| PartⅠ Study on Thalidomide Plus Radiation’s Anti-angiogenesis Effect on Human Esophageal Carcinoma Transplanted Nude MousePurpose: To evaluate the expressions of vascular endothelial growth factor(VEGF)and angiogenesis inhibition effects of thalidomide combined with radiation on the nude mouse transplanted with human esophageal carcinoma cells.Method: Thirty-two nude mice were randomly divided into four groups:healthy control group,thalidomide group,irradiation group and irradiation plus thalidomide group.The irradiation group and irradiation plus thalidomide group were irradiated by 6Me V electron, 20Gy/10f/12 d, 5 times per week. Thalidomide group and radiation plus thalidomide group were daily fed by thalidomide solution(200mg/kg/d)for 12 consecutive days. The nude mice were weighed,and the tumor sizes were measured every two days. The nude mice were sacrificed after irradiation, and the tumor growth inhibition rate was calculated. The expressions of VEGF and microvascular density(MVD) were determined by SP immunohistochemistry.Results: Tumor volume of the control and thalidomide group growed continuously, and the control group growed faster. While the irradiation group and irradiation plus thalidomide group growed first and then shrinked, and the combined group shrinked more obvious. Tumor weight between all groups showed significant differences(P<0.05) and the irradiation plus thalidomide group yielded the highest tumor inhibitory rate of 66.96%.Sensitivity enhancement ratio(SER)of thalidomide was 1.56. Factorial analysis showed that thalidomide and irradiation could result in a synergistic inhibitory effect on tumor volume(Firradiation×thalidomide=4.266,P=0.048). VEGF expressions and MVD value of irradiation group were higher than those of radiation plus thalidomide group(P<0.05).Conclusion: Thalidomide combined with radiation could enhance the irradiation sensitivity. Thalidomide could down regulate VEGF expression as well as decrease the MVD in tumor.PartⅡ Pathologic Response and VEGF Serum Change during Radiotherapy or Chemoradiotherapy Could Predict Prognosis of Patients with Esophageal CarcinomaPurpose: To observe the pathological responses in the tumor tissues and the changes in the serum level of vascular endothelial growth factor(VEGF) in esophageal cancer patients receiving radiotherapy or chemoradiotherapy, in order to study the impacts of these two factors on the prognosis of the patients.Method: Eighty-nine pathologically confirmed esophageal cancer patients were treated with radiotherapy including sixty-five received concurrent chemoradiotherapy and twenty-four received radiotherapy alone. Radiation regimen was three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Chemotherapy regimen was paclitaxel liposome plus cisplatin concomitant with radiotherapy for two cycles and then consolidation for two other cycles. Gastroscopy was performed at the fourth week since the beginning of radiotherapy to collect tumor biopsies for pathological examination. The responses to radiotherapy were classified into three degrees: mild, moderate and intensive. Moreover, serum samples were collected from the patients prior to, at the fourth week of, and one week after radiotherapy, and VEGF serum level was determined. Serum samples from 30 healthy subjects were collected and served as the control.Results: The total complete remission(CR) rate, partial remission(PR) rate and overall response(OR) rate were 56.2%, 40.4% and 96.6%, respectively. Among all patients, one-year,two-year and three-year overall survival(OS) rate were 70.8%, 49.4% and 33.3%, respectively; one-year,two-year and three-year progression-free survival(PFS) rate were 61.8%, 35.3% and 28.2%, respectively; one-year, two-year and three-year local control(LC) rate were 76.9%, 59.7% and 50.0%, respectively. The one-year, two-year and three-year OS rate in the mild response group were significantly lower than those in the intensive response group(P<0.05 in all comparisons). The one-year, two-year and three-year PFS rate in the mild response group were significantly lower than those in the moderate and intensive response groups(P<0.05 in all comparisons). The one-year, two-year and three-year LC rate in the patients with mild response group were significantly lower than those in the moderate and intensive response groups(P<0.05 in all comparisons). The one-year, two-year and three-year OS rate in VEGF increased group were lower than those in the decreased group(P<0.05 in all comparisons). The three-year PFS rate in the VEGF increased group was lower than that in the decreased group(P<0.05). The pathologic response to radiotherapy was correlated with neither pre-radiotherapy VEGF level nor VEGF changing trend(P>0.05).VEGF level in intensive response group decreased significantly after radiotherapy comared with pre-radiotherapy(P < 0.05). Multivariate analysis showed that TNM stage and serum VEGF trend were the independent factors for the prognosis of the patients with esophageal carcinoma(P<0.05).Conclusion: Tumor tissue pathological response and VEGF serum level change in response to radiotherapy or chemoradiotherapy can predict the efficacy of chemoradiotherapy in non-surgical patients with esophageal cancer. Hence, monitoring the pathological responses and VEGF changes during the course of therapy is of utmost importance to evaluate and perform an individualized therapy in clinical practice.PartⅢ Study on Serum Vascular Endothelial Growth Factor Change during Radiotherapy or Chemoradiotherapy and detection timingPurpose: To observe the serum vascular endothelial growth factor(VEGF) change in patients with esophageal carcinoma during radiotherapy or chemoradiotherapy and further explore the optimum detection timing for VEGF.Method: seventy-six patients with esophageal carcinoma who were treated with radiotherapy including fifty-three patients received concurrent chemotherapy and twenty-three received radiotherapy alone. Radiation regimen was three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Chemotherapy regimen was paclitaxel liposome plus cisplatin concomitant with radiotherapy for two cycles and then consolidation for two other cycles. Serum level of VEGF was determined before, during(per week) and after radiotherapy Serum samples from 30 healthy subjects were collected and served as the healthy control.Results: The VEGF levels at different time points were all significantly higher than the level of control group as 79.6±39.2 ng/L(t=2.165~3.896, P<0.05). On the whole, the VEGF level decreased gradually with the proceeding of radiotherapy(F=6.806,P=0.001). Compared with pre-radiotherapy, VEGF level increased in twenty-one patients during radiotherpay, and mostly rised in the second,third week or after radiotherapy.Conclusion: The second, third week since the beginning of radiotherapy and one week during post-radiotherapy might be the optimum timing for screening the VEGF up-regulating patients, and VEGF detection at these time points have much importance for individualized treatment of esophageal carcinoma patients.PartⅣ A Randomized Controlled Study of Thalidomide Combined with Radiochemotherapy in Treating Esophageal CancerPurpose: To evaluate the safety and efficacy of thalidomide combined with radiochemotherapy for the treatment of esophageal cancer.Method: Patients with esophageal squamous cell carcinoma were treated with radiochemotherapy. Radiation regimen was three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Chemotherapy regimen was paclitaxel liposome plus cisplatin concomitant with radiotherapy for two cycles and then consolidation for two other cycles.The level of serum vascular endothelial growth factor(VEGF) was determined before, at the second to the fourth week of, and one week after radiotherapy. Patients showed increased level of serum VEGF during radiotherapy compared to pre-radiotherapy were randomly divided into two groups: test group(n=31) and control group(n=30). Test group were treated with thalidomide during radiochemotherapy, and the control group received regular radiochemotherapy.Results: The main side effect of thalidomide is varied degrees of lethargy. The total complete remission(CR) rate, partial remission(PR) rate and overall response(OR) rate were 68.9%, 24.6% and 93.5%, respectively. Among fifty-one patients valuable, including twenty-six test patients and twenty-five control patients,one-year,two- year and three-year overall survival(OS) rate were 70.6%,34.1% and 22.5%, respectively; one-year,two- year and three-year progression-free survival(PFS) rate were 56.9%、29.5% and 22.0%, respectively; one-year,two-year and three-year local control(LC) rate were 81.0%、59.1% and 52.6%, respectively. Analysis of the locally advanced(stage II and III) patient subgroup showed that the three-year OS rate, three-year PFS rate and three-year LC rate in test group were significantly higher than those in control group(P<0.05 in all comparisons). The PFS curves of the locally advanced two groups were compared, the difference was statistically significant(P<0.05). There were significant differences in the number of patients who showed decreased, stabled and increased serum VEGF levels in the test(14, 14, 2) and control groups(6, 18, 6) after radiotherapy, compared to during radiotherapy(P<0.05). The one-year OS rate, one-year PFS rate and one-year, two-year, three-year LC rate of test group patients who showed decreased serum VEGF after radiotherapy were higher than those in patients who showed increased serum VEGF. Multivariate analysis showed that TNM staging was the independent factor that influence the survival of esophageal cancer patients, TNM staging and if residual tumor exist after radiotherapy were two factors influence the PFS of esophageal cancer patients.Conclusion: Thalidomide may improve the prognosis of patients with locally advanced esophageal cancer who show increased serum VEGF level during radiotherapy, and its side effects can be tolerated. |
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