Introduction: Plasma circulating tumor DNA (ctDNA) is an ideal approach to detecting the epidermal growth factor receptor ( EGFR ) T790M mutation, which is a major mechanism of resistance to first‐generation EGFR‐tyrosine kinase inhibitor (TKI) therapy. The present study aimed to explore the association of ctDNA‐identified T790M mutation with disease failure sites and clinical prognosis in non‐small cell lung cancer (NSCLC) patients. Methods: Patients who progressed on first‐generation TKIs were categorized into failure site groups of chest limited (CF), brain limited (BF) and other (OF). Amplification refractory mutation system (ARMS) and droplet digital PCR (ddPCR) were used to identify the T790M mutation in ctDNA. Prognosis was analyzed with Kaplan–Meier methods. Results: Overall concordance between the two methods was 78.3%. According to both ARMS and ddPCR, patients in the OF group had a significantly higher rate of T790M mutation than did patients in the BF and CF groups ( P < 0.001), and a significantly higher T790M mutation rate was also observed in OF‐group patients than in those in the CF and BF groups ( P < 0.001). AZD9291 was found to be an excellent treatment option and yielded the longest survival for T790M+ patients in all groups who had progressed on EGFR‐TKIs; for other treatments, the prognosis of T790M− patient subgroups varied. Conclusions: The present study demonstrates that T790M mutation in ctDNA is associated with failure sites for NSCLC patients after EGFR‐TKI therapy and indicates that both failure site and T790M mutational status greatly influence treatment selection and prognosis.

Background: Few studies to date have assessed the incidence of radiation pneumonitis (RP) in lung cancer patients who have been treated with volumetric modulated arc therapy (VMAT). This study is aimed at reporting the RP incidence rate and the risk factors associated with a symptomatic RP in patients with lung cancer treated with VMAT. Methods: A total of 77 consecutive lung cancer patients treated with VMAT from 2013 through 2015 were reviewed. RP severity was graded according to the Common Terminology Criteria for Adverse Events (CTCEA) v.4. Univariate and multivariate analyses were performed to identify the significant factors associated with RP. Results: VMAT allowed us to achieve most planning objectives on the target volumes and organs at risk, for PTV V_95% =96.8%±3.1%, for lung V₅ =41.3%±8.7%, V₁₀ =30.0%±7.1%, V₂₀ =20.9%±5.7%, for heart V₅ =43.2%±29.9%, for esophagus V₆₀ =8.1%±12.9%. The maximum dose of spinal cord was 34.4±9.5 Gy. The overall incidence of symptomatic RP (grade ≥2 by CTCAE) was 28.6% in the entire cohort, and the rate of grade ≥3 RP was 11.7%. Based on the multivariate analysis, factors predictive of symptomatic RP included lung volume receiving ≥10 Gy (V₁₀) (P=0.019) and C-reactive protein changing level (P=0.013). Conclusions: Our data showed that the incidence rate of RP was acceptable in lung cancer patients treated with VMAT. Additionally, we found that V₁₀ might be an important factor for predicting the development of RP when VMAT was used; but this observation needs to be validated in future studies.

Background: To investigate the biological radiation dose-response for patients of limited-stage small-cell lung cancer (LS-SCLC) treated with high radiation dose. Methods: Two hundred and five patients of LS-SCLC treated with sequential chemotherapy and thoracic radiotherapy with involved-field between 1997 and 2006 were reviewed retrospectively. Biologically effective dose (BED) was calculated for dose homogenization and was corrected with the factor of overall radiation time. Patients were divided into low BED group (n = 70) and high BED group (n = 135) with a cut-off of BED 57 Gy (equivalent to 60 Gy in 30 fractions over 40 days). Outcomes of the two groups were compared. Results: Median follow-up was 20.7 months for all analyzable patients and 50.8 months for surviving patients. Considering all patients, median survival was 22.9 months (95% confidence interval, 20.6-25.2 months); 2- and 5-year survival rates were 47.2% and 22.3%, respectively. Patients in high BED group had a significantly better local control (p = 0.024), progression-free survival (p = 0.006) and overall survival (p = 0.005), with a trend toward improved distant-metastasis free survival (p = 0.196). Multivariable Cox regression demonstrated that age (p = 0.003), KPS (p = 0.009), weight loss (p = 0.023), and BED (p = 0.004) were significant predictors of overall survival. Conclusions: Our data showed that a high BED was significantly associated with favourable outcomes in the Chinese LS-SCLC population, indicating that a positive BED-response relationship still existed even in a relatively high radiation dose range.

Thoracic radiotherapy (TRT) is a critical component of the treatment of limited-stage small cell lung cancer (LS-SCLC). However, the optimal radiation dose/fractionation remains elusive. This study reviewed current evidence and explored the dose-response relationship in patients with LS-SCLC who were treated with radiochemotherapy. A quantitative analysis was performed through a systematic search of PubMed, Web of Science, and the Cochrane Library. The correlations between the biological effective dose (BED) and median overall survival (mOS), median progression-free survival (mPFS), 1-, 3-, and 5-year overall survival (OS) as well as local relapse (LR) were evaluated. In all, 2389 patients in 19 trials were included in this study. Among these 19 trials, seven were conducted in Europe, eight were conducted in Asia and four were conducted in the United States. The 19 trials that were included consisted of 29 arms with 24 concurrent and 5 sequential TRT arms. For all included studies, the results showed that a higher BED prolonged the mOS (R² = 0.198, p<0.001) and the mPFS (R² = 0.045, p<0.001). The results also showed that increased BED improved the 1-, 3-, and 5-year OS. A 10-Gy increment added a 6.3%, a 5.1% and a 3.7% benefit for the 1-, 3-, and 5-year OS, respectively. Additionally, BED was negatively correlated with LR (R² = 0.09, p<0.001). A subgroup analysis of concurrent TRT showed that a high BED prolonged the mOS (p<0.001) and the mPFS (p<0.001), improved the 1-, 3-, and 5-year OS (p<0.001) and decreased the rate of LR (p<0.001). This study showed that an increased BED was associated with improved OS, PFS and decreased LR in patients with LS-SCLC who were treated with combined chemoradiotherapy, which indicates that the strategy of radiation dose escalation over a limited time frame is worth exploring in a prospective clinical trial.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have become the standard care of patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC), development of acquired resistance is inevitable. A secondary mutation of threonine 790 (T790M) is associated with approximately half of the cases of acquired resistance. Strategies or agents to overcome this type of resistance are still limited. In this study, enhanced antitumor effect of AT-101, a-pan-Bcl-2 inhibitor, on gefitinib was explored in NSCLC with T790M mutation. The effect of cotreatment with AT-101 and gefitinib on the viability of NSCLC cell lines harboring acquired T790M mutation was investigated using the MTT assay. The cellular apoptosis of NSCLC cells after cotreatment with AT-101 and gefitinib was assessed by FITC-annexin V/PI assay and Western blots analysis. The potential underlying mechanisms of the enhanced therapeutic effect for AT-101 was also studied using Western blots analysis. The in vivo anti-cancer efficacy of the combination with AT-101 and gefitinib was examined in a mouse xenograft model. In this study, we found that treatment with AT-101 in combination with gefitinib significantly inhibited cell proliferation, as well as promoted apoptosis of EGFR TKIs resistant lung cancer cells. The apoptotic effects of the use of AT-101 was related to the blocking of antiapoptotic protein: Bcl-2, Bcl-xl, and Mcl-1 and downregrulation of the molecules in EGFR pathway. The observed enhancements of tumor growth suppression in xenografts supported the reverse effect of AT-101 in NSCLC with T790M mutation, which has been found in in vitro studies before. AT-101 enhances gefitinib sensitivity in NSCLC with EGFR T790M mutations. The addition of AT-101 to gefitinib is a promising strategy to overcome EGFR TKIs resistance in NSCLC with EGFR T790M mutations.