Deep Learning Based on Computed Tomography Predicts Response to Chemoimmunotherapy in Lung Squamous Cell Carcinoma.

Non-small-cell lung carcinoma (NSCLC) often carries a dire prognosis. The advent of neoadjuvant chemoimmunotherapy (NCI) has become a promising approach in NSCLC treatment, making the identification of reliable biomarkers for major pathological response (MPR) crucial. This study aimed to devise a deep learning (DL) model to estimate the MPR to NCI in lung squamous cell carcinoma (LUSC) patients and uncover its biological mechanism. We enrolled a cohort of 309 LUSC patients from various medical institutions. A ResNet50 model, trained on contrast-enhanced computed tomography images, was developed, and validated to predict MPR. We examined somatic mutations, genomic data, tumor-infiltrating immune cells, and intra-tumor microorganisms. Post-treatment, 149 (48.22%) patients exhibited MPR. The DL model demonstrated excellent predictive accuracy, evidenced by an area under the receiver operating characteristic curve (AUC) of 0.95 (95% CI: 0.98-1.00) and 0.90 (95% CI: 0.81-0.98) in the first and second validation sets, respectively. Multivariate logistic regression analysis identified the DL model score (low vs. high) as an independent predictor of MPR. The prediction of MPR (P-MPR) correlated with mutations in four genes, as well as gene ontology and pathways tied to immune response and antigen processing and presentation. Analysis also highlighted diversity in immune cells within the tumor microenvironment and in peripheral blood. Moreover, the presence of four distinct bacteria varied among intra-tumor microorganisms. Our DL model proved highly effective in predicting MPR in LUSC patients undergoing NCI, significantly advancing our understanding of the biological mechanisms involved.

Six versus four or five cycles of first-line etoposide and platinum-based chemotherapy combined with thoracic radiotherapy in patients with limited-stage small-cell lung cancer: A propensity score-matched analysis of a prospective randomized trial.

OBJECTIVES: The recommended treatment for limited-stage small-cell lung cancer (LS-SCLC) is a combination of thoracic radiotherapy (TRT) and etoposide plus cisplatin (EP) chemotherapy, typically administered over 4-6 cycles. Nonetheless, the optimal duration of chemotherapy is still not determined. This study aimed to compare the outcomes of patients with LS-SCLC who received either 6 cycles or 4-5 cycles of EP chemotherapy combined with TRT. MATERIALS AND METHODS: In this retrospective analysis, we utilized data from our prior prospective trial to analyze the outcomes of 265 LS-SCLC patients who received 4-6 courses of EP combined with concurrent accelerated hyperfractionated TRT between 2002 and 2017. Patients were categorized into two groups depending on their number of chemotherapy cycles: 6 or 4-5 cycles. To assess overall survival (OS) and progression-free survival (PFS), we employed the Kaplan-Meier method after conducting propensity score matching (PSM). RESULTS: Among the 265 LS-SCLC patients, 60 (22.6%) received 6 cycles of EP chemotherapy, while 205 (77.4%) underwent 4-5 cycles. Following PSM (53 patients for each group), the patients in the 6 cycles group exhibited a significant improvement in OS and PFS in comparison to those in the 4-5 cycles group [median OS: 29.8 months (95% confidence interval [CI], 23.6-53.1 months) vs. 22.7 months (95% CI, 20.8-29.1 months), respectively, p = 0.019; median PFS: 17.9 months (95% CI, 13.7-30.5 months) vs. 12.0 months (95% CI, 9.8-14.2 months), respectively, p = 0.006]. The two-year and five-year OS rates were 60.38% and 29.87% in the 6 cycles group, whereas 47.17% and 15.72% in the 4-5 cycles group, respectively. CONCLUSION: Patients diagnosed with LS-SCLC who were treated with EP regimen chemotherapy combined with TRT exhibited notably enhanced survival when administered 6 cycles of chemotherapy, as compared to those who underwent only 4-5 cycles.

A novel sub-regional radiomics model to predict immunotherapy response in non-small cell lung carcinoma.

BACKGROUND: Identifying precise biomarkers of immunotherapy response for non-small cell lung carcinoma (NSCLC) before treatment is challenging. This study aimed to construct and investigate the potential performance of a sub-regional radiomics model (SRRM) as a novel tumor biomarker in predicting the response of patients with NSCLC treated with immune checkpoint inhibitors, and test whether its predictive performance is superior to that of conventional radiomics, tumor mutational burden (TMB) score and programmed death ligand-1 (PD-L1) expression. METHODS: We categorized 264 patients from retrospective databases of two centers into training (n = 159) and validation (n = 105) cohorts. Radiomic features were extracted from three sub-regions of the tumor region of interest using the K-means method. We extracted 1,896 features from each sub-region, resulting in 5688 features per sample. The least absolute shrinkage and selection operator regression method was used to select sub-regional radiomic features. The SRRM was constructed and validated using the support vector machine algorithm. We used next-generation sequencing to classify patients from the two cohorts into high TMB (≥ 10 muts/Mb) and low TMB (< 10 muts/Mb) groups; immunohistochemistry was performed to assess PD-L1 expression in formalin-fixed, paraffin-embedded tumor sections, with high expression defined as ≥ 50% of tumor cells being positive. Associations between the SRRM and progression-free survival (PFS) and variant genes were assessed. RESULTS: Eleven sub-regional radiomic features were employed to develop the SRRM. The areas under the receiver operating characteristic curve (AUCs) of the proposed SRRM were 0.90 (95% confidence interval [CI] 0.84-0.96) and 0.86 (95% CI 0.76-0.95) in the training and validation cohorts, respectively. The SRRM (low vs. high; cutoff value = 0.936) was significantly associated with PFS in the training (hazard ratio [HR] = 0.35 [0.24-0.50], P < 0.001) and validation (HR = 0.42 [0.26-0.67], P = 0.001) cohorts. A significant correlation between the SRRM and three variant genes (H3C4, PAX5, and EGFR) was observed. In the validation cohort, the SRRM demonstrated a higher AUC (0.86, P < 0.001) than that for PD-L1 expression (0.66, P = 0.034) and TMB score (0.54, P = 0.552). CONCLUSIONS: The SRRM had better predictive performance and was superior to conventional radiomics, PD-L1 expression, and TMB score. The SRRM effectively stratified the progression-free survival (PFS) risk among patients with NSCLC receiving immunotherapy.

Determining the prognosis of Lung cancer from mutated genes using a deep learning survival model: a large multi-center study.

BACKGROUND: Gene status has become the focus of prognosis prediction. Furthermore, deep learning has frequently been implemented in medical imaging to diagnose, prognosticate, and evaluate treatment responses in patients with cancer. However, few deep learning survival (DLS) models based on mutational genes that are directly associated with patient prognosis in terms of progression-free survival (PFS) or overall survival (OS) have been reported. Additionally, DLS models have not been applied to determine IO-related prognosis based on mutational genes. Herein, we developed a deep learning method to predict the prognosis of patients with lung cancer treated with or without immunotherapy (IO). METHODS: Samples from 6542 patients from different centers were subjected to genome sequencing. A DLS model based on multi-panels of somatic mutations was trained and validated to predict OS in patients treated without IO and PFS in patients treated with IO. RESULTS: In patients treated without IO, the DLS model (low vs. high DLS) was trained using the training MSK-MET cohort (HR = 0.241 [0.213-0.273], P < 0.001) and tested in the inter-validation MSK-MET cohort (HR = 0.175 [0.148-0.206], P < 0.001). The DLS model was then validated with the OncoSG, MSK-CSC, and TCGA-LUAD cohorts (HR = 0.420 [0.272-0.649], P < 0.001; HR = 0.550 [0.424-0.714], P < 0.001; HR = 0.215 [0.159-0.291], P < 0.001, respectively). Subsequently, it was fine-tuned and retrained in patients treated with IO. The DLS model (low vs. high DLS) could predict PFS and OS in the MIND, MSKCC, and POPLAR/OAK cohorts (P < 0.001, respectively). Compared with tumor-node-metastasis staging, the COX model, tumor mutational burden, and programmed death-ligand 1 expression, the DLS model had the highest C-index in patients treated with or without IO. CONCLUSIONS: The DLS model based on mutational genes can robustly predict the prognosis of patients with lung cancer treated with or without IO.

Deep learning to estimate durable clinical benefit and prognosis from patients with non-small cell lung cancer treated with PD-1/PD-L1 blockade.

Different biomarkers based on genomics variants have been used to predict the response of patients treated with PD-1/programmed death receptor 1 ligand (PD-L1) blockade. We aimed to use deep-learning algorithm to estimate clinical benefit in patients with non-small-cell lung cancer (NSCLC) before immunotherapy. Peripheral blood samples or tumor tissues of 915 patients from three independent centers were profiled by whole-exome sequencing or next-generation sequencing. Based on convolutional neural network (CNN) and three conventional machine learning (cML) methods, we used multi-panels to train the models for predicting the durable clinical benefit (DCB) and combined them to develop a nomogram model for predicting prognosis. In the three cohorts, the CNN achieved the highest area under the curve of predicting DCB among cML, PD-L1 expression, and tumor mutational burden (area under the curve [AUC] = 0.965, 95% confidence interval [CI]: 0.949-0.978, P< 0.001; AUC =0.965, 95% CI: 0.940-0.989, P< 0.001; AUC = 0.959, 95% CI: 0.942-0.976, P< 0.001, respectively). Patients with CNN-high had longer progression-free survival (PFS) and overall survival (OS) than patients with CNN-low in the three cohorts. Subgroup analysis confirmed the efficient predictive ability of CNN. Combining three cML methods (CNN, SVM, and RF) yielded a robust comprehensive nomogram for predicting PFS and OS in the three cohorts (each P< 0.001). The proposed deep-learning method based on mutational genes revealed the potential value of clinical benefit prediction in patients with NSCLC and provides novel insights for combined machine learning in PD-1/PD-L1 blockade.

A combined predictive model based on radiomics features and clinical factors for disease progression in early-stage non-small cell lung cancer treated with stereotactic ablative radiotherapy.

Purpose: To accurately assess disease progression after Stereotactic Ablative Radiotherapy (SABR) of early-stage Non-Small Cell Lung Cancer (NSCLC), a combined predictive model based on pre-treatment CT radiomics features and clinical factors was established. Methods: This study retrospectively analyzed the data of 96 patients with early-stage NSCLC treated with SABR. Clinical factors included general information (e.g. gender, age, KPS, Charlson score, lung function, smoking status), pre-treatment lesion status (e.g. diameter, location, pathological type, T stage), radiation parameters (biological effective dose, BED), the type of peritumoral radiation-induced lung injury (RILI). Independent risk factors were screened by logistic regression analysis. Radiomics features were extracted from pre-treatment CT. The minimum Redundancy Maximum Relevance (mRMR) and the Least Absolute Shrinkage and Selection Operator (LASSO) were adopted for the dimensionality reduction and feature selection. According to the weight coefficient of the features, the Radscore was calculated, and the radiomics model was constructed. Multiple logistic regression analysis was applied to establish the combined model based on radiomics features and clinical factors. Receiver Operating Characteristic (ROC) curve, DeLong test, Hosmer-Lemeshow test, and Decision Curve Analysis (DCA) were used to evaluate the model's diagnostic efficiency and clinical practicability. Results: With the median follow-up of 59.1 months, 29 patients developed progression and 67 remained good controlled within two years. Among the clinical factors, the type of peritumoral RILI was the only independent risk factor for progression (P< 0.05). Eleven features were selected from 1781 features to construct a radiomics model. For predicting disease progression after SABR, the Area Under the Curve (AUC) of training and validation cohorts in the radiomics model was 0.88 (95%CI 0.80-0.96) and 0.80 (95%CI 0.62-0.98), and AUC of training and validation cohorts in the combined model were 0.88 (95%CI 0.81-0.96) and 0.81 (95%CI 0.62-0.99). Both the radiomics and the combined models have good prediction efficiency in the training and validation cohorts. Still, DeLong test shows that there is no difference between them. Conclusions: Compared with the clinical model, the radiomics model and the combined model can better predict the disease progression of early-stage NSCLC after SABR, which might contribute to individualized follow-up plans and treatment strategies.

Experimental Investigation on Corrosion Behavior of X80 Pipeline Steel under Carbon Dioxide Aqueous Conditions.

A combined steady-state and transient approach is employed to investigate the corrosion behavior of X80 pipeline steel in carbon dioxide-saturated brines. Continuous bubbling of carbon dioxide into a test vessel with 1 liter capacity is performed to simulate the flowing condition. The measurement of time-dependent open-circuit potential, polarization resistance, and electrochemical impedance spectroscopy (EIS) is conducted to interpret the evolution of dissolution processes at the corroding interface. Three distinguishing stages are observed at a temperature of 60 °C during a whole exposure of 144 h. Analyses mainly based on the consecutive mechanism show that after the first stage of the active-adsorption state, the anodic reaction is significantly retarded by the accumulation of (FeOH)ads on the iron surface, causing a sharp increase in the polarization resistance and the open-circuit potential, as well as the disappearance of the inductive loop in EIS. At the third stage, the formation of the corrosion product layer similarly reduces both the anodic and cathodic reactions, which arouses a linear increase in the polarization resistance with time and a capacitive loop in EIS but changes the open-circuit potential slightly. An increase in salinity in this study reduces the polarization resistance and enhances iron dissolution by promoting the formation and relaxation of (FeOH)ads; however, it brings little change to the developing time of the three stages obviously. At a low temperature of 20 °C, a protective product layer is not observed in carbon dioxide-saturated brine, and the dissolution of iron is mainly under activation control during the whole exposure. A notable enlarged polarization resistance and different interfacial processes are observed in an alkaline solution compared with those in acidic environments, which is deduced to be resulted from an impedance in the relaxation of (FeOH)ads by increasing pH. The observations in this study support well that the iron dissolution reaction at the initial stage exposed in carbon dioxide aqueous environments is dominant by water adsorption on the iron surface, and further investigation should be performed on the role that carbon dioxide plays in the evolution of corrosion products and the formation of a protective film on the steel surface by taking into account local water chemistry.

Five-year survival rate analysis: the combination of fortnightly-administration of endostar and concurrent chemoradiotherapy versus concurrent chemoradiotherapy in the treatment of inoperable locally advanced non-small cell lung cancer.

BACKGROUND: A prospective phase II study showed that Endostar combined with concurrent chemoradiotherapy (CCRT) can improve overall survival (OS) in patients with inoperable locally advanced non-small cell lung cancer (NSCLC). This study aimed to retrospectively compare the 5-year survival rates of patients with inoperable locally advanced NSCLC who received a combination of Endostar and CCRT to that of patients receiving CCRT. METHODS: Treatment-naive patients with inoperable locally advanced NSCLC who had long-term follow-up data were included in this study. Patients in CCRT + Endostar group were treated with Endostar plus radical CCRT, and patients in CCRT group received radical CCRT. For patients with a radiation dose ≥60 Gy, Kaplan-Meier method was used for survival analysis, and Cox proportional-hazards regression model was used for univariate analysis. RESULTS: A total of 104 participants were included in the CCRT + Endostar group with 89 participants included in the CCRT group. There were 88 (84.6%) and 74 (83.1%) male patients, respectively. The median follow-up times of two groups were 73.6 (95% CI: 65.6 to 81.7 months) and 66.3 months (95% CI: 52.7 to 79.9 months), respectively. The median overall survival (OS) was 29.7 (95% CI: 22.8 to 36.6 months) and 21.3 months (95% CI: 15.9 to 26.7 months), respectively. CONCLUSIONS: This study showed that the 5-year survival of those patients who received the combination treatment of Endostar and radical CCRT was significantly superior to those who received radical CCRT.

Correction to: Timing of thoracic radiotherapy is more important than dose intensification in patients with limited-stage small cell lung cancer: a parallel comparison of two prospective studies.

Correction to: Strahlenther Onkol 2019 https://doi.org/10.1007/s00066-019-01539-1 The original version of this article unfortunately contained a mistake. The correct version of the funding information are given ….

Final report of a prospective randomized study on thoracic radiotherapy target volume for limited-stage small cell lung cancer with radiation dosimetric analyses.

BACKGROUND: The thoracic radiotherapy (TRT) target volume for limited-stage small-cell lung cancer (SCLC) has been controversial for decades. In this report, the final results of a prospective randomized trial on the TRT target volume before and after induction chemotherapy are presented. METHODS: After 2 cycles of etoposide and cisplatin, patients arm were randomized to receive TRT to the postchemotherapy or prechemotherapy tumor volume in a study arm and a control arm. Involved-field radiotherapy was received in both arms. TRT consisted of 1.5 grays (Gy) twice daily in 30 fractions to up to a total dose of 45 Gy. Lymph node regions were contoured, and intentional and incidental radiation doses were recorded. RESULTS: The study was halted early because of slow accrual. Between 2002 and 2017, 159 and 150 patients were randomized to the study arm or the control arm, respectively; and 21.4% and 19.1% of patients, respectively, were staged using positron emission tomography/computed tomography (P = .31). With a median follow-up of 54.1 months (range, 19.9-165.0 months) in survivors, the 3-year local/regional progression-free probability was 58.2% and 65.5% in the study and control arms, respectively (P = .44), and the absolute difference was -7.3% (95% CI, -18.2%, 3.7%). In the study and control arms, the median overall survival was 21.9 months and 26.6 months, respectively, and the 5-year overall survival rate was 22.8% and 28.1%, respectively (P = .26). Grade 3 esophagitis was observed in 5.9% of patients in the study arm versus 15.5% of those in the control arm (P = .01). The isolated out-of-field failure rate was 2.6% in the study arm versus 4.1% in the control arm (P = .46), and all such failures were located in the supraclavicular fossa or contralateral hilum. The regions 7, 3P, 4L, 6, 4R, 5, and 2L received incidental radiation doses >30 Gy. CONCLUSIONS: TRT could be limited to the postchemotherapy tumor volume, and involved-field radiotherapy could be routinely applied for limited-stage SCLC.

Timing of thoracic radiotherapy is more important than dose intensification in patients with limited-stage small cell lung cancer: a parallel comparison of two prospective studies.

PURPOSE: The optimal radiotherapy dose/fraction for limited-stage small cell lung cancer (SCLC) is undefined. Our objectives were to compare efficacy between hyperfractionated thoracic radiotherapy (TRT; 1.5 Gy 2 times per day [bid] in 30 fractions) and hypofractionated TRT (2.5 Gy once per day [qd] in 22 fractions), and to explore prognostic factors influencing the prognosis, such as the timing of TRT. METHODS: Patients enrolled in two independent prospective studies were combined and analyzed. The primary endpoint was local/regional control (LRC). The prognosis was analyzed using the Cox proportional hazards regression model. RESULTS: Ninety-two and 96 patients were treated with hyperfractionated TRT and hypofractionated TRT, respectively. The 1­ and 2­year LRC rates of the two arms were 82.1 and 60.7%, and 84.9 and 68.8% (P = 0.27), respectively. The median overall survival (OS) times (months) were 28.3 (95% confidence interval, CI 16.4-40.1) and 22.0 (95% CI 16.4-27.5), while the 1­year, 3­year, and 5­year OS rates were 85.2, 40.8, and 27.1%, and 76.9, 34.3, and 26.8% (P = 0.37), respectively. Using a multivariate Cox regression study, time (days) from the initiation of chemotherapy to TRT (TCT) ≤43 was associated with improved LRC (hazard radio, HR 0.39, 95% CI 0.20-0.76; P = 0.005). Time (days) from the start of chemotherapy to the end of TRT (SER) ≤63 (HR 0.50, 95% CI 0.32-0.80; P = 0.003) and prophylactic cranial irradiation (HR 0.43; 95% CI 0.29-0.63; P = 0.000) were favorably related to OS. Grade 2/3 acute radiation esophagitis was observed in 37.0 and 17.7% of patients in the hyperfractionated and hypofractionated arms, respectively (P = 0.003). CONCLUSION: Both hyperfractionated and hypofractionated TRT schedules achieved good LRC and OS for patients with limited-stage SCLC in this study. Keeping TCT ≤43 and SER ≤63 resulted in a better prognosis. The incidence of acute esophagitis was significantly higher in the hyperfractionated arm.

HELPER study: A phase II trial of continuous infusion of endostar combined with concurrent etoposide plus cisplatin and radiotherapy for treatment of unresectable stage III non-small-cell lung cancer.

PURPOSE: The prognosis of unresectable stage III non-small cell lung cancer (NSCLC) was poor even after concurrent chemoradiotherapy. There remains a great need to develop novel therapeutic agents in combination with CCRT to improve outcomes. This prospective study sought to evaluate the efficacy and toxicities of the addition of endostar, an anti-angiogenesis agent, to concurrent etoposide, cisplatin (EP) and radiotherapy for treatment of patients with NSCLC. PATIENTS AND METHODS: Patients with untreated pathologically confirmed inoperable stage III NSCLC were eligible. Radiation at doses of 60-66 Gy, four cycles of endostar (7.5 mg/m2/24 h × 120 h, 14 days/cycle), and two cycles of EP (etoposide 50 mg/m2 on days 1-5 and cisplatin 50 mg/m2 on days 1 and 8, 28 days/cycle) were delivered. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate and overall survival (OS), locoregional relapse-free survival (LRFS) distant metastasis-free survival (DMFS) and adverse events (AE). RESULTS: From November 2012 to June 2015, 73 patients were enrolled, and 67 patients were evaluable. The median age was 59 years. Sixty-six percent of the patients had squamous cell carcinoma. Grade ≥3 AEs occurred in 58.2% of the patients. The most common Grade ≥3 AE was leucopenia (44.8%). The response rate was 76.1%. The median times of PFS and OS were 13.3 months and 34.7 months, respectively. The 2-year PFS, OS, LRFS and DMFS rates were 34.8%, 59.9%, 54.7% and 68.5%, respectively. CONCLUSIONS: For patients with unresectable stage III NSCLC, continuous intravenous endostar in combination with concurrent EP and radiotherapy did not prolong median PFS, although it got preferable OS, promising 2-year PFS with tolerable toxicities.

Association between clinicopathological factors and postoperative radiotherapy in patients with completely resected pathological N2 non-small cell lung cancer.

The function of postoperative radiotherapy (PORT) in patients with completely resected pathologically N2 (pN2) non-small cell lung cancer (NSCLC) remains controversial due to a lack of prospective studies. The present study aimed to evaluate the efficacy of PORT in completely resected pN2 NSCLC when using modern radiation techniques, and to determine the associations between clinicopathological factors and PORT and survival rates. Following patient selection, 246 out of 269 consecutive patients with pN2 NSCLC were enrolled in the present study, with 88 patients having received postoperative chemotherapy (POCT) and PORT, 90 having received adjuvant chemotherapy, 1 having received adjuvant radiotherapy and the remaining 67 having received no adjuvant therapy. Overall survival (OS), local recurrence-free survival (LRFS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. The median age of the patients was 59 years, overall, 175 (71.1%) of the patients were male and the median radiation dose was 50.4 Gy. The median follow-up duration was 38.3 months. The 1-, 3- and 5-year OS rates were 98.9, 71.3 and 54.9%, and 93.0, 58.4 and 36.7% (P=0.011) in the PORT and non-PORT group, respectively. The 1-, 3- and 5-year LRFS rates were 95.5, 84.6 and 78.0%, and 86.6, 70.6 and 52.8% (P<0.001) in the PORT and non-PORT groups, respectively. The 1-, 3- and 5-year DFS rates were 86.5, 55.2 and 37.9%, and 80.9, 40.3 and 26.8% (P=0.132) in the PORT and non-PORT groups, respectively. Univariate analysis revealed that the OS rate was significantly increased in patients with peripheral tumors (P=0.029), pT1-2 (P=0.015), one N2 lymph node (LN) metastasis (P=0.001), single N2 station metastasis (P=0.030), no bronchial involvement (P=0.025), use of PORT (P=0.011) and POCT (P=0.003). Multivariate analysis revealed that PORT (HR, 0.755; 95% CI, 0.498-0.986; P=0.047), POCT (HR, 0.645; 95% CI, 0.420-0.988; P=0.044), bronchial involvement (HR, 1.453; 95% CI, 1.002-2.107; P=0.049) and ≥2 N2 metastases (HR, 1.969; 95% CI, 1.228-3.157; P=0.005) were significant independent predictors of OS. Subgroup analysis demonstrated an increased OS rate with PORT only in the patients with positive bronchial involvement and ≥2 N2 LN metastases. The results revealed that PORT may improve the LRFS and OS rates in completely resected pN2 NSCLC, and that the patients with positive bronchial involvement and ≥2 N2 LN metastases may receive more benefit from PORT.

Simultaneous integrated boost intensity-modulated radiotherapy for locally advanced non-small cell lung cancer in Chinese population: A retrospective study.

OBJECTIVES: To evaluate the clinical efficacy and toxicity of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for patients with locally advanced non-small cell lung cancer (NSCLC). RESULTS: All patients completed definitive radiotherapy and 74 (85.1%) patients administrated platinum-based chemotherapy. The median radiation dose was 50.4Gy to PTV and 64.4 Gy simultaneously to the PGTV. The overall response rate (ORR) was 57.5% (50/87). The median duration of follow up was 24.6 months. The 1, 2, 3-year local control rate was 79.0%, 66.1%, and 60.5%, respectively. The 1, 2, 3-year overall survival (OS) rate was 89.7%, 56.7%, and 30.6%, respectively. Subgroup analysis showed that the median OS in concurrent chemoradiation (CCRT) was much better than non-CCRT (35.7 vs. 26.4 months) (HR: 0.52, 95% CI: 0.32-0.95, P = 0.033). Twenty-two (25.3%) patients experienced acute grade 3 esophagitis and 10 (11.5%) experienced acute grade ≥ 3 radiation pneumonitis. There were 2 (2.6%) late grade 3 pulmonary toxicity and no late grade ≥ 3 esophageal toxicity was observed. MATERIALS AND METHODS: A total of 87 patients with locally advanced NSCLC who received SIB-IMRT from Jan. 2009 to Dec. 2012 in our hospital were retrospectively analyzed. Male accounted for 88.5%, with a median age of 61 years old. The SIB-IMRT plans were designed to deliver 50.4-64.0 Gy in 28-33 fractions (1.8-2.1 Gy/fraction) to PTV while simultaneously delivering 60.0-74.3 Gy in 28-33 fractions (2.0-2.5 Gy/fraction) to PGTV. CONCLUSIONS: SIB-IMRT, especially with concurrent chemotherapy, appears to be an effective and safe option to treat patients with locally advanced NSCLC. More prospective clinical studies should be warranted.

The efficacy and safety of simultaneous integrated boost intensity-modulated radiation therapy for esophageal squamous cell carcinoma in Chinese population: A single institution experience.

PURPOSE: To evaluate the clinical efficacy and toxicity of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) in patients with esophageal squamous cell carcinoma (ESCC) in Chinese population. PATIENTS AND METHODS: Patients with ESCC, who received SIB-IMRT from September 2011 to January 2013 were retrospectively analyzed. The SIB-IMRT plans were designed to deliver primary gross tumor volume at 60-64.4 Gy in 28-30 fractions, and planning target volume at 50.4-56 Gy in 28-30 fractions. Treatment-related toxicities were estimated based on Common Terminology Criteria for Adverse Events version 4.0, and tumor response after the treatment was estimated according to Response Evaluation Criteria in Solid Tumors version 1.0. Overall survival (OS), locoregional progression-free survival (LPFS), and progression-free survival (PFS) were estimated with Kaplan-Meier. RESULTS: All patients completed definitive radiotherapy, 54 (78.3%) received combined chemotherapy, of which 31 (44.9%) were concurrent chemoradiotherapy and 23 (33.3%) were sequential chemotherapy. The objective response rate is 82.6% (56/69), with complete response 11 (15.9%), partial response 45 (65.2%), stable disease 8 (11.6%), and progressive disease 5 (7.2%). The 1-, 2- and 3-year LPFS was 74.4%, 57.8%, and 55.6%, respectively. The 1-, 2- and 3-year PFS was 62.3%, 41.0%, and 34.2%, respectively, and the 1-, 2-, and 3-year OS was 73.8%, 57.4%, and 41.0%, respectively, with a median OS of 27.1 months (4.5-54.9 m). For those who received concurrent chemotherapy, the 1-, 2-, and 3-year OS was 75.9%, 69.0%, and 55.2%, respectively, better than those who had sequential chemotherapy or radiotherapy alone (χ2 = 3.115, P = 0.078). Radiation esophagitis occurred in 63.8% and 14.5% with Grade 2 and 3, respectively. No patients occurred ≥ Grade 3 radiation pneumonia. CONCLUSIONS: It is safe and effective using SIB-IMRT technology to treat patients with ESCC. More prospective clinical studies should be needed.

Prognostic performance of inflammation-based prognostic indices in locally advanced non-small-lung cancer treated with endostar and concurrent chemoradiotherapy.

A proportion of patients with locally advanced non-small-cell lung cancer (NSCLC) may benefit from anti-angiogenic therapy combined with concurrent chemoradiotherapy; however, effective prognostic biomarkers are required for prognosis. In this study, we aimed to establish whether inflammation-based factors offer a prognostic benefit in terms of response rate (RR) and overall survival (OS) in stage III NSCLC patients treated by endostar with concurrent chemoradiotherapy (CCRT). We retrospectively investigated an unselected cohort of stage III NSCLC patients, who were treated by combined endostar and CCRT. The log-rank test was used to analyze the association between each clinical variable and OS. Cox regression models were fitted to identify risk factors associated with OS. A total of 82 patients with stage III NSCLC were treated with a combination of endostar and CCRT and 78 patients were included in the data analysis. A total of 13 patients achieved a complete response, 49 achieved a partial response, 6 had stable disease, 8 had progressive disease and 2 patients could not be evaluated. The median progression-free survival of the entire group was 10.50 months (95% CI: 6.298-14.702), while the median OS was 22.83 months (95% CI: 19.156-26.504). On χ2test analysis, the neutrophil-to-lymphocyte ratio (NLR) exerted a significant effect on RR (P=0.048). The univariate analysis identified the factors associated with OS, including NLR (P=0.004) and monocyte count (P=0.001), whereas the multivariate analysis confirmed NLR [P=0.043, hazard ratio (HR)=0.502] and monocyte count (P=0.011, HR=0.387) as independent prognostic factors for OS. Our results indicated that, in patients with stage III NSCLC treated by a combination of endostar and CCRT, pre-treatment elevated NLR and monocyte number are negatively associated with OS.

Overexpression of the regulator of G-protein signaling 5 reduces the survival rate and enhances the radiation response of human lung cancer cells.

Regulator of G protein signaling 5 (RGS5) belongs to the R4 subfamily of RGS proteins, a family of GTPase activating proteins, which is dynamically regulated in various biological processes including blood pressure regulation, smooth muscle cell pathology, fat metabolism and tumor angiogenesis. Low-expression of RGS5 was reported to be associated with tumor progression in lung cancer. In the present study, we examined the potential roles of RGS5 in human lung cancer cells by overexpressing RGS5 in the cancer cells and further explored the underlying molecular mechanisms. The RGS5 gene was cloned and transfected into the human lung cancer cell lines A549 and Calu-3. The cells were tested for apoptosis with flow cytometry, for viability with MTT, for mobility and adhesion capacity. The radiosensitization effect of RGS5 was measured by a colony formation assay. The mechanisms of RGS5 functioning was also investigated by detection of protein expression with western blot analysis, including PARP, caspase 3 and 9, bax, bcl2, Rock1, Rock2, CDC42, phospho-p53 (Serine 15) and p53. The present study demonstrated that RGS5 overexpression remarkably induced apoptosis in human lung cancer cells, which was suggested to be through mitochondrial mechanisms. Overexpression of RGS5 resulted in significantly lower adhesion and migration abilities of the lung cancer cells (P<0.01). Furthermore, overexpression of RGS5 sensitized the lung cancer cells to radiation. In conclusion, the present study showed that RGS5 played an inhibitory role in human lung cancer cells through induction of apoptosis. Furthermore, RGS5 enhanced the cytotoxic effect of radiation in the human lung cancer cells. Our results indicated that RGS5 may be a potential target for cancer therapy.

Phase II trial of recombinant human endostatin in combination with concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer.

PURPOSE: The objective of this study was to evaluate the efficacy and safety of Endostar combined with concurrent chemoradiotherapy (CCRT) in patients with stage III non-small-cell lung cancer (NSCLC). METHODS: Patients with unresectable stage III NSCLC were treated with Endostar (7.5mg/m(2)/d) for 7days at weeks 1, 3, 5, and 7, while two cycles of docetaxel (65mg/m(2)) and cisplatin (65mg/m(2)) were administered on days 8 and 36, with concurrent thoracic radiation to a dose of 60-66Gy. Primary end points were short-term efficacy and treatment-related toxicity. RESULTS: Fifty patients were enrolled into the study, and 48 were assessable. Of the 48 patients, 83% had stage IIIB and 65% had N3 disease. Median follow-up was 25.0months. Overall response rate was 77%. The estimated median progression-free survival (PFS) was 9.9months, and the estimated median overall survival (OS) was 24.0months. The 1-, 2-, and 3-year local control rates were 75%, 67%, and 51%, PFS rates were 48%, 27%, and 16%, and OS rates were 81%, 50%, and 30%, respectively. All toxicities were tolerable with proper treatment. CONCLUSIONS: The combination of Endostar with CCRT for locally advanced NSCLC patients was feasible and showed promising survival and local control rates.

Sequential chemoradiotherapy with accelerated hypofractionated radiotherapy compared to concurrent chemoradiotherapy with standard radiotherapy for locally advanced non-small cell lung cancer.

To compare the outcomes and treatment-related toxicities of two chemoradiotherapy schedules given to the patients with unresectable locally advanced non-small cell lung cancer (NSCLC): sequential chemotherapy with accelerated hypofractionated radiotherapy (SCRT), and concurrent chemotherapy with standard radiotherapy (CCRT), 68 patients from two prospective clinical trials were included. Thirty-four patients were treated with SCRT using an accelerated hypofractionated radiation schedule, 34 patients received CCRT with standard radiation. Between the two treatment groups there were no significant differences in terms of overall survival, progression-free survival (PFS), locoregional-PFS or distant metastasis-PFS. For the SCRT group, the median survival time and 2- and 4-year overall survival rates were 19 months, 38.2%, and 23.5%, respectively, and for the CCRT group these were 19 months, 44.1%, and 19.6%. Esophageal and constitutional toxicities were more pronounced in the CCRT group, while there was no significant difference in pulmonary toxicities. The results suggest that for unresectable stage III NSCLC, the outcomes of SCRT with accelerated hypofractionated radiotherapy and CCRT with standard radiotherapy are similar, but the toxicities associated with treatment are less in the SCRT group.

Predictive value of primary fluorine-18 fluorodeoxyglucose standard uptake value for a better choice of systematic nodal dissection or sampling in clinical stage ia non--small-cell lung cancer.

PURPOSE: To determine whether the standard uptake value (SUV) of the primary lesion can predict mediastinal lymph node metastasis in clinical stage IA non--small-cell lung cancer (NSCLC). MATERIALS AND METHODS: At 5 centers, patients with clinical stage IA NSCLC from February 2004 to August 2010 were analyzed retrospectively. Data from Shandong Cancer Hospital and from the Cancer Hospital Affiliated to Harbin Medical University were used as a testing set, and data from the other 3 institutions were used as the validation set. Final diagnosis was established based on the histopathologic examination. RESULTS: Data from 144 patients were collected for the study. The primary results in our study showed that maximal SUV (SUVmax) of primary tumor might be a predictor of lymph node metastasis (χ(2) = 10.424; P = .001) and the best cutoff value was 7.25 (P = .029). For the testing set, lymph node metastasis rates in low-grade group (SUVmax < 7.25) and high-grade group (SUVmax > 7.25) were 5% (2/43) and 36% (9/25) (P = .001) For the total data set, lymph node metastasis rate was 7% (6/93) in low-grade group (SUVmax < 7.25) and 26% (13/51) in high-grade group (SUVmax > 7.25) (χ(2)= 10.424; P = .001). A multivariate analysis revealed that no factors were applied to predict the probability of metastasis. But the analysis showed a weak correlation between SUVmax and nodal status (r = 0.21; P = .011) with bivariate correlation. CONCLUSION: Analysis of our data suggested that fluorine-18 fluorodeoxyglucose SUVmax of the primary tumor might be a predictor of lymph node involvement in stage IA NSCLC. The rate of mediastinal lymph node metastasis of patients with a lower fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography SUVmax might be relatively low, which provides more evidence for clinical procedures of clinical stage IA NSCLC.