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Lessons Learned Background We conducted a phase Ib study of radiotherapy plus programmed cell death protein 1 (PD-1) monoclonal antibody camrelizumab as first-line treatment for locally advanced esophageal squamous cell carcinoma (ESCC). Methods We planned to enroll 20 patients with newly diagnosed locally advanced ESCC. Patients received 60 Gy radiation (2.0 Gy/fraction, 5 fractions/week), with camrelizumab (200 mg every 2 weeks) starting with radiotherapy and continuing for 32 weeks (i.e., for 16 cycles). The primary endpoints were safety and feasibility. Secondary endpoints were rates of radiologic and pathologic response, overall survival (OS), and progression-free survival (PFS). Study data were collected by the week during radiotherapy (RT), every month during the maintenance camrelizumab treatment, and every 3 months after treatment. Tumor microenvironment and peripheral blood were monitored at baseline and after 40 Gy radiation for association with efficacy. Results Twenty patients were enrolled and received treatment. One patient (patient 10) was excluded upon discovery of a second tumor in the bladder during treatment, leaving 19 patients for analysis. Toxicity was deemed tolerable. Fourteen (74%) patients had assessed objective response. At a median follow-up time of 31.0 months (95% confidence interval [CI], 27.0–35.1), median OS and PFS times were 16.7 months (95% CI, 5.9–27.9) and 11.7 months (95% CI, 0–30.3), respectively. OS and PFS rates at 24 months were 31.6% and 35.5%, respectively. Kaplan-Meier analysis revealed associations between the following factors and OS/PFS: tumor programmed cell death ligand 1 (PD-L1) expression, PD-1+CD8+, PD-1+CD4+ T cells, and PD-L1+CD4+ T cells; peripheral blood CD4+, CD8+, CD4+ regulatory T cells, and their subsets. Conclusion Radiotherapy plus camrelizumab had manageable toxicity and antitumor efficacy for locally advanced ESCC. Several biomarkers were associated with clinical benefit and deserve further study.

Purpose Thoracic radiotherapy (TRT) is the recommended therapeutic regimen for extensive-stage small cell lung cancer (ES-SCLC). Little is known about TRT benefits in elderly populations. The aim of this study was to evaluate TRT effects on the prognosis of elderly patients with ES-SCLC. Patients and methods This retrospective analysis reviewed the records of patients over 65 years of age with metastatic ES-SCLC treated between 2010 and 2016. Enrolled patients received standard chemotherapy regimens (etoposide plus cisplatin or carboplatin). A total of 93 eligible patients were subjected to propensity score matching, which led to 40 patients being assigned to the TRT group and 40 to the no thoracic radiotherapy (noTRT) group. The cohort of 80 patients (67 males) had the median age of 69 years (range, 65-85 years), with a median of 4 chemotherapy cycle (range, 1-8 cycles), and a median chest irradiation dose of 50 Gy (range, 30-60 Gy). We analyzed overall survival (OS), progression-free survival (PFS), and local recurrence-free survival (LRFS) as endpoints; survival rates were determined by the Kaplan-Meier method and compared across groups with log-rank tests. Multivariate prognostic analysis was performed with Cox regression modeling, and categorical variables were analyzed with Chi-square tests. Results In all patients, the 1-year OS, PFS, and LRFS rates were 38.3%, 16%, and 17.9%, respectively. The TRT group had superior survival outcomes compared to the noTRT group: their 1-year OS, PFS, and LRFS rates were 55% vs. 25% (P < 0.001), 32.1% vs. 0% (P < 0.001), and 31% vs. 2.6% (P < 0.001), respectively. TRT did not increase the incidence of adverse reactions (P = 0.431). Conclusion TRT can improve chest tumor control and survival time in elderly ES-SCLC patients. Large-scale studies to further assess the benefits of TRT are warranted.

BackgroundAccumulated evidence for systemic inflammation response in several solid tumors prompts a possibility of prediction of patients’ prognosis in a more accessible and valuable manner. However, the prognostic value of peripheral blood inflammatory markers in limited-stage small cell lung cancer (LS-SCLC) remains unclear. Therefore, we investigated the prognostic values of pretreatment inflammatory indexes in LS-SCLC patients.MethodsWe retrospectively identified 334 patients with LS-SCLC and collected their pretreatment serum levels of neutrophil, platelet, lymphocyte, leukocyte, hemoglobin, and albumin, then neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII) were calculated. Patients were dichotomized as low-Risk or high-Risk group based on their corresponding cutoff values. Univariate and multivariate analyses were conducted with a Cox proportional hazards model. The least absolute shrinkage and selection operator (LASSO)-Cox regression analysis was performed to construct the inflammation-related prognostic scoring system named Risk for OS. Nomograms were established to provide prognostic information, allowing for more individualized prediction of survival.ResultsHigher pretreatment platelet, lymphocyte, and albumin were indicators of favorable overall survival (OS), whereas higher NLR and SII were accompanied by inferior OS. The prognosis of patients with high Risk was significantly worse than that with low Risk in both the training group and the validation group (both p < 0.001). Comparable area under the curve (AUC) values between the training group and the validation group were observed, yielding 1-, 3-, and 5-year OS rates of 67.3% vs. 69.2%, 66.8% vs. 69.5%, and 66.7% vs. 71.4%, respectively. Multivariate analyses revealed that Risk [hazard ratio (HR) = 0.551, p < 0.001] was an independent negative prognostic indicator for OS, which was further verified in the validation set. The addition of Risk to nomogram (C-index = 0.643) harbored improved predictive accuracy for OS when compared with that of clinical factors alone (C-index = 0.606); the AUC values of 1-, 3-, and 5-year OS rates were 71.7% vs. 66.4%, 73.5% vs. 66.6%, and 71.9% vs. 65.6%, respectively.ConclusionsPretreatment peripheral blood inflammatory indexes may be a noninvasive serum biomarker for poor prognosis in LS-SCLC. The addition of Risk to the nomogram model could serve as a more powerful, economical, and practical method to predict survival for patients with LS-SCLC.

Aim: Adequate lymph node evaluation is recommended in patients with malignant tumors. However, the role of negative lymph nodes (NLNs) remains unclear in breast cancer (BC), especially in patients who have received neoadjuvant chemotherapy and mastectomy. Materials & methods: A total of 435 patients were included in the analysis. On multivariate analysis, NLN count was an independent predictor of 5 year disease-free survival and 5 year overall survival. Results: Patients with NLN count

Purpose To evaluate and analyze the efficacy and prognostic factors of intensity-modulated radiotherapy in 250 patients with cervical and upper esophageal carcinoma. Patients and methods From September 2009 to September 2016, we retrospectively analyzed 250 patients with cervical and upper esophageal carcinoma treated with intensity-modulated radiotherapy (IMRT). In our study, all patients received IMRT, 54 patients with cervical esophageal carcinoma and 196 patients with upper esophageal carcinoma. Treatment response, survival status and failure modes of treatment were observed, and prognostic factors were analyzed. Results The median survival time was 22.60 months and 3-year survival rate was 42%. The median progress-free survival time was 14.52 months and 3-year progress-free survival rate was 29.3%. The median survival time and the median progress-free survival time for cervical esophageal carcinoma were 20.40 and 15.15 months, respectively. The median survival time and the median progress-free survival time for upper esophageal carcinoma were 25.80 and 14.52 months, respectively (P>0.05). The significant clinical factors associated with survival were patient age, radiotherapy dose and T stages (P

OBJECTIVES We investigated whether the combination of systemic chemotherapy (SCT) and liver-directed therapy (LDT) was superior to chemotherapy alone for patients with pancreatic adenocarcinoma and synchronous liver metastases (PACLM). METHODS We reviewed the medical records of 184 patients treated with SCT ± LDT at Tianjin Medical University Cancer Hospital from 2001 to 2015. Overall survival (OS) was the primary end-point. The role of treatment modality and other clinical factors was evaluated by univariate and Cox regression analyses. RESULTS Sixty-four (34.8%) patients in the SCT-LDT group and 120 (65.2%) patients in the SCT group were included in the analysis. Baseline clinical characteristics were similar between the groups (all P > 0.05). The median survival was 8.7 months in the SCT-LDT group and was 6.3 months in the SCT group. The 0.5-, 1-, 2- and 3-year survival rates were 67.2%, 33.4%, 13.3% and 8.9%, respectively, after SCT-LDT, and were 54.9%, 19.0%, 4.5% and 2.0%, respectively, after SCT (P = 0.01). Primary tumor size, ascites, and treatment modality (SCT + LDT vs. SCT) independently predicted survival (P

BACKGROUND: This study was conducted to identify the clinicopathological characteristics and survival outcomes of pulmonary sarcomatoid carcinoma (PSC), and to compare prognostic factors between elderly (≥65 years) and non-elderly (

Patients with locally advanced esophageal squamous cell carcinoma (ESCC) show poor survival after concurrent chemoradiotherapy. This study investigated the safety and feasibility of combining concurrent chemoradiotherapy with the anti-PD-1 antibody camrelizumab as first-line treatment for these patients. In this phase 1b study (ClinicalTrials.gov NCT03671265), patients received concurrent chemotherapy (cisplatin [25 mg/m2] plus docetaxel [25 mg/m2] for 4 weeks) and radiotherapy (2.0 Gy/fraction, total 60 Gy) with camrelizumab (200 mg every 2 weeks for 32 weeks). Primary endpoints were safety and tolerability, and health-related quality of life. Secondary endpoints were radiological and pathological response rates, overall survival (OS), and progression-free survival (PFS). Candidate biomarkers in tumor and peripheral blood were monitored at baseline and after 40 Gy radiation. Twenty patients were enrolled. The most common treatment-related grade 3 adverse events included radiation esophagitis (20%) and esophageal fistula (10%). Serious treatment-related adverse events occurred in eight (40%) patients. No treatment-related deaths were reported. Health-related quality of life did not deteriorate. Thirteen (65%) patients had an objective response after 40 Gy radiation. At a median follow-up of 23.7 months (95% CI 21.9–24.5), OS and PFS time ranged from 8.2–28.5 and 4.0–28.5 months, respectively. The 12-month and 24-month OS rate was 85.0% and 69.6%; PFS rate was 80.0% and 65.0%. Tumor PD-L1 expression and CD11c+ dendritic cells and peripheral-blood IL-27, IL-15, Eotaxin-3, and IL-22 were associated with OS. First-line concurrent chemoradiotherapy plus camrelizumab had a manageable safety profile and promising antitumour efficacy for ESCC, and deserves further study.

In previous studies, the estimated dose of radiation to immune cells (EDRIC) showed a correlation with overall survival (OS) of patients with locally advanced non-small cell lung cancer (LA-NSCLC) who received thoracic radiotherapy. However, several factors such as gross tumor volume (GTV) and lymph node (N) stage may impact EDRIC. The purpose of this study was to identify the factors influencing EDRIC and to further assess the prognostic relevance of EDRIC.We retrospectively analyzed 201 patients with LA-NSCLC who received radiotherapy between 2012 and 2017. EDRIC was calculated based on the model developed by Jin et al. Kaplan-Meier method and Cox proportional hazards regression were used to analyze the correlation of potential factors with OS, local progression-free survival (LPFS), and distant metastasis-free survival (DMFS). Spearman's rank correlation was used to assess the correlation between variables.Both GTV and N stage showed a positive correlation with EDRIC (r = 0.347, P 0.001 and r = 0.249, P 0.001, respectively). EDRIC was independently associated with DMFS (HR 1.185, P 0.001). GTV was associated with OS (HR 1.006, P 0.001), LPFS (HR 1.003, P = 0.017), and DMFS (HR 1.003, P = 0.032). While using GTV as a stratification factor in Kaplan-Meier analysis, EDRIC showed a trend of negative correlation with OS in GTV ≤ 66.6 cmEDRIC was an independent prognostic factor for metastasis and it was affected by GTV and N stage. However, the effect of EDRIC on OS was influenced by GTV.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) are all markers of systemic inflammation response. The role of systemic inflammation in the development of esophageal fistula (EF) has yet to be defined. This study aimed to investigate the predictive value of hematologic measures of inflammation and to set up a predictive model. METHODS: The data of esophageal cancer (EC) patients who received chemoradiotherapy (CRT) in our institution between January, 2015 and January, 2018 were retrospectively collected. The NLR, PLR, and MLR of these enrolled patients were calculated. Univariate and multivariate analyses were performed to find the independent risk factors of EF. Moreover, a nomogram model was developed to predict the probability of fistula occurring in EC patients. RESULTS: For PLR, the optimal cut-off value was 153. Patients with PLR >153 had a higher probability of developing fistula than those with PLR ≤153 (P

The aim of the present study was to explore the safety of apatinib plus S-1 in treating advanced solid tumors after failure of two or more lines of chemotherapy. A total of 33 patients with advanced cancer treated between April 2016 to March 2019 were retrospectively analyzed. Of these, 13 patients had non-small cell lung cancer (NSCLC), 13 patients had SCLC, 4 patients had esophageal cancer and 3 had cervical cancer. All patients were treated with apatinib 250 mg once daily combined with S-1 60 mg/m2 twice daily for 14 days, repeated every 3 weeks. Adverse reactions were observed until aggravation of adverse reactions beyond the tolerable range or disease progression, and the survival rate and clinical benefits were calculated. The results suggested that the incidence rate of adverse effects (grade 3-4) was 45.5% (15/33). The top three severe adverse effects were hypertension (15.2%), thrombocytopenia (12.1%) and proteinuria (9.1%). A total of 2 patients with lung squamous-cell carcinomas died of severe pulmonary hemorrhage. Other adverse reactions were tolerated in the cohort. A total of 10 patients achieved partial response and the objective response rate was 30.3%. Furthermore, 13 patients achieved stable disease and 10 patients had progressive disease, and accordingly, the disease control rate was 72.7%. In conclusion, apatinib plus S-1 for advanced solid tumor patients as palliative treatment have a certain efficacy and was relatively safe but should be used with caution in patients with squamous-cell lung carcinoma and the efficacy and safety requires further assessment.

Aim: To evaluate the prognostic role of EGFR mutations in patients with multi-site metastases from non-small-cell lung cancer (NSCLC). Patients & methods: A total of 215 advanced NSCLC patients with multi-site metastases were included. The overall survival (OS) was the primary end point. Results: EGFR tyrosine kinase inhibitors (TKIs) significantly improved the OS in patients with brain metastases (p = 0.031) and bone metastases (p = 0.048). Meanwhile, it prolonged the OS in patients with lung or adrenal metastases, but not in patients with liver metastases. However, in patients without liver metastases, EGFR TKIs significantly improved the OS (p < 0.001). Conclusion: EGFR TKIs improved the prognosis in NSCLC patients with brain, bone, lung and adrenal metastases, but not in patients with liver metastases.

Prostate cancer is the second most common cancer and the fifth cause of cancer death in males. Currently, there are no effective therapies for prostate cancer yet, and the status of treatment remains severe. In this study, we analyzed the composition of tumor-infiltrating immune cells (TIICs) in prostate cancer and paracancerous samples based on the gene expression profiles using CIBERSORT. Calculation of the TIIC subset proportions in 52 paired prostate cancer and paracancerous samples showed that their proportions were similar in intergroup and varied in intragroup. Compared with the paracancerous samples, the proportion of M0 macrophages was significantly increased in prostate cancer samples. Cox regression analysis using the TIIC subpopulations as continuous variables revealed that high plasma cell proportion was associated with poor 3-year Disease-Free Survival (DFS) in prostate cancer (hazard ratios = 1.8e-76

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.

// Xue Li 1, 2, * , Lujun Zhao 1, * , Wencheng Zhang 1 , Chengwen Yang 1 , Zhen Lian 1 , Shuai Wang 1 , Ningbo Liu 1 , Qingsong Pang 1 , Ping Wang 1 and Jinming Yu 1, 2 1 Department of Radiation Oncology and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China 2 Department of Radiation Oncology, Shandong University Affiliated Shandong Cancer Hospital and Institute, Jinan 250000, China * These authors have contributed equally to this work Correspondence to: Jinming Yu, email: sdyujinming@163.com Keywords: esophageal squamous cell carcinoma, supraclavicular nodes, celiac nodes, common hepatic nodes, radiotherapy Received: February 17, 2017 Accepted: April 17, 2017 Published: May 19, 2017 ABSTRACT The purpose of this study is to assess the prognostic value of supraclavicular nodes, left gastric nodes, celiac nodes and common hepatic nodes metastasis in esophageal squamous cell carcinoma (ESCC) treated with definitive radiotherapy. A total of 293 ESCC patients treated with radiotherapy or chemoradiotherapy entered the study. The results showed that the presence of supraclavicular nodes (χ 2 = 0.075, P = 0.785) and left gastric nodes (χ 2 = 3.603, P = 0.058) metastasis had no significant influence on survival, while celiac nodes (χ 2 = 33.775, P < 0.001) and common hepatic nodes (χ 2 = 42.350, P < 0.001) metastasis were associated with significantly shorter survival, regardless of the sites of primary tumor. Multivariate analysis showed that celiac nodes (HR: 0.457, 95% CI: 0.256-0.816; P = 0.008) and common hepatic nodes (HR: 0.241, 95% CI: 0.092-0.630; P = 0.004) metastasis were independently adverse indicator of survival in upper ESCC. While in the middle and lower ESCC, only the common hepatic nodes (middle ESCC: HR: 0.345, 95% CI: 0.161-0.738, P = 0.006; lower ESCC: HR: 0.377, 95% CI: 0.160-0.890, P = 0.026) metastasis was an independently adverse indicator of survival. In conclusion, our study demonstrated that in ESCC treated with definitive radiotherapy, both of celiac nodes and common hepatic nodes metastasis were adverse indicator of survival in upper ESCC, and common hepatic nodes metastasis were adverse indicator of survival in middle and lower ESCC. Supraclavicular nodes an left gastric nodes metastasis is not associated with patients survival in ESCC.

// Baozhong Zhang 1 , Zhiyong Yuan 1 , Lujun Zhao 1 , Qingsong Pang 1 , Ping Wang 1 1 Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China Correspondence to: Baozhong Zhang, email: baozhongtj@163.com Keywords: non-small cell lung cancer (NSCLC), N2, post-operative chemo-radiotherapy (POCRT), nomogram Received: December 28, 2016 Accepted: March 16, 2017 Published: March 25, 2017 ABSTRACT In this retrospective study, we developed nomograms for predicting the efficacy of post-operation radiotherapy (PORT) in IIIA-N2 non-small cell lung cancer (NSCLC) patients. In total, 334 patients received post-operational chemotherapy and were included in the analysis. Of those, 115 also received either concurrent or sequential post-operational radiotherapy (PORT). Nomograms were developed using Cox proportional hazard regression models to identify clinicopathological characteristics that predicted progression free survival (PFS) and overall survival (OS), and subgroup analyses of the effects of PORT were performed using nomogram risk scores. PFS and OS predicted using the nomogram agreed well with actual PFS and OS, and patients with high PFS/OS nomogram scores had poorer prognoses. In subgroup analyses, PORT increased survival more in patients with low PFS nomogram risk scores or high OS nomogram risk scores. Thus, our novel nomogram risk score model predicted PFS, OS, and the efficacy of PORT in IIIA-N2 NSCLC patients.

Objectives: The characteristics and prognostic factors of small-cell lung cancer (SCLC) patients with bone metastases at first diagnosis have scarcely been reported. This study aimed to analyze the prognostic factors of these patients and to develop a scoring system for survival to provide evidence for clinical treatment decisions. Materials and Methods: The records of 102 SCLC patients with bone metastasis at the time of diagnosis who were seen in our hospital between May 2010 and May 2015 were retrospectively reviewed. The log-rank test and multivariate Cox regression analysis were used to evaluate potential clinical predictors of survival. A scoring system was developed based on the hazard ratios of significant independent prognostic factors. Result: The most common site of bone metastases was the spine (64.7%), and 26 patients (25.6%) had a single bone metastasis. The median survival was 10.4 months, and the 2-year survival rate was 10.3%. Age, number of bone metastases, and occurrence of extraosseous distant metastases were significant independent prognostic factors for overall survival. Based on their scores, patients were divided into three groups. The median survival times of the three groups were 6.4 months, 8.5 months and 12.4 months, and the 2-year survival rates were 0%, 2.9%, and 19.3% (p=0.000). Twenty-six patients (25.5%) developed skeletal-related events (SREs), and the most common SREs were radiation to the bone (22.5%) and spinal cord compression (11.8%). Conclusion: This study includes preliminary clinical data of SCLC patients with bone metastases at the time of diagnosis, and more studies are needed. Keywords: small-cell lung cancer, bone metastases, prognosis, scoring system

The current study was to compare the efficacy and safety between concurrent and sequential chemoradiotherapy after 3-4 cycles of induction chemotherapy for limited-stage small-cell lung cancer (LS-SCLC) with bulky tumor. From July 2012 to September 2015, a total of 68 patients with stage IIIA and IIIB SCLC who had completed 3-4 cycles of etoposide plus cisplatin/carboplatin and achieved clinical complete response (cCR) or clinical partial response (cPR) were randomized into the two groups equally. The concurrent group received radiotherapy combined with oral etoposide and cisplatin and the sequential group received sequential chemoradiotherapy. Thoracic radiotherapy was performed using intensity-modulated radiation therapy (IMRT) with 95% PTV 60Gy/30 times. After completing chemoradiotherapy, patients received prophylactic cranial irradiation. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS) and toxicity. The median follow-up time was 63.3 months (95% confidence interval [CI], 50.8-75.8). Better PFS and OS were observed in concurrent group (median PFS, 26.0 months [95% CI, 9.0-43.0] versus 13.1 months [95%CI, 9.7-16.6], p=0.023; median OS, 35.0 months [95% CI, 25.4-44.6] versus 22.0 months [95% CI, 17.0-27.1], p=0.015). There was no significant difference in the incidence of radiation esophagitis and radiation pneumonitis between the two groups (p=0.795, p=0.525). This study demonstrated that after the completion of 3-4 cycles of chemotherapy with a remission, concurrent chemoradiotherapy with oral etoposide and cisplatin improved survival compared with sequential chemoradiotherapy in LS-SCLC with bulky tumor. ClinicalTrials.gov Identifier: NCT01745445.

Background The role of the dose escalation strategy in brain radiotherapy for small cell lung cancer (SCLC) patients with brain metastases (BMs) has not been identified. This study aims to determine whether an additional radiation boost to whole brain radiation therapy (WBRT) has beneficial effects on overall survival (OS) compared with WBRT-alone. Methods A total of 82 SCLC patients who were found to have BMs treated with WBRT plus a radiation boost (n = 33) or WBRT-alone (n = 49) from January 2008 to December 2015 were retrospectively analyzed. All patients were limited-stage (LS) SCLC at the time of the initial diagnosis, and none of them had extracranial metastases prior to detection of BMs. The primary end point was OS. Results The median OS for all of the patients was 9.6 months and the 6-, 12- and 24-months OS rates were 69.1, 42.2 and 12.8%, respectively. At baseline, the proportion of more than 3 BMs was significantly higher in the WBRT group than in the WBRT plus boost group (p = 0.0001). WBRT plus a radiation boost was significantly associated with improved OS in these patients when compared with WBRT-alone (13.4 vs. 8.5 months; p = 0.004). Further, the survival benefit still remained significant in WBRT plus boost group among patients with 1 to 3 BMs (13.4 vs. 9.6 months; p = 0.022). Conclusion Compared with WBRT-alone, the use of WBRT plus a radiation boost may prolong survival in SCLC patients with BMs. The dose escalation strategy in brain radiotherapy for selected BMs patients with SCLC should be considered.

Baozhong Zhang, Lujun Zhao, Zhiyong Yuan, Qingsong Pang, Ping Wang Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, and Tianjin Lung Cancer Center, Tianjin, People’s Republic of China Objective: The use of postoperative radiotherapy (PORT) remains controversial for Stage IIIA-N2 non-small-cell lung cancer (NSCLC) patients, a possible reason is that IIIA-pN2 NSCLC diseases are a heterogeneous group with different clinicopathologic features. The aim of this research was to prove whether the mediastinal lymph nodes’ (LNs) skipping status could indicate the necessity of the PORT for the pN2 NSCLC patients.Methods: The skip metastasis was defined as pN0N2 (no N1 LN involved), and nonskip metastasis was pN1N2 (one or more N1 LNs involved). Patients were divided into two groups: LNs nonskip and LNs skip, and postoperative chemoradiotherapy (POCRT) and postoperative chemotherapy. Then, the LN nonskip and LN skip groups were further divided into subgroups: POCRT and point of care testing (POCT) for subgroup analysis.Results: There were 220 cases included in the analysis, and 43 of them received PORT. Onunivariate analysis, the median 3-year progression-free survival (PFS) was, respectively, 16 months (27.7%) for the LN skip group and 11 months (15.3%) for the LN nonskip group (P=0.001). The median 3-year overall survival (OS) was, respectively, 35 months (47.0%) for the LN skip group and 27 months (38.7%) for the LN nonskip group (P=0.025). The median 3-year local recurrence-free survival (LRFS) was, respectively, 25 months (41.0%) for the LN skip group and19 months (29.9%) for the LN nonskip group (P=0.014). The median 3-year distant metastasis-free survival (DMFS) was, respectively, 22 months (32.5%) for the LN skip group and 15 months (20.4%) for the LN nonskip group (P=0.013). The median 3-year PFS was, respectively, 17 months (25.6%) for the POCRT group and 12months (18.6%) for the POCT group (P=0.037). Although the POCRT group showed better OS, LRFS, and DMFS than the POCT group, the results showed no statistical significance. In subgroup analysis, there was no statistical significance in the Kaplan–Meier analysis between subgroups, but it showed that POCRT resulted in better PFS, OS, and DMFS in both LN skip and LN nonskip subgroups; this advantage was more obvious in the LN skip subgroup.Conclusion: The LN skip status is closely related to the survival of the IIIA-N2 NSCLC disease, and the LN skip patients may get more benefit in PFS and LRFS than the LN nonskip patients from PORT. Keywords: non-small-cell lung cancer (NSCLC), N2, postoperative chemoradiotherapy (POCRT), LN skip/nonskip, PFS, OS, DMFS

Background Chemoradiotherapy (CRT) plays a central role in the treatment of esophageal squamous cell carcinoma (ESCC). However, no effective biomarkers have been identified for predict CRT sensitivity and prognosis of patients with ESCC. The aim of this study was to investigate cytokine profiles of epidermal growth factor (EGF) and urokinase plasminogen activator receptor (uPAR) in 68 ESCC patients, and to evaluate the clinical utility of these markers. Methods This pilot study enrolled 68 patients who received neoadjuvant CRT followed by radical surgery or definitive CRT between 2015 and 2017. Serum specimen was obtained from each patient before treatment and at the time of administration of total doses of 40 Gy. Cytokines expression analyses were performed in pre- and post-treatment serum using human cytokine antibody arrays which contained 120 known tumor-related cytokines. Results Seven differentially expressed cytokines identified by cytokine antibody arrays in pre- and post-treatment serum from 4 patients with CRT sensitivity and 4 patients with CRT resistance. Of these, up-regulation of EGF and uPAR in serum at the doses of 40 Gy were associated with adverse clinical outcomes. The predictive value of EGF and uPAR were further assessed in a second set of 60 ESCCs. A total of 68 patients enrolled in this study. The median follow-up duration of these patients was 15.87 months (range, 6.21-23.85 months). Cox multivariate survival analyses revealed that high uPAR ratio after CRT independently predicted progression-free survival (PFS) (HR =3.999, 95% CI: 1.503-10.639, P=0.006) and patients with elevated levels of EGF after CRT exhibited significantly worse overall survival (OS) (HR =2.574, 95% CI: 1.046-6.335, P=0.040). Of note, uPAR expression was significantly positive correlation with EGF expression in pre- and post-treatment serum (P=0.0001, P=0.0038). Patients with both high EGF and uPAR ratios had an inferior PFS and OS, compared to patients with a high EGF ratio only or uPAR ratio only or neither (1-year PFS rate 44.2% vs. 61.4%, 1-year OS rate 64.2% vs. 83.4%, P=0.033 and 0.029, respectively). Conclusions The levels of EGF and uPAR in serum are reliable and predictive biomarkers for survival in ESCC patients. Further prospective validation in larger independent cohorts is necessary to fully assess its predictive power. We present the following article in accordance with the REMARK reporting checklist.

BACKGROUND: To investigate the relationship between baseline nutrition status and radiation esophagitis in patients with esophageal cancer treated by radiation therapy. METHODS: A retrospective study was performed on 100 patients with esophageal cancer who was treated with definitive chemoradiotherapy, preoperative chemoradiation and definitive radiotherapy at the Tianjin Medical University Cancer Institute and Hospital from October 2018 and October 2019. We documented the clinical characteristics of patients, including tumor location, clinical stage, treatment, radiation dose, gross tumor volume (GTV), planning tumor volume (PTV) and Atkinson’s Dysphagia score (ADS), and we recorded the nutrition status before radiation, including Patient-Generated Subjective Global Assessment (PG-SGA), body mass index (BMI), weight loss percentage in 3 mouths (WL), the level of albumin (ALB), hemoglobin (HB), C-reactive protein (CRP) and Glasgow prognostic score (GPS). These factors were correlated with radiation esophagitis using univariate and multivariate regression analyses. RESULTS: Of 100 patients, 44% patients with PG-SGA score ≥9 at baseline, suggesting severe malnutrition, 41% patients developed grade ≥2 radiation esophagitis. In univariate analysis, dose >40 Gy (P=0.015), PTV ≥495 cm(3) (P=0.049), PG-SGA score ≥9 (P=0.001), WL ≥10% (P=0.019) and ALB level

Xin Wang, Liming Xu, Zhenzhen Yin, Daquan Wang, Qi Wang, Kunpeng Xu, Jinlin Zhao, Lujun Zhao, Zhiyong Yuan, Ping Wang Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer, Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China Objective: In order to identify risk factors associated with locoregional recurrence (LRR) and assess the role of postmastectomy radiotherapy (PMRT) in early breast cancer (BC), managed with neoadjuvant chemotherapy (NAC) and mastectomy, a retrospective analysis of BC diagnosed with clinical stage T1-2N0-1 was conducted.Patients and methods: A total of 217 patients were included in this analysis. The median age was 50 years (24–72 years). The clinical stage distributions were cT1 in 15 cases, cT2 in 202, cN0 in 53, and cN1 in 161 cases. All patients were treated with NAC and mastectomy, and 128 patients received PMRT.Results: With a median follow-up time of 61 months, the 5-year cumulative LRR rate was 12%. Multivariate analysis demonstrated that pathological N stage, lymph-vascular invasion, and histological grade were independent prognostic factors associated with LRR. A nomogram model based on these factors was established, based on which the patients were deeply stratified into low- and high-risk group. In the low-risk group, radiotherapy did not decrease LRR (3.3% in PMRT group, 1.7% in no PMRT group, P=0.192). While in the high-risk group, PMRT significantly decreased LRR (21.8% in PMRT group, 42.2% in no PMRT group, P=0.031).Conclusion: Lymph-vascular invasion, histological grade, as well as pathological N stage were important prognostic factors associated with LRR in BC patients staged in cT1-2N0-1, who were managed with NAC and mastectomy. In our cohort, not only clinical and pathological stage information but also other risk factors were taken into consideration when adjuvant PMRT was recommended. In the high-risk subgroup, PMRT significantly improved the prognosis. Keywords: breast cancer, neoadjuvant chemotherapy, postmastectomy radiotherapy, prognosis

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 To investigate whether the response to induction chemotherapy (IC) would impact the timing of thoracic radiotherapy (TRT) in limited-stage small-cell lung cancer (LS-SCLC). Methods A total of 146 patients with LS-SCLC who had received two to six cycles of IC followed by TRT from January 2009 to December 2011 at our hospital were included in this study. Patients were divided into two groups based on the time TRT was administered: early TRT (administered after 2–3 cycles of chemotherapy) or late TRT (administered after 4–6 cycles). Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. Multivariate Cox regression analysis was performed to evaluate the independent factors affecting survival. Results The median OS for patients who received early TRT and late TRT was 29.0 and 19.9 months, respectively, (P = 0.018) and the median PFS was 18.5 and 13.8 months, respectively (P = 0.049). In patients who achieved complete remission (CR) or partial remission (PR) after two to three cycles of IC, the median OS was 36.1 and 22.5 months in the early and late TRT subgroups, respectively (P = 0.009); the corresponding median PFS was 20.2 and 13.8 months, respectively (P = 0.038). In the patients who did not achieve CR or PR, no statistic difference was found in OS or PFS between the two subgroups. Conclusion Patients who received early TRT had more favorable outcomes than those who received late TRT. Patients who achieved CR or PR after two to three cycles of IC obtained more benefit from early TRT.

Background Reappraisal of the role of postoperative radiotherapy in pN2 non-small cell lung cancer (NSCLC) patients according to N1 lymph node involvement. Methods A total of 218 pIIIa-N2 NSCLC patients who underwent complete surgical resection with systematic nodal dissections were enrolled. Propensity scores were used for matching N1 involvement. Overall survival (OS) and disease-free survival (DFS) were analyzed retrospectively. Results After matching, pN2b patients without N1 involvement (pN0N2b) exhibited better prognoses than those with N1 involvement (pN1N2b) (5-year OS: 37.5% vs. 7.1%, P = 0.008; 5-year DFS: 31.8% vs. 4.6%, P = 0.004). Similar results were not detected in pN2a disease (5-year OS: 37.8% vs. 31.0%, P = 0.517; 5-year DFS: 27.1% vs. 20.2%, P = 0.788). The five-year OS of patients who received no adjuvant therapy (22 pN2a cases, 7 pN0N2b, 5 pN1N2b), adjuvant chemotherapy alone (74 pN2a cases, 11 pN0N2b, 17 pN1N2b) or chemoradiotherapy (25 pN2a cases, 7 pN0N2b, 6 pN1N2b) were compared (pN2a: 31.3%, 37.0%, and 32.0%, P = 0.808; pN0N2b: 0.0%, 18.2%, and 71.4%, P = 0.108; pN1N2b: 0.0%, 0.0%, and 33.3%, P < 0.0001). The five-year DFS was also analyzed (pN2a: 31.6%, 24.0%, and 18.3%, P = 0.410; pN0N2b: 0.0%, 11.1%, and 57.1%, P = 0.192; pN1N2b: 0.0%, 0.0%, and 16.7%, P < 0.0001). Multivariate analysis revealed that the novel classification based on N1 involvement and pN2a/pN2b staging was an independent prognostic factor of OS and DFS. Conclusion N1 involvement significantly impacted the prognosis of pN2b NSCLC patients. The benefit of adjuvant therapy in pN2a and pN0N2b patients requires confirmation by further study.

Hepatocellular carcinoma (HCC) is the most common malignancy in the world and the most common cause of cancer-related death. Surgical resection is the standard of care for solitary liver-confined HCC and provides the best long-term survival, however, most HCCs are diagnosed at an intermediate to advanced stage, and few meaningful therapeutic options are available at this point. Stereotactic body radiation therapy (SBRT) is a type of external beam radiation therapy (EBRT) that delivers radiotherapy (RT) accurately and precisely to the tumor, more so than conventionally fractionated RT. Several series report high rates of local control and low incidence of complications in SBRT for inoperable HCC. Herein, we discuss the emerging role of SBRT as well as current indications, implementation, efficacy and toxicities after SBRT. It was noted that SBRT was a safe and effective therapeutic option for HCC lesions unsuitable for standard locoregional therapies, with acceptable local control rates and low treatment-related toxicity. The significant correlation between local control (LC) and higher doses and between LC and overall survival (OS) supports the clinical value of SBRT in these patients.

Background This study evaluated the prognosis of patients with extensive-stage small-cell lung cancer (ES-SCLC) that may be associated with timing of thoracic radiotherapy (TRT). Methods ES-SCLC patients (n = 232) without progression were retrospectively analyzed after first-line induction chemotherapy. Patients in the TRT group were stratified as early-TRT (ERT; ≤3 cycles of induction chemotherapy received prior to TRT, n = 65) or late-TRT (LRT; >3 cycles, n = 122). To avoid selection bias, we conducted Propensity Score Matching (PSM) for patients. Overall survival (OS), progression-free survival (PFS), and locoregional recurrence-free survival (LRRFS) were assessed and compared. Results Overall, the median survival time, PFS, and LRRFS were 13.2, 8.7, and 14.6 months, respectively. After matching by PSM, there were 45 patients total in the TRT/non-TRT groups, and 56 patients total in the ERT/LRT groups. OS, PFS, and LRRFS were significantly longer in the TRT group than the non-TRT group (P 0.05, all). Conclusion For ES-SCLC patients without progression, the addition of TRT after first-line chemotherapy benefited survival greatly. Early TRT showed no significant benefit over late TRT.

Background The effect of concomitant chronic hepatitis B (CHB) infection on the risk of colorectal liver metastasis (CRLM) has not been definitively elucidated. Many clinicians believe that CHB is “protective” and although previous reports support their presumption, these studies were limited by small sample size, mixed types of chronic hepatitis and heterogeneous therapies. Methods To explore this issue, we retrospectively studied 7187 newly diagnosed colorectal cancer (CRC) patients. The definitions and diagnostic procedures of synchronous CRLM (synCRLM) were as per our previous report. Results The prevalence of HBsAg+ was 5.12% (364/7111) and HBeAg+ was 1.25% (76/6075). The overall prevalence of synCRLM was 8.72% (627/7187) and was significantly higher in HBsAg+ patients than HBsAg- patients (13.40% vs. 8.54%, P = 0.031). SynCRLM was also more prevalent in HBeAg+ patients compared to HBeAg- patients (19.70% vs. 10.17%, P = 0.031). In univariate logistic regression analysis, HBeAg+ had the highest hazard ratio (HR) [2.947, P Conclusions This study focuses only on the newly diagnosed synCRLM and eliminates the effect of various adjuvant and neoadjuvant therapy. In our previous study of 4033 CRC patients and contrary to much of the reported literature, HBsAg+ was associated with significantly increased prevalence of CRLM. HBeAg+ also trended toward increased CRLM prevalence but didn’t reach statistical significance. When expanded to 7187 subjects, HBeAg+ is finally proved to be a predictor of CRLM, with a HR much higher than that of HBsAg+. Unlike the minimal chance of HBsAg loss, HBeAg seroconversion and HBV-DNA repression can be achieved in many CHB patients with current anti-viral therapies. In summary, HBeAg+ is a clinical risk factor for CRLM that can be readily identified and addressed. Whether antiviral treatment can decrease the risk of CRLM is definitely worth further study. Legal entity responsible for the study The authors. Funding National Natural Science Fund of China (No.81872400). Disclosure L. Zhao: Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: MSD. J. Cao: Speaker Bureau / Expert testimony: Bayer. All other authors have declared no conflicts of interest.

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung adenocarcinoma, and a theoretical basis exists for utilising whole brain radiotherapy (WBRT) combined with erlotinib for the treatment for brain metastases in patients with lung adenocarcinoma. This therapeutic regimen has the potential to be a revolutionary treatment for which the most appropriate indication is lung adenocarcinoma. Currently, there is no difference in the treatment of brain metastasis, especially multiple brain metastases, in patients with lung adenocarcinoma of patients with other lung carcinomas. Furthermore, limited clinical trials that combine a TKI with WBRT to treat multiple lung adenocarcinoma metastases have been conducted, and many clinical questions remain unanswered. Lung adenocarcinoma has a high propensity to metastasize to the brain, and targeted therapy has been widely used; however, clinical trials are necessary to provide data to support the combination of erlotinib and WBRT.

Purpose The use of prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC) with surgical resection has not been fully identified. This study undertook to assess the factors affecting the risk of brain metastases in patients with stage I-III SCLC after surgical resection. The implications of PCI treatment for these patients are discussed. Methods and Materials One hundred twenty-six patients treated with surgical resection for stage I-III SCLC from January 1998-December 2009 were retrospectively analyzed to elucidate the risk factors of brain metastases. Log-rank test and Cox regression model were used to determine the risk factors of brain metastases. Results The median survival time for this patient population was 34 months, and the 5-year overall survival rate was 34.9%. For the whole group, 23.0% (29/126) of the patients had evidence of metastases to brain. Pathologic stage not only correlated with overall survival but also significantly affected the risk of brain metastases. The 5-year survival rates for patients with pathologic stages I, II, and III were 54.8%, 35.6%, and 14.1%, respectively ( P =.001). The frequency of brain metastases in patients with pathologic stages I, II, and III were 6.25% (2/32), 28.2% (11/39), and 29.1% (16/55) ( P =.026), respectively. A significant difference in brain metastases between patients with complete resection and incomplete resection was also observed (20.5% vs 42.9%, P =.028). The frequency of brain metastases was not found to be correlated with age, sex, pathologic type, induction chemotherapy, adjuvant chemotherapy, or adjuvant radiation therapy. Conclusions Stage I SCLC patients with complete resection had a low incidence of brain metastases and a favorable survival rate. Stage II-III disease had a higher incidence of brain metastases. Thus, PCI might have a role for stage II-III disease but not for stage I disease.

Ximei Zhang, Peiguo Wang, Lujun Zhao, Zhiyong Yuan, Ping Wang Department of Radiation Oncology, Tianjin’s Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, People’s Republic of China Background: The aim of this study was to identify the appropriate radiation volume for primary gastric diffuse large B-cell lymphoma (PG-DLBCL).Methods: We retrospectively analyzed the clinical and pathological findings of 68 patients treated with total gastrectomy and D2 lymphadenectomy.Results: There were 23, 14, and 29 patients with stage I, stage II, and stage IIE disease, respectively, and 30 patients had lymph node involvement. Primary tumor location, as well as the depth of invasion, was significantly associated with lymph node involvement. When the tumor was limited to the muscularis, the involved lymph nodes were found to be perigastric nodes. For tumors invading beyond the muscularis, regional lymph nodes were involved.Conclusion: The optimal radiation volume for patients with PG-DLBCL is largely dependent on the primary location and depth of invasion. Larger series and longer follow-up are needed to further delineate the radiation volumes for PG-DLBCL. Keywords: primary gastric lymphoma, failure patterns, radiotherapy, chemotherapy, prognosis

Ximei Zhang,1 Baozhong Zhang,1 Fenglin Zang,2 Lujun Zhao,1 Zhiyong Yuan,1 Ping Wang1 1Department of Radiation Oncology, 2Department of Pathology, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, People’s Republic of China Objectives: Data on breast squamous cell carcinoma (SCC) are rare. The aim of this study was to analyze the clinical characteristics and to explore the rational treatment of patients with breast SCC. Patients and methods: We conducted a retrospective review of breast SCC cases treated at our center from 1966 to 2014. The majority of these patients received primary surgery followed by adjuvant chemoradiotherapy, whilst four elderly patients had lumpectomy only. Results: Patients with breast SCC were usually women, and large masses, large proportion of early stage disease, low levels of estrogen receptor expression, less frequent axillary lymph nodes involvement, and unfavorable prognosis were common. The 5-year overall survival and progression-free survival of all patients were 67.2% and 57.8%, respectively. Axillary nodal involvement was a significant prognostic factor for survival. Conclusion: The current results indicated that breast SCC is clinically aggressive and the outcomes were poor. Distant metastasis was the main failure pattern. New strategies will be needed because of the poor outcomes. Keywords: breast metaplastic carcinoma, breast SCC, treatment, surgery, prognosis

Rad51c is critical for homologous recombination repair and genomic stability and may play roles in tumorigenesis and cancer therapy. We investigated the expression level and clinical significance of Rad51c in non-small cell lung cancer (NSCLC) and determined the effect of Rad51c on NSCLC cell chemosensitivity and radiosensitivity. Rad51c expression was detected using immunohistochemistry and was higher in NSCLC patient samples than in adjacent normal tissues. Kaplan–Meier analysis revealed that high Rad51c expression was an independent predictor of short overall survival (OS) and disease-free survival (DFS) in NSCLC patients receiving chemotherapy and/or radiotherapy. Furthermore, Rad51c knockdown increased the killing effect of ionizing radiation (IR) and enhanced cisplatin-induced apoptotic cells in NSCLC cells by disrupting the repair of cisplatin- and IR-induced DNA damage. In addition, ectopic expression of Rad51c dramatically enhanced NSCLC cell resistance to cisplatin and radiotherapy. These findings suggest that increased expression of Rad51c may confer resistance to chemotherapy and/or radiotherapy of NSCLC, and also be an independent prognostic factor for patient outcome. Therefore, targeting Rad51c may represent an improved therapeutic strategy for NSCLC patients with locally advanced disease.

Background and purpose To evaluate the risk factors for radiation-induced lung toxicity (RILT) from post-operative radiation therapy (PORT) in patients with non-small cell lung cancer (NSCLC). Material and methods Ninety NSCLC patients who received PORT with or without chemotherapy from November 2002 to March 2006 were retrospectively analyzed. Each individual's radiotherapy plans were reviewed to determine the percentage of the whole lung volume that received more than a specific dose of irradiation (Vdose). The endpoint was RILT of grade 2 or higher. Data of potential risk factors for RILT were extracted from the medical records and evaluated by logistic regression modeling, the t-test, and the Chi-square test. Results A total of 20 patients received pneumonectomy, while the remaining 70 received lobectomy. In the lobectomy group, 9 patients (10%) developed ≥grade 2 RILT. Among the clinical factors, only adjuvant chemotherapy was significantly correlated with RILT (p = 0.039). For lung dosimetric factors, V20 through V40 were all significantly higher in the RILT group than in the non-RILT group. In the lobectomy group, the incidence of RILT was 27.3% in patients who received adjuvant chemotherapy and whose V20 was greater than 20%. It was 9.7% in lobectomy patients with one of the risk factors, and 0.0% in those with no risk factors (p = 0.032). Conclusions The lung toxicity of PORT was found to be acceptably low. Adjuvant chemotherapy and lung dosimetric factors of V20–V40 were significantly correlated with RILT risk in NSCLC patients.

Introduction We hypothesized that plasma transforming growth factor-²1 (TGF-²1) level and its dynamic change are correlated with the prognosis of locally advanced non-small cell lung cancer (NSCLC) treated with radiation therapy (RT). Methods Patients with stage IIIA or IIIB NSCLC treated with RT with or without chemotherapy were eligible for this study. Platelet poor plasma was collected from each patient within 1 week before RT (pre-RT) and at the 4th week during RT (during-RT). TGF-²1 level was measured with enzyme-linked immunosorbent assay. The primary end point was overall survival (OS) and the secondary end point was progression-free survival (PFS). Kaplan-Meier and Cox regression were used for risk factor evaluation. Results A total of 65 patients were eligible for the study. The median OS and PFS were 17.7 and 13.7 months, respectively. In univariate analysis, performance status, weight loss, radiation dose, and TGF-²1 ratio (during-RT/pre-RT TGF-²1 level) were all significantly correlated with OS. In the multivariate analysis, performance status, radiation dose, and TGF-²1 ratio were still significantly correlated with OS. The median OS was 30.7 months for patients with TGF-²1 ratio ≤1 versus 13.3 months for those with TGF-²1 ratio more than 1 ( p = 0.0029); and the median PFS was 16.8 months versus 7.2 months, respectively ( p = 0.010). Conclusions In locally advanced NSCLC, the decrease of TGF-²1 level during RT is correlated with favorable prognosis.

Radiation plays an important role in the treatment of thoracic tumors. During the last 10 years there have been several major advances in thoracic RT including the incorporation of concurrent chemotherapy and the application of con-formal radiation-delivery techniques (eg, stereotactic RT, three-dimensional conformal RT, and intensity-modulated RT) that allow radiation dose escalation. Radiation as a local measure remains the definitive treatment of medically inoperable or surgically unresectable disease in NSCLC and part of a multimodality regimen for locally advanced NSCLC, limited stage SCLC, esophageal cancer, thymoma, and mesothelioma.

This study aimed to analyze the prognostic significance of the positive nodal chain ratio (NCR) in non-small-cell lung cancer (NSCLC). A total of 208 pIIIa-N2 NSCLC patients who underwent complete surgical resections with a systematic nodal dissection were enrolled. The median values of NCR and the positive lymph node ratio (LNR) were used to grouping patients. The differences of overall survival (OS) and disease-free survival (DFS) between the different groups were compared. The median values of NCR and LNR were 0.31 and 0.45, respectively. The patients were separated into group A (NCR ≤0.45 and LNR ≤0.31; 91 cases), group B (NCR ≤0.45 and LNR0.31 or NCR0.45 and LNR ≤0.31; 51 cases), and group C (NCR0.45 and LNR0.31; 66 cases) according to their combined LCR and LNR values. Groups A, B, and C exhibited significantly different prognoses (5-year OS: 43.7, 25.2, and 12.3 %, respectively, p 0.0001; 5-year DFS: 30.4, 23.3, and 8.6 %, respectively, p 0.0001). Multivariate analyses revealed that this novel grouping method based on the combination of NCR and LNR was an independent prognostic factor for 5-year OS and 5-year DFS in pIIIa-N2 NSCLC. In group C, patients who received no postoperative treatment, adjuvant chemotherapy alone, or chemoradiotherapy exhibited different 5-year OS rates (0.0, 11.6, and 37.5 %, respectively, p = 0.003) and 5-year DFS rates (0.0, 7.5, and 25.0 %, respectively, p = 0.009). Therefore, postoperative chemoradiotherapy may significantly improve the prognosis of patients displaying NCR0.45 and LNR0.31. NCR combined with LNR may be more effective to guide individualized multimodality therapy including postoperative chemoradiotherapy for pIIIa-N2 NSCLC.

The combination of radiotherapy and targeted therapy is an important approach in the application of targeted therapy in clinical practice, and represents an important opportunity for the development of radiotherapy itself. Numerous agents, including epidermal growth factor receptor, monoclonal antibodies, tyrosine kinase inhibitors, and antiangiogenic therapies, have been used for targeted therapy. A number of studies of radiotherapy combined with targeted therapy in non-small-cell lung carcinoma have been completed or are ongoing. This paper briefly summarizes the drugs involved and the important related clinical research, and indicates that considerable progress has been made with the joint efforts of the two disciplines. Many issues, including drug selection, identification of populations most likely to benefit, timing of administration of medication, and side effects of treatment require further investigation. However, further fundamental research and accumulation of clinical data will provide a more comprehensive understanding of these therapies. Targeted therapy in combination with radiotherapy has a bright future.

Jun Liang,1 Mingyan E,2 Gang Wu,3 Lujun Zhao,4 Xia Li,5 Xia Xiu,6 Ning Li,1 Bo Chen,1 Zhouguang Hui,1 Jima Lv,1 Hui Fang,1 Yu Tang,1 Nan Bi,1 Wenqing Wang,1 Yirui Zhai,1 Tao Li,1 Dongfu Chen,1 Shuangmei Zou,7 Ning Lu,7 Rolando Perez-Rodríguez,8 Junqi Zheng,9 Luhua Wang11Department of Radiotherapy, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China; 2Department of Radiotherapy, Cancer Hospital of Harbin Medical University, Harbin, People's Republic of China; 3Department of Radiotherapy, Tongji Cancer Center Hospital, Wuhan, People's Republic of China; 4Department of Radiotherapy, Cancer Hospital of Tianjin Medical University, Tianjin, People's Republic of China; 5Department of Radiotherapy, LiaoNing Province Cancer Hospital, Shenyang, People's Republic of China; 6Department of Radiotherapy, Beijing Hospital, Beijing, People's Republic of China; 7Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China; 8Center of Molecular Immunology, Havana, Cuba; 9School of Medicine, Tongji University, Shanghai, People's Republic of ChinaObjective: To determine the safety and therapeutic effects of nimotuzumab (h-R3) combined with radiotherapy in esophageal cancer.Methods: This Phase II clinical trial involved 42 patients with stage II (inoperable or refused surgery) to stage IV (supraclavicular lymph node metastasis only) esophageal cancers treated between November 2008 and July 2010. All patients had squamous cell carcinomas, and all received three-dimensional conformal radiotherapy and 200 mg nimotuzumab per week during radiotherapy.Results: There were 9, 25, and 8 patients with stage II, III and IV disease, respectively. All except two patients received 50–70 Gy radiation; 37 patients (88.1%) received more than five nimotuzumab doses. Grade III toxicities (21.4% of all adverse events) included esophagitis and gastrointestinal, dermatological and hematological toxicities. Complete response, partial response, stable disease, and progressive disease were observed in 0, 22 (52.4%), 17 (40.5%) and 3 (7.1%) patients at 1 month after the treatment. The epidermal growth factor receptor (EGFR) overexpression rate was 95.2%. After a median follow-up of 37 months, the median survival time (MST) was 14 months. The 2 year and 3 year overall survival (OS) rates were 33.3% and 26.2%, respectively. The median progression-free survival (PFS) time was 10 months. The 2 year and 3 year PFS rates were 24.5% and 22.1%, respectively. The MST in the 13 patients with (+++) EGFR expression (group A) and 7 patients with (++) EGFR expression (group B) was 15 and 11 months, respectively. The 2 year and 3 year OS rates were 46.2% and 38.5% in group A and 28.6% and 28.6% in group B, respectively (P = 0.405).Conclusion: Although concurrent chemoradiotherapy was the standard care for locally advanced esophageal cancer, radiotherapy was the choice for those who were refused or could not tolerate chemoradiotherapy. Our study shows that nimotuzumab combined with radiotherapy was well tolerated in patients with esophageal cancer. EGFR overexpression was more common than previously reported. OS was higher after combined therapy than after historical control radiotherapy alone. Further studies are required to confirm the therapeutic efficacy of nimotuzumab in esophageal cancer.Keywords: esophageal neoplasms, nimotuzumab, radiotherapy, targeted therapy, treatment outcomes

Purpose Radiation-induced esophageal toxicity (RIET) is a dose-limiting toxicity in lung cancer patients receiving radiotherapy. Accumulating evidence indicates that DNA repair and the cytokine pathways play essential roles in radiation-induced diseases. Genetic polymorphisms of genes in these pathways may affect gene function and/or gene expression and lead to different treatment-related esophageal toxicity. Materials and methods This study investigated the association of 21 polymorphisms in 14 genes, with the occurrence of ⩾grade 2 acute RIET. Genotypes were analyzed among 213 stage III lung cancer patients receiving radiotherapy. Results We used Cox proportional hazard model to examine the effects of genotypes on ⩾grade 2 acute RIET risk and Kaplan–Meier estimator to compare effects of different genotypes on such risk. Multivariate analysis showed that CT or TT genotype of TGF - β1 -509C/T polymorphism was associated with a significantly higher RIET risk (adjusted hazard ratio [HR]=2.47; 95% confidence interval (CI)=1.17–5.24; P =0.018, or HR=3.86; 95% CI=1.50–9.92; P =0.005), respectively, compared with the CC genotype. Moreover, Lys/Gln+Gln/Gln genotypes of XPD Lys751Gln polymorphism were also associated with a significantly decreased RIET risk (adjusted HR=0.55; 95% CI=0.32–0.96; P =0.030). Conclusions This report, for the first time, examined the influence of inherited variation in the DNA repair and the cytokine pathways on RIET.

Purpose Radiation-induced pneumonitis (RP) is the most common dose-limiting complication in lung cancer patients treated with radiotherapy. Accumulating evidence indicates that P53 and the ataxia telangiectasia-mutated protein (ATM)—dependent signaling response cascade play a crucial role in radiation-induced diseases. Consistent with this, our previous study showed that a functional genetic ATM polymorphism was associated with increased RP risk. Methods and Materials To evaluate the role of genetic P53 polymorphism in RP, we analyzed the P53 Arg72Pro polymorphism in a cohort including 253 lung cancer patients receiving thoracic irradiation. Results We found that the P53 72Arg/Arg genotype was associated with increased RP risk compared with the 72Pro/Pro genotype. Furthermore, the P53 Arg72Pro and ATM –111G>A polymorphisms display an additive combination effect in intensifying the risk of developing RP. The cross-validation test showed that 63.2% of RP cases can be identified by P53 and ATM genotypes. Conclusions These results indicate that genetic polymorphisms in the ATM-P53 pathway influence susceptibility to RP and genotyping P53 and ATM polymorphisms might help to identify patients susceptible to developing RP when receiving radiotherapy.

Purpose To determine whether time to treatment (TTT) has an effect on overall survival (OS) in patients with unresectable or medically inoperable Stage III non–small cell lung cancer (NSCLC) and whether patient or treatment factors are associated with TTT. Methods and Materials Included in the study were 237 consecutive patients with Stage III NSCLC treated at University of Michigan Hospital (UM) or the Veterans Affairs Ann Arbor Healthcare System (VA). Patients were treated with either palliative or definitive radiotherapy and radiotherapy alone ( n = 106) or either sequential ( n = 69) or concurrent chemoradiation ( n = 62). The primary endpoint was OS. Results Median follow-up was 69 months, and median TTT was 57 days. On univariate analysis, the risk of death did not increase significantly with longer TTT ( p = 0.093). However, subset analysis showed that there was a higher risk of death with longer TTT in patients who survived ≥ 5 years ( p = 0.029). Younger age ( p = 0.027), male sex ( p = 0.013), lower Karnofsky Performance Score (KPS) ( p = 0.002), and treatment at the VA ( p = 0.001) were significantly associated with longer TTT. However, on multivariate analysis, only lower KPS remained significantly associated with longer TTT ( p = 0.003). Conclusion Time to treatment is significantly associated with OS in patients with Stage III NSCLC who lived longer than 5 years, although it is not a significant factor in Stage III patients as a whole. Lower KPS is associated with longer TTT.

Purpose Since the ataxia telangiectasia mutated (ATM) protein plays crucial roles in repair of double-stranded DNA breaks, control of cell cycle checkpoints, and radiosensitivity, we hypothesized that variations in this gene might be associated with radiation-induced pneumonitis (RP). Methods and Materials A total of 253 lung cancer patients receiving thoracic irradiation between 2004 and 2006 were included in this study. Common Terminology Criteria for Adverse Events version 3.0 was used to grade RP. Five haplotype-tagging single nucleotide polymorphisms (SNPs) in the ATM gene were genotyped using DNA from blood lymphocytes. Hazard ratios (HRs) and 95% confidence intervals (CIs) of RP for genotypes were computed by the Cox model, adjusted for clinical factors. The function of the ATM SNP associated with RP was examined by biochemical assays. Results During the median 22-month follow-up, 44 (17.4%) patients developed grade ≥ 2 RP. In multivariate Cox regression models adjusted for other clinical predictors, we found two ATM variants were independently associated with increased RP risk. They were an 111G > A) polymorphism (HR, 2.49; 95% CI, 1.07–5.80) and an ATM 126713G > A polymorphism (HR, 2.47; 95% CI, 1.16–5.28). Furthermore, genotype-dependent differences in ATM expression were demonstrated both in cell lines ( p p = 0.003), which supported the results of the association study. Conclusions Genetic polymorphisms of ATM are significantly associated with RP risk. These variants might exert their effect through regulation of ATM expression and serve as independent biomarkers for prediction of RP in patients treated with thoracic radiotherapy.

BackgroundRecent research has supported that a variety of cytokines play important roles during radiation-induced lung toxicity. The present study is designed to investigate the differences in early cytokine induction after radiation in sensitive (C57BL/6) and resistant mice (C3H).ResultsTwenty-two cytokines in the lung tissue homogenates, bronchial lavage (BAL) fluids, and serum from 3, 6, 12, 24 hrs to 1 week after 12 Gy whole lung irradiation were profiled using a microsphere-based multiplexed cytokine assay. The majority of cytokines had similar baseline levels in C57BL/6 and C3H mice, but differed significantly after radiation. Many, including granulocyte colony-stimulating factor (G-CSF), interleukin-6 (IL-6), and keratinocyte-derived chemokine (KC) were elevated significantly in specimens from both strains. They usually peaked at about 3–6 hrs in C57BL/6 and 6–12 hrs in C3H. At 6 hrs in lung tissue, G-CSF, IL-6, and KC increased 6, 8, and 11 fold in C57BL/6 mice, 4, 3, and 3 fold in the C3H mice, respectively. IL-6 was 10-fold higher at 6 hrs in the C57BL/6 BAL fluid than the C3H BAL fluid. MCP-1, IP-10, and IL-1α also showed some differences between strains in the lung tissue and/or serum. For the same cytokine and within the same strain of mice, there were significant linear correlations between lung tissue and BAL fluid levels (R2ranged 0.46–0.99) and between serum and tissue (R2ranged 0.56–0.98).ConclusionRadiation induced earlier and greater temporal changes in multiple cytokines in the pulmonary fibrosis sensitive mice. Positive correlation between serum and tissue levels suggests that blood may be used as a surrogate marker for tissue.

Purpose: To study the effects of radiation dose, chemotherapy, and their interaction in patients with unresectable or medically inoperable Stage III non-small-cell lung cancer (NSCLC). Methods and Materials: A total of 237 consecutive Stage III NSCLC patients were evaluated. Median follow-up was 69.0 months. Patients were treated with radiation therapy (RT) alone (n = 106), sequential chemoradiation (n = 69), or concurrent chemoradiation (n = 62). The primary endpoint was overall survival (OS). Radiation dose ranged from 30 to 102.9 Gy (median 60 Gy), corresponding to a bioequivalent dose (BED) of 39 to 124.5 Gy (median 72 Gy). Results: The median OS of the entire cohort was 12.6 months, and 2- and 5-year survival rates were 22.4% and 10.0%, respectively. Multivariable Cox regression model demonstrated that Karnofsky performance status (p = 0.020), weight loss < 5% (p = 0.017), chemotherapy (yes vs. no), sequence of chemoradiation (sequential vs. concurrent; p < 0.001), and BED (p < 0.001) were significant predictors of OS. For patients treated with RT alone, sequential chemoradiation, and concurrent chemoradiation, median survival was 7.4, 14.9, and 15.8 months, and 5-year OS was 3.3%, 7.5%, and 19.4%, respectively (p < 0.001). The effect of higher radiation doses onmore » survival was independent of whether chemotherapy was given. Conclusion: Radiation dose and use of chemotherapy are independent predictors of OS in Stage III NSCLC, and concurrent chemoradiation is associated with the best survival. There is no interaction between RT dose and chemotherapy.« less

Summary Background This study aimed to further investigate the role of circulating TGF-β1 during radiation therapy (RT) in predicting radiation-induced lung toxicity (RILT). Methods and materials Patients with stages I–III non-small cell lung cancer treated with RT based therapy were included in this study. Platelet poor plasma was obtained pre-RT, at 2 and 4 weeks during-RT, and at the end of RT. TGF-β1 was measured using an enzyme-linked immunosorbent assay. The primary endpoint for RILT was ≥grade 2 radiation pneumonitis or fibrosis. Results Twenty-six patients with a minimum follow-up of 12 months were included. Six patients (23.1%) experienced ≥grade 2 RILT. There was no significant difference in absolute TGF-β1 levels pre-RT, at 2 and 4 weeks during-RT, or at the end of RT between patients with and without RILT. The TGF-β1 ratios (over the pre-RT levels) for patients with and without RILT at 2, 4 weeks during-, and the end of RT were 2.8 ± 2.2 and 1.0 ± 0.6 ( P = 0.123), 2.3 ± 1.3 and 0.8 ± 0.5 ( P = 0.001), 1.5 ± 0.9 and 0.8 ± 0.5 ( P = 0.098), respectively. Using 2.0 as a cut-off, the TGF-β1 ratio at 4 weeks during-RT predicted RILT with a sensitivity and specificity of 66.7% and 95.0%, respectively. Conclusion Elevation of plasma TGF-β1 level 4 weeks during-RT is significantly predictive of RILT. The role of plasma TGF-β1 in predicting RILT deserves further study.

Hongqing Zhuang,1–4 Zhiyong Yuan,1–4 Jun Wang,1–4 Lujun Zhao,1–4 Qingsong Pang,1–4 Ping Wang1–41Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, 2National Clinical Research Center of Cancer, 3Tianjin Key Laboratory of Cancer Prevention and Therapy, 4Tianjin Lung Cancer Center, Tianjin, People’s Republic of ChinaAbstract: The aim of this paper is to explore the efficacy of whole brain radiotherapy (WBRT) versus WBRT concurrent with erlotinib in patients with multiple brain metastases of lung adenocarcinoma. WBRT was administered at 30Gy/10f in both arms. In the combination arm, 150 mg erlotinib was given each day, starting the first day of radiotherapy and continuing for 1 month following the end of radiotherapy. Thereafter, pemetrexed or docetaxel monotherapy or the best supportive therapy was given to both arms. The intracranial objective response rate and the local progression-free survival (LPFS) were primary endpoints. Toxicity, progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Thirty-one patients in the WBRT group and 23 patients in the combination group were enrolled from November 2009 to December 2011. In the WBRT and the combination arms, respectively, the objective response rate was 54.84% and 95.65% (P = 0.001), the median local progression-free survival was 6.8 months and 10.6 months (P = 0.003), the median PFS was 5.2 months and 6.8 months (P = 0.009), and median OS was 8.9 months and 10.7 months (P = 0.020). In the combination group, there were no differences of LPFS, PFS, and OS between the epidermal growth factor receptor (EGFR) mutation patients and EGFR wild-type patients. No Grade 4 or higher side effects were observed in either group. A multivariate analysis indicated that erlotinib was the most important prognostic factor for a prolonged survival. Data showed that erlotinib in combination with WBRT had a tolerable toxicity profile and prolonged the LPFS, PFS, and OS of lung adenocarcinoma patients with multiple brain metastases compared with WBRT monotherapy.Keywords: WBRT, tyrosine kinase inhibitor, radiosensitizer, erlotinib