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Objective:To analyze the clinical characteristics of long-term survival patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy combined with primary tumor radiotherapy, and to establish a Nomogram prognostic model, aiming to provide a certain reference for making a decision about the treatment of advanced NSCLC.Methods:A retrospective analysis was made on the data of 260 NSCLC patients who participated in two prospective clinical studies from January 2003 to May 2012 and the data of 138 NSCLC patients admitted to the Affiliated Cancer Hospital of Guizhou Medical University from January 2014 to August 2020. The former 260 cases were used as a training set and the latter 138 cases were used as the validation set. The overall survival (OS) of ≥ 18 months was defined as long-term survival (LTS). The clinical characteristics of LTS patients were compared with those with OS less than 18 months. The clinical characteristics and treatment-related parameters between the two types of patients were compared using the χ2 test. A multivariate analysis was made using logistic regression, and a nomogram model was built using RStudio. Results:The median OS of the training set was 13.4 months (95% CI: 11.9-14.9), with 1-, 2-, and 3-year OS rates of 55.4%, 19.1%, and 11.9%, respectively. In the training set, 87 cases had LTS and were classified as the LTS group, while 173 cases had OS less than 18 months and were classified as the non-LTS group. The univariate analysis showed that the prognostic factors affecting LST included the KPS score, T status, the number of metastatic organs, the number of metastatic lesions, brain metastasis, bone metastasis, the number of chemotherapy cycles, the biologically effective dose (BED) to the primary tumor, hemoglobin level, platelet count, plasma D-dimer, fibrinogen level, lactate dehydrogenase, and lung immune prognostic index (LIPI; χ2=4.72-12.63, P < 0.05). The multivariable analysis showed that the independent prognostic factors of LTS included a number of chemotherapy cycles ≥ 4, BED ≥ 70 Gy, platelets ≤ 220×10 9/L, D-dimer ≤ 0.5 mg/L, and a good LIPI score ( P= 0.002, 0.036, 0.005, 0.008, and 0.002). A nomogram model was established using the meaningful parameters obtained in the multivariable analysis, determining that the training and validation sets had a consistency index (C-index) of 0.750 and 0.727, respectively. As shown by the analytical result of the corrected curves, for the advanced NSCLC patients treated with thoracic radiotherapy, their LTS probability predicted using the nomogram prognostic model was highly consistent with their actual LTS probability. Both the analytical result of the receiver operating characteristic (ROC) curves and the decision curve analysis (DCA) result showed that the composite prediction model was more beneficial than a single prediction model. Conclusions:For patients with advanced NSCLC treated with thoracic radiotherapy, the independent prognostic factors of LTS included the number of chemotherapy cycles, BED, platelet count, pre-chemotherapy D-dimer, and LIPI score. The Nomogram prognostic model built based on these prognostic factors is a convenient, intuitive, and personalized prediction model used to screen patients who can benefit from thoracic radiotherapy.
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Objective:To explore the characteristics of failure patterns of three-dimensional radiotherapy combined with first-line drug therapy for primary tumors of stage Ⅳ non-small cell lung cancer(NSCLC)and investigate the influence of radiotherapy-related factors.Methods:708 patients newly-diagnosed with stage Ⅳ NSCLC from March 2003 to July 2020 were selected. Chi-square test was used for univariate analysis of failure patterns. Kaplan-Meier method, Log-rank test and Cox regression model were employed for multivariate analysis. Results:The incidence of first-line treatment failure in 708 cases was 71.2%, and the incidence of treatment failure was 22.7%, 28.8%, 13.3%, and 6.4% for ≤6 months, >6-12 months, >12-24 months, and>24 months, respectively, and the median survival time was 7.2, 13.4, 22.2, and 37.6 months, which was significantly different( χ2=226.013, P<0.001). The incidence of recurrence failure(RF)was 21.3%.There was no significant difference in the incidence of RF between oligometastasis(OM)and non-oligometastasis(NOM). The incidence of DF was 66.3% and the order of incidence was brain>bone>lung>pleural cavity>liver>distant lymph nodes>adrenal gland>other sites, occurring in approximately 1/2 of AM and 1/3 of PSM cases. Metastatic status, time to treatment failure, pathological type, gender, combined treatment intensity were the independent influencing factors for predicting prognosis. Conclusions:The failure pattern of radiotherapy for primary tumors of stage Ⅳ NSCLC is different from that of first-line drug therapy, with significantly lower local failure and predominantly metastatic failure. The incidence of brain metastasis is the highest. The later time to treatment failure, the longer the overall survival(OS). OM, female, non-squamous cell carcinoma, late treatment failure, 4-6 cycles of chemotherapy over the same period ≥63 Gy are the independent prognostic factors for prolonging survival.
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Objective:To analyze the radiotherapy-related factors affecting the survival of non-small cell lung cancer (NSCLC) patients complicated with malignant pleural effusion (MPE)(MPE-NSCLC).Methods:From 2007 to 2019, 256 patients pathologically diagnosed with MPE-NSCLC received primary treatment. Among them, 117 cases were enrolled in this study. All patients were divided into two groups according to the radiation dose (<63 Gy and≥63 Gy). Propensity score matching (PSM) was performed to further adjust the confounding factors (Calipers value=0.1). The impact of radiotherapy-related factors on the overall survival (OS) was analyzed by Kaplan—Meier method, log-rank test and Cox’s regression model. Results:Primary tumor radiotherapy significantly prolonged the OS ( P<0.001). The radiation dose escalation (36.0-44.1 Gy, 45.0-62.1 Gy, 63.0-71.1 Gy) of primary tumor significantly prolonged the OS ( P<0.001). The corresponding median OS were 5, 13 and 18 months, respectively. Before the PSM, univariate analysis suggested that radiation dose ≥63 Gy, gross tumor volume (GTV)<157.7 cm 3 and stations of metastatic lymph node (S-mlN)≤5 were significantly associated with better OS (all P<0.05) and T 4N 3 was significantly associated with worse OS ( P=0.018). After the PSM, univariate analysis indicated that radiation dose ≥63 Gy was significantly associated with better OS ( P=0.013) and S-mlN ≤5 had a tendency to prolong the OS ( P=0.098). Prior to the PSM, multivariate analysis showed that radiation dose ≥63 Gy was an independent favorable factor of OS ( HR=0.566, 95% CI 0.368-0.871, P=0.010) and GTV<157.7 cm 3 had a tendency to prolong the OS ( HR=0.679, 95% CI 0.450-1.024, P=0.065). After the PSM, multivariate analysis revealed that radiation dose ≥63 Gy was still an independent favorable factor of OS ( HR=0.547, 95% CI 0.333~0.899, P=0.017). No ≥grade 4 radiation toxicity occurred. The incidence rates of grade 3 radiation esophagitis and pneumonitis were 9.4% and 5.1%, respectively. Conclusion:For MPE-NSCLC, radiotherapy dose of primary tumor may play a key role in improving OS on the basis of controllable MPE.
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In recent years, heavy ion beams have received great attention in the field of malignant tumor radiotherapy due to their radiation physics and biological characteristics. The high rate of local tumor control is one of its advantages, but the control rate of metastatic lesions is still crucial in the treatment of most malignant tumors. Clinical studies on the combined conventional radiotherapy and immunotherapy suggest that the combination of the two can not only control the primary lesions, but may also reduce or completely eliminate distant metastatic lesions. High linear energy transfer radiation, especially heavy ion beams, may have stronger potential in combined immunotherapy. Therefore, this article focuses on the basic research progress of heavy ion beams regulating anti-tumor immune effects and their combined application with immunotherapy.
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The prognosis of patients with brain metastases from non-small cell lung cancer (NSCLC) is poor. Tyrosine kinase inhibitor (TKI) significantly improves the prognosis of patients with epidermal growth factor receptor (EGFR) sensitive mutation. EGFR sensitive mutations are associated with the incidence of brain metastases in NSCLC and may affect the efficacy of radiotherapy and TKI therapy. Both EGFR-TKI and radiotherapy are effective for EGFR-mutant NSCLC with brain metastases. Whether the combination of EGFR-TKI and radiotherapy may improve the prognosis compared with EGFR-TKI or radiotherapy alone has been studied. Retrospective studies have indicated that upfront radiotherapy, especially upfront stereotaxic radiosurgery combined with EGFR-TKI may be more advantageous in improving the prognosis, but it is still controversial. Therefore, clinical research progresses on the radiotherapy for EGFR-mutant NSCLC patients with brain metastases were reviewed.
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Objective:To explore the establishment of radiation-induced heart damage (RIDH) SD rat models caused by irradiation of 15Gy/3f and the changes in early detection indicators, and evaluate the effect of irradiation combined with recombinant human endostatin (Endostar).Methods:75 adult male SD rats were randomly divided into the blank control group (C group), Endostar group (E group), 25Gy irradiation group (MHD 25 group), 15Gy irradiation group (MHD 15 group) and 15Gy irradiation combined with Endostar group (MHD 15+ E group), respectively. Blood sample was taken to measure the CK, CK-MB, LDH and CRP at 24h, 48h and 15d after corresponding interventions. After cardiac echocardiography at 1, 3 and 6 months, 5 rats in each group were randomly sacrificed and myocardial tissues were collected for HE and Masson staining. Two-way ANOVA was employed for statistical analysis. Results:Compared with group C, myocardial fibrosis were observed in the MHD 15 group at 6 months ( P<0.05), which occurred later than that in the MHD 25 group. Ejection fraction (EF) and fractional shortening (FS) were significantly decreased after 3 months in each irradiation group (all P<0.05), whereas the degree of decrease was similar among all groups (all P>0.05). The expression levels of myocardial enzymes and inflammatory cytokines did not significantly differ among different groups (all P>0.05). Conclusions:In the early stage, exposure to 15Gy/3f irradiation can cause cardiac function damage in SD rat hearts, such as the reduction of EF and FS, and even lead to myocardial fibrosis in the late stage, which is delayed and less severe than high-dose irradiation. Irradiation combined with Endostar has no significant effect on radiation myocardial injury in rats.
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Objective:To explore the possibility of CD 4+ T cells and CD 4+ /CD 8+ ratio in peripheral blood to predict the survival of patients with stage Ⅳ non-small cell lung cancer (NSCLC), and to establish a Nomogram prediction model. Methods:The influence of CD 4+ T cells and CD 4+ /CD 8+ ratio on the clinical factors and survival of 682 patients pathologically diagnosed with stage Ⅳ NSCLC with no history of cancer treatment was retrospectively analyzed and the Nomogram prediction model was established. Combined with the changes of immune cells levels in 110 patients after treatment, the prognostic and predictive values of CD 4+ T cells and CD 4+ /CD 8+ ratio were verified. Countable data were analyzed by t-test. The survival rate was calculated by Kaplan-Meier method, log-rank test or univariate analysis. The multivariate analysis was performed by Cox regression model. Results:Univariate analysis demonstrated that CD 4+ > 43.15% before treatment significantly prolonged the survival. By multivariate analysis of Cox regression model, CD 4+ >43.15% was an independent prognostic factor to prolong survival for stage Ⅳ NSCLC. The Nomogram model was established and verified that the predicted and actual overall survivals were highly consistent. Further analysis showed that 43.15% as the critical value of CD 4+ T cell level significantly prolonged survival when CD 4+ expressed at a high-level before treatment, after treatment, before and after treatment, or combined with CD 4+ /CD 8+ >1.65. Conclusions:The baseline level of CD 4+ T cells before treatment in peripheral blood is an independent prognostic factor for stage Ⅳ NSCLC. The CD 4+ /CD 8+ ratio before treatment has limited value in predicting the prognosis.
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Objective:To investigate the primary tumor volume change and timing of radiotherapy for patients with stage Ⅳ non-small cell lung cancer with EGFR mutation during molecular targeted therapy.Methods:Simulated CT scanning measurement and analysis were performed to observe the volume changes of primary tumors before and after treatment with a time interval of 10 days in this prospective study. Positioning and volume measurement were terminated when the volume change was 5% or less between two time points before and after treatment or 90 days after treatment. Primary tumor radiation therapy was then performed, acute radiation-induced injury was recorded, and the implementation and simulation of related parameters of radiotherapy plans were compared.Results:Twenty-nine of 30 cases were included in the analysis (1 case dropped off). After EGFR-TKIs treatment, the volume of all primary tumors was decreased, but the shrinking rate was inconsistent with the speed. Until the last simulated CT scanning, the maximum and minimum shrinking rates were 90% and 28%, respectively. There was no case of termination within 30 days of treatment, and the average tumor volume was significantly decreased within 40 days and the average tumor volume significantly differed every 10 days ( P<0.001). After 40 days, the volume shrinking rate of primary tumors ≤5% gradually appeared, and one patient presented with a volume shrinking rate of >5% on 90 days. During this time, the average volume shrinking rate slowed down and became stable, ranging from 49.15% to 54.77%. Moreover, the average volume continued to gradually shrink after slight increase at 70 days. There was no significant difference in the average volume every 10 days ( P>0.05). After the termination of simulated CT scanning, the dose of primary tumor was (69±7) Gy for patients receiving radiotherapy. Two patients had grade 2 acute radiation-induced pneumonitis and 3 patients had grade 3 acute radiation-induced pneumonitis. In addition, 1 patient had grade 2 radiation-induced esophagitis. According to the technology and dose parameters of radiotherapy plan, simulated radiotherapy plans before and 40 days after EGFR-TKIs treatment were designed. The timing of implementation plan was significantly better than that before EGFR-TKIs treatment (all P<0.05), whereas it was similar to that at 40 days after EGFR-TKI treatment ( P>0.05). Conclusions:The primary tumor shrinking rate is gradually slowed down over time after EGFR-TKIs treatment in patients with stage Ⅳ non-small cell lung cancer. The average tumor volume is significantly decreased within 40 days and then the shrinking rate becomes slow. The tumor shrinking rate of each case is inconsistent. Radiotherapy at 40 days after treatment is probably the optimal timing to obtain high dose and control radiation-induced injury.
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Objective:To retrospectively analyze the clinical efficacy and safety of three-dimensional radiotherapy for the primary tumors in patients with stage Ⅳ non-small cell lung cancer complicated with malignant pleural effusion (MPE-NSCLC).Methods:A total of 198 patients who were initially pathologically diagnosed with MPE-NSCLC from January 2007 to April 2018 were enrolled and divided into the untreated group ( n=45), drug group ( n=57) and radiotherapy group ( n=96), respectively. The short-term efficacy, overall survival (OS) and adverse events in the drug and radiotherapy groups were analyzed. The OS rate was analyzed by Kaplan-Meier method and log-rank test. Clinical prognosis was evaluated by multivariate Cox′s regression model. Results:In the radiotherapy group, the objective response rate and non-response rate was 54% and 46%, significantly better than 25% and 75% in the drug group ( P=0.007). In the radiotherapy group, the 1-, 2-, 3-, 5-year OS and median survival was 47%, 18%, 6%, 1% and 12 months, remarkably higher than 15%, 3%, 2%, 0% and 5 months in the drug group, respectively (all P<0.001). Multivariate Cox′s regression analysis showed that radiotherapy for the primary tumors was an independent prognostic factor to prolong the OS ( P<0.001). Radiotherapy at a dose of ≥63 Gy and 4-6 cycles of chemotherapy tended to prolong the OS ( P=0.063 and 0.071). The OS of patients with EGFR mutation receiving radiotherapy combined with molecular target therapy was significantly better than that of those with unknown EGFR status treated with radiotherapy and chemotherapy ( P=0.007). Addition of radiotherapy for the primary tumors did not significantly increase the incidence of adverse events ( P>0.05). Conclusion:Addition of three-dimensional radiotherapy for the primary tumors in MPE-NSCLC patients may prolong the OS and yield tolerable adverse events.
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Objective:The experimental animal model was established to unravel the mechanism of radiation-induced myocardial fibrosis and validate the role of recombinant human endostatin in aggravating the process of radiation-induced myocardial fibrosis via the TGF-β 1, Smad 2 and Smad 3 signaling pathways. Methods:Sixty male adult Sprague-Dawley rats were randomly divided into the following groups: radiotherapy (RT)25 Gy, recombinant human endostatin (RE) 6 mg/kg, RE 12 mg/kg, RT 25 Gy+ RE 6 mg/kg, RT 25 Gy+ RE 12 mg/kg and blank control groups. Five rats were sacrificed in each group at 1 and 3 months after interventions. The myocardial tissues were collected. The pathological changes were observed by Hematoxylin and eosin staining. The degree of fibrosis was assessed by Masson trichrome staining. The expression levels of TGF-β 1, Smad 2, Smad 3 and Collagen-I mRNA and protein were quantitatively measured by real-time PCR and Western blotting. Results:At 3 months after intervention, Masson trichrome staining revealed that the collagen deposition in the RT 25Gy and RT 25Gy+ RE (6 and 12 mg/kg) groups was more significant than that in the control group. In addition, The expression levels of TGF-β 1, Smad 2, Smad 3 and Collagen-I mRNA and protein in these groups were significantly up-regulated compared with those in the control group. Conclusions:Radiation with a total physical dose of 25 Gy can induce myocardial fibrosis in the SD rat models. TGF-β 1 and Smad 2 signaling pathways are the common signaling pathways of myocardial fibrosis induced by radiation combined with recombinant human endostatin.
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Objective To analyze the survival and toxicity after concurrent chemoradiotherapy in patients of different ages with stage Ⅳ non-small cell lung cancer (NSCLC).Methods Clinical data of 282 NSCLC patients in two prospective studies were retrospectively analyzed,who completed the protocol (at least 2 cycles of chemotherapy and thoracic radiation doses of ≥36 Gy).Among them,44 patients were assigned into in the young group (≤ 45 years old),161 patients in the middle-age group (46-64 years old) and 77 patients in the elderly group (≥ 65 years old).The clinical characteristics of patients among different groups were analyzed by x2 test.The overall survival (OS) was calculated by Kaplan-Meier method.Stratified analysis was performed by Log-rank test.Multi-factor prognosis analysis was conducted by Cox's proportional hazards regression model.Results The incidence of NSCLC in the male patients in the elderly group was higher than that in the middle-age and young groups.The 1-,2-,3-and 5-year OS did not significantly differ among different groups (P=0.810).The OS did not significantly differ among patients of the same gender,pathological type,T stage,N stage,metastasis status,same chemotherapy cycle,primary tumor dose and comprehensive treatment and short-term response (all P＞0.05).The incidence of adverse events did not considerably differ among different groups.Multivariate analysis demonstrated that age was not an independent factor for survival (P＞ O.05).Conclusion Patients of different ages with stage Ⅳ NSCLC obtain similar survival benefits and adverse events after concurrent chemoradiotherapy.
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Objective To investigate the impact of the changes of posttreatment karnofsky performance status (KPSpost) on the overall survival (OS) for patients with stage Ⅳ non-small cell lung cancer (NSCLC) underwent concurrent chemoradiation.Methods A total of 279 patients (male 198 and female 81) with histological confirmed stage Ⅳ NSCLC were enrolled in this study with a median age of 58 years old (range 22 to 80 years old).There were 166 cases of squamous carcinoma,87 cases of adenocarcinoma,and 22 cases of unclassified carcinoma,respectively.All enrolled patients received more than 2 cycles of chemotherapy and more than 36 Gy of concurrent radiotherapy.Kaplan-Meier method and Log-rank test were applied to evaluate OS.Multivariate analyses were carried out by the Cox proportionalhazard model.Chi-square test and logistic regression analysis were used to explore the related factors of KPSpost.Results There were 198 patients with improved KPSpost and 81 patients with decreased KPSpost,respectively.Univariate and multivariate analyses indicated that the improvement of KPSpost was associated with longer OS.Logistic regression analysis showed that the improvement of KPSpost was positively related with treatment of more than 4-6 cycles chemotherapy concurrent with over 63 Gy radiation to primary tumor.The improvement of KPSpost also correlated positively with disease control rate (DCR),but negatively with PLT toxicity and radiation esophagitis.Conclusions KPSpost was an independent prognostic factor of OS for patients with stage Ⅳ NSCLC underwent concurrent chemoradiation.Chemotherapy of 4-6 cycles and concurrent over 63 Gy radiotherapy dose to primary tumor,as well as DCR were positive factors for KPSpost improvement.However,stage 3-4 PLT toxicities and radiation esophagitis decreased the KPSpost.
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Objective To evaluate the clinical efficacy and toxicity of concurrent pemetrexed-cisplatin (PP) or docetaxel-cisplatin (DP) with intensity-modulated radiation therapy (IMRT) in patients with stageⅠV lung adenocarcinoma. Methods Stage IV lung adenocarcinoma patients with unknown EGFR mutation status or wild-type admitted to Guizhou Cancer Hospital from 2011 to 2016 were randomly assigned into the PP (n=50) and DP groups (n=51).All patients received concurrent IMRT of the chest at a prescription dose of 60-70 Gy. Primary endpoint was 1-year survival rate, and secondary endpoint was acute toxicity. Results The overall response rate was 68. 0％ and 72. 5％ in the PP and DP groups (χ2=0. 250, P=0. 617) . The median survival time was 19. 6 months ( 95％CI 13. 9-25. 3) versus 12. 1 months ( 95％CI 10. 7-13. 5) in the PP and DP groups. The 1-, 2-and 3-year overall survival rates were 72. 0％ versus 52. 9％, 28. 0％ versus 17. 6％, and 16. 0％ versus 13. 7％, respectively in the PP and DP groups ( P=0. 049) . In the PP and DP groups, the incidence of grade 3-4 leukopenia was declined by 48％ and 63％( P=0. 098) , and the incidence of grade 3-4 neutropenia was decreased by 34％ and 65％( P=0. 002) , the incidence of grade 3-4 anemia was reduced by 38％ and 10％(P=0. 024), and the incidence of grade 3-4 thrombocytopenia was declined by 40％ and 14％( P=0. 003) . The incidence rate of grade 2 pneumonitis ( P=0. 625) and grade 3 esophagitis ( P=0. 484) were similar in both groups. No patients experienced ≥grade 3 pneumonitis or ≥ grade 4 radiation esophagitis. Conclusions Pemetrexed-cisplatin combined with chemoradiotherapy yields higher clinical efficacy compared with docetaxel-cisplatin plus concurrent chemoradiation in the treatment of stageⅠV lung adenocarcinoma. The incidence of radiation pneumonitis and esophagitis is similar. The incidence and severity of hematological toxicity does not significantly differ between two groups.Treatment-related toxicity is tolerable in both groups. Clinical Trial Registration Chinese Clinical Trial Registry ( ChiCTR-TRC-13004184) .