Establishment and identification of C57BL/6 mouse model with radiation-induced pulmonary fibrosis / 中华放射肿瘤学杂志

Objective:To establish the mouse model with radiation-induced pulmonary fibrosis, and to identify and analyze it from the aspects of function, imaging and pathology.Methods:Thirty C57BL/6 mice were randomly divided into the control group, 16 Gy irradiation group and 20Gy irradiation group. The mice in the irradiation groups received a single 16 Gy or 20 Gy chest X-ray irradiation, and underwent functional examination, imaging examination and pathological examination at 3 and 6 months after irradiation.Results:At 6 months after irradiation, hair on the chest and back of the mice turned white and fell off, and the airway resistance was increased significantly. CT images showed extensive patch shadows and consolidation in the lung. Three dimensional reconstruction suggested that the lung of mice was distorted and deformed, and the volume was decreased significantly. Pathological examination confirmed that there was extensive pulmonary fibrosis.Conclusions:Significant pulmonary fibrosis occurs after 6 months of chest irradiation in mice. The animal model of radiation-induced pulmonary fibrosis in C57BL/6 mice was successfully established.

Active surveillance and response evaluation strategy after neoadjuvant therapy for esophageal cancer / 中华放射肿瘤学杂志

A considerable proportion of esophageal carcinoma patients could achieve pathological complete response (pCR) after neoadjuvant therapy, for whom accurate response evaluation and active surveillance rather than surgery-aiming to avoid the complications, mortality and reduced quality of life after surgery-has become a research hotspot. To detect residual disease and predict pCR accurately by appropriate method(s) is the key of active surveillance strategy. In this article, we elaborated the active surveillance strategy of esophageal cancer and characteristics of different evaluation methods in terms of radiology, pathology and combined detection.

Simultaneous integrated boost vs. routine IMRT in limited-stage small-cell lung cancer: an open-label, non-inferiority, randomized, phase 3 trial / 中华放射肿瘤学杂志

Objective:Simultaneous integrated boost radiation technique in limited-stage small cell lung cancer is lack of evidence. This prospective study aims to evaluate whether the simultaneous integrated boost is as efficacious and safe as conventional fractionated radiotherapy.Methods:Patients diagnosed with treatment-naive and confirmed limited-stage SCLC were eligible. Participants were randomly assigned (1: 1) to receive simultaneous integrated boost radiotherapy (PGTV 60.2 Gy/2.15 Gy/28F, PTV 50.4 Gy/1.8 Gy/28F) or conventional fractionated radiotherapy (PTV 60 Gy/2 Gy/30F). The primary endpoint was 2-year progression-free survival, and the secondary endpoints were 2-year overall survival, 2-year local-regional recurrence-free survival and toxicity.Results:Between February 2017 and July 2019, 231 patients were enrolled. We analyzed 216 patients whose follow-up time was more than 2 years or who had died, among whom 106 patients in the conventional fractionated radiotherapy group and 110 patients in the simultaneous integrated boost radiotherapy group. The median follow-up time was 37 months (95% CI: 35.2-38.7). The 2-year progression-free survival rates were 45.2% vs. 38.2%( HR=1.22, 95% CI: 0.87-1.72, P=0.2). The 2-year overall survival rates were 73.5% vs. 60.9%( HR=1.35, 95% CI: 0.90-2.04, P=0.14). The 2-year local-regional recurrence-free survival rates were 68.7% vs. 69.9%( HR=0.98, 95% CI: 0.62-1.56, P=1.0). Multivariate analysis showed that early radiotherapy yielded better 2-year progression-free survival, overall survival and local-regional recurrence-free survival than delayed radiotherapy in two groups ( HR=1.69, 95% CI: 1.18-2.41, P=0.003; HR=1.72, 95% CI: 1.09-2.70, P=0.018; HR=1.66, 95% CI: 1.01-2.73, P=0.046). Tumor staging was an influencing factor of overall survival (stage Ⅲ vs. stage Ⅰ-Ⅱ, HR=3.64, 95% CI: 1.15-11.57, P=0.028). The most common grade 3-4 adverse events were myelosuppression (21.7% vs. 15.4%, P=0.83), radiation pneumonitis (4.7% vs. 2.7%, P=0.44) and radiation esophagitis (3.8% vs. 1.8%, P=0.51). Conclusions:Simultaneous integrated boost radiotherapy yields equivalent efficacy and toxicities to conventional fractionated radiotherapy for limited-stage small cell lung cancer. Early radiotherapy can enhance clinical prognosis.

Comparison of setup errors in supraclavicular regions of lung and esophageal cancer treated with radiotherapy / 中华放射肿瘤学杂志

Objective:To compare the setup errors in the supraclavicular regions of two different postures (arms placed on each side of the body, namely the body side group; arms crossed and elbows placed above forehead, namely the uplifted group) using the chest and abdomen flat frame fixation device in lung and esophageal cancer.Methods:Clinical data of patients with stage Ⅰ to Ⅳ lung or esophageal cancer who received three-dimensional radiotherapy with chest and abdomen flat frame fixation device in our institution from November 2020 to April 2021 were retrospectively analyzed. The setup errors of two postures were compared.Results:A total of 56 patients were included, including 31 patients (55%) in the body side group and 25 patients (45%) in the uplifted group. A total of 424 CBCTs were performed in the whole group. The overall setup errors in the X, Y and Z directions were similar in both groups ( P>0.05). The setup errors of sternoclavicular joint in the X and RZ directions in the body side group were significantly smaller than those in the uplifted group [(0.163±0.120) cm vs. (0.209 ±0.152) cm, P=0.033; 0.715°±0.628° vs. 0.910°±0.753°, P=0.011]. The setup errors of acromioclavicular joint in the Y, Z and RZ directions in the body side group were significantly smaller than those in the uplifted group [(0.233±0.135) cm vs. (0.284±0.193) cm, P=0.033; (0.202±0.140) cm vs. (0.252±0.173) cm, P=0.005; 0.671°±0.639° vs. 0.885°±0.822°, P=0.023]. The margins of target volume for setup errors were smaller in the X (0.45 cm vs. 0.54 cm) and Y (0.54 cm vs. 0.65 cm) directions of the sternoclavicular joint, as well as in the Y (0.59 cm vs. 0.78 cm) and Z directions (0.53 cm vs. 0.72 cm) of the acromioclavicular joint in the body side group. Conclusions:For lung and esophageal cancer patients requiring supraclavicular irradiation, the body side group yields smaller setup errors and corresponding margins of target volume than the uplifted group. In clinical practice, it is necessary to take comprehensive consideration of the accuracy of radiotherapy and additional radiation of the limbs to select appropriate posture.

Postoperative radiotherapy for non-small cell lung cancer treated with neoadjuvant chemotherapy followed by surgery / 中华放射肿瘤学杂志

Neoadjuvant chemotherapy followed by surgery (NCS) is a common therapy pattern of non-small cell lung cancer (NSCLC). However, patients treated with NCS still suffer from relatively high locoregional recurrence. Postoperative radiotherapy (PORT) plays an important role in improving locoregional control, whereas its effect on survival remains controversial. Some studies propose that PORT yields no survival benefits for stage Ⅱ-Ⅲ A(N 2) patients treated with NCS, whereas other researches indicate that PORT can bring survival benefits for high-risk patients. The indications of PORT include R 1/R 2 resection and ypN 2. PORT is recommended with three-dimensional conformal therapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) within the dose range of 50-54 Gy (R 0 resection). The target volume is inconclusive and the irradiation range of mediastinum involving with the metastatic lymph node regions is recommended in many studies. The adverse effects of PORT are acceptable in most studies.Nevertheless, the evidence level of relevant studies is relatively low. These results remain to be clarified by prospective randomized clinical trials.

Research Progress on Risk Factors of Brain Metastasis in Non-small Cell Lung Cancer / 中国肺癌杂志

Brain metastasis of non-small cell lung cancer (NSCLC) is a common treatment failure mode, and the median survival time of NSCLC patients with brain metastasis is only 1 mon-2 mon. Prophylactic cranial irradiation (PCI) can delay the occurrence of brain metastasis, but the survival benefits of NSCLC patients are still controversial. It is particularly important to identify the patients who are most likely to benefit from PCI. This article reviews the high risk factors of brain metastasis in NSCLC.
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Long-term outcomes and failure patterns of prophylactic cranial irradiation in limited-stage small cell lung cancer patients managed with modern chemoradiotherapy and diagnostic methods / 中华放射肿瘤学杂志

Objective:To evaluate the clinical efficacy and failure patterns of prophylactic cranial irradiation (PCI) in patients with limited-stage small cell lung cancer (LS-SCLC) on the basis of modern chemoradiotherapy and diagnostic techniques.Methods:In this retrospective study, clinical data of 201 LS-SCLC patients treated with chemotherapy (EP/CE regimens, ≥4 cycles) and intensity-modulated radiotherapy (IMRT) in Cancer Hospital of Chinese Academy of Medical Sciences from 2006 to 2014 were reviewed. All patients were primarily managed with concurrent or sequential chemoradiotherapy and achieved complete response (CR) or partial response (PR). Ninety percent of patients were revaluated for brain metastasis (BM) by MRI and 10% by CT scan. Long-term survival and failure patterns were compared between the PCI ( n=91) and non-PCI groups ( n=110). Results:The median follow-up time was 77.3 months (95% CI 73.0-81.5 months). The median overall survival (OS), 2-and 5-year OS rates were 58.5 months, 72.5% and 47.7% in the PCI group, and 34.5 months, 61.7% and 35.8% in the non-PCI group ( P=0.075). The median progression-free survival (PFS), 2-and 5-year PFS rate were 22.0 months, 48.0% and 43.4% in the PCI group, significantly higher than 13.9 months, 34.4% and 26.7% in the non-PCI group ( P=0.002). The 2- and 5-year cumulative incidence of BM were 6.6% and 12.2% in the PCI group, and 30.0% , 31.0% in the non-PCI group ( P=0.001). The median time and rate of BM as an isolated first site of relapse were 11.9 months and 4.4% in the PCI group, and 8.7 months and 25.5% in the non-PCI group ( P<0.001). Multivariate analysis showed that response after chemoradiotherapy ( P<0.001) and PCI ( P=0.033) were the independent prognostic factors for PFS. Stratified analysis demonstrated that PCI significantly improved the 5-year PFS in patients who achieved CR (72.7% vs. 48.0%, P=0.013), while it did not improve the 5-year PFS in patients who obtained PR (26.1% vs. 20.2%, P=0.213). Conclusion:In the new era of standard chemoradiotherapy and more accurate diagnostic methods for BM, PCI was associated with improved PFS and lower incidence of BM in LS-SCLC patients.

Multicenter 5-year survival analysis of weekly Endostar combined with concurrent chemoradiotherapy for unresectable locally advanced non-small cell lung cancer / 中华放射肿瘤学杂志

Objective:To evaluate the 5-year survival outcome of patients with unresectable locally advanced non-small cell lung cancer (NSCLC) treated with Endostar in combination with platinum-based concurrent chemoradiotherapy.Methods:From March 2009 to June 2015, 115 patients with the unresectable locally advanced NSCLC from two prospective studies[Clinical trials 2009-2012(ClinicalTrials.gov NCT01894) and 2012-2015(ClinicalTrials.gov, NCT01733589)] were treated with Endostar in combination with platinum-based concurrent chemoradiotherapy. A total dose of 60-66 Gy was delivered in 30-33 fractions. Endostar was given 1 week prior to the beginning of radiotherapy, and repeated fortnightly during the concurrent chemoradiotherapy. After long-term follow up, survival outcome was evaluated in 104 patients treated with radiation dose of ≥60 Gy. Kaplan-Meier method was used for survival analysis. Univariate survival analysis was performed using the log-rank test.Results:Of 104 eligible patients, 60.6% of them had squamous carcinoma and 65.4% were classified in stage Ⅲ B. All the patients received ≥2 cycles of Endostar and 93.3% of them received 4 cycles of Endostar. The median follow-up time was 68.3 months. The median overall survival (OS) and median progression-free survival (PFS) were 31.3 and 13.9 months, respectively. The 3-year and 5-year OS were 45.6% and 35.7%, respectively. The 3-year and 5-year PFS were 27.1% and 24.9%, respectively. Univariate analysis indicated that sex, ECOG, pathological type, clinical stage, radiotherapy technique, chemotherapy regimen, chemotherapy cycle and cycle of Endostar use were not associated with OS. Late radiation injury occurred in 14.4% of patients, and no grade 4-5 late injury was observed. Conclusion:Patients with unresectable locally advanced NSCLC treated with Endostar fortnightly in combination with platinum-based concurrent chemoradiotherapy achieve better OS than historical data with tolerable toxicities.

Clinical application of machine learning in radiation oncology / 中华放射医学与防护杂志

Radiation therapy is one of the main treatment methods for cancer. Machine learning can be used in all aspects of clinical practice in radiation therapy, including clinical decision support, automatic segmentation of target volumes, prediction of treatment efficacy and side effects. Despite the challenges of lacking structured data and poor interpretability of models, the application of machine learning in radiotherapy will become increasingly profound and extensive. This review contains three aspects: introduction of machine learning, the clinical application of machine learning in radiotherapy, challenges and solutions.

Consensus and disputes on the adjuvant therapy for non-small cell lung cancer with positive surgical margins / 中华放射肿瘤学杂志

For non-small cell lung cancer (NSCLC) patients with positive surgical margins, the survival rates can be dramatically decreased. However, high-level evidence is lacking in the standard adjuvant treatment for NSCLC patients with positive surgical margins. In this article, consensus and disputes on the adjuvant therapy for NSCLC patients with positive surgical margins were reviewed.

Analysis of local recurrence pattern for limited stage small cell lung cancer after IMRT plus chemotherapy / 中华放射肿瘤学杂志

Objective To investigate localized regional recurrence after chemotherapy and chest radiotherapy in limited stage small cell lung cancer (LS-SCLC),and explore the relationship between recurrence location and radiotherapy and chemotherapy and its influencing factors.Methods From 2006 to 2014,pathological LS-SCLC treated in CAMS,125 patients had local recurrence,Kaplan-Meier statistical method was used to analyze the survival rate and PFS of each recurrence site.Log-rank was used to compare the survival rate of each group.Univariate analysis includes Chi-squareand t-test for the factors for the recurrence site.Multivariate analysis using Logistic regression.Results The 1-,2-and 5-year overall survival rates were 92.0％,46.4％ and 14.7％,respectively.The median progression time was 12.96 months,The median survival time after progression was 1 1.5 months,and the 1-,2-,and 5-year overall survival rates were 45.0％,23.0％,and 10.0％,respectively.The recurrence sites include intrapulmonary recurrence (67 patients),regional lymph nodes (21 patients),simultaneous intrapulmonary and regional lymph nodes (28 patients),and contralateral or supraclavicular lymph nodes (9 patients).The median survival time were 23.96 months,24.76 months,23.23 months,and 18.66 months,and the 2-year survival rates were 49％,52％,46％,and1 1％,respectively (P=0.000,0.004,0.008).In 6 patients (4.0％),5 patients were located in the supraclavicular region,and 1 patient (0.8％) in the field.Conclusions For LS-SCLC undergoing IMRT and chemotherapy,the local failure location is mainly located in the pulmonary,and further treatment of the split dose and targets requires further clinical exploration.

Research progress onneoadjuvant therapy in stage ⅢA-N2 non-small cell lung cancer / 中华放射肿瘤学杂志

Ⅲ A-N2 NSCLC is a group of heterogeneous diseases.The optimal treatment modality remains controversial.How to choose suitable neoadjuvant treatment modalities including chemotherapy,radiotherapy,target therapy and immunotherapy remains unclear.In this article,research progress on neoadjuvant therapy of NSCLC was reviewed to evaluate the efficacy and safety for different modalities.

Research progress onneoadjuvant therapy in stage ⅢA-N2 non-small cell lung cancer / 中华放射肿瘤学杂志

ⅢA-N2 NSCLC is a group of heterogeneous diseases. The optimal treatment modality remains controversial. How to choose suitable neoadjuvant treatment modalities including chemotherapy, radiotherapy, target therapy and immunotherapy remains unclear. In this article, research progress on neoadjuvant therapy of NSCLC was reviewed to evaluate the efficacy and safety for different modalities.

Progress in adjuvant therapy decision-making after endoscopic resection of early esophageal cancer / 中华放射肿瘤学杂志

Both endoscopic resection and surgery are the common treatment modes for early esophageal cancer. Compared with radical surgery, endoscopic resection has the advantages of less trauma, quicker recovery, lower cost, less complications, the preservation of the normal anatomy, the physiological function of the esophagus, and higher postoperative quality of life. For patients with a high risk of lymph node metastasis, endoscopic resection alone can lead to inadequate treatment, which need adjuvant therapies. Currently, the common adjuvant therapies consist of adjuvant radiochemotherapy and adjuvant radiochemotherapy combined with surgery. How to combine endoscopic resection with adjuvant therapy to bring maximal benefits to patients has become the hot topic in the field of clinical researches. In this article, the current research status, progress and challenges in the combination of endoscopic resection and adjuvant therapy for the treatment of high-risk patients were reviewed.

Analysis of risk factors of radiation-induced lung toxicity in non-small cell lung cancer patients treated with postoperative radiotherapy / 中华放射肿瘤学杂志

Objective@#To evaluate the incidence and risk factors of symptomatic radiation-induced lung toxicity (SRILT) in non-small cell lung cancer (NSCLC) patients treated with modern radiotherapy after surgery.@*Methods@#Clinical data of consecutive NSCLC patients treated with postoperative three-dimensional conformal or intensity-modulated radiotherapy in Cancer Hospital of Chinese Academy of Medical Sciences between November 2002 and December 2011 were retrospectively analyzed. According to the Common Terminology Criteria for Adverse Events (CTCAE, version 3.0), SRILT was defined as ≥grade 2 radiation-induced lung toxicity. Potential clinical risk factors and dosimetric parameters for SRILT were evaluated using logistic regression model.@*Results@#Among 227 enrolled patients, 190 cases underwent lobectomy and 37 patients received pneumonectomy. Twenty-three patients (10.1%) developed SRILT after lobectomy. Seventeen patients experienced grade 2 SRILT, 5 cases of grade 3 SRILT and 1 case of grade 4 SRILT. Univariate analysis showed that postoperative concurrent chemoradiotherapy, relatively large PTV, mean lung dose and V20- V40 were significantly correlated with the incidence of SRILT (P=0.015, 0.048 and<0.001). Multivariate analysis demonstrated that postoperative concurrent chemoradiotherapy and V20 were significantly associated with the incidence of SRILT (P=0.017 and P=0.009).@*Conclusions@#The incidence of SRILT is relatively low in NSCLC patients after postoperative radiotherapy. Concurrent chemoradiotherapy and V20 are risk factors of SRILT.

Analysis of risk factors of radiation-induced lung toxicity in non-small cell lung cancer patients treated with postoperative radiotherapy / 中华放射肿瘤学杂志

Objective To evaluate the incidence and risk factors of symptomatic radiation-induced lung toxicity (SRILT) in non-small cell lung cancer (NSCLC) patients treated with modern radiotherapy after surgery.Methods Clinical data of consecutive NSCLC patients treated with postoperative three-dimensional conformal or intensity-modulated radiotherapy in Cancer Hospital of Chinese Academy of Medical Sciences between November 2002 and December 2011 were retrospectively analyzed.According to the Common Terminology Criteria for Adverse Events (CTCAE,version 3.0),SRILT was defined as ≥ grade 2 radiationinduced lung toxicity.Potential clinical risk factors and dosimetric parameters for SRILT were evaluated using logistic regression model.Results Among 227 enrolled patients,190 cases underwent lobectomy and 37 patients received pneumonectomy.Twenty-three patients (10.1％) developed SRILT after lobectomy.Seventeen patients experienced grade 2 SRILT,5 cases of grade 3 SRILT and 1 case of grade 4 SRILT.Univariate analysis showed that postoperative concurrent chemoradiotherapy,relatively large PTV,mean lung dose and V20-V40 were significantly correlated with the incidence of SRILT (P=0.015,0.048 and＜0.001).Multivariate analysis demonstrated that postoperative concurrent chemoradiotherapy and V20 were significantly associated with the incidence of SRILT (P =0.017 and P =0.009).Conclusions The incidence of SRILT is relatively low in NSCLC patients after postoperative radiotherapy.Concurrent chemoradiotherapy and V20 are risk factors of SRILT.

Dose-response relationship of radiation-induced pulmonary fibrosis in mouse models based on CT-derived parameters / 中华放射肿瘤学杂志

Objective To investigate the radiation induced pulmonary fibrosis with a dose-response mouse model, based on the CT image changes of pulmonary fibrosis.Methods Female C57BL6 mice aged 8-10 weeks were randomly divided into 20 Gy or escalated doses of X-ray whole thoracic irradiation ( WTI) groups. CT scan was performed at different time points before and after radiation. The average lung density and lung volume changes were obtained by three-dimensional segmentation algorithm. After gene chip and pathological validation, the parameters of CT scan were subject to the establishment of logistic regression model. Results At the endpoint of 24 weeks post-irradiation, the lung density in the 20 Gy irradiation group was (-289.81± 12.06) HU, significantly increased compared with (-377.97± 6.24) HU in the control group ( P<0.001) . The lung volume was ( 0.66±0.01) cm3 in the control group, significantly larger than ( 0.44±0.03) cm3 in the irradiated mice ( P<0.001) . The results of quantitative imaging analysis were in accordance with the findings of HE and Mason staining, which were positively correlated with the fibrosis-related biomarkers at the transcriptional level ( all R2=0.75, all P<0.001) . The ED50 for increased lung density was found to be ( 13.64± 0.14) Gy ( R2=0.99, P<0.001) and ( 16.17± 4.36) Gy ( R2=0.89, P<0.001) for decreased lung volume according to the logistic regression model. Conclusions Quantitative CT measurement of lung density and volume are reliable imaging parameters to evaluate the degree of radiation-induced pulmonary fibrosis in mouse models. The dose-response mouse models with pulmonary fibrosis changes can provide experimental basis for comparative analysis of high-dose hypofractioned irradiation-and half-lung irradiation-induced pulmonary fibrosis.

Research progress on radiotherapy for brain metastasis from non-small-cell lung cancer with ALK rearrangement / 中华放射肿瘤学杂志

Brain metastasis is common in non-small-cell lung cancer (NSCLC) with driver gene mutations.At present,brain radiotherapy combined with tyrosine kinase inhibitor (TKI) is a hot topic.Anaplastic lymphoma kinase (ALK) gene rearrangement is one of the common driver mutations in NSCLC.However,the treatment of brain metastasis from NSCLC with ALK gene rearrangement has been rarely investigated.The prognosis of these patients,the role of brain radiotherapy and the proper comb ination of radiotherapy with ALK-TKI are worthy of further exploration.

Prognostic value of pretreatment neutrophil-to-lymphocyte ratio (NLR) in locally advanced non-small cell lung cancer patients treated with thoracic radiation / 中华肿瘤杂志

Objective@#The aim of this retrospective study was to evaluate the prognostic significance of pretreatment Neutrophil-to-Lymphocyte Ratio(NLR) in locally advanced non-small cell lung cancer(NSCLC) patients treated with thoracic radiotherapy.@*Methods@#We retrospectively analyze 420 patients who received thoracic radiotherapy alone, sequential chemoraiotherapy or concurrent chemoradiotherapy for locally advanced stage NSCLC from January 2007 to December 2010 of our hospital. The patients were divided into two groups (high NLR group and low NLR group) with appropriate cutoff point using the receiver operating characteristic (ROC) curve method. The survival curve was established by Kaplan-Meier method. The Log-rank test was used to compare the survival of the two NLR groups and the multivariate analysis was carried out by Cox regression model.@*Results@#Among the 420 patients, 99 received radiotherapy alone, 139 received sequential chemoradiotherapy and 182 received concurrent chemoradiotherapy. 345 patients died and 75 were still alive. The median follow-up time was 5.2 years and the median overall survival was 22 months. The cut-off value of pretreatment NLR was 2.1. The 5-year PFS and OS rates in high NLR group and low NLR group were 10.6% vs 15.7% (P=0.033) and 15.5% vs 22.7% (P=0.012). Multivariate analysis confirmed that pretreatment NLR (hazard ratio 1.06, P=0.041) was independent prognostic factor of OS.@*Conclusions@#Our study revealed that the pretreatment NLR is the independent prognostic factor of OS in patients with locally advanced stage NSCLC treated with thoracic radiotherapy. However, NLR is still greatly influenced by patient′s condition and treatment which needs further research.

Application mechanisms of radiotherapy combined with immune checkpoint inhibitors / 中华放射肿瘤学杂志

Remarkable advances have been made in immunotherapy,especially immune checkpoint inhibitors.However,only less than 30％ patients would respond to single checkpoint inhibitors.Radiotherapy can augment the anti-tumor immune responses elicited by immunotherapy,either by way of synergy or complementation.This article reviews the mechanisms,the advances and challenges in combination therapy.