Radiotherapy For Non-small Cell Lung Cancer Research Articles

Enhanced radiosensitivity by 6-thio-dG via increasing telomere dysfunction and ataxia telangiectasia mutated inhibition in non-small cell lung cancer

ObjectiveTo investigate the radiosensitivity of 6-thio-dG and its underlying molecular mechanisms in non-small cell lung cancer (NSCLC). MethodsH1299 and A549 NSCLC cells were pretreated with 6-thio-dG for one week and then exposed to γ-irradiation. Cell proliferation and survival were quantified using clonogenic assays. DNA damage was assessed using immunofluorescence for γH2AX. Telomere dysfunction-induced foci analysis was performed by the co-localization of telomere signals (FISH) and γH2AX. Telomere fusion was defined as two telomere signals merged into one at the chromosome by immuno-FISH in metaphase spreads. Proteins related to the DNA damage response were detected using Western blot analysis. Apoptosis wasanalyzed using flow cytometry and Western blot. ResultsThe presence of 6-thio-dG increased the radio sensitivity of H1299 and A549 ​cells (P<0.05), but had no effect on the normal human lung fibroblast line, MRC5. 6-thio-dG pretreatment significantly reduced the clonogenic potential induced by γ-ray irradiation and aggravated genomic DNA and telomeric DNA damage (P<0.05). In addition, 6-thio-dG pretreatment effectively increased γ-ray irradiation induced telomere dysfunction (P<0.05), resulting in disruption of chromosome stability and inhibition of the ATM pathway, thereby impairing genomic DNA and telomeric DNA repair, which was closely associated with enhanced drug-mediated radiation-induced apoptosis. Conclusions6-thio-dG increases the radiosensitivity of NSCLC by inhibiting ATM and inducing telomere dysfunction, which can potentially be used as a strategy for radiotherapy for NSCLC.

Elevated BTG2 improves the radiosensitivity of non-small cell lung cancer (NSCLC) through apoptosis.

BackgroundTo identify radio‐responsive genes and explore the biological function of encoded proteins in non‐small cell lung cancer (NSCLC).MethodsRadio‐responsive genes in irradiated H460 cells were screened from microarray data deposited in the Gene Expression Omnibus (GEO) database. A quantitative real time polymerase chain reaction assay was used to detect the expression of candidate radio‐responsive genes in irradiated cells. CCK‐8 assay, EDU assay, clone formation assay, immunofluorescence and flow cytometry were conducted to evaluate the biological function of B cell translocation gene 2 (BTG2) in NSCLC.ResultsBioinformatic analysis using GES20549 showed that BTG2 was a radio‐responsive gene in irradiated H460 cells. The mRNA expression level of BTG2 was lower in H460 cells compared with that in BEAS‐2B normal lung epithelial cells. BTG2 expression was elevated upon IR exposure, in a dose‐dependent but not a time‐dependent manner. CCK‐8 and EDU assays revealed that BTG2 overexpression inhibited the growth rate of irradiated cells. Clone formation showed that elevated BTG2 promoted DNA damage of irradiated H460 cells. The number of γ‐H2AX foci induced by DNA damage was also markedly increased upon BTG2 overexpression. Flow cytometry showed that BTG2 increased IR‐induced cell apoptosis.ConclusionsBTG2 may be a novel radio‐responsive factor and a promising therapeutic target for radiotherapy of NSCLC.

Automatic delineation of organs at risk in non-small cell lung cancer radiotherapy based on deep learning networks*

Abstract Objective To introduce an end-to-end automatic segmentation method for organs at risk (OARs) in chest computed tomography (CT) images based on dense connection deep learning and to provide an accurate auto-segmentation model to reduce the workload on radiation oncologists. Methods CT images of 36 lung cancer cases were included in this study. Of these, 27 cases were randomly selected as the training set, six cases as the validation set, and nine cases as the testing set. The left and right lungs, cord, and heart were auto-segmented, and the training time was set to approximately 5 h. The testing set was evaluated using geometric metrics including the Dice similarity coefficient (DSC), 95% Hausdorff distance (HD95), and average surface distance (ASD). Thereafter, two sets of treatment plans were optimized based on manually contoured OARs and automatically contoured OARs, respectively. Dosimetric parameters including Dmax and Vx of the OARs were obtained and compared. Results The proposed model was superior to U-Net in terms of the DSC, HD95, and ASD, although there was no significant difference in the segmentation results yielded by both networks (P &gt; 0.05). Compared to manual segmentation, auto-segmentation significantly reduced the segmentation time by nearly 40.7% (P &lt; 0.05). Moreover, the differences in dose-volume parameters between the two sets of plans were not statistically significant (P &gt; 0.05). Conclusion The bilateral lung, cord, and heart could be accurately delineated using the DenseNet-based deep learning method. Thus, feature map reuse can be a novel approach to medical image auto-segmentation.

The Diverse Analysis Identifies Mutated KRAS Associated With Radioresistance in Non-Small Cell Lung Cancer.

BackgroundTo analyze the relationship between V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) status and radioresistance in non-small cell lung cancer (NSCLC), we identified potential genotypic differences and pathways involved.MethodsWe retrospectively analyzed epidermal growth factor receptor (EGFR) and KRAS status in patients undergoing definitive radiotherapy for NSCLC between 2004 and 2018. Cox proportional hazard models were used to evaluate local progression-free survival (LPFS). Using clonogenic survival and measurement of γH2AX foci, we analyzed the difference in radiosensitivity between NSCLC cell lines with different KRAS status. The Cancer Genome Atlas (TCGA) analysis was used to explore the potential pathways involved.ResultsThe results showed that of the 286 patients identified, 68 (24%) had local tumor progression (mean ± standard deviation (SD), 27 ± 17.4 months); of these patients, KRAS mutations were found in 14 (23%), and KRAS status was associated with LPFS. After adjusting for concurrent chemotherapy, gross tumor volume, and mutation status in multivariate analysis, KRAS mutation was associated with shorter LPFS (hazard ratio: 1.961; 95% confidence interval: 1.03 - 2.17; P = 0.032). KRAS mutation showed higher radioresistance in vitro. TCGA data showed that the ERK1/2 pathway, phosphatidylinositol I3 kinase (PI3K)/mTOR, p38 MAPK pathway, cell cycle checkpoint signaling, DNA damage, repair pathways, and EGFR/PKC/AKT pathway were differentially expressed in patients with KRAS mutations or cell lines compared with their expression in the wild-type group.ConclusionsDiverse analyses identified that KRAS mutation was associated with radioresistance in NSCLC. KRAS mutation status may be helpful as a biomarker of radioresistance and a potential target to increase radiosensitivity.

Tumor-Tropic Adipose-Derived Mesenchymal Stromal Cell Mediated Bi2 Se3 Nano-Radiosensitizers Delivery for Targeted Radiotherapy of Non-Small Cell Lung Cancer.

With the successful marriage between nanotechnology and oncology, various high-Z element containing nanoparticles (NPs) are approvedas radiosensitizers to overcome radiationresistancefor enhanced radiotherapy (RT). Unfortunately, NPsthemselves lack specificity to tumors. Due to the inherent tropism nature of malignant cells, mesenchymal stem cells (MSCs) emergeas cell-mediated delivery vehicles for functional NPs to improve their therapeutic index. Herein, radiosensitive bismuth selenide (Bi2 Se3 ) NPs-laden adipose-derived mesenchymal stromal cells (AD-MSCs/Bi2 Se3 ) are engineered for targeted RT of non-small cell lungcancer(NSCLC). The results reveal that the optimized intracellular loading strategy hardly affects cell viability, specific surface markers, or migration capability of AD-MSCs, and Bi2 Se3 NPs can be efficiently transportedfrom AD-MSCs to tumor cells.In vivo biodistribution testshows that the Bi2 Se3 NPs accumulationin tumor is increased 20 times via AD-MSCs-mediated delivery. Therefore, AD-MSCs/Bi2 Se3 administrationsynchronizedwith X-ray irradiation controls the tumor progress well in orthotopicA549 tumor bearing mice. Considering that MSCs migrate better to irradiated tumor cells in comparison to nonirradiated ones andMSCs preferentially accumulate within lung tissues after systemic administration into accounts, the tumor-tropic MSCs/NPs system is feasible and promising for targeted RT treatment of NSCLC.

A comparison of machine learning methods for predicting recurrence and death after curative-intent radiotherapy for non-small cell lung cancer: Development and validation of multivariable clinical prediction models.

SummaryBackgroundSurveillance is universally recommended for non-small cell lung cancer (NSCLC) patients treated with curative-intent radiotherapy. High-quality evidence to inform optimal surveillance strategies is lacking. Machine learning demonstrates promise in accurate outcome prediction for a variety of health conditions. The purpose of this study was to utilise readily available patient, tumour, and treatment data to develop, validate and externally test machine learning models for predicting recurrence, recurrence-free survival (RFS) and overall survival (OS) at 2 years from treatment.MethodsA retrospective, multicentre study of patients receiving curative-intent radiotherapy for NSCLC was undertaken. A total of 657 patients from 5 hospitals were eligible for inclusion. Data pre-processing derived 34 features for predictive modelling. Combinations of 8 feature reduction methods and 10 machine learning classification algorithms were compared, producing risk-stratification models for predicting recurrence, RFS and OS. Models were compared with 10-fold cross validation and an external test set and benchmarked against TNM-stage and performance status. Youden Index was derived from validation set ROC curves to distinguish high and low risk groups and Kaplan-Meier analyses performed.FindingsMedian follow-up time was 852 days. Parameters were well matched across training-validation and external test sets: Mean age was 73 and 71 respectively, and recurrence, RFS and OS rates at 2 years were 43% vs 34%, 54% vs 47% and 54% vs 47% respectively. The respective validation and test set AUCs were as follows: 1) RFS: 0·682 (0·575–0·788) and 0·681 (0·597–0·766), 2) Recurrence: 0·687 (0·582–0·793) and 0·722 (0·635–0·81), and 3) OS: 0·759 (0·663–0·855) and 0·717 (0·634–0·8). Our models were superior to TNM stage and performance status in predicting recurrence and OS.InterpretationThis robust and ready to use machine learning method, validated and externally tested, sets the stage for future clinical trials entailing quantitative personalised risk-stratification and surveillance following curative-intent radiotherapy for NSCLC.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

MiR-145 modulates the radiosensitivity of non-small cell lung cancer cells by suppression of TMOD3.

Radioresistance is a major problem encountered in the treatment of non-small cell lung cancer (NSCLC). Aberrant microRNA (miRNA) expression contributes to multiple cancer-associated signaling pathways and profoundly influences effects of radiotherapy (RT) in cancers. MicroRNA-145-5p (miR-145) is recognized as a tumor suppresser in NSCLC. However, the roles of miR-145 during radiotherapy of NSCLC are largely unknown. The present study aimed to investigate the function and underlying mechanism of miR-145 in modulation of radiosensitivity in NSCLC. We generated radioresistant H460 and A549 subclones, named H460R and A549R, respectively, and found that irradiation (IR) could suppress the expression levels of miR-145 in radioresistant NSCLC cells. Furthermore, overexpression of miR-145 could sensitize radioresistant NSCLC cells to IR, whereas knockdown of miR-145 in NSCLC cells acted the converse manner. Mechanically, miR-145 was able to directly target 3'UTR of tropomodulin 3 (TMOD3) mRNA and decrease the expression of TMOD3 at the levels of mRNA and protein. Additionally, we confirmed that miR-145 could enhance the radiosensitivity of radioresistant NSCLC cells by targeting TMOD3 in vitro and in vivo, and could be used as a target in clinical treatment of NSCLC. Collectively, restoration of miR-145 expression increases the radiosensitivity of radioresistant NSCLC cells by suppression of TMOD3, and miR-145 can act as a new radiosensitizer for NSCLC therapy.

ProCaLung – Peer review in stage III, mediastinal node-positive, non-small-cell lung cancer: How to benchmark clinical practice of nodal target volume definition and delineation in Belgium☆

Background and purposeThe Quality Assurance project for stage III non-small cell lung cancer radiotherapy ProCaLung performed a multicentric two-step exercise evaluating mediastinal nodal Target Volume Definition and Delineation (TVD) variability and the opportunity for standardization. The TVD variability before and after providing detailed guidelines and the value of qualitative contour reviewing before applying quantitative measures were investigated. Materials and methodsThe case of a patient with stage III NSCLC and involved mediastinal lymph nodes was used as a basis for this study. Twenty-two radiation oncologists from nineteen centers in Belgium and Luxembourg participated in at least one of two phases of the project (before and after introduction of ProCaLung contouring guidelines). The resulting thirty-three mediastinal nodal GTV and CTV contours were then evaluated using a qualitative-before-quantitative (QBQ) approach. First, a qualitative analysis was performed, evaluating adherence to most recent guidelines. From this, a list of observed deviations was created and these were used to evaluate contour conformity. The second analysis was quantitative, using overlap and surface distance measures to compare contours within qualitative groups and between phases. A ‘most robust’ reference volume for these analyses was created using the STAPLE-algorithm and an averaging method. ResultsFive GTV and seven CTV qualitative groups were identified. Second step contours were more often in higher-conformity groups (p = 0.012 for GTV and p = 0.024 for CTV). Median Residual Mean Square Distances improved from 2.34 mm to 1.36 mm for GTV (p = 0.01) and from 4.53 mm to 1.58 mm for CTV (p < 0.0001). Median Dice coefficients increased from 0.81 to 0.84 for GTV (p = 0.07) and from 0.82 to 0.89 for CTV (p ≤ 0.001). Using HC-contours only to generate references translated in more robust quantitative evaluations. ConclusionVariability of mediastinal nodal TVD was reduced after providing the ProCaLung consensus guidelines. A qualitative review was essential for providing meaningful quantitative measures.

Silencing of the lncRNA H19 enhances sensitivity to X-ray and carbon-ions through the miR-130a-3p /WNK3 signaling axis in NSCLC cells

BackgroundThe lncRNA H19 is believed to act as an oncogene in various types of tumors and is considered to be a therapeutic target and diagnostic marker. However, the role of the lncRNA H19 in regulating the radiosensitivity of non-small cell lung cancer (NSCLC) cells is unknown.MethodsThe expression profiles of lncRNAs in NSCLC were explored via transcriptome sequencing. CCK-8, EdU incorporation and clonogenic survival assays were conducted to evaluate the proliferation and radiosensitivity of NSCLC cells. Flow cytometry and Western blotting were conducted to measure the level of apoptosis. The binding relationship between the lncRNA H19 and miR-130a-3p was determined by a dual-luciferase reporter assay. A binding relationship was also identified between miR-130a-3p and With-No-Lysine Kinase 3 (WNK3).ResultsExpression patterns of lncRNAs revealed that the lncRNA H19 was upregulated in radioresistant NSCLC (A549-R11) cells compared with A549 cells. Knockdown of the lncRNA H19 enhanced the sensitivity of NSCLC cell lines to X-ray and carbon ion irradiation. Mechanistically, the lncRNA H19 serves as a sponge of miR-130a-3p, which downregulates WNK3 expression. The lncRNA H19–miR-130a-3p–WNK3 axis modulates radiosensitivity by regulating apoptosis in NSCLC cell lines.ConclusionKnockdown of the lncRNA H19 promotes the sensitivity of NSCLC cells to X-ray and carbon ion irradiation. Hence, the lncRNA H19 might function as a potential therapeutic target that enhances the antitumor effects of radiotherapy in NSCLC.

Prognosis biomarker and potential therapeutic target CRIP2 associated with radiosensitivity in NSCLC cells

Radiotherapy plays a major role in non-small cell lung cancer (NSCLC) treatment. The curative efficacy of advanced NSCLC is unsatisfactory because of its radioresistance to conventional radiotherapy. The biomarkers which can be used to diagnose radiosensitivity or predict for prognosis are beneficial in promoting curative effects. In this study, NSCLC cell lines with acquired radioresistance to X-rays were obtained through fractionated irradiation. The differentially expressed proteins (DEPs) between the self-established radioresistant NSCLC cell line A549-R11 and control (A549-CK) were measured by proteomic analysis. Among the detected DEPs, CRIP2, ARHGDIB, and PADI3 were validated to be up-regulated in radioresistant cells, in mRNA and protein levels. Further analysis of bioinformatics deciphered that CRIP2, as a potential biomarker for diagnosis and a key biomarker for prediction of prognosis, may impact the X-ray radiosensitivity of NSCLC by regulating the occurrence of apoptosis and cell cycle arrest; as such, it may serve as a potent therapeutic target to facilitate NSCLC radiotherapy. CRIP2 and other DEPs may shed new light on the recognition of complex factors associated with radiation-responsiveness and finally be beneficial in the advancement of personalized therapies and precision medical treatment.

Altered Wnt5a expression affects radiosensitivity of non-small cell lung cancer via the Wnt/β-catenin pathway.

It has been reported that upregulation of wingless-type protein 5a (Wnt5a) is associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). Wnt5a expression is often upregulated in radiation-resistant NSCLC cells. However, the biological functions or molecular mechanisms of radiosensitivity in NSCLC remain unknown. In the present study, MTT assay and flow cytometric analysis were performed to assess the effect of overexpression or knockdown of Wnt5a and/or radiation on the proliferation and apoptosis of NSCLC cells. Furthermore, western blot analysis was performed to detect canonical Wnt signaling (β-catenin) in H1650 and A549 cells. The results demonstrated that Wnt5a knockdown combined with irradiation inhibited proliferation and induced apoptosis in NSCLC cells compared with Wnt5a knockdown or radiotherapy alone. In addition, the combination of Wnt5a knockdown and irradiation decreased nuclear and increased cytoplasmic β-catenin expression in H1650 and A549 cells, the effects of which were reversed following overexpression of Wnt5a. The combination of overexpressing Wnt5a and irradiation resulted in significant tumor regression, while β-catenin knockdown reversed Wnt5a overexpression-induced NSCLC cell proliferation. Taken together, these results suggest that Wnt5a may be involved in the activation of β-catenin-dependent canonical Wnt signaling, and thus may influence the effectiveness of radiation therapy in NSCLC.

PD-1 iNhibitor and chemotherapy with concurrent IRradiation at VAried tumor sites in advanced Non-small cell lung cAncer: the Prospective Randomized Phase 3 NIRVANA-Lung Trial

Advanced non-small cell lung cancer (NSCLC) remains a high unmet medical need. The first line standard-of-care therapy comprises concurrent chemotherapy-immunotherapy with pembrolizumab. Concurrent irradiation with pembrolizumab has been shown to significantly improve survival benefit compared with immunotherapy alone in a pooled analysis of 2 randomized phase 2 trials. We present the rationale and study design of the “PD-1 iNhibitor and chemotherapy with concurrent IRradiation at VAried tumor sites in advanced Non-small cell lung cAncer” (NIRVANA-Lung) trial (ClinicalTrials.gov identifier, NCT03774732). This study is a national multicenter 1:1 randomized phase III trial testing in 460 patients, the addition of multisite radiotherapy in advanced NSCLC treated with standard immune checkpoint inhibitors (pembrolizumab)-chemotherapy in first line. The primary objective of the trial is to compare the overall survival between the 2 arms at year 1 of the study. The secondary objective is to compare the progression-free survival and cancer-specific survival at year 1 and 2, as well as to determine quality of life, local and distant control in irradiated and nonirradiated sites at 6 months and year 1.

Endostar (Rh-Endostatin) Enhanced the (Chemo)Radiosensitivity in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Previous clinical trials using Endostar, an anti-angiogenesis agent, in combination with chemoradiotherapy have indicated better survival and local control with no severe adverse events in non-small cell lung cancer (NSCLC). However, high-level evidence is lacking for routine use of Endostar concurrent with chemoradiotherapy in locally advanced NSCLC. This meta-analysis aimed to clarify the benefits of the addition of Endostar into (chemo)radiotherapy versus (chemo)radiotherapy alone for NSCLC.PubMed, Embase, Cochrane Central Register of Controlled Trials, Wanfang and Chinese National Knowledge Infrastructure (CNKI) were systematically screened from inception to August 2020 using the pre-specified terms. Prospective trials (evaluating or) comparing the efficacy of Endostar combined with (chemo)radiotherapy versus (chemo)radiotherapy for NSCLC were included. Primary endpoints were risk ratios (RRs) for objective response rate (ORR) and disease control rate (DCR). The secondary endpoints were RRs for overall survival (OS) and adverse events (AEs).Fifteen studies with 1036 patients were included for this meta-analysis. Endostar combined with (chemo)radiotherapy significantly improved ORR and DCR compared with (chemo)radiotherapy. The RRs of ORR and DCR for Endostar combined with concurrent chemoradiotherapy (CCRT) versus CCRT were 1.263 (95% CI: 1.137-1.403, P < 0.001) and 1.274 (95% CI: 1.124-1.444, P < 0.001), respectively. The RRs of ORR and DCR for Endostar combined with radiotherapy (RT) versus RT alone were 1.237 (95% CI: 1.009-1.518, P = 0.041) and 1.096 (95% CI: 1.005-1.196, P = 0.039), respectively. Endostar combined with CCRT significantly improved one-year OS rate compared with CCRT (RR = 1.113, 95% CI: 1.006-1.231, P = 0.038). Endostar combination treatments had similar incidences of main AEs compared with (chemo)radiotherapy (P > 0.05).Endostar combined with (chemo)radiotherapy is associated with significantly higher ORR and DCR than (chemo)radiotherapy with similar incidences of main AEs in NSCLC.

Research Progress and Challenges in the Treatment of Central Nervous System Metastasis of Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors and has high morbidity and mortality rates. Central nervous system (CNS) metastasis is one of the most frequent complications in patients with NSCLC and seriously affects the quality of life (QOL) and overall survival (OS) of patients, with a median OS of untreated patients of only 1–3 months. There are various treatment methods for NSCLC CNS metastasis, including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, which do not meet the requirements of patients in terms of improving OS and QOL. There are still many problems in the treatment of NSCLC CNS metastasis that need to be solved urgently. This review summarizes the research progress in the treatment of NSCLC CNS metastasis to provide a reference for clinical practice.

P05.03 Comparison of Stereotactic Body Radiotherapy and Radiofrequency Ablation for Early-Stage NSCLC: A Systemic Review and Pooled Analysis

Both stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) offer promising therapeutic options for patients with inoperable early-stage non-small cell lung cancer (NSCLC), but it is unclear which treatment would provide superior benefits for patients. In this systematic review and pooled analysis, we compare clinical outcomes and safety between SBRT and RFA for patients with inoperable early-stage NSCLC.

Current Treatment Strategies for Non-Small-Cell Lung Cancer with Comorbid Interstitial Pneumonia.

Simple SummaryInterstitial pneumonia is a poor prognostic comorbidity in patients with non-small-cell lung cancer. No matter how effective the treatment for lung cancer is, once an acute exacerbation of pre-existing interstitial pneumonia occurs, it will be fatal to the patient at a high rate. Therefore, it is important to choose a therapy that is unlikely to induce acute exacerbation of interstitial pneumonia. In this review article, we summarize the current evidence on pharmacotherapy, surgery and perioperative treatment, and radiation therapy for non-small-cell lung cancer with comorbid interstitial pneumonia, and discuss future perspectives.Of patients with advanced non-small-cell lung cancer (NSCLC), 5–10% have interstitial pneumonia (IP) at the time of diagnosis. To avoid fatal acute exacerbations of pre-existing IP, appropriate patient selection and low-risk treatment choices are warranted. Risk factors for acute exacerbation of pre-existing IP with cytotoxic drugs include honeycomb lungs on computed tomography (CT) and low forced vital capacity, but risk factors with immune checkpoint inhibitors (ICIs) have not been fully investigated. For advanced or recurrent NSCLC with comorbid IP, carboplatin plus nanoparticle albumin-bound paclitaxel is the standard of care for first-line treatment, but second-line or later treatment has not been established. ICI holds great promise for long-term survival, but many challenges remain, including safety and appropriate patient selection. Since the indications for pharmacotherapy and radiotherapy for NSCLC with comorbid IP are quite limited, surgical resection should be considered as much as possible for patients with operable stages. A scoring system has been reported to predict the risk of postoperative acute exacerbation of pre-existing IP, but perioperative treatment has not been established. In the future, it is necessary to accumulate more cases and conduct further research, not only in Japan but also worldwide.

PO-1165 Dosimetric parameters in hypofractionated radiotherapy in NSCLC cohort during SARS-COV-2 pandemia

Purpose or Objective: Moderate hypofractionation has been more popular in the last years, however no standard dosimetric parameters has been stablished. The majority of the dose-volume-constraints (DVCs) published refer to conventional 2 Gy/ fraction. In this study, we analyse different dosimetric parameters in patients (pts) with non-small cell lung cancer (NSCLC) treated with concomitant radiochemotherapy (RCT) or radiotherapy (RT) alone with radical intention and hypofractionated scheme in pandemic era. Due to the lack of consensus on this aspect, we analyse the relationship between tolerance to treatment and dosimetric parameters to aid its use in the clinic. Materials and Methods: Retrospective and multicentric study of 49 pts with locally advanced NSCLC treated from November 2019 to December 2020. During SARS-CoV-2 pandemic, hypofractionated schedules have allowed to decrease the duration of thoracic radiotherapy. The hypofractionated scheme used was 20 fractions of 2.75 Gy/daily (total dose 55 Gy, BED10=70 Gy). 3-dimensional conformal radiation therapy (3DCRT), intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) were allowed. We report gross tumour volume (GTV), planning tumour volume (PTV) and D98% and D95% PTV. Organ-at-risk (OARs) examined included lungs- GTV (V20<35% and mean-dose<20Gy), heart (V25<10%) and oesophagus (V50<40% and mean-dose<34 Gy). To evaluate toxicity during the treatment, we use CTCAE v.5 scale. Results: Mean GTV was 85.6 cc (3.3cc-581.3cc) and mean PTV was 268.8 cc (13cc-1047.4cc). Mean D98% PTV was 53 Gy and mean D95% PTV was 53.8 Gy. Most pts had G1-G2 cardiac toxicity like pericarditis, oesophagitis and pneumonitis. Only two pts (4%) had G3 oesophagitis and G3 pneumonitis (2%). No grade 4-5 toxicity was reported. In the analysis of DVCs, lungs-GTV V20<35% and lungs-GTV mean-dose < 20 Gy were associated with more pneumonitis regardless of grade (p 0.018 and p 0.027). In terms of oesophagitis, V50<40%, was associated with more oesophagitis regardless of grade (p 0.037). Mean dose < 34 Gy in oesophagus and heart DVCs were no associated with more toxicity in our study. There were not differences between T stage (<T3 vs ≥ T3) and N stage (<N2 vs ≥ N2) and mean PTV (p 0.55 and p 0.178). There were not differences in terms of cancer-specific survival and PTV (p 0.195). Conclusion: In moderately hypofractionation, it is important to consider that dosimetric parameters cannot be the same as in standard fractionation (2 Gy/fraction). Due to changing radiotherapy technique, DVCs may need to be adjusted based on different dose distribution. According to our results, hypofractionated radiotherapy in NSCLC is well-tolerated with low rates of grade 3-4- 5 toxicity but lungs-GTV V20<35%, lungs-GTV mean-dose < 20 Gy and oesophagus V50<40% were associated with more toxicity regardless of grade. Because of that, we consider it worth investigating the relationship between dosimetric parameters and toxicity in order to reach a consensus in daily clinical practice.

Neutrophil–Lymphocyte Ratio and Absolute Lymphocyte Count as Prognostic Markers in Patients Treated with Curative-intent Radiotherapy for Non-small Cell Lung Cancer

AimsThe neutrophil–lymphocyte ratio (NLR) and the absolute lymphocyte count (ALC) have been proposed as prognostic markers in non-small cell lung cancer (NSCLC). The objective of this study was to examine the association of NLR/ALC before and after curative-intent radiotherapy for NSCLC on disease recurrence and overall survival. Materials and methodsA retrospective study of consecutive patients who underwent curative-intent radiotherapy for NSCLC across nine sites in the UK from 1 October 2014 to 1 October 2016. A multivariate analysis was carried out to assess the ability of pre-treatment NLR/ALC, post-treatment NLR/ALC and change in NLR/ALC, adjusted for confounding factors using the Cox proportional hazards model, to predict disease recurrence and overall survival within 2 years of treatment. ResultsIn total, 425 patients were identified with complete blood parameter values. None of the NLR/ALC parameters were independent predictors of disease recurrence. Higher pre-NLR, post-NLR and change in NLR plus lower post-ALC were all independent predictors of worse survival. Receiver operator curve analysis found a pre-NLR > 2.5 (odds ratio 1.71, 95% confidence interval 1.06–2.79, P < 0.05), a post-NLR > 5.5 (odds ratio 2.36, 95% confidence interval 1.49–3.76, P < 0.001), a change in NLR >3.6 (odds ratio 2.41, 95% confidence interval 1.5–3.91, P < 0.001) and a post-ALC < 0.8 (odds ratio 2.86, 95% confidence interval 1.76–4.69, P < 0.001) optimally predicted poor overall survival on both univariate and multivariate analysis when adjusted for confounding factors. Median overall survival for the high-versus low-risk groups were: pre-NLR 770 versus 1009 days (P = 0.34), post-NLR 596 versus 1287 days (P ≤ 0.001), change in NLR 553 versus 1214 days (P ≤ 0.001) and post-ALC 594 versus 1287 days (P ≤ 0.001). ConclusionNLR and ALC, surrogate markers for systemic inflammation, have prognostic value in NSCLC patients treated with curative-intent radiotherapy. These simple and readily available parameters may have a future role in risk stratification post-treatment to inform the intensity of surveillance protocols.

Radiotherapy for oligometastatic non-small cell lung cancer: a narrative review.

Preclinical and early clinical evidence suggest that radical radiotherapy of oligometastatic disease in non-small cell lung cancer (NSCLC) patients can impact outcomes with relatively limited toxicity. Whilst data from phase 2 randomized trials suggesting an improved overall survival (OS) with this treatment is promising, it has also illustrated the heterogeneity in this patient population and treatment. Oligometastatic disease in itself comprises a broad spectrum of patients, in terms of tumor load and location, stage of the disease and treatment history. This real-life variety in patient characteristics is often reflected in studies to a certain extent, hinting to the fact that all might benefit from radical radiotherapy to limited metastatic disease, yet leaving the question unanswered as to whom the ideal candidate is. Furthermore, differences between and within studies with regards to treatment modality, timing, radiation technique, and radiation dose are substantial. Also, preclinical and early clinical trials suggest that radiotherapy can work synergistically with checkpoint inhibitors by acting as an in situ cancer vaccine, therefore the combination of these two treatments in oligometastatic patients might entail the largest benefit. Ongoing randomized controlled phase 3 trials and prospective registry trials will further elucidate the true extent of benefit of this local treatment strategy and aid in identifying the ideal patient population and therapy. The current narrative review summarizes the clinical evidence on radiotherapy for oligometastatic NSCLC and highlights the remaining unknowns.

Impact of high-dose rate radiotherapy on B and natural killer (NK) cell polarization in peripheral blood mononuclear cells (PBMCs) via inducing non-small cell lung cancer (NSCLC)-derived exosomes.

BackgroundNon-small cell lung cancer (NSCLC) is the most commonly diagnosed solid tumor. While it has been established that stereotactic body radiotherapy for NSCLC plays an important role in antitumor immune response, the possible effects of the dose rate on this response has not been fully clarified.MethodsIn vitro, A549 cells were irradiated on a Varian TrueBeam® Linear Accelerator with dose and dose rate escalation using the flattening filter-free (FFF) technique, which was followed by coculturing with peripheral blood mononuclear cells (PBMCs). The exosomes from irradiated A549 cells were isolated and then cocultured with PBMCs. Flow cytometry was performed to analyze the proportion of lymph cell clusters in PBMCs.ResultsThe proportion of CD3− immune cell clusters in PBMCs was significantly higher in the 10 Gy treatment group than in the nonirradiated group and other lower-dose (2, 6 Gy) treatment groups at the dose rate of 1,000 MU/min. However, no influence was observed on the proportion of CD3+ T cell subsets. Further results showed that both natural killer (NK) and B cell proportions reached peaks in the 14 Gy treatment group when a dose rate of 1,200 MU/min was used. Notably, the peak values of these two cell proportions were reached at a lower radiation dose of 10 Gy when a greater dose rate, ranging from 1,600 to 2,400 MU/min, was used. We further found that a single, high dose of irradiation (10 Gy), as compared with a single, low dose of irradiation (2 Gy), could markedly stimulate the A549-related exosome secretion in a radiation dose rate-dependent manner. The ultrahigh dose rate radiation–derived exosomes contributed to the polarization of B and NK cell subsets in PBMCs.ConclusionsThe optimized radiation regime, which depends on the appropriate radiation dose and dose rate, results in the production of exosomes derived from NSCLC cells and eventually the redistribution of immune cells in PBMCs.