Different administration routes of recombinant human endostatin combined with concurrent chemoradiotherapy might lead to different efficacy and safety profile in unresectable stage III non-small cell lung cancer: Updated follow-up results from two phase II trials.

BACKGROUND: There are two main choices of administration route of recombinant human endostatin (Endostar) available and the treatment options of concurrent chemoradiotherapy (CCRT) have changed over time. The aim of this study was to observe the long-term efficacy and safety of different administration routes of Endostar combined with CCRT. METHODS: Patients with unresectable stage III non-small cell lung cancer (NSCLC) from two phase II trials were included as two cohorts. Both were treated with Endostar combined with CCRT. Endostar was administrated by intravenous injection (7.5 mg/m2 /day, seven days) in the IV arm and by continuous intravenous pumping (7.5 mg/m2 /24 hours, 120 hours) in the CIV arm. RESULTS: A total of 48 patients were included in the IV arm and 67 patients in the CIV arm. The median progression-free survival (PFS), overall survival (OS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) in the IV arm and CIV arm were 9.9 months versus 15.4 months (HR = 0.751, 95% CI 0.487-1.160, P = 0.200), 24.0 months versus 38.5 months (HR = 0.746, 95% CI 0.473-1.178, P = 0.209), 32.3 months versus 27.1 months (HR = 1.193, 95% CI 0.673-2.115, P = 0.546), 20.1 months versus 49.7 months (HR = 0.603, 95% CI 0.351-1.036, P = 0.067). The one, three, five-year PFS in the IV arm and CIV arm was 45.8% versus 52.9%, 18.3% versus 31.4%, and 18.3% versus 27.7% and the one, three, five-year OS was 81.2% versus 82.1%, 31.1% versus 50.3%, and 31.1% versus 41%, respectively. Incidence of hematological adverse reactions were numerically lower in the CIV arm than the IV arm. CONCLUSIONS: Endostar delivered by CIV with CCRT may be a better option than IV in terms of potential survival and safety for unresectable stage III NSCLC. KEY POINTS: Significant findings of the study Endostar delivered by continuous intravenous pumping might achieve more favorable survival over intravenous injection and reduce adverse hematological reactions in patients with unresectable stage III NSCLC treated with Endostar combined with CCRT.What this study adds The administration route of recombinant human endostatin is also one key factor for survival and safety to consider when treating patients with unresectable stage III NSCLC.

Analysis of failure patterns and survival after SBRT for 147 cases of T 1-2N 0M 0 stage non-small cell lung cancer / 中华放射肿瘤学杂志

Objective:To analyze the failure patterns and survival after stereotactic body radiotherapy (SBRT) in patients with T 1-2N 0M 0 non-small cell lung carcinoma (NSCLC). Methods:Clinical data of early-stage NSCLC patients who received SBRT at Zhejiang Cancer Hospital from January 2012 to September 2018 were retrospectively analyzed. The primary observed endpoint was the pattern of disease progression, which was divided into intra-field recurrence, regional lymph node recurrence and distant metastasis. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan-Meier method. Univariate analysis was conducted by log-rank test, and multivariate analysis was performed by Cox's model.Results:A total of 147 patients with 156 lesions were included. The median follow-up time was 44.0 months (16.5-95.5 months). A total of 57 patients (38.8%) progressed: 14 patients (24.5%) had recurrence with the 1-, 3-, and 5-year local recurrence rates of 2.0%, 10.9%, and 14.3%, respectively; 36 patients (63.2%) had Distant metastasis with the 1-, 3- and 5-year distant metastasis rates of 12.2%, 22.4% and 28.6%, respectively; and 7 patients (12.3%) had recurrence complicated with distant metastasis. The 3-, 5- and 7-year OS rates were 80.5%, 64.2% and 49.9% for all patients, respectively. The median OS was 78.4 months. The 3-, 5- and 7-year PFS rates were 64.8%,49.5% and 41.5%, with a median PFS of 57.9 months (95% CI: 42.3-73.5 months). Univariate and multivariate analyses showed that biologically equivalent dose and age were the factors affecting the efficacy of SBRT (both P<0.05). Conclusion:Distant metastasis is the main failure pattern in patients with T 1-2N 0M 0 NSCLC after SBRT. High-risk population should be selected for further systematic treatment to improve the efficacy.

Failure mode and long-term survival after neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma / 中华放射肿瘤学杂志

Objective:To analyze the fail mode of neoadjuvant therapy combined with surgery for locally advanced esophageal squamous cell carcinoma (ESCC) after long-term follow-up.Methods:Clinical data of consecutive 238 patients with locally advanced resectable ESCC who underwent neoadjuvant therapy combined with surgery in Zhejiang Cancer Hospital from September 2012 to October 2019 were retrospectively analyzed. The failure mode in the whole cohort was analyzed after long-term follow-up. The overall survival (OS) and disease free survival (DFS) rates were analyzed by Kaplan-Meier method. Survival differences were determined by log-rank test.Results:The pathological complete response (pCR) rate was 42.0% in 238 patients. After a median follow-up of 46.1 months, tumor progression occurred in 96 patients (40.3%), including 25 patients (10.5%) with local recurrence, 61 patients (25.6%) with distant metastases, and 10 patients (4.2%) with simultaneous local recurrence and distant metastases. The median OS and DFS were 64.7 months and 49.9 months. And the 3-, 5-, and 7-year OS and DFS rates were 70.0%, 52.8%, 36.4% and 63.5%, 42.5%, and 30.0%, respectively. The 3-, 5-, and 7-year locoregional recurrence-free survival rates and distant metastasis-free survival rates were 86.0%, 71.4%, 61.2% and 70.6%, 55.9%, 43.0%. Compared with non-pCR patients, the overall progression rate and distant metastasis rate of pCR patients were lower (26.0% vs. 50.7%, 16.0% vs. 32.6%, both P<0.05). And the 3-, 5-, and 7-year OS (83.0% vs. 60.2%, 69.7% vs. 41.7%, 50.4% vs. 27.7%, all P<0.001) and DFS rates (80.4% vs. 51.4%, 63.9% vs. 31.2%, 45.9% vs. 20.3%, all P<0.001) were significantly better in pCR patients. Conclusions:Distant metastasis is the main failure mode of patients with locally advanced ESCC after neoadjuvant therapy. Patients with postoperative pCR can achieve better long-term survival.

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.

A prospective study of hippocampal-avoidance prophylactic cranial irradiation in small cell lung cancer patients with limited stage / 中华放射肿瘤学杂志

Objective:To analyze the feasibility of hippocampal-avoidance (HA) prophylactic cranial irradiation (PCI) in small cell lung cancer patients (SCLC)(limited stage) after chemotherapy and thoracic radiation.Methods:From June 2016 to March 2019, 40 eligible SCLC patients were recruited and randomly divided into the routine PCI ( n=22) and hippocampal-avoidance PCI (HA-PCI) groups ( n=18). The HA zone was contoured according to the criteria of RTOG 0933. Volumetric-modulated arc therapy (VMAT) was adopted in the HA-PCI group. After radiotherapy, Hopkins verbal learning test (HVLT) and MRI were performed. Results:The average hippocampus volume was (4.01±1.57) cm 3, the average HA volume was (20.13±4.14) cm 3, HA D 100% was (7.19±0.38) Gy and HA D max was (14.38±1.18) Gy. During HVLT, 1-month-after-PCI vs. before-PCI (trial3, trial4, learning, percent retained), 1-month-after-PCI vs. after-PCI (trial3, learning), HA-PCI cohort showed advantages over PCI in HVLT scores. The average follow-up time was (17.00±8.47) months. Two patients with brain metastases which were out of the HAZ received routine PCI. Conclusions:PCI using VMAT technology to protect hippocampus is feasible in dosimetry. The test results indicate that the protective effect of hippocampus protection on memory is worthy of further promotion in clinical practice.

BRAF/ KRAS and PIK3CA mutation characteristics and clinical significance in primary small cell lung caner / 中华放射肿瘤学杂志

Objective To detect the frequency of BRAF/ KRAS and PIK3CA mutations in the small cell lung cancer (SCLC) specimens from a large population of Chinese patients and to analyze the gene mutation and clinical characteristics. Methods A total of 557 samples were collected from SCLC patients from 2009 to 2014.BRAF,KRAS,PIK3CA,NRAS and MEK1 gene mutations were detected by the dideoxy sequencing. Chi-square test was adopted to analyze the correlation between clinical factors and gene mutation. Kaplan-Meier method was utilized for survival analysis. Cox model was used for multivariate prognostic analysis. Results BRAF mutations were detected in 13 out of 557 specimens. The mutation types included V600E (n= 5) ,V600A (n= 2) ,V600M (n= 1) ,D594G (n= 1),G464E (n= 1),K601R (n= 2) and S605N (n= 1).KRAS mutation was detected in 6 cases including G12C (n= 3),G12A (n= 1),G12D (n=1) andG13D (n= 1).PIK3CA mutation was observed in 4 samples including E545G (n= 2) and H1047R (n= 2).Besides,NRAS mutation (Q61R) was detected in 1 case and MEK1 mutation (D61Y) was noted in 1 case. These gene mutations were not significantly correlated with the age, gender, smoking status and clinical staging of the patients. Univariate survival analysis demonstrated the median survival time of patients with gene mutation was (10.30±0. 751) months (95％CI:8. 829-11. 771 months),significantly shorter than (12.80±0. 543) months (95％CI:11. 736-13. 864 months) of their counterparts without gene mutation (P=0. 011). Conclusions BRAF/ KRAS and PIK3CA gene mutation is detected in a small proportion of SCLC patients. These gene mutations are not significantly correlated with the clinical characteristics. Univariate survival analysis demonstrates that negative these gene mutations are negatively correlated with the clinical prognosis of SCLC patients.

Final report of a prospective randomized study on thoracic radiotherapy target volumes for limited-stage small cell lung cancer / 中华放射肿瘤学杂志

Objective In view of the controversy over radiotherapy target volume for patients with limited-stage small cell lung cancer ( SCLC), a prospective randomized controlled trial was conducted to compare the impact of different radiotherapy target volumes on prognosis. Methods After 2 cycles of EP chemotherapy,patients without progressive disease were randomly assigned to receive thoracic radiotherapy (TRT) to either the post-or pre-chemotherapy primary tumour extent as study arm or control. Involved field radiotherapy (IFRT) to the entire metastatic lymph node regions was applied for both arms. TRT consisted of 45 Gy/30Fx/19 d administered concurrently with cycle 3 chemotherapy. Prophylactic cranial irradiation was administered to patients achieved complete or partial remission. Kaplan-Meier method was used for survival analysis. Results Between June 2002 and December 2017,159 and 150 patients were randomly assigned to study arm and control respectively. The 1-,2-,and 5-year local/regional control rates were 79. 4%,61. 5% and 60. 1% respectively in the study arm versus 79. 8%,66. 5%,and 57. 3% in the control arm (P=0. 73). The median OS time was 22. 1 months in the study arm (95%CI,18. 2-26. 0 months) and 26. 9 months (95%CI,23. 5-30. 3 months) in the control arm,the 1-,3-,5-,and 7-year OS rates were 81. 1%,31. 6%, 23. 9% and 22. 2% respectively in the study arm versus 85. 3%,36. 6%,26. 1% and 20. 0% in the control arm (P=0. 51).Grade 2-3 acute esophagitis was developed in 32. 9% and 43. 2% of patients respectively in study arm and control arm (P=0. 01),while grade 2-3 pulmonary fibrosis was observed in 2. 0% and 10. 9% of patients ( P= 0. 01 ) respectively. Conclusions For patients with limited-stage SCLC who received induction chemotherapy,thoracic radiotherapy can be limited to post-chemotherapy tumour extent and IFRT can be routinely applied.

Effects of hyperfractionated radiotherapy versus hypofractionated radiotherapy combined with concurrent chemotherapy on prognosis of limited-stage small-cell lung cancer / 中华放射肿瘤学杂志

Objective To investigate the effects of hyperfractionated radiotherapy versus hypofractionated radiotherapy combined with concurrent chemotherapy on the prognosis of limited-stage small-cell lung cancer (SCLC).Methods A total of 188 patients with limited-stage SCLC were enrolled in this study and divided into hyperfractionated group (n=92) and hypofractionated group (n=96).The hyperfractionated group received thoracic radiotherapy at 45 Gy in 30 fractions twice a day, while the hypofractionated group received 55 Gy in 22 fractions once a day.The Kaplan-Meier method was used to calculate survival rates, and the Cox model was used for multivariate prognostic analysis.Results There were not significant differences in 1-, 2-, and 5-year progression-free survival (PFS) rates and 1-, 2-, and 5-year overall survival (OS) rates between the hyperfractionated group and the hypofractionated group (82% vs.85%, 61% vs.69%, 59% vs.69%, P=0.27;85% vs.77%, 41% vs.34%, 27% vs.27%, P=0.37).The multivariate analysis showed that the time from the initiation of chemotherapy to the initiation of thoracic radiotherapy ≤43 days was favorable prognostic factor for PFS (P=0.005).The time from the initiation of chemotherapy to the end of thoracic radiotherapy ≤63 days and prophylactic cranial irradiation were favorable prognostic factors for OS (P=0.044;P=0.000).There were significant differences in incidence rates of grade 2 and 3 acute radiation esophagitis between the two groups (28% vs.16%, 9% vs.2%, P=0.009).Conclusions Both hyperfractionated radiotherapy and hypofractionated radiotherapy combined with chemotherapy can improve the PFS and OS of patients with limited-stage SCLC.The time from the initiation of chemotherapy to the initiation of thoracic radiotherapy ≤43 days and the time from the initiation of chemotherapy to the end of thoracic radiotherapy ≤63 days are favorable prognostic factors for PFS and OS, respectively.However, the hyperfractionated group has significantly higher incidence rates of grade 2 and 3 acute radiation esophagitis than the hypofractionated group.

Value of nutritional risk screening-2002 in evaluating nutritional status of patients with esophageal cancer undergoing radiotherapy / 中华放射肿瘤学杂志

Objective To apply Nutritional Risk Screening-2002(NRS-2002) to perform primary screening for nutritional risk in patients with esophageal cancer who undergo radiotherapy, and assess their nutritional status, and to investigate the value of NRS-2002 in such patients.Methods A total of 97 patients who were diagnosed with esophageal cancer and underwent radiotherapy in Zhejiang Cancer Hospital from January 2010 to April 2014 were analyzed retrospectively.The Kaplan-Meier method was applied to analyze the difference in survival, and the chi-square test and the Pearson correlation analysis were applied to analyze the correlation between NRS-2002 score and blood parameters.Results Of all patients, 26.8%had nutritional risk before radiotherapy, which gradually increased with the progress of radiotherapy.The 1-year overall survival rates of the patients with NRS-2002scores of ≤3 and ≥4 on admission were 91.1%and 61.9%, respectively (P=0.010).As for the patients with the highest NRS-2002 scores of ≤2 and ≥3 during treatment, the 1-year overall survival rates were 94.2% and 77.5%, respectively (P=0.012).As for the patients with the lowest NRS-2002 scores of ≤3 and ≥4 during treatment, the 1-year overall survival rates were 91.3% and 54.5%, respectively ( P=0.018).The NRS-2002 score was correlated with prealbumin on admission and at week 1 of radiotherapy (P=0.000 and 0.002), and the NRS-2002 score was correlated with albumin at week 3 of radiotherapy (P=0.036).The multivariate analysis showed that the TNM stage of esophageal cancer and the highest NRS-2002 score during treatment were the independent prognostic factors in esophageal cancer (P=0.001 and 0.005).Conclusions The patients with esophageal cancer undergoing radiotherapy have high nutritional risk, and NRS-2002 score is the independent prognostic factor in these patients and can be used as a tool for primary screening for nutritional risk.

A prospective phase Ⅰ / Ⅱ study of recombinant endostatin (Endostar) combined with concurrent radio-chemotherapy in patients with unresectable stage Ⅲ non-small cell lung cancer / 中华放射肿瘤学杂志

Objective To evaluatc the efficacy and safcty of recombinant endostatin (Endostar)combined with concurrent radio-chemotherapy (CRCT) in patients with unresectable stage Ⅲ non-small cell lung cancer (NSCLC).Methods From March 2009 to November 2011,47 patients received threedimensional conformal radiotherapy of 60-66 Gy in 30-33 fractions over 6-7 weeks And concurrent chemotherapy of docetaxel 65 mg/m2 and cisplatin 65 mg/m2.Endostar was administered once a week before and on week 2,4,6 during CRCT at a dose level of 7.5 mg/m2/d.Tumor response was evaluated with thoracic CT scans performed 4 weeks after completion of treatment in accordance with RECIST 1.1 criteria.Acute toxicities were evaluated in accordance with CTCAE 3.0.Results Forty-four patients completed treatment and toxicity evaluation,42 patients completed evaluation of efficacy.Five patients achieved complete response,29 partial response,3 stable disease,and 5 progressive disease,2 were net assessed.Overall response rate was 77％.One-year overall survival rate was 81％,and one-year progression-free survival rate was 51％.Twelve patients died,2 died of treatment related toxicities,8 of cancer,and 2 of unknown causes.Nineteen patients developed grade 3/4 neutrocytopenia,grade 3 acute esophagitis and pneumonitis were observed in 4 and 4 patients,respectively,and 1 patient died of pneumonitis.No patient developed cardiovascular toxicities and hemorrhage.Conclusions Endostar combined with CRCT for unresectable stage Ⅲ NSCLC was safe and the short term outcomes were promising.Further investigations are warranted.

Involved-field radiotherapy versus elective nodal irradiation in combination with concurrent chemotherapy for locally advanced non-small cell lung cancer: A prospective randomized clinical study / 中华放射肿瘤学杂志

ObjectiveTo evaluate the local failure and the impact on survival by prospectively comparing involved field radiotherapy (IFRT) and elective nodal irradiation (ENI) in combination with concurrent chemotherapy for locally advanced non-small cell lung cancer ( LA-NSCLC ).Methods LANSCLC patients were treated with 2 cycles of carboplatin ( AUC =5 - 6,d1 ) combined with paclitaxel ( 175mg/m2 ),followed assessment without distant metastasis,then randomized into IFRT (45 patients) or ENI (54 patients) arm.IFRT included primary tumor,ipsilateral hilar and positive mediastinal lymph nodes;ENI included the primary lesion,ipsilateral hilar,hilateral mediastinal lymph node drainage and bilateral supraclavicular area.The prescription dose was given as high as possible with V20 ≤35％ and spinal cord dose ≤50 Gy,combined weekly paclitaxel 40 mg/m2 concurrent chemotherapy.The Kaplan-Meier method was used to estimate survival data and the log-rank method was used to test distribution of survival time between arms.ResultsThe follow-up rate was 99％.49,29 and 17 patients were followed-up for 1-,2-and 3-year,respectively.More patients from group IFRT received ＞60 Gy than ENI (49％ vs.26％,x2 =5.59,P =0.018 ).The local failure rates were 29％ and 36％,respectively ( x2 =0.46,P =0.497 ).The 1-,2-and 3-year local tumor progression-free survival rates were 76％,69％,65％ and 80％,53％,49％ ( x2 =0.74,P =0.389),respectively; the 1-,3-and 5-year overall survival rates were 80％,41％,33％ and 69％,32％,13％ (x2 =3.97,P =0.046),respectively.There were no significant differences in acute and late toxicities between the arms ( x2 =3.910 - 0.155,P =0.142 - 0.925 ).ConclusionsIFRT improved radiation dose and survival rate and did not increase the failure of elective lymph node region compared with ENI.The toxicities were no differences between IFRT and ENL Further investigation with big size sample is warranted.

A Review of the Genotoxicity and Reproductive Toxicant of Acrylamide / 环境与健康杂志

Acrylamide(AA)is a chemical used in many industries around the world and more recently was found to form naturally in foods cooked at high temperatures.Acrylamide was shown to be a neurotoxicant,reproductive toxicant,and carcinogen in animal species.Only the neurotoxic effects were observed in humans and only at high levels of exposure in occupational settings. The present review is a synopsis of research on the genotoxicity and reproductive toxicant of acrylamide.

Toxic Effect of Acrylamide on Mouse Sperm / 环境与健康杂志

Objective To study the toxic effect of acrylamide (AA) to sperm quality of mice in order to provide scientific data to elucidate the reproductive toxicity of AA. Methods 25 male KM mice aged 7-8 weeks,25-30 g,were randomly divided into negative control group (H2O),AA groups (20,40 and 60 mg/kg) and positive control group (cyclophosphamide). The mice were treated with AA by gavage,once a day,for 5 consecutive days. The mice were sacrificed on the 14th day after the first administration,the quantity,motility,morphology of sperms were examined. Results The sperm quantity in each AA group reduced significantly (P

Nursing for Acute Complication after Traumatic Cervical Spine Cord Injury / 中国康复理论与实践

@#Objective To study the precaution and nursing for the acute complication after traumatic cervical spine cord injury. Methods 56 patients with acute traumatic cervical spine cord injury were analyzed retrospectively.Results All the complication had been cured and none died because of the complication. Conclusion It is important to do something to relieve or prevent the complication as soon as possible.