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Purpose This study aimed to compare erlotinib (E) and etoposide/cisplatin (EP) with concurrent radiation therapy (RT) for patients with stage IIIA/B unresectable advanced non-small cell lung cancer with activating epidermal growth factor receptor mutation (EGFRm+). Methods and Patients This was a multicenter, randomized, open-label, phase 2 trial conducted across 19 institutions in China (December 2012 to January 2016). Enrolled patients were randomized (1:1) to E + RT (oral erlotinib 150 mg/d for 2 years or until disease progression or intolerable toxicity and RT 200 cGy/d, 5 d/wk for 6 weeks from the first day of erlotinib) or EP + RT (etoposide 50 mg/m2 intravenously on days 1-5 and 29-33; cisplatin 50 mg/m2 intravenously on days 1, 8, 29 and 36; and RT as for E + RT). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate and safety. Results Two hundred fifty-two patients were screened, and 20 patients with EGFRm+ in each group received the allocated E + RT or EP + RT treatment. Patient characteristics were well balanced between groups. Compared with EP + RT, median PFS with E + RT was significantly longer (24.5 vs 9.0 months [hazard ratio, 0.104; 95% confidence interval, 0.028-0.389; P Conclusions The primary endpoint of PFS was met, and the data showed that E + RT might provide PFS improvement compared with EP + RT, with similar tolerability. However, definitive statements regarding the efficacy of concurrent E + RT in patients with unresectable stage III non-small cell lung cancer with activating EGFRm+ cannot be made, and slow patient accrual will likely make it infeasible to conduct a phase 3 study.

Background Concurrent epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) with radiotherapy in patients with EGFR‐mutant unresectable stage III non‐small cell lung cancer (NSCLC) might improve survival. However, both treatments carry a potential risk of pneumonitis. Methods Between May 2012 and December 2017, patients with unresectable stage III NSCLC treated with concurrent radiotherapy and EGFR‐TKI were enrolled in this retrospective study. The baseline characteristics were evaluated to determine correlations with toxicity development. Results Among 45 eligible patients, 20 (44.4%) had an EGFR mutation and 44 (97.8%) received 50–66 Gy of radiotherapy. The median follow‐up was 62.7 months. The median progression free survival (PFS) and overall survival (OS) for patients with EGFR‐mutations were 27.9 (95% CI: 18.7–37.2) and 49.7 (95% CI: 27.7–71.8) months, and 13.8 (95% CI: 8.8–18.9) and 31.1 (95% CI: 9.8–52.4) months for EGFR wild‐type/unknown patients. A total of 17 patients (37.7%) developed radiation pneumonitis/pneumonitis (14 grade 2, 3 grade 3). In 16 patients, pneumonitis occurred within the radiation field and one patient had bilateral pneumonitis. The median time from the initial radiotherapy to pneumonitis was 74 days. Logistic regression analysis revealed a trend between the time of EGFR‐TKI and the development of G2+ pneumonitis. For late toxicity, only two patients had G2+ fibrosis. The daily dyspnea symptoms of patients with G2+ pneumonitis recovered significantly after the phase of pneumonitis (P = 0.007). Conclusions Combined EGFR‐TKI and radiotherapy showed favorable survival in EGFR‐mutant patients with inoperable stage III NSCLC, with a 6.7% incidence of grade 3 radiation pneumonitis/pneumonitis, despite a higher incidence of mild‐to‐moderate radiation pneumonitis. Key points Significant findings of the study We evaluated the outcomes and radiation pneumonitis after EGFR‐TKI during interval radiotherapy. EGFR‐TKI plus radiotherapy increased survival in patients with EGFR‐mutant inoperable stage III NSCLC. The mild‐to‐moderate radiation pneumonitis incidence increased but no grade 4–‐5 adverse events occurred. What this study adds The combination of EGFR‐TKI and radiotherapy might carry a risk of pneumonitis; however, there are limited data concerning dose constraints. Our results showed a slightly higher incidence of mild or moderate radiation pneumonitis by strict dose limitation., Our study evaluated the outcomes and radiation pneumonitis which occurred in patients following EGFR‐TKI during interval radiotherapy. The results of combined EGFR‐TKI and radiotherapy showed favorable survival in EGFR‐mutant patients with inoperable stage III NSCLC, a higher incidence of mild to moderate radiation pneumonitis was observed and no grades 4‐5 adverse events occurred.

Background The PACIFIC study has defined a new standard of care for patients with unresectable stage III non‐small cell lung cancer (NSCLC) in the form of immune checkpoint inhibitor (ICI) consolidation therapy. However, there is little specific data pertaining to the safety and efficacy of this approach in Chinese NSCLC patients. Methods This was a prospective multicenter cohort study. Between September 2018 and January 2020, patients with unresectable stage III NSCLC that had undergone chemoradiation therapy (CRT) and ICI consolidation treatment were enrolled in this study. The short‐term safety, tolerability, and efficacy of ICI combination with CRT were evaluated in these patients. Results Of the 20 Chinese patients eligible for inclusion, 17 (85.0%) underwent concurrent CRT treatment. In these patients, a median period of 40.5 days (range: 1–85 days) passed between the end of CRT and initiation of consolidation therapy. Pneumonitis occurred in 80.0% of patients, with seven (35.0%) being diagnosed with grade 1 pneumonitis and nine (45.0%) with grade 2 pneumonitis. No patients experienced grade 3 or higher pneumonitis or other ICI‐related toxicities. Lung V20 ≥ 20% was associated with higher grade 2 pneumonitis (77.8%; ≥20% vs. 18.2%, These data indicate that ICI consolidation therapy can achieve favorable short‐term efficacy, while exhibiting good safety and acceptable toxicity profiles in Chinese patients with inoperable stage III NSCLC.

Introduction: The high intracranial efficacy of EGFR-TKI challenges the role of upfront intracranial radiation therapy (RT) in non-small cell lung cancer (NSCLC) patients with EGFR mutation and brain metastases (BM). Therefore, we conducted a retrospective analysis to demonstrate the role of upfront RT in these patients. Materials and Methods: Patients that had histologically confirmed NSCLC with EGFR mutation, brain metastases, and received TKI or upfront RT with TKI were included in this study. Intracranial progression was estimated using the Fine-Gray competing risks model. Kaplan-Meier analysis and Log-rank test were used to evaluate and compare intracranial progression-free survival (iPFS), systemic PFS (sPFS), time to second-line systematic therapy (SST) and overall survival (OS). Results: Among the 93 patients included, 53 patients received upfront RT and TKI, and 40 patients received TKI only. Upfront RT group showed lower intracranial progression risk with adjusted SHR 0.38 (95% CI, 0.19 to 0.75, P= 0.006) and longer median time to sPFS (15.6 vs 8.9 months, P= 0.009). There were 9 out of 36 (25%) and 16 out of 34 (47.1%) patients who had oligo-progression received salvage RT in the RT group and TKI group, respectively. After the salvage RT, upfront RT did not prolong the median time to SST (23.6 vs 18.9 months, P=0.862) and OS (median time, 35.4 vs 35.8 months, P=0.695) compared to TKI alone. Conclusion: Compared to upfront intracranial RT, the salvage RT to oligo-progressive disease allowed patients getting TKI to have similar time on initial TKI and OS despite worse iPFS. The best timing of intracranial RT remains to be further verified.

Aim:To assess helical tomotherapy (TOMO) current clinical application and practice in mainland China.Materials and methods:Data were collected for all TOMO units clinically operational in mainland China by 30 April 2016, including (a) the distribution of installation and staffing levels; (b) types of cancers treated; (c) utilisation efficiency; (d) quality assurance; (e) maintenance; (f) optional features; and (g) satisfaction levels. The data were collected as a census and analysed qualitatively and quantitatively.Results:As of 30 April 2016, 23 TOMO units were used clinically by 22 hospitals in mainland China. In the same period, 22,558 cancer patients were treated. For TOMO units with more than a year of clinical utilisation, a median of 378 cases were treated annually per machine. The median daily operation was 10·5 hours, and treatment headcount was 38·3 patients. The median service outage rate was 2·6%, and the most common cause was malfunction of the multi-leaf collimator. In terms of overall satisfaction levels, 3 hospitals were very satisfied, 16 were satisfied and 3 considered their satisfaction level as average.Findings:The overall operation of TOMO is good, but there are some problems due to running at full capacity, lack of clinical efficacy research and insufficient quality assurance regulations.

Objective To investigate the safety and efficacy of nimotuzumab combined with radiotherapy for elderly patients with non-resectable esophageal carcinoma (EC). Methods Eligible patients were aged 70 years or older and had treatment-naive, histologically proven inoperable locally advanced EC. Enrolled patients received radiotherapy with a total dose of 50-60 Gy in 25-30 fractions, concurrent with weekly infusion of nimotuzumab. The primary end point was the rate of more than grade 3 toxicities. Results From June 2011 to July 2016, 46 patients with stage II-IV EC with a median age of 76.5 years were enrolled. There were 10, 28 and 8 patients with stage II, III and IV disease, respectively. The common acute toxicities included esophagitis (grade 1-2, 75.4%; grade 3, 8.7%), pneumonitis (grade 1, 4.3%; grade 2, 6.5%; grade 3, 2.2%), leukopenia (grade 1-2, 60.9%; grade 3-4, 4.4%), gastrointestinal reaction (grade 1-2, 17.3%; grade 3, 2.2%), thrombocytopenia (grade 1-2, 21.7%; grade 3, 2.2%), and radiothermitis (grade 1-2, 39.2%). The incidence of grade 3-4 adverse effects was 17.4%. No grade 5 toxicities were observed. Clinical complete response, partial response, stable disease, and progressive disease were observed in 1 (2.2%), 31 (67.4%), 12 (26.1%), and 2 (4.3%) patients, respectively. The median overall survival (OS) and progression-free survival (PFS) were 17 and 10 months, respectively. The 2-, 3-, and 5-year OS and PFS rates were 30.4%, 21.7%, 19.6%, and 26.1%, 19.6%, 19.6%, respectively. Conclusions Nimotuzumab combined with radiotherapy is a safe and effective therapy for elderly patients who are not surgical candidates. Further studies are warranted to confirm its therapeutic effects in elderly EC patients.

Purposes This study aimed to evaluate the role of radiotherapy (RT) and intensity modulated radiation therapy (IMRT) in adjuvant and definitive settings of tracheal-bronchial adenoid cystic carcinoma (TACC) treatment. Materials/methods TACC patients (n = 133) treated with surgery and/or RT curatively in our institution between January 1st, 1984 and December 31st, 2017 were analyzed retrospectively. Results Among the 116 patients undergoing surgery, 50 (43.1 %) achieved complete resections and 66 (56.9 %) had positive surgical margins. For patients with positive margins, overall adjuvant RT was correlated with no significantly improved OS (10-year: 58.0 % vs. 47.9 %; P = 0.340) and a slight LRFS benefit (5-year: 81.9 % vs.75.6 %; P = 0.056), but adjuvant IMRT showed significant superiority in both OS (10-year: 82.9 % vs. 47.9 %; P = 0.031) and LRFS (5-year: 100.0 % vs. 75.6 %; P = 0.001) in comparison with no postoperative RT. Multivariate analysis also identified adjuvant IMRT as a significant favorable factor with OS (HR = 0.186, 95 %CI: 0.039–0.883; P = 0.034). For 17 patients receiving definitive RT, IMRT achieved promising 5-year OS of 88.9 % and LRFS of 64.3 %, yet no significant difference from non-IMRT group was reached (P = 0.447 and 0.706). Different therapies presented no significantly different impact on DMFS, whilst DMFS explained more of the OS variances (P Conclusion IMRT could confer greatly improved OS and LRFS in postoperative setting for TACC patients with positive surgical margins. IMRT was also a good therapeutic option for definitive TACC with promising survival and local control.

Immune checkpoint inhibitors (ICIs) are recommended to treat advanced non-small-cell lung cancer (NSCLC), whereas brain radiotherapy (RT) is the mainstream therapy for patients with brain metastases (BMs). This systematic review and meta-analysis investigated whether the combination of brain RT and ICIs would generate a synergistic effect without unacceptable toxicity to treat NSCLC with BMs.Literature searching was performed in PubMed, Embase, Web Of Science, and The Cochrane Library up to December 20, 2020. Heterogeneity, sensitivity analysis, forest plots, and publication bias were analyzed using Stata 15.0.Nineteen studies were included. In the comparison of the brain RT+ICIs arm and brain RT alone arm, the pooled effect size (ES) for overall survival (OS) (hazard ratio [HR] = 0.77; 95% confidence interval [CI] 0.71-0.83; I² = 0; P.001; n = 4) and grade 3-4 neurological adverse events (AEs) (risk ratio [RR] = 0.91; 95% CI 0.41-2.02; I² = 26.5; P = .809; n = 4) indicated that the brain RT+ICIs model had significantly better systemic efficacy and similar neurological AEs compared with brain RT alone for NSCLC. Concurrent RT+ICIs were identified as the optimal model, which achieved the best efficacy without significantly increased AEs compared with sequential RT+ICIs.Combined ICIs and brain RT exhibited favorable efficacy and acceptable toxicity for NSCLC patients with BMs, among which, the concurrent model might be the optimal option. Our results could guide the design of future randomized controlled trials and clinical practice.

ObjectiveCirculating tumor cells (CTCs) can predict the efficacy of anti-cancer treatments and indicate prognosis. Here we investigate the significance of CTCs in relation to the prediction of treatment efficacy and prognosis in patients with small cell lung cancer (SCLC) who have received prophylactic cranial irradiation (PCI).MethodsCTCs were detected in 20 patients with SCLC before and after PCI using the oHSV1-hTERT-GFP method. The primary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsEleven patients had limited-stage SCLC, and nine had extensive-stage SCLC. All patients completed chemo-radiotherapy and received PCI. The median baseline CTC count before PCI was 12. After PCI, the median CTC count was 4. The median follow-up time for all enrolled patients was 39.2 months. The median PFS and OS were significantly reduced in patients with ≥4 CTCs after PCI compared to those with ConclusionIn SCLC patients who receive PCI, the CTC count and rate of CTC decline after PCI significantly correlate with prognosis.

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 score1 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).

Background The aim of this study was to evaluate the efficacy of postoperative radiotherapy (PORT) in stage pIIIA‐N2 non‐small cell lung cancer (NSCLC) patients with positive surgical margins. Methods Between January 2003 and December 2015, patients who had undergone lobectomy or pneumonectomy plus mediastinal lymph node dissection or systematic sampling in our single institution were retrospectively reviewed. Those with pIIIA‐N2 NSCLC and positive surgical margins were enrolled into the study. The Kaplan‐Meier method was used for survival analysis, and the log‐rank test was used to analyze differences between the groups. Univariate and multivariate analyses using Cox proportional hazards regression models were performed to evaluate potential prognostic factors for OS. Statistically significant difference was set as P, Postoperative radiotherapy (PORT) has been recommended to treat patients with positive surgical margins. However, the existing evidence is controversial and high‐level evidence is lacking. In our study, the PORT group had markedly, but not statistically significant, longer median OS compared with the non‐PORT group in R1 resection patients. OS was significantly longer in the R1 resection patients receiving adjuvant CRT than the surgery alone group.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare but severe pulmonary complication of malignant tumors. It is characterized by the presence of multiple microscopic tumor emboli attached to the endothelium of small pulmonary arteries and induces fibrointimal proliferation and the activation of coagulation. The main clinical manifestations of PTTM are dyspnea, dry cough, hypoxemia, pulmonary hypertension, right heart failure, thrombocytopenia, and disseminated intravascular coagulation (DIC). Chest computed tomography (CT) shows no distinctive findings, and PTTM is often unrecognized and universally underdiagnosed, with an appalling prognosis. An antemortem diagnosis of PTTM is also difficult due to a lack of specific clinical and imaging features. Moreover, there is presently no therapeutic management and the illness rapidly progresses to death. Early identification and timely and effective use of oncotherapy can help to alleviate symptoms and improve prognosis. According to recent reports, targeting angiogenesis factors including platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) have marginally improved survival. In this article, we report the case of a patient with advanced lung adenocarcinoma complicated with PTTM and DIC. A combined therapeutic regimen of bevacizumab with pemetrexed successfully improved chest CT findings, respiratory symptoms, DIC, and short-term outcomes. Anti-angiogenesis drugs modify the pulmonary vascular structure, and rapidly improve the lung tumor microenvironment. and therefore, it may be a potentially effective drug for the treatment of PTTM.

BACKGROUND: Chemoradiotherapy is the recommended treatment for patients with unresectable locally advanced non-small cell lung cancer (NSCLC). This study aimed to determine the impact of age on the survival outcomes and risk of radiation pneumonitis (RP) in patients with unresectable locally advanced NSCLC. METHODS: The data of patients with unresectable locally advanced NSCLC who were treated with radiotherapy (RT), sequential chemoradiotherapy, or concurrent chemoradiotherapy between January, 2013, and December, 2017, in our institution were retrospectively reviewed and analyzed. Student’s t-test and χ(2) test were used to evaluate the differences between groups divided by optimal cutoff. Survival rates were calculated using the Kaplan-Meier method, and multivariate cox regression was performed to determine the prognostic factors for survival outcomes. RESULTS: A total of 749 patients were included in this analysis. Based on the optimal cutoff, the patients were stratified into two age groups

Background The objectives of this study were to determine the objective effective response rate, survival, and safety of radiotherapy combined with gefitinib in patients with locally advanced non-small cell lung cancer (NSCLC) who were unfit for surgery or concurrent chemoradiotherapy. Methods The patients with the locally advanced NSCLC who were unfit to receive surgery or concurrent chemoradiotherapy, received thoracic intensity-modulated radiotherapy (IMRT) combined with gefitinib 250 mg daily. Results 29 patients were enrolled between July 2014 and March 2017. 28 patients was in the analysis. Of the 28 patients, 21 (75.0%) experienced a partial response, 5 (17.9%) had stable disease, and 2 (7.1%) experienced progression of disease. The objective response rate was 75.0%, and the disease control rate was 92.9%. The median follow-up time was 51 months. The disease progression showed in 25 (89.3%) patients, including local progression in 19 (67.9%) and distant metastasis in 16 (57.1%). The median overall survival and progression-free survival time (PFS) were 26 and 11 months, respectively. The 3-, 4-, 5-year survival rates were 39.0, 30.1 and 30.1%, respectively. The 3-, 4-, 5-year PFS rates were 14.3, 9.5 and 9.5%. Two patients developed grade 3 acute adverse events. Seven patients developed grade 2 acute irradiation pneumonitis, and there was no grade 3 acute irradiation pneumonitis. Conclusions For patients with locally advanced NSCLC who are not eligible for surgery or concurrent chemoradiotherapy, IMRT combined with gefitinib can improve the objective effective rate and is generally well-tolerated.

Background Baseline lung immune prognostic index (LIPI) was reported as a potential predictive biomarker of immune checkpoint inhibitor treatment and a prognostic biomarker for metastatic non-small cell lung cancer (NSCLC). However, it remains unclear whether LIPI is associated with outcomes in locally advanced NSCLC (LA-NSCLC). Materials/methods Patients with LA-NSCLC receiving radiotherapy between 2000 to 2017 were retrospectively reviewed. Based on pretreatment dNLR and LDH level made up LIPI per previous publications, patients were divided into good group (0 score) and intermediate-poor group (1 or 2 scores). Propensity score matching (PSM) was conducted to balance confounding variables. Results A total of 1079 patients were eligible for analysis. Patients with intermediate-poor pretreatment LIPI had inferior overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) than those with good LIPI. Multivariate analysis suggested that LIPI was an independent prognostic marker for OS (hazard ratio [HR] = 1.19, 95% CI: 1.02–1.40), PFS (HR = 1.18, 95% CI: 1.02–1.36), and LRRFS (HR = 1.22, 95% CI: 1.05–1.41) in patients with inoperable LA-NSCLC. PSM analysis further verified that intermediate-poor LIPI was an independent prognostic factor for shorter survivals (OS, PFS and LRRFS). Conclusions LIPI is a simple and promising prognostic marker for patients with unresectable LA-NSCLC. Further prospected studies are warranted to validated these findings.

Background There is no consensus on the therapeutic approach to ECOG 2 patients with locally advanced non-small-cell lung cancer (LA-NSCLC), despite the sizable percentage of these patients in clinical practice. This study focused on the efficacy, toxicity and the optimal chemotherapy regimen of CCRT in ECOG 2 patients in a phase III trial. Methods Patients capable of all self-care with bed rest for less than 50% of daytime were classified as ECOG 2 subgroup. A subgroup analysis was performed for ECOG 2 patients recruited in the phase III trial receiving concurrent EP (etoposide + cisplatin)/PC (paclitaxel + carboplatin) chemotherapy with intensity-modulated radiation therapy (IMRT) or three-dimensional conformal external beam radiation therapy (3D-CRT). Results A total of 71 ECOG 2 patients were enrolled into the study. Forty-six (64.8%) patients were treated with IMRT technique. The median overall survival (OS) and progression free survival (PFS) for ECOG 2 patients were 16.4 months and 9 months, respectively. No difference was observed in treatment compliance and toxicities between ECOG 2 patients and ECOG 0–1 patients. Within the ECOG 2 group (31 in the EP arm and 40 in the PC arm), median OS and 3-year OS were 15.7 months and 37.5% for the EP arm, and 16.8 months and 7.5% for the PC arm, respectively (p = 0.243). The incidence of grade ≥ 3 radiation pneumonitis was higher in the PC arm (17.5% vs. 0.0%, p = 0.014) with 5 radiation pneumonitis related deaths, while the incidence of grade 3 esophagitis was numerically higher in the EP arm (25.8% vs. 10.0%, p = 0.078). Conclusions CCRT provided ECOG 2 patients promising outcome with acceptable toxicities. EP might be superior to PC in terms of safety profile in the setting of CCRT for ECOG 2 patients. Prospective randomized studies based on IMRT technique are warranted to validate our findings. Trial registration ClinicalTrials.gov registration number: NCT01494558. (Registered 19 December 2011).

Backgrounds: Chemoradiation therapy (CRT) is the standard care for unresectable locally advanced non-small cell lung cancer (LA-NSCLC). The optimal management of patients with epidermal growth factor receptor gene (EGFR) mutant LA-NSCLC is not determine. Methods: We retrospectively collected data from patients with unresectable stage III lung adenocarcinoma (LAC) harboring EGFR mutations from 2012 to 2018 and categorized their primary treatment as CRT (group 1), combined radiation therapy (RT) and EGFR-tyrosine kinase inhibitors (TKI) with/without chemotherapy (group 2), or EGFR-TKI alone until tumor progression (group 3). Inverse probability of multiple treatment weighting (IPTW) of propensity score was used to compare overall survival (OS) and progression free survival (PFS) between treatments and account for confounding. Findings: EGFR mutations were present in 24.1% of genotyped patients (N=516/2137). Of 440 patients with adequate information, 104, 105, and 231 patients were in groups 1-3. Upon IPTW analysis, adjusted median PFS was 12.4, 26.2 and 16.2 months (log-rank P=0.001) for groups 1-3, and median OS was 51.0, 67.4 and 49.3 months (log-rank P= 0.084), respectively. Comparing to CRT, RT+TKI with/without chemotherapy significantly improved both PFS (adjusted HR [aHR], 0.40; 95% CI, 0.29-0.54; P= 0.001) and OS (aHR, 0.61; 95% CI, 0.38-0.98; P=0.039);TKI alone prolonged PFS (aHR=0.66; 95%CI, 0.50-0.87; P=0.003) but not OS (aHR,0.90; 95% CI, 0.62-1.32; P= 0.595). Similar findings were found in doubly robust IPTW analysis and multivariable Cox regression analysis. Interpretation: First-line use of RT+TKI with/without chemotherapy was associated with the longest PFS and OS compared with CRT or TKI alone in patients with EGFR-mutant unresectable LA-NSCLC. Trial Registration: The study was registered with Clinical Trials.gov, number NCT04304638. Funding Statement: This trial was funded by the National Natural Sciences Foundation Key Program (81572971); CAMS Innovation Fund for Medical Sciences (No. 2017-I2M-1-005), and Sanming Project of Medicine in Shenzhen (No. SZSM201612063) Declaration of Interests: All authors have declared no conflicts of interest. Ethics Approval Statement: The study protocol was approved by the ethics review boards of the Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College. Each participating center obtained regulatory approval per their institutional ethics guidelines.

OBJECTIVES: This study aimed to: (1) assess the prognostic significance of serum tumor markers in locally advanced squamous cell carcinoma in lung (LA-SCCL); (2) generate a nomogram to predict the overall survival (OS) and (3) identify a prognostic stratification to assist the therapeutic decision-making. METHODS: LA-SCCL patients receiving definitive radiotherapy and baseline tumor marker measurement were eligible for this retrospective study. Cox proportional hazards regression was used to determine independent factors associated with various survival indexes and a nomogram was created to estimate the 5-year OS probability for individual patient. The identified prognostic factors were recruited into a recursive partitioning analysis (RPA) for OS to stratify patients with distinct outcome. RESULTS: A total of 224 patients were eligible for analysis. Increased cytokeratin-19 fragment (CYFRA 21-1) was independently associated with inferior OS, progression free survival (PFS) and a borderline decreased local-regional progression free survival (LRPFS). Elevated carcino-embryonic antigen (CEA) served as an unfavorable determinant for OS and increased neuron-specific enolase (NSE) was predictive of poor distant metastasis free survival (DMFS). A nomogram integrating KPS, TNM stage, CEA and CYFRA 21-1 was created, resulting in a c-index of 0.62. RPA identified 4 prognostic classifications, with median OS of 27.6, 19.9, 17.3 and 10.9 months for low, intermediate, high and very-high risk groups, respectively. CONCLUSIONS: Baseline tumor marker panel including CYFRA 21-1, CEA and NSE can be prognostic of outcome for LA-SCCL receiving definitive radiotherapy. The RPA identified four prognostic subgroups, which could assist personalized therapy and clinical trial design in LA-SCCL.

BACKGROUND & AIMS Pulmonary transit time (PTT) is the transit time of blood from the right side of the heart to the left side of the heart. The aim of the present study was to evaluate the role of the PTT derived from pulmonary angiography in the diagnosis of hepatopulmonary syndrome (HPS). METHODS From December 2014 to September 2015, all patients with chronic liver disease and/or portal hypertension undergoing a venous interventional radiologic procedure at our institution were eligible for inclusion in this prospective study. Pulmonary angiography was performed in all patients, and the PTT, which was defined as the time between opacification of the pulmonary trunk and the right border of the left atrium, was determined. RESULTS A total of 53 patients were included, 20 of whom had a positive contrast-enhanced echocardiography result and an elevated alveolar-arterial oxygen gradient were considered to have HPS. PTT was significantly shorter in patients with HPS than in those without [median, 3.34 (interquartile range, 3.01-3.67) seconds vs 4.0 (interquartile range, 3.67-4.17) seconds; P

OBJECTIVES: MicroRNAs (miRNAs) play a key role in governing posttranscriptional regulation through binding to the mRNAs of target genes. This study is to assess miRNAs expression profiles for identifying brain metastasis-related miRNAs to develop the predictive model by microarray in tumor tissues. METHODS: For this study, we screened the significant brain metastasis-related miRNAs from 77 lung adenocarcinoma (LUAD) patients with brain metastasis (BM+) or non-brain metastasis (BM−). A predictive model was developed from the training set (n=42) using a random Forest supervised classification algorithm and a Class Centered Method, and then validated in a test set (n=35) and further analysis in GSE62182 (n=73). The independence of this signature in BM prediction was measured by multivariate logistic regression analysis. RESULTS: From the training set, the predictive model (including hsa-miR-210, hsa-miR-214 and hsa-miR-15a) stratified the patients into two groups with significantly different BM subtypes (90.4% of accuracy). The similar predictive power (91.4% of accuracy) was obtained in the test cohort. As an independent predictive factor, it was closely associated with BM and had high sensitivity and specificity in predicting BM in clinical practice. Moreover, functional enrichment analysis demonstrated that this signature involved in the signaling pathways positively correlated with cancer metastasis. CONCLUSION: These results suggested that the three-miRNA signature could develop a new random Forest model to predict the BM of LUAD patients. These findings emphasized the importance of miRNAs in diagnosing BM, and provided evidence for selecting treatment decisions and designing clinical trials.

Background Heath-related quality of life (HRQoL) among survivors with unresectable locally-advanced non-small cell lung cancer (LA-NSCLC) treated with radiotherapy and chemotherapy still is not clear. The current study were performed to determine HRQoL for long-term survivors with unresectable LA-NSCLC and to identify risk factors for poor HRQoL. Methods Among patients with LA-NSCLC receiving radiotherapy and chemotherapy between January 2006 and December 2010, 82 long-term survivors beyond 5 years were identified in this cross-sectional study. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and the lung cancer-specific questionnaire QLQ-LC13 were employed to gather information on HRQoL. HRQoL scores were compared between different subgroups to analyze factors related to HRQoL. Results Fifty-five out of 82 (67%) long-term survivors completed the HRQoL survey. They reported a mild reduction in global health status and physical and emotional functioning. Fatigue, dyspnea, coughing, and financial difficulties ranked the highest scores in the symptom scales. Analysis of risk factors for HRQoL showed age, exercise, smoking status, and treatment regimen were associated with global health status and functional scores, while age, gender, radiation pneumonitis, weight loss, and exercise were associated with symptom scores. Conclusions This study provides the first description of the HRQoL of long-term LA-NSCLC survivors receiving radiotherapy and chemotherapy who may experience a relatively high HRQoL. Factors related to poorer HRQoL are potential targets for intervention.

Importance The role of postoperative radiotherapy (PORT) has not been well defined in resected pIIIA-N2 non–small cell lung cancer (NSCLC). Objective To evaluate the effect of PORT using modern techniques on survival and safety in patients with pIIIA-N2 NSCLC after complete resection and adjuvant chemotherapy. Design, Setting, and Participants The PORT-C randomized clinical trial was conducted in 394 patients with pIIIA-N2 NSCLC treated with complete resection and 4 cycles of platinum-based chemotherapy between January 2009 and December 2017. Data were analyzed between March 2019 and December 2020. Interventions Patients were randomized equally into the PORT arm (n = 202) or the observation arm (n = 192). The total dose of PORT was 50 Gy. Main Outcomes and Measures The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS), locoregional recurrence–free survival (LRFS), distant metastasis–free survival, and toxic effects. Results In total, 394 patients were enrolled and 364 were eligible, with a median (range) age of 55 (25-70) years. There were 202 (55.5%) male and 162 (44.5%) female patients. The median follow-up was 46.0 (95% CI, 41.9-51.4) months, and 230 DFS events were reported. There were 184 patients in the PORT arm and 180 patients in the observation arm. The 3-year DFS rates were 40.5% with PORT vs 32.7% with observation (median, 22.1 vs 18.6 months), and the difference in DFS was not statistically significant without adjustment (hazard ratio [HR], 0.84; 95% CI, 0.65-1.09;P = .20), though it was significant with preplanned yet exploratory analysis (stratified analysis by the number of detected lymph nodes and positive lymph nodes, HR, 0.75; log-rankP = .04). The 3-year OS rates were 78.3% vs 82.8% (HR, 1.02;P = .93), and LRFS was 66.5% vs 59.7% (HR, 0.71; 95% CI, 0.51-0.97;P = .03), respectively. For 310 per-protocol patients (140 with PORT and 170 with observation), PORT significantly improved DFS (42.8% vs 30.6%; HR, 0.75; 95% CI, 0.57-1.00;P = .05) but not OS (HR, 0.83; 95% CI, 0.53-1.30;P = .41). The 3-year local recurrence only rates were 9.5% and 18.3% in the 2 arms, respectively (Fine-Gray HR, 0.55; Gray testP = .04). No radiotherapy-related grade 4 or 5 adverse event was observed. Conclusions and Relevance In this phase 3 randomized clinical trial of patients with pIIIA-N2 NSCLC after complete resection and adjuvant chemotherapy, PORT did not improve DFS. Further studies exploring patients who might best benefit from PORT are needed. Trial Registration ClinicalTrials.gov Identifier:NCT00880971

Background Systematic inflammation has been thought to play a crucial role in tumorigenesis and metastasis. This study is aimed to evaluate the prognostic value of time-series behavior of systematic inflammation-immune status before and after definitive chemoradiotherapy (dCRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). Methods The relation between systematic inflammation-immune score (SIS, defined as pretreatment peripheral platelet count × neutrophil count / lymphocyte count) and prognosis was tested in a retrospective study of 386 consecutive LA-NSCLC patients (Group A) with pretreatment SIS and 161 patients (Group B) with SIS before and one month after dCRT. Results SIS of 1400 × 109 was found to be an optimal cutoff point to stratify the patients into high (>1400 × 109) and low (≤1400 × 109) SIS groups. Univariate and multivariate analyses revealed that the SIS, whether before or after dCRT, was an independent predictor for overall survival (OS), progress-free survival (PFS) and distant metastasis-free survival (DMFS). High SIS (>1400 × 109) was shown to predict poor 3-year OS (p=0.006, hazard ratio [HR]=2.427), PFS (p=0.001, HR=2.442) and DMFS (p=0.015, HR=2.119). However, SIS was not related with Local regional recurrence-free survival either in Group A (p=0.346) or Group B (p=0.486). Further, the area under the receiver operating characteristic curve of the SIS for OS was higher than neutrophil count / lymphocyte count ratio, platelet count / lymphocyte count ratio and other conventional clinic-pathological indices. Conclusions The SIS is a stable and more sensitive survival predictor than other inflammation‑based factors and conventional clinical indices, which may aid in more accurately stratifying patients for risk assessment and treatment decision.

TPS8580 Background: Pembrolizumab, an anti‒PD-1 antibody is standard of care therapy for metastatic non‒small-cell lung cancer (NSCLC) as monotherapy and in combination with chemotherapy. Durvalumab, an anti–PD-L1 antibody, is approved for unresectable, stage III NSCLC without disease progression following concurrent chemoradiation therapy (CCRT). Early trials of pembrolizumab in combination with chemoradiotherapy, either concurrently or as consolidation, showed acceptable tolerability and promising PFS in patients with unresectable stage III NSCLC. Early data suggest the combination of poly(ADP-ribose) polymerase (PARP) plus anti–PD-(L)1 inhibition can enhance treatment effects. KEYLYNK-012 (NCT04380636) is evaluating pembrolizumab plus CCRT followed by pembrolizumab with/without the PARP inhibitor olaparib vs CCRT followed by durvalumab in patients with unresectable, locally advanced, stage III NSCLC. Methods: This global phase 3, randomized, placebo- and active-controlled, double-blind study is enrolling patients aged ≥18 y with previously untreated, pathologically confirmed, stage IIIA–C NSCLC, an ECOG PS of 0 or 1, and a tumor sample available for PD-L1 evaluation. Patients are randomized 1:1:1 to CCRT (platinum-doublet chemotherapy [cisplatin plus pemetrexed or etoposide; or carboplatin plus paclitaxel] plus radiotherapy 60 Gy over 6 wks [cycles 2–3]) with pembrolizumab 200 mg Q3W (groups A and B) or CCRT alone (group C) for 3 cycles. This is followed by pembrolizumab 200 mg Q3W for 17 cycles plus placebo (group A) or olaparib 300 mg BID (group B); or durvalumab 10 mg/kg Q2W for 26 cycles (group C). Randomization is stratified by disease stage (IIIA vs IIIB/IIIC), tumor histology (squamous vs nonsquamous), PD-L1 tumor proportion score (≥50% vs < 50%) and region (East Asia vs North America/Western Europe/UK vs other). PFS (RECIST v1.1 by blinded independent central review [BICR]) and OS are dual primary endpoints. Secondary endpoints include ORR, duration of response, safety and tolerability, and quality-of-life outcomes. Tumor response will be evaluated per RECIST v1.1 by BICR after CCRT and at regular intervals throughout the study until disease progression, new cancer therapy, study withdrawal, or death. AEs will be graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Enrollment began July 6, 2020 and is ongoing at 204 sites in 24 countries. Clinical trial information: NCT04380636.

Purpose The efficiency of radiation delivery via volumetric modulated arc therapy (VMAT) is indisputable, but outcomes after VMAT for thoracic esophageal carcinoma are largely unknown. Methods and materials We retrospectively analyzed 65 patients with thoracic esophageal cancer who received VMAT to 50.4 Gy (range, 45-50.4 Gy) with concurrent chemotherapy from November 2012 to March 2016 at a single tertiary cancer center. We then used propensity score matching to match these 65 patients with 130 other patients treated with step-and-shoot intensity modulated radiation therapy (ssIMRT) and concurrent chemotherapy. Differences in continuous and categorical variables were examined with independent-sample t or Wilcoxon tests and χ 2 tests. Results Dosimetrically, VMAT had a higher conformity index (87.75 ± 10.70 VMAT vs 83.20 ± 9.42 ssIMRT, P = .003), a higher heart V5, and a lower V50 than ssIMRT, but lung V5-20, heart V30, heart V40, cord max , and homogeneity index were similar. At median follow-up intervals of 14.3 months (range, 3.8-34.5 months) for VMAT and 31.8 months (range, 1.8-117.2 months) for ssIMRT, overall survival rates were similar between the treatments (93.5% VMAT vs 91.5% ssIMRT at 1 year; 60.0% VMAT and 61.4% ssIMRT at 2 years; P = .868). Recurrence-free survival rates were similar (73.3% VMAT vs 79.5% ssIMRT at 1 year, 59.9% VMAT and 61.8% ssIMRT at 2 years; P = .614), as were pathologic complete response rates (31.2% VMAT vs 23.3% ssIMRT; P = .41) and toxicity and postoperative complications (radiation pneumonitis 9% VMAT vs 15.4% ssIMRT; pericardial effusion 2% VMAT vs 7% ssIMRT; esophageal fistula and stricture 9% VMAT vs 13% ssIMRT; all P > .05). Conclusion Compared with ssIMRT, VMAT had better target conformity with similar organ sparing and comparable rates of survival, recurrence, and toxicity. These results suggest that VMAT can be safe and effective for esophageal cancer.

// Shuangtao Zhao 1, * , Shuangsang Fang 2, * , Yanhua Liu 3, 4, 5, * , Xixi Li 3, 6 , Shengyou Liao 2 , Jinwen Chen 2 , Jingjia Liu 2 , Lianhe Zhao 2 , Hui Li 2 , Wei Zhou 3, 4, 5 , Wenzhi Shen 3, 4, 5 , Xiaoli Dong 3, 4, 5 , Rong Xiang 3, 4, 5 , Luhua Wang 1 , Yi Zhao 2 1 Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China 2 The Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China 3 The School of Medicine, Nankai University, Tianjin, China 4 The Collaborative Innovation Center for Biotherapy, Nankai University, Tianjin, China 5 The Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Tianjin, China 6 Department of Pathology, Nankai University, Tianjin, China * Co-first author Correspondence to: Rong Xiang, email: rxiang@nankai.edu.cn Luhua Wang, email: wlhwq@yahoo.com Yi Zhao, email: biozy@ict.ac.cn Keywords: diffuse large B-cell lymphoma, long non-coding RNA, NONHSAG026900, prognosis, biomarker Received: January 17, 2017 Accepted: February 24, 2017 Published: March 13, 2017 ABSTRACT Long non-coding RNAs are known to be involved in cancer progression, but their biological functions and prognostic values are still largely unexplored in diffuse large B-cell lymphoma. In this study, long non-coding RNAs expression was characterized in 1,403 samples including normal and diffuse large B-cell lymphoma by repurposing 7 microarray datasets. Compared with any stage of normal B cells, NONHSAG026900 expression was significantly decreased in tumor samples. And in germinal center B-cell subtype, the significantly higher expression of NONHSAG026900 indicated it was a favorable prognosis biomarker. Then the prognostic power of NONHSAG026900 was validated with another independent dataset and NONHSAG026900 improved the predictive power of International Prognostic Index as an independent factor. Moreover, functional prediction and validation demonstrated that NONHSAG026900 could inhibit cell cycle activity to restrain tumor proliferation. These findings identified NONHSAG026900 as a novel prognostic biomarker and offered a new therapeutic target for diffuse large B-cell lymphoma patients.

Background Consistent results are lacking as regards the comparative effectiveness of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) versus conventional intensity-modulated radiotherapy in patients with locally advanced non-small-cell lung cancer (LA-NSCLC). Therefore, we conducted a retrospective analysis to demonstrate the role of SIB-IMRT for patients. Methods Patients who had histologically confirmed NSCLC, stage III disease and received thoracic IMRT between 2014 and 2016 were retrospectively reviewed. The survival, toxicities and dose to organs at risk (OAR) were compared among patients irradiated with different techniques. The SIB-IMRT plans were designed to deliver 45–59.4Gy (median: 50.4Gy) to PTV while simultaneously delivering 50-70Gy (median: 59.92Gy) to PGTV. As for conventional IMRT plans, a total dose of 50-70Gy (median: 60Gy) was delivered to PTV. Results 426 patients with stage III NSCLC were eligible for analysis, including 128 with SIB-IMRT and 298 with conventional IMRT. The SIB-IMRT group had more stage IIIB disease (69.5% vs. 53%, P = 0.002), larger planning treatment volumes (median: 504 ml vs. 402 ml, P

Background Total resection may not be achieved in patients with thymic carcinoma, particularly those with Masaoka stage III disease. Debulking surgery plus postoperative radiotherapy and radiation alone are treatment options for such patients. We aimed to compare the overall survival (OS) between patients with thymic carcinoma who underwent debulking surgery plus postoperative radiotherapy and those who underwent radiation alone. Methods This was a single-center retrospective study of patients histologically diagnosed as having Masaoka stage III thymic carcinoma between January 1980 and January 2010. Patients were classified into the following groups according to treatments received: debulking surgery plus radiotherapy (group A) and radiotherapy alone (group B). Data on demographics, histology, invasion, radiotherapy, chemotherapy, and survival were collected. Survival time was calculated and compared between the groups using the Kaplan–Meier method. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results Of the 47 enrolled patients, 26 and 21 patients were categorized into groups A and B, respectively. There are no significant differences in the Eastern Cooperative Oncology Group performance status score, histological type, great vessel invasion, and chemotherapy proportion between the groups. The median radiation dose was 60 Gy in both groups. The 5-year OS rates were 54.4 and 0% in groups A and B, respectively (p = 0.019). No operation-induced mortality was recorded. Conclusion For patients with unresectable Masaoka stage III disease, debulking surgery with radiotherapy is preferred, as this was proven to be more efficient than the radiation-alone procedure.

Background Systematic inflammation-immune status has been thought to play a crucial role in tumorigenesis and progress. This study evaluated the prognostic value of systematic inflammation-immune status in patients with resected non-small cell lung cancer with pathological N2 nodal involvement (pN2-NSCLC). Methods The relation between the preoperative systematic inflammation-immune score (SIS), defined as preoperative peripheral platelet count × neutrophil count/lymphocyte count, and prognosis was tested in a retrospective study of 660 consecutive patients with completed resected pN2-NSCLC and validated by a prospective study of 189 patients enrolled (NCT00880971). Results SIS of 650 × 109 was an optimal cutoff point to stratify the patients with pN2-NSCLC into high (>650 × 109) and low (≤650 × 109) SIS groups in the training cohort. Univariate and multivariate analyses revealed that the SIS was an independent predictor for overall survival, disease-free survival, and distant metastasis-free survival. In the validation group, high SIS (>650 × 109) predicted poor 5-year overall survival (hazard ratio [HR], 2.418; P = .006), disease-free survival (HR, 1.542; P = .042), and distant metastasis-free survival (HR, 1.682; P = .024). In addition to the number of positive lymph nodes, the area under the receiver operating characteristic curve of the SIS for outcomes was higher than the neutrophil count-to-lymphocyte count ratio, platelet count-to-lymphocyte count ratio, and other conventional clinicopathologic indices. Conclusions The preoperative SIS is a more sensitive survival predictor than most of the other conventional clinical indices and may aid in more accurately stratifying patients for risk assessment and treatment decision.

Background Consistent results are lacking as regards the comparative effectiveness of intensity-modulated radiotherapy (IMRT) versus three-dimensional conformal radiotherapy (3DCRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). Patients and methods Patients treated with definitive radiotherapy (RT) between 2002 and 2010 were retrospectively reviewed. Overall survival (OS), local-regional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) were compared among patients irradiated with different techniques. The association between RT technique and survival indexes was assessed in a Cox proportional hazard regression model. Propensity score matching (PSM) was used to balance known confounding factors. Results A total of 652 patients were eligible for analysis, including 206 with 3DCRT and 446 with IMRT. The median OS of the 3DCRT and IMRT groups were 19.4 and 23.3 months, with the 5-year rate of 13% and 19%, respectively (p = .043). Multivariate analysis identified IMRT as an independent favorable factor associated with LRPFS and DMFS. PSM analysis further verified the beneficial effect of IMRT on LRPFS. No difference in OS or PFS was observed between the two techniques. Subgroup analysis revealed that IMRT might be differentially more effective in both OS and LRPFS among patients who were female, nonsmokers, with adenocarcinoma, or without weight loss. There was a significant reduction of lung toxicity and similar esophagus toxicity in the IMRT group when compared with the 3DCRT group. Conclusion IMRT may confer superior LRPFS and comparable OS than can be achieved with 3DCRT in LA-NSCLC, along with the reduction of pulmonary toxicity. Implications for practice Based on the largest number of patients from a single institution, the present study demonstrated that intensity-modulated radiotherapy (IMRT) could provide superior local-regional progression-free survival and similar overall survival compared with the traditional three-dimensional conformal radiotherapy (3DCRT) for stage III non-small cell lung cancer (NSCLC). IMRT was also found to be associated with the significantly decreased incidence of pulmonary toxicity. These results suggest that IMRT should be considered a surrogate for 3DCRT in locally advanced NSCLC and might be the preferred option for a female nonsmoker with adenocarcinoma and a potentially high risk of pulmonary toxicity from radiotherapy.

// Wei Jiang 1 , Nan Bi 1 , Wen-Jue Zhang 1 , Li-Hong Wu 1 , Li-Pin Liu 1 , Yu Men 1 , Jing-Bo Wang 1 , Jun Liang 1 , Zhou-Guang Hui 1 , Zong-Mei Zhou 1 , Lu-Hua Wang 1 1 Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Correspondence to: Lu-Hua Wang, e-mail: wlhwq@yahoo.com Keywords: small cell lung cancer, limited-disease, single nucleotide polymorphisms, microRNA, apoptosis pathway Received: November 26, 2015 Accepted: February 21, 2016 Published: March 16, 2016 ABSTRACT We examined the impact of single nucleotide polymorphisms (SNPs) at miRNA binding sites in the 3′-UTRs of genes in the apoptosis pathway on the prognosis of patients with limited disease-small cell lung cancer (LD-SCLC). Twelve tagSNPs in seven genes were genotyped using blood samples from 146 LD-SCLC patients treated with chemoradiotherapy. Cox proportional hazard regression models and recursive partitioning analysis were performed to identify SNPs significantly associated with overall survival. Three SNPs, CASP8: rs1045494 (C > T), PIK3R1: rs3756668 (A > G) and CASP7: rs4353229 (T > C), were associated with longer overall survival in LD-SCLC patients after chemoradiotherapy. The adjusted hazard ratios (95% confidence intervals) were 0.480 (0.258–0.894), 0.405 (0.173–0.947) and 0.446 (0.247–0.802), respectively, and remained significant after multiple comparison correction. Moreover, subset analysis showed these SNPs were still predictive of overall survival in stage III patients. Recursive partitioning analysis enabled patients to be classified into three risk subgroups based on unfavorable genotype combinations of the rs1045494 and rs4353229 SNPs. These findings suggest miRNA-related polymorphisms in the apoptosis pathway may be useful biomarkers for selection of LD-SCLC patients likely to benefit from chemoradiotherapy.

Objective Combined small cell lung cancer (C-SCLC) is an uncommon subgroup of small cell lung cancer (SCLC) and few clinical data can be referred. Our study is to investigate the clinical features and prognostic factors of C-SCLC, as well as the role of multimodality treatment. Methods Between January 2004 and December 2012, patients with histologically diagnosed C-SCLC were retrospectively analyzed. The survivals were evaluated with the Kaplan-Meier method. Univariate and multivariate analyses were used to evaluate potential prognostic factors. Results One hundred and fourteen patients were enrolled, with a median age of 59 (range: 20−79) years old. The most common combined component was squamous cell carcinoma (52.6%). Among these patients, the disease was stage I, II, III and IV in 9.6%, 19.3%, 46.5% and 24.6% of the patients, respectively. Eighty patients (70.2%) received at least two of the three modalities containing chemotherapy, radiotherapy and surgery. The median follow-up was 32.5 months. The median time of overall survival (OS) was 26.2 months. On univariate analysis, smoking (P=0.029), Karnofsky performance score (KPS) 10% (P=0.000) and non-multimodality treatment (P=0.004) were associated with poor OS. Multivariate analysis confirmed that smoking, advanced TNM stage, positive resection margin and positive lymph nodes ratio >10% were poor prognostic features. Conclusions C-SCLC has a relatively early stage and good prognosis, which may due to the underestimated diagnosis in non-surgical patients. Multimodality therapy is recommended, especially for limited disease. Smoking, advanced TNM stage, positive resection margin and positive lymph nodes ratio >10% are poor prognostic factors.

Purpose: To evaluate the usefulness of helical tomotherapy (HT) in the treatment of advanced esophageal cancer (EC) and compare target homogeneity, conformity and normal tissue doses between HT and fixed-field intensity-modulated radiotherapy (ff-IMRT).Methods: In all, 23 patients with cT3-4N0-1M0-1a thoracic EC (upper esophagus, 9 patients; middle esophagus, 6; distal esophagus, 6 and esophagogastric junction, 2) who were treated with ff-IMRT (60 Gy in 30 fractions) were re-planned for HT and ff-IMRT with the same clinical require­ments. Comparisons were performed using the Wilcoxon matched-pair signed-rank test.Results: Compared with ff-IMRT, HT significantly reduced the homogeneity index for thoracic, upper, middle and distal ECs by 38%, 31%, 36% and 33%, respectively (P < 0.05). The conformity index was increased by HT for thoracic, upper and middle ECs by 9%, 9% and 18%, respectively (P < 0.05). Target coverage was improved by 1% with HT (P < 0.05). The mean lung dose was significantly reduced by HT for thoracic and upper ECs (P < 0.05). The V20 (volume receiving at least 20 Gy) and higher dose volumes of the lungs were decreased by HT in all cases, but the differences were significant for thoracic, upper and distal ECs (P < 0.05), with reductions of 2.1%, 3.1% and 2.2%, respectively. HT resulted in a larger lung V5 for thoracic, upper, middle and distal ECs, with increases of 3.5%, 1.5%, 7.2% and 3.2%, respectively. Heart sparing was significantly better with HT than with ff-IMRT in terms of the V30 and V40 for thoracic, upper, middle and distal ECs (P < 0.05).Conclusions: Compared to ff-IMRT, HT provides superior target coverage, conformity and homogeneity, with reduced the volume of high doses to the lungs and heart for advanced EC. HT may be a treatment option for advanced EC, especially upper EC.

Background To investigate the clinical outcomes and toxicity of hypofractionated radiotherapy for medically inoperable stage I non-small cell lung cancer (NSCLC). Methods Patients treated with radiotherapy at a dose of 4–6 Gy per fraction using fixed-field intensity modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT) at our hospital from June 2005 to December 2013 were analyzed. The total prescription doses ranged from 50–78 Gy with 4–6 Gy per fraction. The median follow-up period was 24 months. Results A total of 65 patients with stage I NSCLC were analyzed, including 43 primary NSCLC patients and 22 patients with recurrent or second primary NSCLC. An objective response (complete or partial response) was achieved at six months in 84.6% of patients. The three-year local control rate was 90.8%. Kaplan–Meier estimates of local failure-free, progression-free, overall, and cancer-specific survival rates at three years were 90.3%, 64.3%, 68.9%, and 88.8%, respectively. The rate of symptomatic radiation pneumonitis was 16.9%, and no grade 4–5 toxicity was observed. Conclusion Favorable local control and outcome was achieved with hypofractionated radiotherapy in patients with inoperable stage I NSCLC with acceptable toxicity. The most common schedule of 6 Gy × 12 fractions may be a promising regimen, and a prospective study is in process.

Background Programmed death ligand 1 (PD-L1) is a ligand for the inhibitory programmed cell death protein 1 (PD-1), which are targeted by several anti-PD-1 and PD-L1 drugs for a variety of human cancers. However, only a few studies have evaluated PD-L1 expression in esophageal squamous cell carcinoma (ESCC) with a large Chinese cohort. Our present study is to evaluate the association of PD-L1 expression with clinicopathological features on ESCC. Methods Using tissue microarray and immunohistochemistry, PD-L1 expression on tumor cells and tumor-infiltrating immune cells was studied in 378 advanced ESCC patients without neoadjuvant chemoradiotherapy. Its correlation with clinicopathological parameters was analyzed. Results PD-L1 was expressed on 29.9% (113/378) ESCC tumor cells and 40.2% (152/378) tumor-infiltrating immune cells. PD-L1 expression in tumor cells was significantly correlated with age, degree of differentiation, T stage, N stage and metachronous hematogenous metastasis, and PD-L1 expression in tumor-infiltrating immune cells was significantly associated with N stage (P

Importance Treatment of locally advanced non–small cell lung cancer (NSCLC) remains challenging. The rationale of combining a cyclooxygenase 2 (COX-2) inhibitor with concurrent chemoradiation (CCRT) was based on results of preclinical research and prospective clinical studies; however, no randomized clinical trial has provided evidence of a direct comparison with CCRT alone. Objective To determine the effect of combined selective COX-2 inhibition with standard CCRT on survival among patients with unresectable stage III NSCLC. Design, Setting, and Participants A single-center, open-label, randomized phase 2 clinical trial was performed among 96 patients who had histologically and cytologically confirmed unresectable stage III NSCLC. Participants were enrolled from November 2011 to August 2015. Data were analyzed from February to October 2018. Intervention Patients were randomized to receive thoracic radiation, 60 Gy, for 6 weeks concurrent with etoposide and cisplatin or the same regimen of CCRT combined with 200 mg of celecoxib, taken twice daily. Main Outcomes and Measures The primary end point was overall survival. The secondary end points were the proportion of patients with treatment-related toxic effects, progression-free survival, and overall survival in subgroups with and without the COX-2 genotype. Results A total of 100 patients were randomized. Following the exclusion of 4 outliers, 96 participants (96.0%) were analyzed (51 randomized to CCRT alone and 45 randomized to CCRT with celecoxib; mean [SD] age, 60.0 [8.3] years; 73.0 [76.0%] male). The median overall survival time was 32.8 (95% CI, 17.0-48.5) months in the group that received CCRT with celecoxib and 35.5 (95% CI, 25.8-45.2) months in the group that received CCRT alone (P = .88). Celecoxib with CCRT was well tolerated; the incidence of symptomatic radiation pneumonitis was 6.6% (95% CI, 1.4%-18.0%) in the group that received CCRT with celecoxib and 11.8% (95% CI, 4.4%-23.9%) in the group that received CCRT alone (P = .49). Among patients with the high-risk genotype, celecoxib plus CCRT was not associated with higher progression-free survival (hazard ratio, 0.36; 95% CI, 0.13-1.04;P = .05) or overall survival (hazard ratio, 0.50; 95% CI, 0.15-1.72;P = .26) compared with CCRT alone. Conclusions and Relevance In unresectable stage III NSCLC, adding celecoxib to concurrent chemoradiation did not improve survival. A smaller, not statistically significant proportion of patients in the CCRT with celecoxib group compared with the CCRT alone group developed symptomatic radiation pneumonitis. Among patients with the high-risk genotype, adding celecoxib to CCRT did not improve overall or progression-free survival. Trial Registration ClinicalTrials.gov identifier:NCT01503385

IMPORTANCE: Increasing evidence suggests the significance of the role of the immune system in the progression of smoldering multiple myeloma (SMM) to symptomatic multiple myeloma (MM). Boosting the immune system via vaccination in the earlier, asymptomatic SMM stage may provide a novel strategy to prevent or slow progression to active MM. OBJECTIVE: To determine the safety, tolerability, immunogenicity, and anti-MM activity of the PVX-410 multipeptide vaccine with or without lenalidomide. DESIGN, SETTING, AND PARTICIPANTS: This 3-cohort phase 1/2a multicenter dose-escalation study accrued 22 adults (≥18 years) with SMM with normal organ/marrow function who were human leukocyte antigen A2-positive and at moderate or high risk of progression to MM. INTERVENTIONS: Patients received 6 doses of PVX-410 emulsified in Montanide ISA 720 VG, 0.4 mg total (0.1 mg/peptide) (n = 3) or 0.8 mg total (0.2 mg/peptide) (n = 9), biweekly via subcutaneous injection. In the combination cohort (n = 10), patients also received three 21-day cycles of lenalidomide, 25 mg, orally daily every 28 days. All patients received 0.5 mL (1 mg) poly-ICLC (2 mg/mL) via intramuscular injection with each PVX-410 dose. MAIN OUTCOMES AND MEASURES: Adverse events (AEs) were evaluated using the Common Terminology Criteria for Adverse Events, version 4.03. PVX-410–specific T lymphocytes by flow cytometry to assess tetramer and interferon (IFN)-γ response. Disease response was assessed by investigators using the International Myeloma Working Group (IMWG) and modified European Group for Bone Marrow Transplantation (EBMT) criteria. RESULTS: Overall, 14 (64%) patients were men and the median age at enrollment was 56 years in the monotherapy and 57 years in the combination cohorts (overall range, 39-82 years). Six of 12 patients in the monotherapy and 9 of 10 in the combination cohorts were at moderate risk. The PVX-410 vaccine was well tolerated. The most common AEs were mild-to-moderate injection site reactions and constitutional symptoms. Of note, PVX-410 was immunogenic as monotherapy (10 of 11 patients) and in combination with lenalidomide (9 of 9 patients), as demonstrated by an increase in percentage of tetramer-positive cells and IFN-γ cells in the CD3(+)CD8(+) cell population. The combination resulted in greater mean fold increases in proportions of CD3(+)CD8(+) T cells that were tetramer-positive and IFN–γ-positive, statistically significant for IFN–γ-positive cells after 2 and 4 vaccinations. An increase and persistence of vaccine-specific effector memory cells was noted. In total, 7 of 12 patients in the PVX-410–alone cohort had stable disease with 2 of 3 (low-dose cohort) and 1 of 9 of the target-dose cohort progressing (median TTP, 36 weeks), whereas 5 of 12 patients in the combination cohort showed, clinical response, with 1 patient progressing (median TTP not reached). CONCLUSIONS AND RELEVANCE: Overall, these results suggest that the vaccine is safe and immunogenic in this patient population and support continued study of PVX-410 in SMM. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01718899

Objective About 50–70% non-small cell lung cancer (NSCLC) patients with EGFR mutation go through brain metastases (BM). Radiotherapy is the standard treatment before the tyrosine kinase inhibitor (TKI) era. However, the TKI has more than 70% intracranial response rate. Here, we performed a meta-analysis to compare clinical outcomes of up-front radiotherapy and TKI with TKI alone for NSCLC with BM and EGFR mutations. Methods and materials We searched Embase, Pubmed, Web of Science, Medline, the Cochrane Library and important oncology meetings comparing the up-front radiotherapy (RT) and TKI with TKI alone in NSCLC patients with newly diagnosed BM and EGFR mutation from database inception to December 2017. We conducted meta-analyses evaluating intracranial progression-free survival (iPFS) and overall survival (OS) with hazard ratios (HR) and 95% confidence intervals (CI) based on the HR of individual study. Results Seven studies with 1086 patients were eligible for meta-analyses. Compared to TKI alone, up-front RT and TKI showed better iPFS (HR = 0.72, 95%CI: 0.53-0.97, p = 0.028) and OS (HR = 0.70, 95%CI 0.53–0.93, p = 0.015). Meta regression analyses and subgroup analyses demonstrated patients with limited number of brain metastases benefited more from up-front RT on OS (HR: 0.54, 95% CI: 0.41-0.72, p = 0.000). Conclusion Compared with TKI alone, up-front RT and TKI had a higher iPFS and OS, especially for patients with limited number of brain metastases. Larger randomized trials evaluating these two treatment arms are needed to identify optimal treatments for specific patients.

Background Sample quality is critical for biomarker detection in oncology, and platelet degradation and contamination in plasma have a remarkable impact on the ability to accurately quantify many blood-based biomarkers. Platelet factor 4 (PF4) can be used as an indicator to monitor sample quality. This multicenter study aimed to determine the impact of critical components of the blood sample handling process on platelet degradation/contamination and to establish an optimal method for collecting platelet-poor plasma samples. Methods At each of six participating centers, blood samples were drawn from 12-13 healthy volunteers. Serum and plasma samples were prepared from whole blood samples using nine different methods that have been commonly used in ongoing multicenter trials. PF4 levels in the prepared samples were measured by enzyme-linked immunosorbent assay (ELISA). Paired t-tests were used for statistical analysis. Results Blood samples were collected from 74 subjects enrolled in six centers. PF4 levels were significantly higher in serum samples than in plasma samples (P

Background This study investigates the outcome of synchronous stage IV non-small cell lung cancer (NSCLC) patients who received radical thoracic radiotherapy (TRT). Methods We retrospectively reviewed the charts of stage IV NSCLC patients treated with TRT between January 2007 and December 2011. Radiotherapy was considered radical if it was the primary therapy with non-symptom driven intent, or consolidation therapy after initial chemotherapy and the biologically equivalent dose ≥53 Gy halted disease progression. The patients' demographics, disease characteristics, and treatment parameters were uniformly collected. Results Eighty-one patients were irradiated with radical intent, including 52% with more than five metastatic lesions. The minimum follow-up was 31.5 months for survivors. The median overall survival (OS) was 20.8 months, with three and four-year OS rates of 23% and 18%, respectively. The median progression-free survival (PFS) was 8.2 months, with one and two-year PFS rates of 23% and 9%, respectively. Partial response (PR) after TRT and administration of targeted therapy were predictive of longer OS. The factors associated with favorable PFS included earlier local tunor node stage, absence of concurrent chemotherapy, and post-TRT PR. No correlation was found between the number of metastatic lesions and survival outcome. Incidences of grade ≥2 toxicities in the lung and esophagus were 9% and 26%, respectively. Conclusions Radical TRT may result in advantageous outcomes for selected stage IV NSCLC patients, regardless of the number of metastatic foci. Patients who achieved post-TRT PR attained the best outcomes.

Background The aim of this study was to investigate the clinical characteristics and outcomes of patients with primary malignant mediastinal non-seminomatous germ cell tumor (MMNSGCT) by comparing the efficacies of different treatment modalities. Methods The charts of 62 consecutive patients with MMNSGCT between 1990 and 2010 were reviewed. Analyses included Kaplan-Meier survival and Cox multivariate regression. Results There was sufficient data of 61 patients for inclusion in the study. The median age was 25 years. At diagnosis, 35 patients had tumors located in the mediastinum, 26 had lung and/or distant metastases. At a median follow-up of 47.2 months, 32 patients had died and 43 had developed progressive disease. The one, three, and five-year overall survival (OS) and progression-free survival (PFS) rates were 72.1%, 50.8%, 49.2% and 47.5%, 32.8%, 32.8%, respectively. Patients who received radiotherapy in the primary treatment regimen showed improved five-year OS (68.2% vs. 38.5%, P = 0.043), PFS (45.5% vs. 20.5%, P = 0.023), and local recurrence-free survival (LRFS) (77.3% vs. 38.5%, P = 0.003) compared with those who did not receive radiotherapy. Multivariate analysis revealed that radiotherapy was an independent prognostic factor of five-year OS (hazard ratio [HR] 0.39, P = 0.037), PFS (HR 0.42, P = 0.017), and LRFS (HR 0.31, P = 0.019). Conclusion Radiotherapy in a chemotherapy-based treatment regimen could significantly reduce local recurrence and improve survival of MMNGCT patients.

Background To establish a prediction model in selecting fit patients with resected pIIIA-N2 non-small cell lung cancer (NSCLC) for postoperative radiotherapy (PORT), and evaluate the model in clinical practice. Methods Between January 2003 and December 2005, 221 patients with resected pIIIA-N2 NSCLC were retrospectively analyzed. The effect of PORT on overall survival (OS) of patients with different clinicopathological factors was evaluated and the results were used to establish a prediction model to select patients fit for PORT. Results Compared with the control, PORT significantly improved the OS of patients with a smoking index ≤400 (P = 0.033), cN2 (P = 0.003), pT3 (P = 0.014), squamous cell carcinoma (SCC) (P = 0.013), or ≥4 positive nodes (P = 0.025). Patients were divided from zero to all five factors into low, middle, and high PORT index (PORT-I) groups (scored 0–1, 2, and 3–5, respectively). PORT did not improve OS (3-year, P = 0.531), disease free survival (DFS) (P = 0.358), or loco-regional recurrence free survival (LRFS) (P = 0.412) in the low PORT-I group. PORT significantly improved OS (P = 0.033), and tended to improve DFS (P = 0.064), but not LRFS (P = 0.287) in the middle PORT-I group. PORT could significantly improve OS (P = 0.000), DFS (P = 0.000), and LRFS (P = 0.006) in the high PORT-I group. Conclusion The prediction model is valuable in selecting patients with resected pIIIA-N2 NSCLC fit for PORT. PORT is strongly recommended for patients with three or more of the five factors of smoking index ≤400, cN2, pT3, SCC, and ≥4 positive nodes.

Treatment of inoperable, locally advanced non-small cell lung cancer (LA-NSCLC) is challenging and requires a multidisciplinary approach considering both local therapy and systemic therapy. Based on the results from several phase III studies and 2 meta-analyses, the use of concomitant chemoradiation therapy (ChRT) could significantly improve overall survival and is considered the standard of care in LA-NSCLC with good performance status. Currently, no evidence has shown a significant survival benefit of third-generation regimens applied in combination with ChRT compared with second-generation regimens. For regimens concomitant with radiation therapy, full-dose chemotherapy (such as cisplatin and etoposide or cisplatin and vinblastine) might be preferred. Additional full-dose consolidation paclitaxel-carboplatin is recommended when patients receive weekly paclitaxel-carboplatin ChRT. Effective novel chemotherapy agents or targeted therapies are required to further improve the outcome of patients with LA-NSCLC. In addition, personalized medicine concomitant with radiation therapy is a promising approach. However, little evidence exists concerning the effectiveness of this novel approach.