified. Forty (20 photon, 20 proton) patients exhibited grade ≥2 RP after therapy. Dose volume histograms for the uninvolved lung were extracted for each patient. The percent lung volumes receiving above various dose levels were obtained in addition to V20Gy and Dmean. These dosimetric parameters and patient characteristics were evaluated with univariate and multivariate logistic regression tests. Receiver operating characteristic curves were generated to obtain the optimal dosimetric constraints through analyzing RP and non-RP sensitivity and specificity values. ResultsThe multivariate analysis showed V40Gy and Dmean to be statistically significant for proton and photon patients, respectively. V35Gy to V50Gy were strongly correlated to V40Gy for proton patients. Based on the receiver operating characteristic curves, V35Gy to V50Gy had the highest area under the curve compared with other dose levels for proton patients. A potential dosimetric constraint for RP predictor in proton patients is V40Gy ≤ 23%. ConclusionsIn addition to V20Gy and Dmean, the lung volume receiving higher doses, such as V40Gy, may be used as an additional indicator for RP in LA-NSCLC patients treated with proton therapy.

Investigating the loco-regional control of simultaneous integrated boost intensity-modulated radiotherapy with different radiation fraction sizes for locally advanced non-small-cell lung cancer: clinical outcomes and the application of an extended LQ/TCP model

BackgroundTo investigate the loco-regional progression-free survival (LPFS) of intensity-modulated radiotherapy (IMRT) with different fraction sizes for locally advanced non-small-cell lung cancer (LANSCLC), and to apply a new radiobiological model for tumor control probability (TCP).MethodsOne hundred and three LANSCLC patients treated with concurrent radiochemotherapy were retrospectively analyzed. Factors potentially predictive of LPFS were assessed in the univariate and multivariate analysis. Patients were divided into group A (2.0 ≤ fraction size<2.2Gy), B (2.2 ≤ fraction size<2.5Gy), and C (2.5 ≤ fraction size≤3.1Gy) according to the tertiles of fraction size. A novel LQRG/TCP model, incorporating four “R”s of radiobiology and Gompertzian tumor growth, was developed to predict LPFS and compared with the classical LQ/TCP model.ResultsWith a median follow-up of 22.1 months, the median LPFS was 23.8 months. Fraction size was independently prognostic of LPFS. The median LPFS of group A, B and C was 13.8, 35.7 months and not reached, respectively. Using the new LQRG/TCP model, the average absolute and relative fitting errors for LPFS were 6.9 and 19.6% for group A, 5.5 and 8.8% for group B, 6.6 and 9.5% for group C, compared with 9.5 and 29.4% for group A, 16.6 and 36.7% for group B, 24.8 and 39.1% for group C using the conventional LQ/TCP model.ConclusionsHypo-fractionated IMRT could be an effective approach for dose intensification in LANSCLC. Compared with conventional LQ model, the LQRG model showed a better performance in predicting follow-up time dependent LPFS.

Impact of chemoradiotherapy (CRT) on immune-related tumor microenvironment and the efficacy of anti-PD-1 therapy after the recurrence of CRT in unresectable locally advanced NSCLC patients.

e21719 Background: Chemoradiotherapy (CRT) followed by durvalumab as maintenance therapy prolonged progression-free survival (PFS) and overall survival (OS) in unresectable locally advanced NSCLC (LA-NSCLC). Additionally, the history of radiotherapy and CRT has been reported to increase the efficacy of PD-1 blockade in advanced NSCLC patients. We evaluated the efficacy of anti-PD-(L)1 antibody therapy after CRT failure, and how CRT changes the status of PD-L1 expression on tumors and tumor infiltrated lymphocytes (TILs) in tumor microenvironment (TME) in unresectable LA-NSCLC patients. Methods: We retrospectively reviewed unresectable LA-NSCLC patients treated with CRT between December 2007 and December 2018, and evaluated the efficacy of PD-1 blockade after CRT failure. We also analyzed PD-L1 (clone: 22C3) expression on tumor cells, and CD8 positive TILs using the paired specimens that had been obtained pre-CRT and post-CRT failure. Results: We identified 422 patients who received CRT. Median follow-up was 36.1 months (range 2.7–138.1 months). Among these patients, sixty-five patients who had progressed post-CRT received anti-PD- (L)1 therapy (PD-1 therapy: 61 patients, PD-L1 therapy: 4 patients). Response rate (RR) and PFS of anti-PD-(L)1 therapy were 48% (95% CI, 35–60) and 8.7 (95% CI, 4.5–13.0) months. The RR and PFS did not differ according to PD-L1 expression levels (Table). Of the 18 patients, 9, 7, and 2 showed upregulation in PD-L1 expression or down- or no change, respectively, post-CRT. In contrast, the density of CD8 positive TILs in TME increased by CRT treatment ([pre-CRT]: median, 110 ± 239 /mm2 vs. [post-CRT]: median, 470 ± 533 /mm2, p = 0.025). Conclusions: The clinical outcome of anti-PD-(L)1 therapy after CRT failure in LA-NSCLC patients could be better than advanced NSCLC patients, but did not differ according to PD-L1 expression levels. The efficacy of PD-(L)1 therapy enhanced by CRT treatment could be due to the infiltration of CD8 T-cells into TME. [Table: see text]