| Background: Ovarian cancer is one of the three major malignant tumors in gynecology.It has a high degree of malignancy and poor prognosis,which seriously threatens women's health.Surgery plays an important role in the treatment of ovarian cancer,but for advanced recurrent ovarian cancer which failed in multiline chemotherapy,the treatment methods are limited.More and more researchers are turning their attention to targeted drugs.Apatinib is a small molecule anti-angiogenesis target drug developed independently in China.Its binding to the ATP site of VEGFR-2 is highly specific and convenient for oral administration.In recent years,its efficacy in treating various tumors has been confirmed.However,there are few reports on the efficacy and predictors of Apatinib in the treatment of ovarian cancer.This article will discuss the above issues.Objective: To evaluate the efficacy and safety of apatinib in patients with advanced epithelial ovarian cancer who failed to receive second-line or more chemotherapy.To explore the effects of the location of recurrence and metastasis,peritoneal effusion,recurrence type,number of medication lines,medication regimen,dosage,adverse reactions after medication,such as hypertension,proteinuria,hand-foot syndrome and the number of adverse reactions(? 3)on Progressive Free Survival(PFS)and Overall Survival(OS).At the same time,immunohistochemistry(IHC)was used to detect the expression of VEGFR-2 and HIF-1 in ovarian cancer tissues,and to explore the relationship between the expression of VEGFR-2 and HIF-1 and the prognosis of ovarian cancer treated with Apatinib,so as to screen early ovarian cancer patients who benefit from Apatinib and better guide the treatment.Methods: A retrospective analysis was made of the complete clinical data of 29 patients with advanced epithelial ovarian cancer who received oral Apatinib from June 2016 to August 2018 in the First Affiliated Hospital of Dalian Medical University and the Second Affiliated Hospital of Dalian Medical University.Three weeks is a treatment cycle,Regular follow-up,The curative effect was evaluated according to RECIST 1.1 and CA125.The safety of apatinib was assessed according to the National Cancer Institute's General Toxicity Standard(NCI-CTC 4.0).Observed indicators included objective response rate(ORR),disease control rate(DCR),PFS and OS.Kaplan-Meier method was used for single factor analysis and survival curve was drawn.Log-rank test was used to compare the differences among data groups.Cox risk regression model was used for multi-factor analysis.P < 0.05 was the significant difference.Ovarian cancer tissue specimens from 9 patients with oral Apatinib were collected.The expression of VEGFR-2 and HIF-1 in tissues was detected by immunohistochemistry.To analyze the correlation between the expression of VEGFR-2 and HIF-1,and its effect on clinical benefit rate,PFS and OS.Results:(1)The median medication time of 29 patients was 8.0 months(95% CI: 6.9-13.0 months).According to RECIST 1.1:ORR was 20.7%(6/29)and DCR was 82.8%(24/29).According to the level of CA125:ORR was 34.5%(10/29)and DCR was 86.2%(25/29).The median PFS was 5.0 months(95% CI: 5.1-10.4 months)and the median OS was 11.7 months(95% CI: 9.7-14.9 months).(2)Univariate analysis showed that PFS was significantly correlated with recurrence type(P=0.022)and hand-foot syndrome(P=0.049).However,there was no significant correlation with the location of recurrence and metastasis,peritoneal effusion,number of medication lines,medication regimen,dosage,hypertension,proteinuria and the number of grade 3 adverse reactions(P > 0.05).There was no significant correlation between OS and recurrence type,location of recurrence and metastasis,peritoneal effusion,number of medication lines,medication regimen,dosage,hypertension,proteinuria,hand-foot syndrome and the number of adverse reactions(? grade 3)(P > 0.05).Cox multivariate analysis showed that PFS was longer in platinum-sensitive relapse patients than in platinum-resistant relapse patients(HR = 0.246,95% CI: 0.084-0.72,P = 0.01),and longer in patients with proteinuria than in patients without proteinuria(HR = 3.847,95% CI: 1.214-12.193,P = 0.022).(3)The main adverse reactions included hypertension in 15 cases(51.7%),proteinuria in 9 cases(31%),hand-foot syndrome in 9 cases(31%),bone marrow depression in 4 cases(13.8%),fatigue in 2 cases(6.9%),pharyngalgia in 1 case(3.5%),oral ulcer in 2 cases(6.9%),nausea and vomiting in 3 cases(10.3%),diarrhea in 4 cases(13.8%)hemorrhage in 1 case(3.5%).Among them,5 patients had grade III adverse reactions(grade III hypertension in 4 cases,grade III hand-foot syndrome in 1 case),and no grade IV adverse reactions occurred.(4)In 9 specimens of ovarian cancer,There were 5 cases(55.6%)with high expression of VEGFR-2.Among them,1 case(20%)was initial diagnosis with ascites and 4 cases(80%)had platinum-resistant relapse for the first time.4 cases(44.4%)had high expression of HIF-1.Among them,1 case(25%)was initial diagnosis with ascites and 3 cases(75%)had platinum-resistant relapse for the first time.(5)In ovarian cancer tissues,the expression of VEGFR-2 was positively correlated with HIF-1,and the correlation coefficient was 0.685,P=0.042.(6)According to RECIST 1.1: The ORR and DCR of patients with high expression of VEGFR-2 and HIF-1 were higher than those of patients with low expression(40% vs.0,100% vs.50%,25% vs.20%,100% vs.60%).According to the level of CA125: The ORR and DCR of patients with high expression of VEGFR-2 and HIF-1 were higher than those of patients with low expression(80% vs.0,100% vs.25%,75% vs.20%,100% vs.40%).The PFS of patients with high expression of VEGFR-2,HIF-1 and co-expression of VEGFR-2 and HIF-1 was prolonged in patients with low expression of VEGFR-2,HIF-1 and co-expression of VEGFR-2 and HIF-1(5.5 vs.3.5 months,9.25 vs.4 months,5.5 vs.2 months),but there was no statistical significance(P > 0.05).Conclusion:(1)The clinical benefit rate,PFS or OS of Apatinib in the treatment of recurrent epithelial ovarian cancer after failure of second-line chemotherapy are comparable to those of conventional therapy at present.The adverse reactions are mild,controllable and tolerable.(2)The PFS of ovarian cancer patients with platinum-sensitive recurrence and adverse reactions of hand-foot syndrome and proteinuria was longer after oral administration of Apatinib.The recurrence type and proteinuria were independent prognostic factors of PFS.(3)Compared with benign ovarian tumors,the expression of VEGFR-2 and HIF-1 is higher in ovarian cancer tissues,and they have certain synergy,which indicates that they are related to the occurrence and development of ovarian cancer.The PFS of patients with high expression of VEGFR-2,HIF-1 and co-expression of VEGFR-2 and HIF-1 was prolonged in patients with low expression of VEGFR-2,HIF-1 and co-expression of VEGFR-2 and HIF-1.Therefore,VEGFR-2 and HIF-1 could be potential biomarkers for predicting the efficacy of apatinib in the treatment of ovarian cancer. |
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