Treatment-Related Pneumonitis of EGFR Tyrosine Kinase Inhibitors Plus Thoracic Radiation Therapy in Patients With Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Thoracic radiation therapy (RT) for non-small cell lung cancers may overcome resistance to tyrosine kinase inhibitors (TKIs). However, the risk of severe treatment-related pneumonitis (TRP) is a major concern, and the results of the combined treatment remain controversial. Therefore, we aimed to systematically review existing publications and provide a meta-analysis of TRP from a combined therapy of thoracic RT and TKIs. A systematic literature review was performed using the PubMed-MEDLINE and Embase databases to identify eligible publications. The number of severe TRP cases of grade 3 or higher was extracted and then analyzed by fixed or randomized model meta-analysis. Heterogeneity tests were performed using the I² and τ² statistics. Subgroup analyses were conducted on the types of RT and the sequence of the combined treatment. Our literature search identified 37 eligible studies with 1143 patients. Severe TRP occurred in 3.8% (95% CI, 1.8%-6.5%) of patients overall, and fatal pneumonitis occurred rarely in 0.1% (95% CI, 0.0%-0.3%). In the subgroup analysis, the severe TRP proportion was 2.3% (95% CI, 1.0%-4.1%) for patients under definitive (chemo)RT (19 studies, n = 702) versus 2.9% (95% CI, 1.3%-5.1%) for patients who received local stereotactic body RT or palliative RT (15 studies, n = 361). The severe TRP rate was 4.9% (95% CI, 2.4%-8.1%) for concurrent TKI and RT (26 studies, n = 765), which was significantly higher than TRP of 0.4% (95% CI, 0.0%-3.1%) for sequential therapy (6 studies, n = 200). Our meta-analysis showed that combined thoracic RT and epidermal growth factor receptor-TKI therapy has an acceptable risk of severe TRP and rare mortality in patients with non-small cell lung cancers. Concurrent treatment is less tolerable and should be administered with caution. Further investigations using osimertinib are required as the data on its effects are limited.

Effect of radiation fractionation on IDO1 via the NF-κB/COX2 axis in non-small cell lung cancer.

Radiotherapy (RT) is the mainstay treatment modality for lung cancer. We recently reported that conventionally fractionated radiotherapy (CRT) with daily fractionation of 2Gy significantly increased the activity of indoleamine 2,3-dioxygenase (IDO1), a known immune checkpoint, which predicted poorer long-term survival in patients with non-small cell lung cancer (NSCLC), while stereotactic body radiotherapy (SBRT) using fractionation size of 10Gy did not increase IDO1 activity and had better survival. Here we hypothesized that the hypofractionated SBRT kind of dose fraction stimulates host antitumor immunity via downregulating IDO1 in which CRT could not. We tested this hypothesis in vitro and in vivo using 10Gyx1 and 2Gyx8 fractionations in the laboratory. The results demonstrated that, although there was an initial downregulation after RT, the expression of IDO1 was ultimately upregulated by both fractionation regimens. The 10Gyx1 regimen had minimum upregulation, while the 2Gyx8 regimen significantly increased in IDO1 expression which was positively correlated with the elevated expressions of p-NF-κB and COX2. Pharmacological inhibition of COX2 abolished RT-induced IDO1 expression. Furthermore, the IDO1 inhibitor, D-1-methyl-tryptophan (D-1MT), exerted RT-related tumor-killing effects in the NSCLC cell lines and mouse models. These findings suggest that, in addition to being an immune suppressor, IDO1 may serve as an adaptive resistance factor in RT. Furthermore, an unappreciated mechanism may exist, where a larger fraction size might be superior to conventional sizes in cancer treatment. This study may provide a rationale for future research in using IDO1 as a biomarker to personalize RT dose fractionation and COX2 inhibitor to decrease radiation immune suppression from CRT.

CT-based radiomics nomogram may predict who can benefit from adaptive radiotherapy in patients with local advanced-NSCLC patients.

BACKGROUND: Although adaptive radiotherapy (ART) has many advantages, ART is not universal in the clinical appliance due to the consumption of a lot of labor, and economic burden. It is necessary to explore a CT stimulation-based radiomics model for screening who can get more benefits from ART in locally advanced non-small cell lung cancer (NSCLC) patients. METHOD: 183 cases of NSCLC patients receiving concurrent chemoradiotherapy with an adaptive approach were enrolled as a primary cohort, while 28 cases from another hospital served as an independent external validation cohort. Tumor regression assessment was conducted based on GTV reduction (Criteria A) or according to RECIST Version 1.1(Criteria B). The radiomics features were extracted by the "PyRadiomics" package and further screened by the LASSO method. Then, logistic regression was used to establish the model. Bootstrap and external validation were applied to verify the stability of the model. The receiver operating characteristic (ROC) curve was delineated to assess the predictive efficacy of the radiomics model. Dose-volume histograms were quantitatively compared between the initial and composite ART plans. Clinical endpoints included overall survival (OS) and progression-free survival (PFS). RESULT: There were no significant differences in clinical features between tumor regression-resistant (RR) and tumor regression-sensitivity (RS) groups. The AUC values of the Criteria A model and Criteria B model were 0.767 and 0.771, respectively. Bootstrapping validation and external validation confirmed the stability of models. In all patients, there was a significant benefit of ART in the lung, heart, cord, and esophagus compared to non-ART, particularly in RS patients. Furthermore, PFS and OS from ART were significantly longer in RS as defined by Criterion B than in RR patients with the same ART application. CONCLUSION: CT-based radiomics can screen out the patients who can gain more benefits from ART, which contribute to guiding and popularizing the application of ART strategy in the clinic within economic benefits and feasibility.

Efficacy and Failure Patterns of Early SBRT to the Primary Tumor in Advanced EGFR-Mutation-Positive Lung Cancer with EFGR-TKI Treatment: A Prospective, Single Arm, Phase II Study.

Early stereotactic body radiation therapy (SBRT) to the primary tumor combined with epidermal growth factor receptor tyrosine kinase inhibitor (EFGR-TKI) treatment may increase progression-free survival (PFS) by delaying resistance in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). In this prospective, single arm, phase II study, patients with advanced NSCLC were treated with EGFR-TKI (icotinib 125 mg tid or gefitinib 250 mg qd) for one month followed by SBRT (40-60 Gy/5-8 F/5-10 d) to the primary tumor with concurrent EGFR-TKI until disease progression. The primary endpoint was PFS and the patterns of failure. Overall survival (OS) and adverse effects (AEs) were secondary endpoints. Overall, 41 advanced NSCLC patients with EGFR mutations received treatment with 24.42 months of median follow-up time. On average, SBRT was initiated 1.49 months after EGFR-TKI administration. Tumors were found to have an average shrinkage rate of 42.50%. Median PFS was 15.23 months (95% CI 13.10-17.36), while median OS was 27.57 months (95% CI 23.05-32.09). Thirty-three patients were found to have disease progression, of which new site failure (NF) (22 patients, 66.66%) was the most common pattern, followed by original site failure (OF) (7 patients, 21.21%) and simultaneous OF/NF (ONF) (4 patients, 12.12%). There were no Aes equal to or greater than grade 3, with the most frequent AE being radiation pneumonitis. Therefore, administering therapy targeted at the primary tumor using early SBRT after EGFR-TKI initiation is a new potentially safe and effective approach to treat EGFR-mutant advanced NSCLC.

The critical components for effective adaptive radiotherapy in patients with unresectable non-small-cell lung cancer: who, when and how.

Adaptive radiotherapy (ART) is a new radiotherapy technology based on image-guided radiation therapy technology, used to avoid radiation overexposure to residual tumors and the surrounding normal tissues. Tumors undergoing the same radiation doses and modes can occur unequal shrinkage due to the variation of response times to radiation doses in different patients. To perform ART effectively, eligible patients with a high probability of benefits from ART need to be identified. Confirming the precise timetable for ART in every patient is another urgent problem to be resolved. Moreover, the outcomes of ART are different depending on the various image guidance used. This review discusses 'who, when and how' as the three key factors involved in the most effective implementation for the management of ART.

Adaptive radiotherapy (ART) is an image-guided radiotherapy technology used to treat tumors. This article explores who can gain more benefits from ART, when is the optimal time to conduct ART and how to better implement ART. Non-small-cell lung cancer patients with large tumor lesions and high radiosensitivity are the most suitable people for ART. The period of 30­50 Gy and 15­25 fractions of radiotherapy may be the most appropriate time for ART. All imaging guidances have their advantages and disadvantages. Although ART has more benefits, ART is not universally used in the clinic because of the associated labor, economic burden and need for equipment updating. This paper helps guide and popularize the application of the ART strategy in the clinic within economic benefits and feasibility.

Radiotherapy improves the outcomes of immunotherapy with Sintilimab in non-small-cell lung cancer: A real-world analysis.

Introduction: Radiotherapy may augment systemic antitumor responses to immunotherapy. We did a retrospective study to infer whether radiotherapy improves outcomes to immunotherapy in patients with stage III and IV non-small-cell lung cancer (NSCLC). Methods: This retrospective study conducted at Enze Medical Center enrolled 259 patients with histopathology confirmed NSCLC from December 2018 to December 31, 2021. All were treated with Sintilimab, some patients received radiotherapy at an appropriate time point. Radiation type includes conventional radiotherapy and stereotactic body radiotherapy. The progression-free survival (PFS), and overall survival (OS) were the primary endpoint. Results: A retrospective analysis was performed on 259 patients, of whom 140 had been treated with immunotherapy lonely and 119 had been remedied with immunotherapy plus radiotherapy. Baseline variables were well balanced between the two groups, including gender, age, smoking status, TNM staging, number of metastases, ECOG score, pathological type and lines of previous systemic therapy. The median PFS in the immunotherapy alone group was 5.00 months (95%CI 4.38-5.62) versus immunotherapy plus radiotherapy was 9.00 months (5.95-12.05; p<0.001). The median OS in the immunotherapy alone group was 16.00 months (12.59-19.42) versus immunotherapy plus radiotherapy was 30.00 months (20.75-39.25; p=0.027). PFS was finer in the radiotherapy plus immunotherapy group than the immunotherapy group alone in both stage III(P=0.0069) and Stage IV(P=0.006) patients. In the univariate analysis, radiotherapy, male, ECOG=0 and <2 lines of previous systemic therapy were connected with an observably better PFS (P<0.001; P=0.03; P=0.002;P=0.021). In a multivariate analysis, radiotherapy, ECOG=0 and <2 lines of previous systemic therapy were independent prognostic factors with a markedly better PFS (P<0.001; P=0.006;P=0.009). An univariate analysis, radiotherapy, male, stage III, non-metastasis, ECOG=0 and squamous carcinoma were associated with a significantly better OS (P=0.032, P=0.036,P=0.002,P<0.001,P=0.002,P=0.025). A multivariate analysis, non-metastasis was a standalone prognostic indicator with a significantly better OS (P=0.006). However, radiotherapy was a tendency indicator with a better OS (HR0.70 95% CI 0.47-1.06). There were also no obvious increases in adverse events in the combination group. Conclusions: Radiotherapy with addition of immunotherapy was observably linked to a better outcome in patients with III and IV staging NSCLC.

A Novel Prognosis Signature Based on Ferroptosis-Related Gene DNA Methylation Data for Lung Squamous Cell Carcinoma.

Ferroptosis-related genes regulating an iron- and lipid reactive oxygen species (ROS)-dependent form of programmed cell death suggest critical roles for ferroptosis in cancers. However, the prognostic value of ferroptosis-related epigenetic features such as DNA methylation in lung squamous cell carcinoma (LUSC) needs to be studied. Ferroptosis-related genes are collected from the FerrDb database, and the methylation data of these related genes in LUSC methylation data downloaded from the TCGA are retrieved. The DNA methylation data (362 LUSC samples) were analyzed to screen prognostic ferroptosis-related methylation sites. After patients with complete overall survival (OS) information were randomly separated into training cohort (n = 200) and validation cohort (n = 162), the least absolute shrinkage and selection operator (LASSO) and the Cox regression were used to establish and validate the prognostic signature. The time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival curve analyses, Harrell's concordance index (C-index), calibration analysis, and decision curve analysis (DCA) were performed to evaluate the risk signature and related nomogram. A series of other bioinformatics approaches such as mexpress, cbioportal, maftools, string, metascape, TIMER, and Kaplan-Meier survival curve analysis were also used to determine the methylation, mutation status, protein interaction network or functional enrichment, effects on immune cell infiltration, or expression level prognosis of those signature-related genes. A total of 137 DNA methylation sites were identified as prognostic predictors corresponding to 109 ferroptosis-related genes (FRGs). The methylation signature containing 31 methylation sites proved to be superior predictive efficiency in predicting the 1-, 3-, 5-, and 10-year OS. 8 out of 28 signature-related genes were significantly related to OS time or OS state in patients with LUSC. In addition, DUSP1, ZFN36, and ALOX5 methylation status also correlated with pathological M and ALOX5 methylation correlated with pathological N. The prognostic prediction efficiency of T, N, M, and the stage was inferior to that of the DNA methylation signature. LUSC patients in the high-risk group own a significantly larger number of variants of FRGs than those in the low-risk group. In addition, negative or positive correlation patterns were presented among the different infiltrating immune cells with risk scores or signature-related genes in patients with LUSC. The expression level of 15 signature-related genes showed a significant relationship with OS of LUSC patients. A novel prognostic nomogram survival model containing 4 factors including age, pathologic T, stage, and risk group was constructed and validated, AndC-index, decision curve analysis (DCA), and calibration analysis demonstrated its excellent predictive performance. The FRG DNA methylation data-based prognostic model acts as a powerful prognostic prediction indicator in LUSC patients and is advantageous over the traditional model based on T, N, M, and stage.

Synergistic Antitumor Effects of Anlotinib Combined with Oral 5-Fluorouracil/S-1 via Inhibiting Src/AKT Signaling Pathway in Small-Cell Lung Cancer.

Background: Small-molecule tyrosine inhibitor anlotinib which developed in China has been approved as a third-line treatment for patients with small-cell lung cancer (SCLC). Our previous clinical study found that anlotinib combined with S-1 has better short-term ORR than the single-agent anlotinib of SCLC and other small-molecule vascular targeted drug therapies in the treatment of SCLC. However, the molecular mechanism of those effect remains unclear. Methods: SCLC cell line H446 was treated with either anlotinib, 5-FU alone, or combination. The cellular effects including cell viability, cell apoptosis, cell cycle, cell migration, and invasion were explored to evaluate the cell proliferation level. Western blot was performed to determine the protein levels of the combined action of the two drugs. The xenograft mouse model was established by injection of H446 cells into mouse, and the animals were randomized and assigned for the drug treatments. Body weights and tumor sizes were recorded. WB was conducted using tumor tissues. All data were collected and statistically analyzed using t-test to reveal the underlying molecular mechanism. Results: When anlotinib was combined with 5-FU, the IC50 value of cells was significantly reduced. And apoptosis, cell cycle arrest, and cell motility rates were stronger when anlotinib combined with 5-FU than in the anlotinib or 5-FU alone. In H446 cell-derived xenograft mouse model, tumor volumes were significantly decreased in Anlo/5-FU combination group than anlotinib or 5-FU alone group. Western blot showed the decreasing expression of p-Src/p-AKT in the Anlo/5-FU group. Conclusion: Our data revealed that the treatment of combination of antitumor angiogenesis agent anlotinib with chemotherapy drug 5-FU may have synergistic cytotoxicity to SCLC in vitro and in vivo. This treatment modality reduced cell proliferation and migration via Src/AKT pathway. This new strategy may be a promising treatment for SCLC but needs to be confirmed in future clinical trials.

The prognostic value of circulating lymphocyte counts and ABO blood group in lung cancer stereotactic body radiation therapy: a retrospective study.

Background: Clinically, there is a lack of simple and feasible indicators to predict the efficacy of stereotactic body radiation therapy (SBRT). Circulating lymphocyte counts (CLCs) is considered to be related to curative effect in conventional radiotherapy of lung cancer, and blood groups are also associated with the survival. In this study, we investigate the prognostic value of CLCs and ABO blood groups in lung cancer patients treated with SBRT. Methods: We retrospectively analyzed 191 patients who were treated with lung cancer SBRT in Taizhou Hospital of Zhejiang Province from September 2014 to December 2018. The medical record system of Taizhou Hospital was used to collect relevant clinical data, such as stage, CLC, ABO blood groups and other important clinical co-variates. The effects of SBRT were evaluated by patient reexamination image data and telephone follow-up. The RECIST 1.1 standard was used to evaluate the short-term efficacy in the first, third, and sixth months after SBRT. Progression-free survival (PFS) was defined as the time from the day of SBRT to disease progression or death from any cause. Overall survival (OS) was measured from the day of SBRT until the last follow-up or death. Survival curves and univariate, multivariate logistic-regression analyses were used to expound the prognostic factors for local control (LC), PFS, and OS of lung cancer SBRT patients. Results: Univariate and multivariate analysis results showed that post-SBRT CLCs were independent factors for the short-term efficacy 3 and 6 months after lung cancer SBRT [hazard ratio (HR) =0.249, P=0.037; HR =0.347, P=0.012]. Survival analyses showed that the PFS and OS of lung cancer SBRT patients with A blood type was significantly shorter than that in the other three non-A blood groups (PFS: 6.5 vs. 10 months, HR =1.535, P=0.020; OS: 24 vs. 41 months, HR =1.578, P=0.048). Moreover, the patients with high post-SBRT CLCs in the non-A blood group had the longest PFS and OS after lung cancer SBRT (HR =0.551, P=0.043). Conclusions: Lung cancer SBRT patients with high-post-SBRT CLCs and non-A blood groups seem to exhibits best curative effect, which represent a potential opportunity to improve the clinical management of these patients. The mechanisms of this association deserve further verification and investigation.

Enhanced CT-Based Radiomics to Predict Micropapillary Pattern Within Lung Invasive Adenocarcinoma.

OBJECTIVE: We aimed to investigate whether enhanced CT-based radiomics can predict micropapillary pattern (MPP) of lung invasive adenocarcinoma (IAC) in the pre-op phase and to develop an individual diagnostic predictive model for MPP in IAC. METHODS: 170 patients who underwent complete resection for pathologically confirmed lung IAC were included in our study. Of these 121 were used as a training cohort and the other 49 as a test cohort. Clinical features and enhanced CT images were collected and assessed. Quantitative CT analysis was performed based on feature types including first order, shape, gray-level co-occurrence matrix-based, gray-level size zone matrix-based, gray-level run length matrix-based, gray-level dependence matrix-based, neighboring gray tone difference matrix-based features and transform types including Log, wavelet and local binary pattern. Receiver operating characteristic (ROC) and area under the curve (AUC) were used to value the ability to identify the lung IAC with MPP using these characteristics. RESULTS: Using quantitative CT analysis, one thousand three hundred and seventeen radiomics features were deciphered from R (https://www.r-project.org/). Then these radiomic features were decreased to 14 features after dimension reduction using the least absolute shrinkage and selection operator (LASSO) method in R. After correlation analysis, 5 key features were obtained and used as signatures for predicting MPP within IAC. The individualized prediction model which included age, smoking, family tumor history and radiomics signature had better identification (AUC=0.739) in comparison with the model consisting only of radiomics features (AUC=0.722). DeLong test showed that the difference in AUC between the two models was statistically significant (P<0.01). Compared with the simple radiomics model, the more comprehensive individual prediction model has better prediction performance. CONCLUSION: The use of radiomics approach is of great value in the diagnosis of tumors by non-invasive means. The individualized prediction model in the study, when incorporated with age, smoking and radiomics signature, had effective predictive performance of lung IAC with MPP lesions. The combination of imaging features and clinical features can provide additional diagnostic value to identify the micropapillary pattern in IAC and can affect clinical diagnosis and treatment.

Reduced PHLPP Expression Leads to EGFR-TKI Resistance in Lung Cancer by Activating PI3K-AKT and MAPK-ERK Dual Signaling.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in advanced EGFR-mutation non-small cell lung cancer (NSCLC) but the magnitude of tumor regression varies, and drug resistance is unavoidable. The pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) levels are reduced or lost and acts as a tumor suppressor in many cancers. Here, we hypothesized that PHLPP is a key regulator of EGFR-TKI sensitivity and a potential treatment target for overcoming resistance to EGFR-TKI in lung cancer. METHODS: Cell proliferation and growth inhibition were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assay. PHLPP- knockdown stable cell lines were generated by lentivirus-mediated delivery of PHLPP shRNAs. The expression of PHLPP mRNA and protein levels was detected by real-time quantitative polymerase chain reaction (qPCR) and Western blotting. Immunohistochemical (IHC) staining was performed to detect the PHLPP expression in clinical patient tissue samples. A transcriptomic assay of genome-wide RNA expressions of PHLPP in NSCLC cell lines according to gefitinib sensitivity was obtained from Gene Expression Omnibus (GEO) database. Murine xenograft model was established to verify the function of PHLPP in gefitinib resistance in vivo. RESULTS: PHLPP highly expressed in gefitinib-sensitive NSCLC cell lines than gefitinib-resistant NSCLC cell lines. In gefitinib-acquired resistance cell line HCC827-GR, PHLPP expression even dramatically reduced. Knockdown of PHLPP in NSCLC cells decreased cell death induced by the EGFR-TKI, while overexpression PHLPP in gefitinib-resistance NSCLC cells can enhance or restore EGFR-TKIs sensitivity. Mechanism study indicated that PHLPP downregulation attenuates the effect of EGFR-TKI on the both AKT and ERK pathway, thereby decreasing the cell death sensitivity to EGFR inhibitors. In xenograft mice, knockdown of PHLPP decreased tumor response to gefitinib and advanced tumor cells re-growth after gefitinib treatment. In clinical, PHLPP expression were reduced in the post-relapse tumor compared to that of pre-treatment, and lower pre-treatment PHLPP levels were significantly correlated with shorter progression-free survival (PFS) in patients with EGFR-mutant lung adenocarcinoma whom treated with EGFR-TKI. CONCLUSIONS: Our data strongly demonstrated that loss of PHLPP function was a key factor of EGFR-TKI resistance in NSCLC. Downregulated PHLPP expression activated PI3K-AKT and MAPK-ERK pathway which strengthened cell survival to EGFR-TKI. Therefore, PHLPP expression level was not only a potential biomarker to predict EGFR-TKIs sensitivity but also as a therapeutic target in EGFR-TKIs therapy, enhancing PHLPP expression may be a valuable strategy for delaying or overcoming EGFR-TKIs drug resistance.

FLVCR1 Predicts Poor Prognosis and Promotes Malignant Phenotype in Esophageal Squamous Cell Carcinoma via Upregulating CSE1L.

OBJECTIVE: Dysregulation of feline leukemia virus subgroup C receptor 1(FLVCR1) expression has been investigated in several tumors. However, the expression and role of FLVCR1 in esophageal squamous cell carcinoma (ESCC) remain largely unknown. METHODS: FLVCR1 expression in tissues was measured by immunohistochemical staining (IHC). Celigo assay, MTT assay, colony formation, caspase 3/7 activity analysis, wound healing assay, Transwell migration, and invasion assay were applied to assess the effects of FLVCR1 on ESCC tumorigenesis. Coimmunoprecipitation (Co-IP) and liquid chromatography-mass spectrometry (LC-MS) were used to identify protein interactions with FLVCR1. An in vivo imaging system (IVIS) was used to investigate the functions of FLVCR1 on the growth and metastatic capability of ESCC cells in a xenograft model and a tail vein metastasis model. RESULTS: Elevated expression of FLVCR1 was detected in ESCC tissues and predicted poor survival. Upregulated FLVCR1 was positively correlated with lymph node metastasis (N stage) and late tumor-node-metastasis (TNM) stage. FLVCR1 knockdown inhibited cell proliferation and colony formation ability, induced cell apoptosis, and repressed cell migration and invasion of ESCC in vitro. Inhibition of FLVCR1 markedly repressed tumorigenicity and metastasis of ESCC cells in vivo. Mechanistically, chromosome segregation 1-like (CSE1L) was identified to interact with FLVCR1 using a Co-IP assay. Moreover, the inhibitory effect of FLVCR1 knockdown on proliferation and migration was counteracted by the exogenous expression of CSE1L. CONCLUSION: FLVCR1 plays a pivotal role in ESCC cell survival, growth, and migration. These functions may be partially dependent upon the protein interaction between FLVCR1 and CSE1L. In addition, FLVCR1 can be applied as a clinical prognostic marker for patients with ESCC.

Radiation-induced lung damage in patients treated with stereotactic body radiotherapy after EGFR-TKIs: is there any difference from stereotactic body radiotherapy alone?

BACKGROUND: To quantitatively evaluate lung damage after treatment of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and stereotactic body radiotherapy (SBRT) in patients with nonsmall cell lung cancer (NSCLC), and compare that of SBRT only treatment. METHODS: Eligible patients from an IRB-approved prospective clinical trial had one month of EGFRTKIs treatment followed by SBRT (TKI + SBRT) and with 3-month follow-up high resolution CT. NSCLC patients treated with SBRT alone during the same time period without EGFR-TKIs or other systemic therapies were identified as controls. The lung damage was assessed clinically by pneumonitis and quantitatively using by CT intensity (Hounsfield unit, HU) changes. The mean HU values were extracted for regions of the lungs receiving the same dose range at 10 Gy intervals to generate dose-response curves (DRC). The relationship of HU changes and radiation dose was modeled using a Probit model. RESULTS: Four out of 20 (25%) TKI + SBRT patients and none of 19 (0%) SBRT alone patients had developed grade 2 and above pneumonitis (P=0.053), respectively. Sixty percent of TKI + SBRT patients and 30% SBRT alone patients had HU changes of the normal lung density >200 HU, respectively. There were significant differences in the DRC and in lung HU changes between the two groups (all P<0.05). The physical dose for a 50% complication risk (TD50) of CT lung damage was 52 Gy (CI: 46-59) in TKI + SBRT group versus 72 Gy (CI: 58-107) in SBRT alone group (P<0.01). CONCLUSIONS: Compared to patients treated with SBRT alone, patients treated with EGFR-TKIs followed by SBRT were more incline to develop radiation pneumonitis, and resulted in greater lung CT intensity changes and steeper dose-CT lung damage response relationship at 3 months post treatment. Future study with larger number of patients and longer follow-up period is warranted to validate this finding.

Adaptive intensity-modulated radiotherapy with simultaneous integrated boost for stage III non-small cell lung cancer: Is a routine adaptation beneficial?

PURPOSE: Tumor and anatomical changes during radiotherapy have been observed in stage III non-small cell lung cancer (NSCLC) from many previous studies. We hypothesized that a routinely scheduled adaptive radiotherapy would have clinical important dose benefits to lower the risk of toxicities, without increasing the tumor recurrences. METHODS: We retrospectively reviewed 92 consecutive patients with inoperable stage III NSCLC between November 2017 and March 2019. All eligible patients should received simultaneously integrated boost (SIB) using intensity-modulated radiation therapy (IMRT). A mid-treatment CT simulation and a new adapted plan were routinely given after the first 20 fractions. The organs at risk (OARs) were delineated per RTOG 1106 atlas. Dose-volume histograms were quantitatively compared between the initial and composite adaptive plans. Logistic regression was applied to analyze the dose-response relationship. Clinical endpoints included acute symptomatic radiation pneumonitis (RP2) and esophagitis (RE2), local and regional tumor control, and progression-free survival (PFS). RESULTS: Sixty-four eligible patients received adaptive SIB-IMRT were consecutively included. The GTVs reduced by a median of -38.2% after 42 to 44 Gy in 20 fractions of radiotherapy. By adapting to tumor and anatomical changes, dosimetric parameters of OARs decreased significantly. The mean lung dose decreased by an average of -74.8 cGy, and mean esophagus dose was lower by 183.1 cGy. We found grade 2 or higher acute RP in 11 patients (17.2%), and RE2 in 28 patients (43.8%). Commonly used lung and esophagus dose metrics were significantly associated with RP2 and RE2. The adaptation could reduce RP2 probability by 3%, and RE2 risk by 5%. Subgroups with higher OARs dose or larger tumor shrinkage may get more dose and toxicities benefits. The estimated median PFS was 12.5 months from the start of radiotherapy. CONCLUSIONS: We demonstrated that the routinely adaptive SIB-IMRT strategy could significantly reduce the dose to surrounding normal tissues, potentially lower the associated acute RP and RE, without increasing the risk of tumor recurrences.

Intermediate Dose-Volume Parameters, Not Low-Dose Bath, Is Superior to Predict Radiation Pneumonitis for Lung Cancer Treated With Intensity-Modulated Radiotherapy.

PURPOSE: Although intensity-modulated radiotherapy (IMRT) is now a preferred option for conventionally fractionated RT in lung cancer, the commonly used cutoff values of the dosimetric constraints are still mainly derived from the data using three-dimensional conformal radiotherapy (3D-CRT). We aimed to compare the prediction performance among different dosimetric parameters for acute radiation pneumonitis (RP) in patients with lung cancer received IMRT. METHODS: A total of 236 patients treated with IMRT were retrospectively reviewed in two independent groups of lung cancer from January 2014 to August 2018. The primary endpoint was grade 2 or higher acute RP (RP2). Dose metrics were generated from the bilateral lung volume outside GTV (VdoseG) and PTV (VdoseP). The associations of RP2 with clinical variables, dose-volume parameters and mean lung dose (MLD) were analyzed by univariate and multivariate logistic regression. The power of discrimination among each predictor was assessed by employing the bootstrapped area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and the integrated discrimination improvement (IDI). RESULTS: Thirty-four (14.4%) out of 236 patients developed acute RP2 after the end of IMRT. The clinical parameters were identified as less important predictors for RP2 based on univariate and multivariate analysis. In both studied groups, the significance of association was more convincing in V20P, V30P, and MLDP (smaller Ps) than V5G and V5P. The largest bootstrapped AUC was identified for the V30P. We found a trend of better discriminating performance for the V20P and V30P, and MLDP than the V5G and V5P according to the higher values in AUC, IDI, and NRI analysis. To limit RP2 incidence less than 20%, the V30P cutoff was 14.5%. CONCLUSIONS: This study identified the intermediate dose-volume parameters V20P and V30P with better prediction performance for acute RP2 than low-dose metrics V5G and V5P. Among all studied predictors, the V30P had the best discriminating power, and should be considered as a supplement to the traditional dose constraints in lung cancer treated with IMRT.

Endostar improved efficacy of concurrent chemoradiotherapy with vinorelbine plus carboplatin in locally advanced lung squamous cell carcinoma patients with high serum Lp(a) concentration.

BACKGROUND: The role of vascular targeting therapy combined with concurrent chemoradiotherapy (CRT) has produced many inconsistent results in locally advanced non-small-cell lung cancer (NSCLC), especially in lung squamous cell carcinoma (LSCC). Lipoprotein (a) [Lp(a)] may be critical in the development of tumor angiogenesis, and its levels are individualized and determined genetically. This study aimed to determine whether Lp(a) is correlated with effects of recombinant human endostatin (Endostar) combined with concurrent CRT for locally advanced LSCC. METHODS: Patients with locally advanced LSCC from December 2008 to December 2017 were retrospectively analyzed. Patients were divided into two groups: (I) a chemoradiotherapy group (CRT group) which received weekly vinorelbine and carboplatin concurrently with radiotherapy 60Gy, and (II) an Endostar in combination with chemoradiotherapy group (ECRT group) which received Endostar intravenous drip for 1-14 days (every 3 weeks) concurrently with CRT. Fasting venous blood samples for serum Lp(a) in all patients were collected before the treatment. The effect of Endostar was assessed by stratified analysis. RESULTS: A total of 94 patients were recruited in this study. There were 59 cases in the CRT group and 35 cases in the ECRT group. Overall, the median progression-free survival (PFS) was 9.6 vs. 14.2 months (P=0.0671), and the overall survival (OS) was 15.0 vs. 20.6 months (P=0.114), in the CRT and ECRT groups respectively. The median of Lp(a) was 218 mg/L. In patients with serum Lp(a) less than 218 mg/L, the median PFS was 10.0 vs. 9.4 months (P=0.406), and the OS was 15.4 vs. 16.3 months (P=0.958) in the CRT and ECRT groups, respectively. However, in patients with serum Lp(a) higher than 218mg/L, the median PFS was 9.0 vs.15.8 months (P=0.011), and the OS was 14.0 vs. 21.1 months (P=0.055), in the CRT and ECRT groups, respectively. Cox proportional hazard model analysis revealed that a high concentration of Lp(a), ≥218 mg/L, is a prognostic factor for PFS [hazard rate (HR), 0.43 (0.23-0.81)] and OS [HR, 0.52 (0.27-0.98)] in locally advanced LSCC (P<0.05). CONCLUSIONS: The serum concentration of Lp(a) may serve as a biomarker to identify the patients who would benefit from Endostar treatment with concurrent CRT in stage III LSCC.

GBP1 Facilitates Indoleamine 2,3-Dioxygenase Extracellular Secretion to Promote the Malignant Progression of Lung Cancer.

IDO1-mediated immune escape can lead to the malignant progression of tumors. However, the precise mechanism of IDO1 remains unclear. This study showed that IDO1 can bind to GBP1 and increase the extracellular secretion of IDO1 with the assistance of GBP1, thereby promoting the malignant proliferation and metastasis of lung cancer. In vitro study showed that the high expression levels of IDO1 and GBP1 in lung cancer cells promoted cell invasion and migration. In vivo study revealed that knock-down of IDO1 and GBP1 inhibited tumor growth and metastasis. In addition, Astragaloside IV reduces the extracellular secretion of IDO1 by blocking the interaction of IDO1 and GBP1, thereby reducing T cell exhaustion and inhibiting tumor progression. These results suggest that blocking the extracellular secretion of IDO1 may prevent T cell exhaustion and thereby enhance the effect of PD-1 inhibitors on cancer treatment.

Excluding PTV from lung volume may better predict radiation pneumonitis for intensity modulated radiation therapy in lung cancer patients.

BACKGROUND: Lung dose-volume histogram (DVH) in radiotherapy could be calculated from multiple normal lung definitions. The lung dosimetric parameters generated from various approaches are significantly different. However, limited evidence shows which definition should be used to more accurately predict radiation pneumonitis (RP). We aimed to compare the RP prediction accuracy of dosimetric parameters from three lung volume methods in lung cancer patients treated with Intensity-Modulated Radiation Therapy (IMRT). METHODS: We retrospectively reviewed 183 consecutive lung cancer patients treated with IMRT from January 2014 to October 2017. The normal lungs were defined by total bilateral lung volume (Total Lung), excluding PTV (Lung-PTV) or PGTV (Lung-PGTV). V5, V20, and mean lung dose (MLD) have been extracted from three definitions. The primary endpoint was acute grade 2 or higher RP (RP2). Correlation between RP2 and dose parameters were analyzed by logistic regression. We evaluated prediction performance using area under the receiver operating characteristic curve (AUC) and normal tissue complication probability (NTCP) model. RESULTS: Twenty-six patients (14.2%) developed acute RP2 after IMRT treatment. Significant dosimetric differences were found between any 2-paired lung volumes (Ps < 0.001). To limit RP2 incidence less than 20%, the cutoff MLDs were 12.5 Gy, 14.2 Gy, and 15.0 Gy, respectively, for Lung-PTV, Lung-PGTV, and Total Lung methods. There were 54% (13% vs. 20%) and 45% (20% vs. 29%) RP2 probability variances detected at each MLD cutoff points from Lung-PTV and Lung-PGTV definitions. The best RP prediction performance was found in MLD from Lung-PTV method (AUC = 0.647), which is significantly better (P = 0.006) than the MLD from Lung-PGTV method (AUC = 0.609). CONCLUSION: There are significant differences in acute RP2 rate prediction using dosimetric parameters from various normal lung definitions. Excluding PTV from total lung volume may be more accurate and promising to predict acute symptomatic radiation pneumonitis in IMRT treated lung cancer patients.